Metabolic dysfunction-associated steatotic liver disease(MASLD)is a prevalent liver condition among elderly individuals,which is closely linked to cardiovascular and renal diseases,metabolic abnormalities,and a range of hepatic complications. Given the global trend towards an aging population,the prevalence of MASLD in elderly cohorts has markedly increased. Although the direct impact of MASLD on all-cause mortality is relatively limited,its negative effects on specific disease-related mortality and patient quality of life cannot be disregarded. The therapeutic measures for elderly patients with MASLD encompass active lifestyle modifications,pharmacotherapy,and necessary surgical procedures. Early-stage screening and individualized precise treatment plans are of vital importance for enhancing the prognosis of patients. Future relevant research will aim to refine diagnostic and therapeutic protocols for MASLD in elderly populations,with a focus on developing novel pharmacotherapies,and endeavoring to bring more benefits to patients.

This study aimed to provide Chinese data on Days Alive and Out of Hospital (DAOH) following video-assisted thoracoscopic surgery (VATS) lobectomy or segmentectomy. The analyzed data was derived from a prospective cohort study. Consecutive patients who underwent either VATS lobectomy or segmentectomy from April 2021 to July 2022 were included. The primary outcome was DAOH within the first 90 days postoperatively (DAOH90). The secondary outcomes were identifying the predominant complications and reasons for readmission during the DAOH90. Additionally, we utilized multivariate logistic regression to identify factors independently associated with decreased DAOH90. A total of 919 primary lung cancer patients were included. The median DAOH90 was 86 days (IQR, 85–87). The predominant postoperative complications within postoperative 90 days (POD90) were pneumonia (22.5

PSMA-targeted radiopharmaceuticals have substantially advanced the management of prostate cancer; however, high nonspecific uptake in organs such as salivary glands and kidneys remains a clinical challenge. In our previous studies, incorporation of non-canonical amino acid linkers was shown to reduce off-target uptake while preserving or even enhancing tumor accumulation of PSMA-targeted radiotracers. Here, we present a first-in-human head-to-head comparison in which each of four linker-optimized PSMA radiotracers-[68Ga]Ga-PSMA-HK4, [68Ga]Ga-PSMA-HK7, [68Ga]Ga-PSMA-Y55, and [68Ga]Ga-PSMA-Y81-was individually compared with either [68Ga]Ga-PSMA-617 or [68Ga]Ga-PSMA-11, evaluating their in vivo pharmacokinetics and diagnostic performance in eight prostate cancer patients. Preclinical data demonstrated that all four radiotracers achieved comparable or enhanced tumor uptake, with [68Ga]Ga-PSMA-Y55 and [68Ga]Ga-PSMA-Y81 showing reduced renal accumulation relative to [68Ga]Ga-PSMA-617. Clinically, [68Ga]Ga-PSMA-HK4 and [68Ga]Ga-PSMA-HK7 exhibited lower salivary gland uptake, whereas [68Ga]Ga-PSMA-Y55 and [68Ga]Ga-PSMA-Y81 showed decreased renal retention compared with reference tracers. Tumor uptake of [68Ga]Ga-PSMA-HK4 and [68Ga]Ga-PSMA-Y55 was comparable to [68Ga]Ga-PSMA-617, while [68Ga]Ga-PSMA-HK7 and [68Ga]Ga-PSMA-Y81 displayed prolonged blood pool and cardiac retention. These clinical findings indicate that β3-amino acid linkers effectively reduced salivary gland uptake, while linker stereochemistry modulated renal clearance of PSMA radiotracers. Even subtle atomic-level linker variations resulted in substantial preclinical and clinical pharmacokinetic divergence, highlighting the necessity of precise molecular engineering in PSMA radiopharmaceuticals to achieve an improved tumor therapeutic index while reducing nonspecific toxicity.

