Elevated serum homocysteine (HCY) is associated with cardiovascular and other systemic risks. This study aimed to develop serum-based secondary candidate reference materials (Can-RMs) for metrological traceability and validating their dual utility as commutability-verified materials for external quality assessment (EQA). First, 41 fresh serum samples were analyzed by isotope dilution liquid chromatography-tandem mass spectrometry reference method and four routine detection systems to evaluate baseline comparability. Second, the commutability of Can-RMs, EQA materials spiked with purified reference standards (Sta-EQA materials), and in-house prepared EQA materials with serum matrix (Ser-EQA materials) was assessed via Deming regression and bias analysis. Third, the commutable Can-RMs were deployed in a 62-laboratory EQA program; performance (CV, bias, total error) were evaluated per biological variation-based minimum analytical quality specifications (6.23%, 12.94%, and 23.21%). Routine systems exhibited positive proportional biases (0.5%-13.1%) versus the reference method. The Can-RMs (L1-L5) and Ser-EQA materials were commutable across all systems (with only Can-RM L1 for the Leadman system was inconclusive under IFCC criteria). All Sta-EQA materials were non-commutable under both approaches. In the EQA program, the average laboratory pass rates for TE, bias, and CV were 91%, 87%, and 98%, respectively, with the Roche and Strong Biotechnologies systems achieving 100% pass rate. In-house prepared serum-based Can-RMs and Ser-EQA materials exhibit excellent commutability, supporting reliable standardization assessment and accurate trueness validation for clinical procedures. A major limitation is that all reagents were tested on a single Roche Cobas c701 analyzer; future multi-instrument trials are required to verify generalizability.
To determine whether weight regain after metabolic bariatric surgery reflects a systematic reorganization of neural decision signals elicited by food cues and longitudinal affective states, and to develop an interpretable, trackable, and stratifiable multimodal computational psychiatry framework. This study was based on a multi-timepoint longitudinal cohort of patients undergoing primary metabolic bariatric surgery, integrating a standardized food-choice task, 64-channel EEG, psychometric measures, and longitudinal affective-state data. Food stimuli were first standardized across five domains: subjective experience, health/naturalness attributes, reward-control attributes, nutritional composition, and visual features. EEG data underwent predefined quality-control procedures, after which N2, P3, centroparietal positivity, feedback-related negativity, feedback P3, and frontal theta indices were extracted. Food-choice behavior was decomposed using a hierarchical drift-diffusion model into drift rate, boundary separation, starting point, and non-decision time. A multimodal RT-by-frontal-theta interaction model was then fitted, and GIMME dynamic network modelling was used to characterize shared, subgroup-specific, and individual pathways within affect-reward-control states. Food stimuli were decomposed into 39 auditable variables, forming a continuous representational space spanning health, reward, control, nutritional, and visual-salience dimensions, with high reliability across domains. EEG quality control preserved clinically expected heterogeneity while excluding recordings at high risk of biasing ERP and time-frequency estimates. Behavioral and DDM results showed that the weight-regain group had longer mean reaction times than the maintained-weight-loss group (0.726 s vs. 0.651 s), together with lower drift rate (0.93 vs. 1.27), lower boundary separation (1.20 vs. 1.37), lower starting point (0.42 vs. 0.51), and longer non-decision time (0.31 s vs. 0.27 s). ERP findings indicated that weight-regain-related differences spanned early control/conflict monitoring, posterior stimulus evaluation, evidence accumulation, and feedback processing, with posterior P3/CPP and feedback-related components contributing the dominant late-stage separation. The multimodal interaction model showed an RT-by-frontal-theta interaction of approximately 0.92% points in the primary adjusted model (95% CI, 0.36-1.49), with a consistent direction across alternative model specifications. GIMME identified stable affect-reward-control dynamic pathways and separated three psychological dynamic subtypes: affect-reactive, reward-sensitized, and control-resilient. Weight regain after metabolic bariatric surgery is not merely an endpoint of body-weight change, but a dynamic risk process shaped jointly by food-cue evaluation, evidence-accumulation efficiency, frontal control modulation, and longitudinal affect-reward state transitions. This multimodal computational framework reframes postoperative weight regain as a mechanistically interpretable neurobehavioral phenotype, providing a translational basis for earlier risk stratification, individualized follow-up, and interventions targeting emotion, craving, and control.
