Translating fine-grained intracellular dynamics into predictable systemic clinical phenotypes remains a core challenge in biomedical research. This review explores the architectural continuum and translational value of artificial intelligence (AI) virtual patients (AIVPs) for bridging the gap between microscale biological mechanisms and macroscale clinical manifestations. We clarify the computational hierarchy of AIVPs, covering AI-based virtual cells, AI-based virtual extracellular vesicles, and AI virtual organoids. These modules jointly form the mechanistic basis of the integrated AIVP models. This review also clearly distinguishes between the epistemological connotations of AIVPs and digital twins (DTs). AIVPs act as population-level synthetic archetypes optimized for in silico clinical trials, whereas DTs serve as individualized longitudinal replicas updated by real-world data assimilation. Focusing on pharmaceutical research and development and regulatory science, we discuss the capacity of AIVP cohorts to reduce developmental risks in drug research. These in silico models can be used to construct synthetic control arms, optimize dynamic precision dosing, and accelerate regulatory progress via Model-Informed Drug Development. We further summarize the key obstacles restricting the clinical translation of AIVPs, including epistemological limitations, inadequate infrastructure, and complex socio-regulatory constraints. Resolving data fragmentation, reducing algorithmic bias, and unifying verification and validation standards are critical for transforming AIVPs from theoretical prototypes into credible regulatory and clinical tools (Graphical Abstract).
The endoplasmic reticulum (ER) and mitochondria are critical organelles in maintaining cellular homeostasis and regulating cell fate. However, current biological and chemical approaches for modulating ER and mitochondrial functions often lack specificity and spatiotemporal controllability, potentially leading to off-target or systemic effects that limit their clinical applications. Here, by synthesizing a physical stimulus-based acoustoelectric nanoregulator, barium zirconate titanate (BZT) nanoparticles (NPs) with enhanced piezoelectric properties, we aimed to modulate ER and mitochondrial functions by regulating intracellular concentrations of calcium ions (Ca2+) and hydrogen ions (H+), thereby enabling spatiotemporally controllable modulation of cell fate. BZT NPs significantly modulated calcium ion dynamics and pH in tumor cells under ultrasound stimulation, accompanied by perturbations in ER and mitochondrial homeostasis, induction of ER stress and mitophagy, and ultimately alterations in cell fate. In the tumor-bearing mouse model, the acoustoelectric nanoregulator spatiotemporally modulates the intracellular environment through electrical signaling and ionic dynamic modulation under ultrasound stimulation, expanding the application prospects of physical stimulation-based strategies for abnormal cell function regulation. Our findings provide fresh perspectives for understanding cellular stress responses and cell fate determination processes, and lay the foundation for developing novel interventions in precision therapy and cell engineering applications.
Background/Aims Achieving functional cure (hepatitis B surface antigen [HBsAg] loss) and discontinuing lifelong nucleos(t)ide analog (NUCs) therapy are critical clinical goals in chronic hepatitis B (CHB) management. This study evaluated the long-term clinical outcomes and cost-effectiveness of different treatment strategies aimed at functional cure in hepatitis B e antigen (HBeAg)-negative patients with CHB across Asia-Pacific income strata. Methods A Markov state-transition model was developed to project 30-yr hepatitis B virus (HBV) disease outcomes in HBeAg-negative patients. Three finite strategies, PegIFN add-on to NUCs (PegIFN+NUC), switching from NUCs to PegIFN (Switch), and bepirovirsen add-on to NUCs (Bepi+NUC), were compared with lifelong NUC therapy. Analyses were stratified by country income level (high-income country [HIC], upper-middle-income country [UMIC], and lower-middle-income country [LMIC]). Costs were estimated from the health care payer perspective in 2023 USD. Incremental cost-effectiveness ratios (ICERs), probabilistic sensitivity analyses, and cost-effectiveness acceptability curves were generated across a range of willingness-to-pay thresholds. Results Switch led to the largest reduction in hepatocellular carcinoma (31%) and HBV-related deaths (32%). In HIC, Switch was the dominant strategy (lower cost and higher quality-adjusted life years [QALYs] than standard care). In UMIC and LMIC settings, Switch remained highly cost-effective with ICERs of 1774 and 2200 per QALY gained, respectively. Probabilistic sensitivity analysis demonstrated a >89% probability of finite PegIFN strategies being cost-effective at 1× GDP per capita thresholds across all income strata. In contrast, the bepirovirsen add-on strategy was dominated in all settings due to high acquisition costs and the impact of modeled seroreversion on long-term gains. Conclusions Finite PegIFN-based combination therapies are cost-effective toward functional cure in AP region. While bepirovirsen represents a major milestone in HBV drug development, its current economic viability is limited by high costs and durability concerns. Policy efforts should prioritize optimizing established immunomodulatory combinations to accelerate global hepatitis B elimination.