Metabolic diseases, cardiovascular diseases (CVD), and chronic kidney disease (CKD) often coexist. To understand the complex relationships between these conditions, the American Heart Association first proposed the concept of cardiovascular-kidney-metabolic (CKM) syndrome in 2023. This syndrome is recognized by pathophysiological interplays among metabolic risk factors, CKD, and CVD, which results in multi-organ disorders and increased adverse cardiovascular outcomes. The core effect of the liver in metabolism has been revealed gradually. Sharing extensive overlapping pathological mechanisms with metabolic syndrome (MS), metabolic dysfunction-associated steatotic liver disease (MASLD) is the hepatic component of MS. The risk of developing CVD and CKD is considerably elevated in patients with MASLD. Therefore, from the perspective of endocrinologists, the concept of metabolic associated liver-cardiovascular-kidney syndrome (MALCKS) more accurately describes the impairment to vital organs caused by metabolic abnormalities. By examining the implications of CKM syndrome and its relationship with MASLD, this article elucidates the mechanisms linking MASLD to metabolic syndrome and cardiorenal diseases, and demonstrates that MASLD is associated with cardiovascular, renal, and endocrine metabolic disorders, thereby expanding the concept of CKM syndrome to MALCKS. Furthermore, multidisciplinary managements under the MALCKS framework are advocated to improve patient prognosis. Nevertheless, its formal adoption as a clinical syndrome will require clear operational definitions, validation through robust cohort studies, demonstration of unique clinical utility, and multidisciplinary consensus.

Background:High-fat diet (HFD)-driven hepatic steatosis is associated with impaired mitochondrial fatty acid oxidation and dysregulated expression of genes that control lipid disposal. Carnitine palmitoyltransferase 1α (CPT1α), encoded by Cpt1a, is the rate-limiting enzyme for mitochondrial fatty acid β-oxidation and responds to nutritional stress. However, the chromatin mechanisms that regulate Cpt1a in diet-induced steatosis remain incompletely defined. Objectives:To map histone modifications at the hepatic Cpt1a locus and determine whether berberine (BBR) is associated with the restoration of Cpt1a transcription through histone acetylation remodeling. Methods:Male Sprague-Dawley rats were assigned to the normal diet (ND), high-fat diet (HFD), or berberine (BBR)+HFD group (n = 8 initially), with individual rats as the experimental unit. ChIP-qPCR was performed on archived liver samples (ND, n = 6; HFD, n = 8; BBR+HFD, n = 8) and normalized to input DNA. In BRL cells, TSA (100 nM) and SAHA (20 μM) were used to assess HDAC-sensitive regulation of Cpt1a. Results:HFD reduced H3/H4 acetylation and increased H3K9 methylation at Cpt1a regulatory regions. BBR restored H3/H4 acetylation, selectively reduced H3K9me3 at +12 kb, and attenuated HFD-induced increases in HDAC2 and SIRT2 mRNA (approximately 40-fold and 3.8-fold, respectively) toward baseline. TSA and SAHA increased Cpt1a mRNA at 24 h by approximately 8.1-fold and 5.4-fold, respectively. Palmitate reduced Cpt1a expression by approximately 58%, and this repression was reversed by BBR or TSA. Conclusions:BBR alleviates HFD-induced hepatic steatosis, concomitant with the restoration of Cpt1a histone acetylation and modulation of HDAC2/SIRT2. These data support, but do not prove, an HDAC2/SIRT2-linked chromatin mechanism and should be interpreted as a candidate pathway requiring further functional validation.