Adults with congenital urologic conditions, such as bladder exstrophy and vesicoureteral reflux, often require lifelong care that begins with childhood surgical reconstructions and extends through adolescence and adulthood with ongoing surveillance, follow-up care, and revision procedures when needed. Measurement of "success" can be difficult to quantify, as the definition of success may differ between parents and patients later in adulthood, and the definition of success should extend beyond f technical success to the broader care interventions and long-term outcomes, which often requires decades of follow-up time. The traditional clinician-defined endpoints may not capture what patients consider as "success" in the context of the adult patients' evolving goals for urinary function, sexual health, fertility, body image, and mental health across the lifetime. Patient-centered outcomes research offers a framework for centering patient voices, yet this has rarely been applied in adult congenital urology. Guided by the Patient-Centered Outcomes Research Institute (PCORI) foundational expectations in patient engagement, we developed a structured community-partnership methodology for the patient-centered research process in lifetime congenital urologic care. The framework includes six steps: (1) partnership formation; (2) inclusive recruitment and relationship building; (3) co-defining research questions; (4) collaborative data generation and interpretation; (5) dissemination and knowledge return; and (6) iterative reflection and process evaluation. We illustrate its application through two collaborations. First, with the Unsilenced Movement (UM), a patient advocacy group addressing medical trauma related to childhood voiding cystourethrogram testing, to qualitatively analyze patient narratives and co-interpret themes related to post-traumatic stress and healthcare avoidance; second, with the Association for the Bladder Exstrophy Community (ABEC) to co-design a patient-driven survey to assess goals, needs, and barriers across the lifespan for those living with bladder exstrophy. In both partnerships, patient representatives served as core research team members, co-authors, and co-presenters of findings, and ensured that patients' lived experiences were translated accurately in a rigorous methodology. This framework shows how early and sustained collaboration with patient advocacy communities can reshape research prioritization, outcome selection, and interpretation of data in lifetime congenital urologic care. By centering patients' lived experiences and defining success together, researchers can move beyond clinician-defined metrics towards outcomes that better reflect patient priorities. This methodology is adaptable to other congenital and chronic conditions requiring complex medical and urological care.
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Breast cancer (BC) remains the most prevalent malignancy among women worldwide, with persistent challenges such as drug resistance and tumor progression despite significant therapeutic advancements. The roles of ferroptosis and long non-coding RNAs (lncRNAs) in BC are not yet fully elucidated, underscoring the need for novel therapeutic targets. In this study, we investigated the function of LINC01929 in BC through a combination of in vitro and in vivo experiments, bioinformatics analysis, RNA pull-down mass spectrometry, and clinical tissue validation. We found that LINC01929 is significantly overexpressed in BC tissues and is associated with poor patient prognosis. Mechanistically, LINC01929 promoted malignant phenotypes in BC cells and was associated with reduced ferroptosis-related stress, with these effects being at least partly dependent on transferrin receptor (TFRC). Conversely, silencing LINC01929 led to reduced TFRC expression and induced ferroptosis in BC cells. Clinical data further confirmed that elevated TFRC levels correlate with aggressive tumor features and unfavorable outcomes. These findings suggest that targeting LINC01929 to regulate TFRC-mediated ferroptosis could represent a promising therapeutic strategy for BC, positioning both LINC01929 and TFRC as potential biomarkers and therapeutic targets.
