As populations age at an unprecedented pace globally, frailty has emerged as a critical challenge in perioperative care. While clinicians broadly acknowledge the value of frailty assessment, embedding it systematically in care pathways remains difficult to implement systematically. We compared perioperative frailty guidelines from the United Kingdom, United States, Europe, and the Asia-Pacific, finding significant inconsistencies in tool selection, risk stratification criteria, and pathway design. Strikingly, approximately 99.6% of frailty research remains confined to risk characterization, whereas only 0.4% is directed toward improving care, highlighting a substantial gap between evidence and practice. Digital technologies promise a wider uptake of frailty screening, and yet algorithmic bias threatens to under-detect frailty in underserved groups if left unchecked. We outline five policy priorities: first, an internationally coordinated consensus on core assessment standards needs to be reached; second, end-to-end pathways that span screening, graded assessment, targeted intervention, and outcome tracking need to be devised; third, digital technology needs to be accelerated along with the devising of explicit safeguards for equity; fourth, high-quality evidence needs to be generated through function-centered outcomes and cost-effectiveness analyses to demonstrate the real-world value of frailty-focused care pathways; and fifth, frailty management needs to be integrated into national chronic-disease frameworks. Closing the gap between detection and action will require global collaboration and a reframing of frailty, not as a passive label but as a call to intervene.

Frailty has become a pressing health concern in Japan as it has entered a super-aged society. Early identification of frailty is essential to preventing disability, hospitalization, and dependency on long-term care, and yet the implementation of standardized screening across clinical settings remains inconsistent. This review synthesizes current evidence on frailty assessment practices in Japan, highlights key challenges in routine implementation, and examines the potential of emerging digital tools. The feasibility of recent digital innovations — including artificial intelligence analysis of home electricity data, wearable-based mobility monitoring, and EMR-integrated frailty indices — has been demonstrated in pilot settings, though evidence of their large-scale clinical effectiveness remains limited. International comparisons have revealed that countries and regions such as the United Kingdom, Canada, Australia, and Singapore are increasingly implementing electronic frailty indices with policy-level support, offering valuable insights for Japan. Overall, although Japan has made significant progress in recognizing the importance of frailty assessment, substantial gaps remain in standardization, system integration, and clinical implementation. Strengthening national policy frameworks, enhancing workforce training, and accelerating a digital transformation may enable the development of a more comprehensive and scalable frailty-screening system to support healthy aging.

Frailty significantly influences perioperative outcomes and healthcare resource utilization among older adults. Although the importance of intervention has been recognized, guidelines vary significantly across regions. This review synthesizes geriatric, perioperative, and specialty guidelines from the UK, the US, Europe, and the Asia-Pacific region. We found that, although they widely share core principles such as the use of validated tools and comprehensive geriatric assessment (CGA), guidance specific to the perioperative setting remains limited. Existing recommendations are often restricted to the preoperative phase and lack standardization of risk thresholds. However, high-quality evidence on the clinical and economic impact of frailty-based pathway redesigns is limited. Future research should focus on multicenter pragmatic trials that evaluate integrated care pathways extending from preoperative optimization through postoperative care. In parallel, further development of automated screening using electronic health records and electronic frailty indices is warranted. Such initiatives will require careful evaluation of feasibility and equity to support successful implementation in routine clinical practice. We recommend that clinicians routinely incorporate validated frailty screening into preoperative evaluation for all patients age 65 and older and that healthcare systems prioritize the development of an interoperable data infrastructure to enable the seamless transfer of community-derived frailty information into surgical decision-making workflows.

Indocyanine green (ICG) test is a popular and widely implied assessment of hepatic functional reserve (HFR) due to its safety and efficiency. However, as the application of ICG expanded, an exceedingly rare disorder, the constitutional ICG excretory defect (CIED), gradually emerged. CIED is considered as a harmless dye excretory defect, which features remarkable ICG plasma retention (plasma ICG 15-min retention rate is higher than 50%) without any severe liver impairments. Previous investigations revealed that it has no particular symptoms and it is not a contraindication of surgical treatments. The deficiency of the organic anion transporting polypeptide 1B3 is affirmed to be the underlying cause of CIED. It is of great significance to identify this disorder from other reasons elevating ICG-R15 and provide such patients with effective and safe treatments. The utility of ^99mTc-GSA liver scintigraphy, Child-Pugh and ALBI scores, and liver biopsy in identification and supplementary HFR assessment in CIED has been affirmed. Moreover, other methods based on radioactive tracers, serum biomarkers and imaging examinations have potential. Based on existing evidence, we proposed a clinical strategy that prioritizes ALBI and Child-Pugh scores, as well as imaging examinations, such as computerized tomography and ultrasound examinations, for the initial identification of CIED. Thereafter, ^99mTc-GSA liver scintigraphy or biopsy is used to verify CIED and assess HFR. In conclusion, we comprehensively reviewed the characteristics, mechanisms and coping strategies of CIED, aiming to provide updated insights of this disorder.