Background Optimizing elective surgical scheduling is a core component of modern hospital management. While weekend–weekday differences have been reported in selected high-risk settings, evidence regarding intra-week variation in elective thoracic surgery remains limited and inconsistent. This study aims to explore the postoperative outcomes of patients with early-stage lung cancer who underwent video-assisted thoracoscopic surgery early or late in the week. Methods From August 2022 to April 2023, we enrolled patients with early-stage lung cancer who underwent video-assisted thoracoscopic surgery from three hospitals. Patients treated surgically between Monday and Wednesday and between Thursday and Saturday were classified into early and late groups based on institutional scheduling practices, respectively. Propensity score matching(PSM) was performed to minimize confounding bias. Traditional clinical outcomes includuing complications, postoperative length of stay, as well as patient-reported outcomes (PROs) assessing postoperative symptoms and functional recovery, were compared between groups. Results 203 patients were included in finally analysis. PSM resulted in 148 patients (74 in each) in the subsequent analysis, and there were no significant differences in the demographic and tumor characteristics. No significant differences were observed between early-week and late-week groups in intraoperative complications, in-hospital complications, 30-day postoperative complications, or patient-reported outcomes. Apparent differences in postoperative length of stay were attenuated after stratification by institutional discharge policies.The uniformly low and comparable patient-reported outcome scores observed in both groups suggest that patient-perceived recovery trajectories after VATS are stable across the surgical week Conclusion These findings suggest that contemporary VATS-based perioperative care for early-stage lung cancer delivers consistent clinical and patient-centered outcomes throughout the surgical week, supporting the stability and reliability of current surgical scheduling practices

BACKGROUND:Hepatocellular carcinoma (HCC) in high-risk patients can be diagnosed by imaging alone, avoiding biopsy. However, whether liver iron concentration (LIC) affects MRI diagnostic performance remains uncertain. PURPOSE:To investigate the impact of different degrees of LIC on MRI feature assessment and LI-RADS v2018 category assignment in high-risk HCC patients. STUDY TYPE:Retrospective. POPULATION:One hundred sixty-three consecutive HCC patients (mean age, 55.73 ± 9.65 years; 152 male) with 167 lesions. FIELD STRENGTH/SEQUENCE:3.0 T. Protocol followed LI-RADS with extra sequences (R2*, PDFF). Contrast agents included gadoxetate disodium (49 lesions), gadobenate dimeglumine (114 lesions), and Magnevist (4 lesions). ASSESSMENT:According to hepatic R2* values, patients were divided into three groups: non-iron overload (80 lesions), mild (54 lesions), and moderate-to-extreme (33 lesions). Three observers independently evaluated LI-RADS v2018 major, ancillary, and LR-M features, categories, and T1 signal. STATISTICAL TESTS:ANCOVA/Kruskal-Wallis H test, chi-square/Fisher's exact tests, and logistic regression. A two-sided p < 0.05 was considered statistically significant. RESULTS:The incidences of T1 iso-/hyperintensity, nonperipheral "washout", enhancing "capsule" and HBP hypointensity differed significantly among groups. Moderate-to-severe hepatic iron overload independently influenced T1 iso-/hyperintensity (OR = 14.38 [95% CI: 4.08-50.70]) and nonperipheral "washout" (OR = 0.14 [95% CI: 0.05-0.41]). Hepatic iron overload was independently associated with enhancing "capsule" (mild: OR = 0.34 [95% CI: 0.16-0.72]); moderate-to-severe: (OR = 0.15 [95% CI: 0.06-0.37]). HBP hypointensity was influenced by Child-Pugh class B (OR = 14.51 [95% CI: 1.13-185.88]), total bilirubin (OR = 0.09 [95% CI: 0.83-0.97]), albumin (OR = 1.49 [95% CI: 1.18-1.89]), PLT (OR = 0.99 [95% CI: 0.98-1.00]) and moderate-to-severe hepatic iron overload (OR = 0.01 [95% CI: 0.00-0.25]). Proportions of LR-4 and LR-5 differed significantly among groups, and only moderate-to-severe hepatic iron overload was associated with LR-5 assignment (OR = 0.08 [95% CI: 0.02-0.28]). CONCLUSION:Hepatic iron overload, especially moderate-to-extreme, may affect the visual assessment of selected MRI features and alter LI-RADS v2018 category assignment. LEVEL OF EVIDENCE: 3: TECHNICAL EFFICACY STAGE:2.