As of 2004, sponsors of studies submitted under the Clinical Trials Regulation are required to confirm that the chosen gender distribution is appropriate for identifying gender-specific differences-unlike research studies submitted under professional regulations. One of the best-known examples illustrates why sex and gender should also be taken into account in these types of studies: in the case of heart attacks, warning symptoms differ between men and women, resulting in women being less likely to receive guideline-based treatment and more likely to die than men. The objective of the present study was to obtain an overview of how gender-related aspects are considered in medical research projects submitted to an ethics committee for review. The analysis of 171 research proposals submitted to the Ethics Committee of the University of Marburg in 2021 was conducted using two self-developed scoring systems. The first score assessed the extent to which gender and diversity aspects were considered in the research proposal. The second score evaluated the availability and quality of existing knowledge of gender and diversity differences related to the topic of each proposal, as reflected in the medical literature. Literature searches were performed in PubMed (PM) using a dedicated search string and in the GENDERMED database (GM). A comparison of the two scoring systems indicates that in more than 70% of the research proposals that did not address gender or diversity aspects, the scientific literature nevertheless contained relevant evidence on gender- or diversity-related differences pertaining to the respective research topic. This result is noteworthy, as institutions that support science and research, such as the German Research Foundation (DFG), have long been recommending that applicants appropriately consider sex/gender and diversity in the planning stage of their research projects. Further studies are needed to determine which hurdles and barriers exist on the part of researchers. At key points within the research landscape, such as ethics committees, researchers could be made aware of these aspects at the planning stage and, where appropriate, be offered guidance.
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) accelerate disease progression and increase mortality. Accurate severity assessment is essential for standardised clinical management. Traditional Chinese Medicine (TCM) shows efficacy in treating AECOPD, but no practical TCM-specific severity assessment tool exists. This study integrates multidimensional Western and TCM variables to develop an AECOPD severity assessment model, aiming to support clinical evaluation, improve treatment efficacy and prognosis and offer methodological insights for related research. The overall study design comprises four sequential steps. First, factors influencing AECOPD severity will be preliminarily screened through literature review and the first round of expert questionnaire surveys. Second, a multicentre cross-sectional study will be performed to establish a clinical information database; multiple statistical methods, combined with a second expert questionnaire survey, will be employed to identify the relevant variables associated with disease severity. Third, based on the established clinical database and identified variables, a disease-syndrome integrated AECOPD severity assessment model will be developed using both Classification and Regression Trees and Backpropagation Neural Networks. Fourth, the models will undergo comprehensive evaluation and validation to determine an accurate, practical, reproducible and externally valid disease severity assessment tool. The study protocol and all required documents have been submitted for review and approval to the Independent Ethics Committees of all the participating sites. All participants will provide their written informed consent on study entry, and all the recorded data will be treated as confidential. Ethical approval for this study was granted by the Institutional Review Board of the First Affiliated Hospital of Henan University of Chinese Medicine (Approval No. 2025HL-342) TRIAL REGISTRATION NUMBER: NCT06918353.
The regimen of rituximab we not determined based on evidence from pharmacokinetics. However, rituximab exhibited significant pharmacokinetic variability among different clinical populations, which might be a key factor influencing individual exposure and response to this monoclonal antibody. This systematic review aimed to analyze the traditional and population pharmacokinetics of rituximab and to investigate covariates influencing its pharmacokinetics. A systematic search was conducted in three English databases (Medline, Embase, Cochrane Central Register of Controlled Trials) and two Chinese database (China National Knowledge Infrastructure and Wanfang Data). Traditional and population pharmacokinetics of rituximab conducted in humans were included. Study designs, population characteristics, pharmacokinetic parameters, and covariates were extracted. The ClinPK's checklist was used to assess the reporting quality of the included studies. The PROSPERO registered ID was CRD420251085784. The systematic research yield 25 traditional pharmacokinetics studies and 26 population pharmacokinetics studies. The included studies mainly investigated the pharmacokinetics of rituximab in patients with non-Hodgkin's lymphoma, rheumatoid arthritis, kidney disease and anti-neutrophil cytoplasmic antibody-associated vasculitis. Significant variability in pharmacokinetic parameters existed among different clinical populations as well as among different subjects encountering similar clinical conditions. Most (23, 88.5%) population pharmacokinetics studies used a two-compartment model to describe rituximab pharmacokinetics. However, the elimination kinetics were inconsistent including the first-order elimination, time-varying elimination and target-mediated drug disposition. Body size descriptors such as body surface area, body mass index and body weight were the most frequently observed significant covariates, which appeared in 17 studies. Other significant covariates included gender, basal CD19+/20+ count, tumor stage, baseline total metabolic tumor volume, anti-drug antibodies, disease progression, urinary protein to creatinine ratios and the number of rituximab treatment courses. In addition, the pharmacokinetic parameters of rituximab biosimilars were proved to be non-inferior to that of the originators. Compared with intravenous administration, subcutaneous administration with a specific dose of 1600 mg or 1400 mg could achieve non-inferior Ctrough in chronic lymphocytic leukemia and diffuse large B-cell lymphoma respectively. This systematic review presented a comprehensive overview of rituximab's pharmacokinetics across various clinical populations. It highlighted the complexity and variability of rituximab's pharmacokinetics. Future research should place emphasis on the model informed precision dosing of rituximab based on pharmacokinetics and various influencing factors in clinical practice.