Photoaging is a distinct form of pathological skin aging driven primarily by chronic ultraviolet (UV) radiation, which clinically manifests as wrinkles, dyspigmentation, and loss of elasticity. Although core molecular events induced by UV—such as oxidative stress and DNA damage—are relatively well-understood, there is still a lack of a systematic and integrated understanding of how diverse cell types in the skin collectively drive photoaging through complex interactive networks. This review systematically elaborates the cellular and molecular mechanisms underlying skin photoaging. The key pathways involved are examined, including oxidative stress, apoptosis, dysregulated autophagy, activation of inflammatory cascades, and degradation of the extracellular matrix (ECM). This review further details the pivotal roles of and reciprocal crosstalk among fibroblasts, keratinocytes, melanocytes, and various immune cells. By providing an integrated perspective on these interactions, this review outlines the cellular and molecular mechanism of UV-associated senescence, which uniquely integrates the roles of the immune microenvironment and cellular crosstalk, providing a roadmap for next-generation anti-photoaging strategies.

Hepatocellular carcinoma (HCC) exhibits marked sexual dimorphism, with females demonstrating superior survival, yet the underlying molecular mechanisms remain unclear. We integrated bulk transcriptomics (GSE39791, TCGA-LIHC, GSE14520) and single-cell RNA sequencing (five datasets, n = 58 patients, 238,982 cells) with machine learning (LASSO, SVM, random forest) to identify female-protective genes driving HCC disparities. Activating transcription factor 5 (ATF5) emerged as a female-protective gene with higher expression in females versus males across cohorts. Single-cell analyses revealed ATF5 defines a female-enriched, low-grade malignant subcluster with elevated apoptotic programs and reduced proliferative signaling, and pseudotime analysis showed coordinated ATF5-GPER1 downregulation during malignant progression (Spearman ρ = −0.52 and −0.48; both p < 0.001). In the immune compartment, ATF5 marked a female-enriched IFN-γ⁺ macrophage state with enhanced immunostimulatory programs and preferential CXCL9/10–CXCR3-mediated communication with CD8/NK cells. Mechanistically, ATF5 transcriptionally activates G protein-coupled estrogen receptor 1 (GPER1), forming an estrogen-responsive regulatory module that functionally suppresses proliferation, induces apoptosis (HepG2: 26.45% vs. 11.88%, p < 0.0001), and inhibits migration in a GPER1-dependent manner as demonstrated by rescue experiments. Tissue microarray validation (n = 167) confirmed high ATF5 expression predicts improved recurrence-free survival specifically in female patients (HR = 0.34, p = 0.040) but not males (p = 0.080). The ATF5-GPER1 axis represents a female-protective circuit operating through tumor-intrinsic suppression and immune remodeling, offering mechanistic insight into HCC sexual dimorphism and identifying ATF5 as a sex-specific prognostic biomarker with potential therapeutic implications.

While bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and dolutegravir plus lamivudine (DTG+3TC) are first-line regimens for treatment-naive people with HIV (PWH), long-term real-world head-to-head comparisons of their metabolic and renal outcomes remain limited. We conducted a retrospective cohort study of ART-naive PWH initiating these regimens in China, utilizing 1:2 propensity score matching (PSM) to balance baseline covariates for 1,445 participants (901 BIC/FTC/TAF; 544 DTG+3TC). Over a 24-month follow-up, the study demonstrated comparable virologic suppression (99.7% vs. 100.0%; p = 0.623), weight changes, and cumulative incidence of metabolic abnormalities between the two groups. Conversely, although the crude 24-month incidence of eGFR decline was higher with DTG+3TC (54.8% vs. 40.7%; p = 0.039), adjusted Cox models revealed that the regimen was not independently associated with this decline (HR 1.20; 95% CI 0.97–1.48; p = 0.18).These findings indicate that both regimens offer comparable long-term virologic efficacy and metabolic safety profiles, supporting their routine clinical utility while highlighting the need for cautious interpretation of renal markers during integrase inhibitor-based therapy.