Aim: To investigate the effects and potential mechanisms of thrombospondin 1 (Thbs1) in metabolic dysfunction-associated steatohepatitis (MASH). Methods: Serum Thbs1 concentrations were quantified in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) before and after intervention, and in a biopsy-proven cohort. Moreover, a diet-induced MASH mouse model was established using a Western diet and fructose water. The involvement of CD47 was evaluated in mice with liver-specific CD47 overexpression. Further, the immunomodulatory effects of Thbs1 were assessed in lipopolysaccharide-treated RAW264.7 macrophages. Results: Serum Thbs1 levels significantly decreased in patients with MASLD after treatment. Additionally, patients with MASH exhibited higher Thbs1 levels than non-MASH individuals. This elevated Thbs1 level was modestly associated with histopathological severity. Furthermore, short-term Thbs1 administration was associated with reduced hepatic inflammation and early fibrotic features, accompanied by decreased hepatic macrophage infiltration and M1 macrophage-associated signatures in MASH mice. However, liver-specific CD47 overexpression attenuated the observed effects of Thbs1. In vitro, Thbs1 reduced lipopolysaccharide-induced M1 macrophage-associated signatures and pro-inflammatory cytokine expression. Conclusion: Thbs1 suppresses M1 macrophage-associated signatures via CD47 signaling, thereby attenuating liver inflammation and early fibrotic features in MASH mice. These data highlight the Thbs1-CD47 axis as a potential stage-informed target for MASH treatment.

INTRODUCTION:Pancreatitis and pancreatic cancer lead to excess mortality in the general population. Excessive intrapancreatic fat deposition (IPFD) is a common driver of diseases of the exocrine pancreas according to the PANDORA hypothesis. However, the relationship of IPFD with mortality has never been investigated. We aimed to explore the association of IPFD with mortality. METHODS:Participants from the UK Biobank were divided into 2 cohorts based on the availability of IPFD quantified using MRI. The Kaplan-Meier survival analysis and multivariable Cox-proportional hazard model were used. Genome-wide association study on IPFD and Mendelian randomization analysis were performed. An IPFD-linked polygenic risk score (PRS) was applied in the MRI-naïve cohort. RESULTS:A total of 55,058 participants were analyzed, 695 (1.26%) of whom died during a median follow-up of 4.9 years. Excessive baseline IPFD was significantly associated with an increased risk of all-cause mortality (hazard ratio = 1.081, P < 0.05) and mortality from vascular diseases (hazard ratio = 1.247, P < 0.001). Genome-wide association study identified 38 significant IPFD-associated single nucleotide polymorphisms. The PRS derived from these single nucleotide polymorphism showed significant associations with all-cause mortality and mortality from vascular diseases. In the MRI-naïve cohort of 354,761 participants, consistent results were obtained using the PRS as a genetic proxy for IPFD. DISCUSSION:Excessive IPFD is associated with elevated risk of future mortality especially from vascular diseases in the general population.

Fluorescence-guided surgery (FGS) offers a potential strategy to improve complete tumor resection in prostate cancer (PCa); however, clinical application has been limited by an insufficient tumor-to-background ratio (TBR) of available probes. Here, we report the development of GGA-sNIR, a near-infrared (NIR) fluorescent probe engineered by conjugating a high-affinity DNA aptamer specific for a prostate stem cell antigen (PSCA) with a monocarboxy indocyanine green (ICG) derivative. The conjugate adopts a stable three-dimensional structure that not only enables precise target recognition but also protects against nuclease degradation, markedly enhancing its in vivo stability. GGA-sNIR exhibits nanomolar binding affinity (K d = 54.91 nM) and is specifically internalized by PSCA-positive cells. In subcutaneous tumor models, the probe achieved a peak TBR of 26 and showed prolonged tumor retention exceeding 48 h. Crucially, in an orthotopic PCa model, GGA-sNIR allowed real-time, high-contrast visualization of tumor margins during laparoscopic surgery, facilitating precise and complete resection. Further validation using ex vivo human lymph node specimens confirmed its ability to selectively detect PSCA-positive metastases. With its ultrahigh contrast, demonstrated efficacy in intraoperative guidance, and strong translational potential, GGA-sNIR represents a promising molecular tool for advancing precision surgery in prostate cancer.