Lung cancer remains one of the most prevalent and lethal malignancies worldwide. Oridonin (ORI) exhibits remarkable anti-lung cancer activity. Nevertheless, its clinical application in lung cancer therapy is severely hindered by poor solubility, fast metabolism, insufficient tumor penetration, and low selectivity. In this study, we developed a redox-responsive polymeric micelle (HA-cys-TOS) targeting the CD44 receptor to improve ORI bioavailability and tumor targeting. The polymer was synthesized via esterification and verified by 1H NMR. Our data showed that ORI@HA-cys-TOS exhibited good stability, biosafety and redox-responsive sustained release. Compared to HepG2 cells, ORI@HA-cys-TOS exhibited significantly enhanced internalization ability in A549 cells, likely due to HA binding to the CD44 receptor overexpressed on A549 cells. Unexpectedly, the enhanced targeted accumulation of ORI@HA-cys-TOS micelles in vivo was also observed in both subcutaneous and in situ lung cancer tissues. In vivo and in vitro antitumor studies demonstrated that ORI@HA-cys-TOS micelles exhibited significantly greater antitumor activity compared to free ORI. Notably, no side-effects were observed during the 21 days experimental period. This study provides an experimental basis for advancing ORI toward clinical personalized lung cancer therapy by targeting CD44 and responding to the tumor redox microenvironment.
Diarrheagenic Escherichia coli (DEC) is a leading cause of infectious diarrhea globally, yet its epidemiology in high-altitude human populations remains largely unexplored. This study aimed to determine the prevalence, pathotype distribution, antimicrobial resistance, and genetic diversity of DEC among Tibetan herdsmen in Nagqu, Tibet, China, during June 2025, with comparison to a low-altitude cohort from Zhejiang Province. In this cross-sectional, observational study, a total of 209 fecal samples were collected from Tibetan herdsmen in Nagqu. DEC isolates were identified by MALDI-TOF MS and PCR-based pathotyping. Antimicrobial susceptibility was assessed by broth microdilution, and genetic relatedness was evaluated using Fourier-transform infrared (FT-IR) spectroscopy. For ecological comparison, 187 DEC isolates from 799 fecal samples in Zhejiang Province were analyzed using identical molecular methods. Of 111 confirmed E. coli isolates from Nagqu, 36 (32.4%, 95% CI: 23.8%-42.1%) were identified as DEC, including 32 EAEC, 2 STEC/EPEC, and 2 STEC strains. The predominant virulence genes were aggR (50.0%) and astA (47.2%). All isolates were susceptible to β-lactam/β-lactamase inhibitor combinations, carbapenems, and tigecycline, while moderate resistance was observed to ampicillin (38.9%) and cefazolin (27.8%). FT-IR typing revealed 36 distinct lineages, indicating an absence of clonal clustering among DEC isolates. Pathotype distribution in Nagqu (EAEC predominance, 88.9%) differed markedly from that in Zhejiang, where EAEC (51.9%) and STEC/EPEC (47.6%) were co-dominant. DEC in this high-altitude population exhibits an EAEC-dominated pathotype profile, low antimicrobial resistance, and remarkable genetic heterogeneity. These findings suggest that rather than micro-evolutionary adaptations to high altitude, the remote, low-antibiotic pastoral environment acts as an evolutionary sanctuary that preserves ancestral, non-clonal lineages and restricts the selective sweeps of multidrug-resistant clones common in lowlands. This unique baseline provides a data-driven rationale for integrating nomadic populations into national surveillance; monitoring this pristine pathogen ecology within a One Health framework offers a vital evolutionary control to better track and mitigate enteric pathogen dissemination across socio-ecologically diverse settings.