Postoperative cognitive dysfunction (POCD) is a common neurological complication severely affecting patient prognosis. Preoperative acute sleep deprivation, a frequent perioperative stressor, significantly exacerbates POCD severity. Sigma-1 receptor (σ-1R), an endoplasmic reticulum molecular chaperone, plays a crucial role in modulating neuroinflammation and oxidative stress. However, whether σ-1R can serve as an interventional target to mitigate sleep deprivation-aggravated cognitive impairment remains insufficiently elucidated. This study aimed to clarify the regulatory role of σ-1R in a mouse model combining preoperative sleep deprivation with exploratory laparotomy, focusing on Keap1/Nrf2 signaling, and to evaluate its clinical translational potential. Behavioral, molecular biological, and morphological methods were utilized. Sleep deprivation exacerbated postoperative cognitive impairment, accompanied by a compensatory upregulation of σ-1R expression in hippocampal microglia. Notably, exogenous potentiation of σ-1R with the agonist PRE-084 reversed cognitive deficits, suppressed neuroinflammation and oxidative stress, promoted Nrf2 nuclear translocation, and upregulated downstream genes HO-1 and NQO1; conversely, the antagonist BD-1047 worsened the damage. Mechanistically, σ-1R physically associated with Keap1, promoting Nrf2 release. The Nrf2 inhibitor ML385 blocked PRE-084’s protective effects. In vitro experiments confirmed PRE-084 alleviated inflammation and oxidative stress via an Nrf2-dependent pathway. Moreover, σ-1R signaling may partially contribute to the neuroprotective effects of dexmedetomidine. In conclusion, this study reveals that σ-1R activation is associated with protective effects in sleep deprivation-exacerbated POCD, potentially through regulating the Keap1/Nrf2 signaling pathway, a mechanism rarely reported in this context, suggesting σ-1R as a potential avenue for further investigation in POCD prevention.
Aim: To trace the historical evolution of hospital nursing centrism in China (1835-present) and examine how institutional path dependence has shaped the subordinate status of nursing within a doctor-dominated healthcare system. Background/introduction: Despite major expansions in nursing education and policy advocacy, China's nursing profession remains structurally marginalized. Understanding the roots of this subordination requires a historical and institutional lens. Methods: Drawing on path dependence theory, this study analyzes five critical phases in the development of nursing in China from 1835 to the present. A four-dimensional analytical framework that encompasses professional, organizational, fiscal, and governance institutions was applied to archival records, policy documents, academic studies, and interview data. Results or findings: Findings reveal that nursing has been persistently embedded in a "doctor-led, nurse-subordinate" governance structure. Although educational and legislative reforms expanded nursing's professional scope, entrenched institutional arrangements across the four dimensions have locked nursing into a structurally dependent position. Discussion: The historical institutionalization of nursing as an auxiliary role has limited its professional identity, participation in governance, and access to resources. The analysis highlights the limitations of reforms focused solely on education and policy without restructuring governance mechanisms. Conclusion: The professional development of nursing in China has been constrained by enduring path-dependent forces. To achieve true professionalization, reforms must address deep-seated institutional logics. Implications for nursing and nursing policy: Professional empowerment requires the redesign of nursing roles, decision-making power, and career pathways within hospital governance. Policy reforms should dismantle hierarchical governance structures and institutionalize nurses' participation in leadership, ensuring equitable distribution of authority and resources.