SLC26A4 is a major causative gene for hereditary hearing loss, its mutation spectrum shows pronounced population specificity. In Chinese populations, patients predominantly carry biallelic mutations, and compound heterozygous genotypes are prevalent, which results in a wide spectrum of auditory phenotypes. However, how different alleles interact within these contexts to shape phenotypic variability remains poorly understood. We employed cellular and mouse models to explore the allele-specific mechanisms associated with two novel mutations, a frameshift mutation and a missense mutation, in compound heterozygous that share the same splice-site pathogenic allele. In vitro, wild-type (WT) and mutant (c.574delC, c.1211C>A) SLC26A4 constructs were expressed in HeLa cells to assess pendrin localization. Both mutations reduced membrane enrichment and increased intracellular retention. In vivo, compound heterozygous knock-in mouse models (Slc26a4^{c.574delC/c.919-2A>G} and Slc26a4^{c.1211C>A/c.919-2A>G}) were generated using CRISPR/Cas9. The auditory function and cochlear pathology were investigated. Both compound mutants exhibited elevated ABR thresholds, with more severe hearing loss in Slc26a4^{c.574delC/c.919-2A>G} mice. Correspondingly, these mice showed marked hair cell disruption, stereociliary loss, and cochlear structural abnormalities, whereas the Slc26a4^{c.1211C>A/c.919-2A>G} mice displayed milder changes. Transcriptomic profiling examined by bulk RNA-sequencing revealed broader differential expression in Slc26a4^{c.574delC/c.919-2A>G} mice, enriched in structural and developmental pathways, while the missense model showed predominantly immune-related signatures. Our findings demonstrate that allele-specific functional divergence in compound heterozygous SLC26A4 mutations leads to distinct auditory dysfunction, cochlear pathology, and transcriptional programs. These findings provide mechanistic insight into the phenotypic heterogeneity of hearing loss and may indicate future allele-specific interventions or therapeutic strategies.

Hepatitis B virus (HBV) infection remains a major global health burden, affecting approximately 296 million people worldwide, and yet progress in mechanistic studies and development of antivirals has been limited by the lack of physiologically relevant and sustainable in vitro models. This study established a human induced pluripotent stem cell (hiPSC)-derived multilineage hepatic organoid system that robustly supports the complete HBV life cycle, including viral entry, replication, covalently closed circular DNA (cccDNA) formation, antigen secretion, and production of infectious progeny virus. These organoids exhibit stable expression of sodium taurocholate cotransporting polypeptide (NTCP), a key receptor for HBV entry, and remain viable long term under infection conditions for at least 20 days, with sustained secretion of HBsAg and HBeAg. Importantly, the model recreates key pathological features of chronic HBV infection, including downregulation of hepatocyte functional genes (e.g., ALB and CYP3A4) and induction of fibrosis-associated markers such as COL1A1, reflecting early extracellular matrix remodeling. Moreover, results indicated the utility of this platform in the evaluation of antivirals. Treatment with tenofovir effectively reduced viral DNA and antigen production without affecting cccDNA levels, whereas bulevirtide resulted in stage-specific inhibition of viral entry, highlighting the model's capacity to resolve mechanism-of-action differences. At the same time, drug-induced hepatotoxicity was assessed within the same system. Collectively, this hiPSC-derived hepatic organoid model provides a scalable and physiologically relevant platform that bridges the gap between conventional cell culture and in vivo systems, offering a powerful tool for studying HBV pathogenesis, host–virus interactions, and preclinical antiviral discovery.

Hereditary Multiple Osteochondromas (HMO) is a rare autosomal dominant skeletal disorder caused by heterozygous loss-of-function mutations in EXT1 or EXT2, which encode glycosyltransferases essential for heparan sulfate (HS) biosynthesis. Whether haploinsufficiency alone suffices or biallelic inactivation is required for osteochondroma formation remains a central unresolved question. In this study, we employed CRISPR/Cas9 combined with PiggyBac transposon technology to introduce a second pathogenic mutation (c.1883+1G>T) into patient-derived induced pluripotent stem cells (iPSCs) carrying a heterozygous EXT1 c.1126C>T mutation. This approach enabled the generation of isogenic iPSC lines: wild-type (WT), single-mutant (SM), and double-mutant (DM). These iPSCs were differentiated through induced mesenchymal stem cells (iMSCs) into chondrocytes. Biallelic EXT1 mutation in DM cells led to significant upregulation of SOX9, COL2A1, and ACAN, elevated glycosaminoglycan (GAG) levels, and markedly reduced HS, whereas SM cells remained indistinguishable from WT. Three-dimensional (3D) chondrogenic organoid cultures revealed that DM organoids were enlarged and structurally disorganized, partially recapitulating key histopathological features of osteochondromas. Transcriptomic analysis identified the Wnt signaling pathway as the most significantly enriched pathway among differentially expressed genes following EXT1 loss. Collectively, these findings provide direct human cellular evidence that complete EXT1 inactivation—not haploinsufficiency—drives aberrant chondrogenesis, likely through impaired sequestration of morphogen ligands, thereby supporting the Two-hit pathogenic model.