Microtia is a common congenital craniofacial malformation, and auricular reconstruction with expansion method is one of the primary surgical treatments. This research introduces a novel technique involving a supra-auricular incision during the second stage of single-flap auricular reconstruction. A total of 86 patients with unilateral microtia who underwent auricular reconstruction between June 2023 and August 2024 were included in this retrospective analysis. All 86 patients progressed to the second stage of single-flap auricular reconstruction 2-3 months after the first stage of retro-auricular expander implantation. Among them, 40 cases were operated on using previous retro-auricular incision (Group A), and 46 cases were operated on using new supra-auricular incision (Group B). Postoperative outcomes, patient satisfaction, and complications were monitored during follow-up. The mean follow-up time was 11 ± 3.3 months. Immediately after the operation, the cranioauricular angles of Group A and Group B were 28.64° ± 2.49° and 31.06° ± 1.84°, respectively. At the final follow-up (mean duration: 11 ± 3.3 months), the cranioauricular angles of Group A and Group B were 27.83° ± 2.27° and 30.69° ± 1.87°, respectively. Differences were observed between the two groups (p < 0.001). Additionally, the appearance of other subunits, such as the helix and scapha, showed improvement. Functional assessments indicated better performance in glasses and mask wear in Group B, with higher patient satisfaction scores (average 1.87 vs. 1.775). Complications included flap necrosis and hypertrophic scarring in Group A (2 cases each), and one case each of infection and hypertrophic scarring in Group B. In the second-stage operation of single-flap auricular reconstruction, a novel supra-auricular incision for the placement of the auricular scaffold can be employed to achieve improved esthetic and functional surgical outcomes. This approach demonstrates clinical superiority over conventional methods and suggests broader applicability in auricular reconstruction. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
To compare the site-specific optical coherence tomography (OCT) biomarkers that appear prior to the formation of large hypertransmission defects (hyperTDs) with the eye-level OCT biomarkers that were shown to predict disease progression in eyes with intermediate AMD (iAMD). Retrospective subgroup analysis of a prospective cohort study. A prospectively enrolled cohort of eyes with iAMD, imaged with swept-source OCT (SS-OCT), was retrospectively reviewed to identify eyes that developed large hyperTDs. Large hyperTDs were defined as bright lesions with a greatest linear dimension (GLD) of ≥250 μm on an en face sub-retinal pigment epithelium (RPE) slab image created using segmentation boundaries positioned 64-400 μm below Bruch's membrane (BM). All visits prior to the formation of the large hyperTDs were retrospectively reviewed to identify the OCT biomarker at the retinal location where the initial large hyperTD formed. 82 of 171 eyes (48%) with iAMD developed at least one large hyperTD. At the first visits when the large hyperTD developed, a total of 119 large hyperTDs were detected. Hyperreflective foci (HRF) were the most frequent OCT biomarker at the sites prior to the formation of hyperTDs (88/119, 74%). Soft drusenoid lesions were the second-most frequent biomarker (77/119, 65%); however, 67 of these lesions occurred in conjunction with HRF. Calcified drusen (CaD) were present at 19 of 119 sites (16%). Of these 19 CaD lesions, 7 contained hyporeflective cores (hypoRC-CaD), and 11 were associated with HRF. Non-calcified hyporeflective core drusen (hypoRCD) were present at 16/119 (13%) sites, with three of the hypoRCD associated with HRF. Basal laminar deposits (BLamD) were present at 2 of 119 sites (2%), both of which were associated with HRF. Single cases of a vitelliform lesion and a small hyperTD were also identified prior to the large hyperTDs. Site-specific analysis showed that HRF were the most frequent OCT biomarker at the sites prior to the formation of large hyperTDs. Soft drusenoid lesions and HRF were frequently observed together, consistent with our previous eye-level multivariable analysis, which showed that drusen volume was not independently predictive of the future formation of large hyperTDs.