Polycystic ovary syndrome(PCOS)is a prevalent endocrine disorder among women of reproductive age,with a global prevalence ranging from 5％to 18％(Shrivastava and Conigliaro,2023).Currently,a total of 12.13 million cases of infertility(Liu et al.,2024)and 0.24 million cases of cardiovascular disease(Wan et al.,2024)are attributable to PCOS worldwide,and nearly 8 billion US dollars are spent in the USA and Europe for the management of PCOS every year.However,there are still many challenges in understanding and treatment of PCOS.

Background & Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is associated with a >10-fold increase in liver-related mortality. However, biomarkers predicting both MASH and mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are missing. We developed a metabolome-derived prediction score for MASH and examined whether it predicts mortality in Chinese and European cohorts. Methods: The MASH prediction score was developed using a multi-step machine learning strategy, based on 44 clinical parameters and 250 serum metabolites measured by proton nuclear magnetic resonance in 311 Chinese adults undergoing a liver biopsy. External validation was conducted in a Finnish liver biopsy cohort (n = 305). We investigated associations of the score with all-cause and cause-specific mortality in the population-based Shanghai Changfeng study (n = 5,893) and the UK biobank (n = 111,673). Results: A total of 24 clinical parameters and 194 serum metabolites were significantly associated with MASH in the Chinese liver biopsy cohort. The final MASH score included BMI, aspartate aminotransferase, tyrosine, and the phospholipid-to-total lipid ratio in VLDL. The score identified patients with MASH with AUROCs of 0.87 (95% CI 0.83-0.91) and 0.81 (95% CI 0.75-0.88) in the Chinese and Finnish cohorts, with high negative predictive values. Participants with a high or intermediate risk of MASH based on the score had a markedly higher risk of MASLD-related mortality than those with a low risk in Chinese (hazard ratio 23.19; 95% CI 4.80-111.97) and European (hazard ratio 20.15; 95% CI 10.95-37.11) individuals after 7.2 and 12.6 years of follow-up, respectively. The MASH prediction score was superior to the Fibrosis-4 index and the NAFLD fibrosis score in predicting MASLDrelated mortality. Conclusion: The metabolome-derived MASH prediction score accurately predicts risk of MASH and MASLD-related mortality in both Chinese and European individuals.

Hematopoietic stem cells (HSCs) undergo a functional decline during aging. The intrinsic characteristics of aged HSCs have been well-described and include a strong myeloid bias, an increase in total number, and a decrease in functionality during transplantation. The impact of the aged bone marrow microenvironment, or niche, on HSCs is less well understood. It is critical to understand the changing condition of the niche during aging, and its ability to support HSCs, as this could reveal the very signals and mechanisms needed to improve HSC fitness. Furthermore, heterochronic transplantation provides an approach to test the influence of an aged recipient niche on young donor HSCs, and conversely, of a young recipient niche on aged donor HSCs. Importantly, these experiments demonstrated that donor HSC engraftment is reduced if the recipient niche is aged, and conversely, the young niche can rejuvenate aged donor HSCs. Here we will focus on the interactions between aged HSCs and their microenvironment. We will highlight current controversies, research gaps, and future directions.

We designed and synthesized a novel type of PSMA radioligand incorporating (2S, 3R) β-branched aromatic α-amino acids within the linker segment of its structure. In vivo PET/CT imaging and biodistribution analysis revealed that β-branched aromatic α-amino acids modified PSMA radioligands could maintain or even improve tumor targeting while exhibiting a more rapid renal clearance rate than [68Ga]Ga-PSMA-617. With average renal uptake of less than 10%ID/g, as opposed to 25%ID/g for [68Ga]Ga-PSMA-617, this substantial decrease in renal accumulation translates to a significantly improved safety profile by minimizing nephrotoxic risks. Our findings establish (2S,3R) β-branched aromatic α-amino acids as multifunctional pharmacophores that simultaneously enhance two critical performance parameters: target-binding affinity and renal clearance efficiency. Notably, [68Ga]Ga-PSMA-Y55 emerged as the lead compound, exhibiting an optimal balance of high tumor uptake and low renal accumulation, rendering it a promising candidate for next-generation prostate cancer radioligand therapy.