Animal manure is an agricultural by-product that presents both nutrient value and environmental challenges, particularly through nutrient leaching and greenhouse gas (GHG) fluxes. Hydrothermal carbonization (HTC) offers a potential management strategy that converts wet manures into hydrochar, which is a more stable and nutrient-retentive amendment. This study evaluated how hydrochar derived from dairy manure, swine manure, and poultry litter, applied at 15 or 30 metric tons/ha, influences GHG fluxes and corn biomass production in a controlled greenhouse experiment using soil mesocosms with two fertilization histories (dairy-manure vs. inorganic/chemical-only). All treatments received an equal total nitrogen input through combinations of hydrochar-derived N and urea. Hydrochar treatments tended to reduce cumulative N2O fluxes, although not always significantly, compared to the urea-only control, with the largest reductions occurring after the second urea application. Across feedstocks, hydrochar treatments tended to show higher cumulative CO2 fluxes, although not statistically significant, relative to the control, with 15 tons/ha applications producing higher CO2 fluxes and more corn biomass compared to 30 tons/ha. Methane fluxes exhibited no consistent treatment-level trends. Corn biomass tended to be higher in the 15 tons/ha hydrochar treatments and lower in the 30 tons/ha treatments relative to the control. Overall, findings indicate that partially replacing urea fertilizer with hydrochar, can potentially increase biomass while reducing cumulative N2O fluxes. Generally, the increases in CO2 fluxes from hydrochar did not fully offset the reductions in N2O fluxes at the system level. The results suggest that hydrochar amendments can offer an agronomically efficient and environmentally beneficial nutrient-management strategy.
Acute liver injury (ALI) is characterized by massive hepatocyte necrosis and rapid deterioration of liver function, which is closely associated with a cytokine storm mediated by the excessive activation of macrophages. Currently, there is a lack of effective targeted drugs in clinical practice. This study aimed to investigate the protective effects and mechanisms of protocatechualdehyde (PCA) against ALI. PCA exerts its biological effects by inhibiting macrophage-driven inflammation. The protective effects and mechanisms of PCA were experimentally validated using both in vivo and in vitro assays. In vivo, mice with ALI induced by lipopolysaccharide (LPS), acetaminophen (APAP), or carbon tetrachloride (CCl₄) showed reduced liver tissue damage, decreased serum transaminase levels, and downregulated inflammatory cytokine levels after PCA treatment, indicating that PCA protects against ALI induced by multiple causes. In vitro experiments further demonstrated that, within a safe concentration range, PCA significantly inhibit the expression of inflammatory cytokines in LPS-induced RAW264.7 cells and suppress necroptosis. Mechanistically, PCA functions through multiple pathways. It directly binds to RIPK1 to inhibit necroptosis in macrophages. Furthermore, it downregulates IFN-γ, subsequently blocking the JAK1/STAT1 signaling pathway and reducing the release of IL-17a and Ccl20. A reduction in these cytokines diminishes the infiltration of neutrophils and T cells, thereby improving the inflammatory milieu in ALI. In conclusion, PCA synergistically attenuates macrophage-driven inflammatory injury by inhibiting RIPK1-mediated necroptosis and regulating the IFN-γ/JAK1/STAT1 signaling axis, providing experimental evidence of its potential as a therapeutic agent for ALI.
Breast cancer remains a leading cause of cancer-related mortality, particularly due to its metastatic potential. Circulating tumor cells (CTCs) have emerged as critical players in metastasis, offering potential as prognostic and predictive markers. Among CTC populations, those undergoing epithelial-to-mesenchymal transition (EMT) exhibit enhanced invasiveness, motility, and resistance to therapy. EMT-CTCs, often associated with cancer stem cell-like traits, contribute significantly to tumor progression and treatment failure. However, their detection is challenging due to their heterogeneous nature and partial EMT states. This chapter explores advanced methodologies for detecting EMT-CTCs, their molecular characteristics, and their clinical relevance in breast cancer. Biomarkers such as TWIST1, vimentin, and PLS3 are highlighted for their roles in identifying EMT-CTCs and tracking their transition states. The prognostic implications of EMT-CTCs, particularly their correlation with poor outcomes and resistance to therapy, underscore their potential utility in personalized medicine. Further research into standardizing detection techniques and understanding the complex interplay between EMT-CTCs and the tumor microenvironment is essential for integrating these insights into clinical practice.