OBJECTIVE:To explore the relationship between free triiodothyronine (FT3) and diabetic peripheral neuropathy (DPN) in euthyroid patients with type 2 diabetes mellitus. METHODS:We enrolled 1422 hospitalized patients with type 2 diabetes from Zhongshan Hospital, Fudan University. All participants underwent electromyographic examinations, including nerve conduction velocity (NCV), distal motor and sensor latency (DML and DSL), sensory nerve action potential (SNAP) amplitude, and compound muscle action potential (CMAP) amplitude. RESULTS:A total of 519 (36.5%) patients with type 2 diabetes could be diagnosed as DPN according to their clinical symptoms and results of electromyography. Compared with those without DPN, the patients with DPN had a longer duration of diabetes, poorer blood glucose control, and lower BMI levels, accompanied with higher proportions of diabetic retinopathy, diabetic nephropathy, and cardiovascular disease (all P < .05). Serum FT3 level were significantly lower in patients with DPN than those without DPN (4.08 ± 0.64 vs 4.39 ± 0.63 pmol/L, P < .001), and FT3 was inversely correlated with the nerve DML and DSL, and positively correlated with the CMAP, SNAP, and NCV of all nerves we measured in the patients with DPN (all P < .05). The inverse correlation between serum FT3 and risk of DPN remained significant after multivariate adjustment for potential confounders (P < .05). A Mendelian randomization analysis also indicated a causal effect of serum FT3 on the risk of DPN. CONCLUSION:Low FT3 is a risk factor of DPN among euthyroid patients with type 2 diabetes.

Differential susceptibilities to various diseases and corresponding metabolite variations have been documented across diverse ethnic populations, but the genetic determinants of these disparities remain unclear. Here, we performed large-scale genome-wide association studies of 171 directly quantifiable metabolites from a nuclear magnetic resonance-based metabolomics platform in 10,792 Han Chinese individuals. We identified 15 variant-metabolite associations, eight of which were successfully replicated in an independent Chinese population (n = 4,480). By cross-ancestry meta-analysis integrating 213,397 European individuals from the UK Biobank, we identified 228 additional variant-metabolite associations and improved fine-mapping precision. Moreover, two-sample Mendelian randomization analyses revealed evidence that genetically predicted levels of triglycerides in high-density lipoprotein were associated with a higher risk of coronary artery disease and that of glycine with a lower risk of heart failure in both ancestries. These findings enhance our understanding of the shared and specific genetic architecture of metabolites as well as their roles in complex diseases across populations.

To evaluate the diagnostic performance of virtual monoenergetic images (VMIs) at 40 keV obtained from dual-layer spectral CT (DLCT) for small HCC (sHCC, ≤ 30 mm) using the LI-RADS version 2018 (i.e., LR-5) by intraindividual comparison with conventional CT images (CIs) and MRI. From February 2020 to December 2024, patients who were at high risk of HCC with at least one small noncystic observation (≤ 30 mm) and who underwent both DLCT and multiphase MRI within one month were retrospectively enrolled. VMIs at 40 keV derived from DLCT in the arterial and portal venous phases were reconstructed. Two blinded radiologists independently evaluated the LI-RADS imaging features and assigned categories to CIs, VMIs, and MRI. Sensitivities and specificities for sHCC were compared across modalities using generalized estimating equations. In total, 136 patients (median age, 56 years [IQR, 48–61 years]; 115 males) with 200 treatment-naïve small observations confirmed by pathology or clinical follow-up were studied. There were 118 HCCs, 23 non-HCC malignancies, and 59 benign observations. When the LR-5 criteria were used, VMIs had significantly higher sensitivity than CIs (reader 1, 76.3

The purpose of this study is to evaluate the PSMA PET imaging parameters in association with outcomes among patients with oligorecurrent prostate cancer. This retrospective single-center study included 101 patients (median age 71; interquartile range 65-75) with biochemically recurrent prostate cancer who underwent PSMA PET between May 2021 and May 2022, revealing 5 or fewer sites of metastases (oligometastatic disease). Multiple variables including maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), and molecular tumor volume (MTV) were measured and analyzed on a per-patient basis, along with total MTV and molecular tumor burden (MTB). Multivariable Cox proportional-hazards regression models were used to identify factors associated with progression-free survival (PFS). PSMA PET revealed a total of 216 lesions across all patients, of which 134 (62.0%) involved the lymph nodes and 56 (25.9%) involved the bone. A total of 61 (60.4%) patients received combined metastasis-directed and hormone therapy, and 40 (39.6%) received hormone therapy only. The median subsequent follow-up from PSMA PET detection of oligorecurrent disease was 18.2 months (IQR 10.3-25.0). MTV on PSMA PET was associated with worse PFS (hazard ratio: 1.05, 95% CI 1.00-1.11; P = 0.04). Molecular tumor volume on PSMA PET is associated with worse clinical outcomes in patients with oligorecurrent prostate cancer.

Epigenetic drift refers to the gradual and stochastic accumulation of epigenetic changes, such as DNA methylation variability, with advancing age. Although increasingly recognized for its potential role in aging biology, its extent, biological significance, and population specificity remain insufficiently characterized. Here, we present the first comprehensive epigenome-wide drift study (EWDS) in a large Chinese cohort (n = 3538), with replication in two independent Chinese (total n = 1467) and two European cohorts (total n = 956), to investigate the scale and relevance of epigenetic drift across populations. Through simulation, we identify White's test as the most powerful method among four alternatives for detecting age-associated methylation variability. Our EWDS reveals that 10.8% (50,385 CpGs) of sites on the 850 K EPIC array exhibit epigenome-wide significant drift, with 99% showing increased interindividual variability (positive drift) and 1% showing decreased variability (negative drift). Integration with single-cell RNA-seq data demonstrates that positive drift-CpGs are associated with increased transcriptional variability and upregulation in specific cell types, whereas negative drift-CpGs exhibit the opposite effect. We develop epigenetic drift scores (EDSs) to quantify individual drift burden; these scores are strongly age-associated and correlate with lipidomic profiles and clinical aging indicators. Longitudinal data confirm within-individual accumulation of drift over time. Finally, a GWAS of EDS identifies genetic determinants of drift magnitude, including heritable loci (e.g., ASTN2, SOCS5). Collectively, these findings establish epigenetic drift as a pervasive, directional, and biologically meaningful feature of human aging.

Background:Prostate cancer remains a significant global health burden, with biochemical recurrence (BCR) affecting 20-50% of patients post-radical prostatectomy. This study aimed to investigate the relationship between preoperative PSA levels and BCR-free survival in Asian populations. Methods:We conducted a retrospective cohort study of 3,092 prostate cancer patients who underwent radical prostatectomy at Yonsei University College of Medicine, Korea (1992-2014). The exposure variable was preoperative PSA level, and the primary outcome was BCR-free survival. Covariates included age, Gleason score, pathological stage, surgical margins, and other clinical factors. Patients were followed quarterly for two years post-surgery, semi-annually for three years, then annually thereafter (median follow-up: 66 months). Results:Using piecewise linear regression, we identified a significant threshold effect at PSA 5.1 ng/mL. Above this threshold, each unit increase in LnPSA was associated with a 6.10-month reduction in BCR-free survival (95% CI: -7.64 to -4.56, P<0.0001). Higher PSA levels correlated with increased adverse pathological features and shorter BCR-free survival across all risk groups. Conclusion:This study establishes a critical PSA threshold of 5.1 ng/mL for BCR risk stratification in Asian populations. Above this threshold, each unit increase in LnPSA correlates with a 6.10-month reduction in BCR-free survival, providing valuable guidance for post-operative monitoring and personalized treatment strategies.