Redox-responsive lipid nanoparticles (LNPs) are emerging as a powerful platform for precision nanomedicine by exploiting disease-associated redox imbalances, such as elevated glutathione and reactive oxygen species, to trigger controlled cargo release and structural activation. This strategy is of great importance for developing gene-based therapeutics, where efficient cytosolic delivery is essential. In addition to nucleic acids, redox-responsive LNPs have been also explored in delivering small molecules, proteins, and theranostic agents, broadening their potential in both cancer and non-cancer diseases. This review summarizes the biological basis of redox responsiveness, key design principles for responsive chemical structures, and major advances in payload delivery and targeting capability of LNP carriers. Moreover, some major bottlenecks, including redox heterogeneity, stability, responsiveness trade-offs, and translational complexity, are critically discussed. Future directions are also highlighted, particularly for organ-selective delivery, multifunctional theranostics, and clinically translatable LNP-based medicines.
Stressful life events (SLEs) across the life course have been associated with cognitive decline, but evidence on their cumulative impact and potential modifiers remains limited. We aimed to examine the associations between SLE exposure in childhood, adulthood, or both life stages and cognitive trajectories, and to investigate whether these associations vary by sex and education. We used data from the China Health and Retirement Longitudinal Study, a nationally representative cohort of adults aged ≥45 years. Participants with complete data on SLEs, cognition, and covariates were included (n = 5922). SLEs were retrospectively assessed for childhood and adulthood. Cognitive function was measured using a composite score (range 0-21) across three waves (2011-2015). Linear mixed-effects models examined longitudinal associations, adjusting for sociodemographic factors, health behaviors, and chronic conditions, with interaction analyses for sex and education. Compared with participants reporting no SLEs, cumulative exposure showed the strongest association with cognitive decline (β = -0.52, 95% CI -0.69 to -0.35), followed by childhood-only (β = -0.34, -0.48 to -0.20) and adulthood-only exposure (β = -0.22, -0.37 to -0.07). Sex significantly moderated the associations for childhood and cumulative exposure, with women exhibiting greater cognitive vulnerability. Higher educational attainment attenuated the associations between single-period stress and cognitive decline, with only partial protection observed against cumulative adversity. Cumulative life-course stress is associated with accelerated cognitive decline in Chinese middle-aged and older adults. Women appear more vulnerable to stress-related cognitive effects, whereas higher education confers partial resilience, highlighting the need for sex-sensitive and education-informed prevention strategies.
Oligometastatic prostate cancer (omPC) represents a specific state with improved outcomes following cytoreductive radical prostatectomy (cRP). Prognostic factors that guide disease progression are yet to be fully elucidated, and the role of pelvic lymph node dissection (LND) in this setting is controversial. This study aimed to evaluate the impact of LND on biochemical progression and castration-resistant prostate cancer (CRPC) in patients with omPC. A total of 169 omPC patients who underwent cRP with (n = 123) or without LND (n = 46) between January 2015 and February 2024 at multiple centers were retrospectively analyzed. Biochemical progression-free survival (bPFS) and time to CRPC were analyzed using Kaplan-Meier curves and Cox proportional hazards models. Subgroup analysis stratified by nodal status was performed to explore differential treatment effects. In the overall cohort, multivariable analysis identified initial PSA > 30 ng/mL as an independent predictor of biochemical progression (HR = 2.53, 95% CI: 1.40-4.58, p = 0.002). For CRPC progression, no variable reached conventional statistical significance in the multivariable model. Stratified analysis revealed that among patients with node-positive disease (N1, n = 40), LND was associated with significantly prolonged bPFS (p = 0.018) and delayed progression to CRPC (p = 0.014). Notably, within the LND cohort (n = 123), N1 patients had significantly higher Gleason scores and T stages, and experienced worse CRPC than N0 patients (p = 0.02). In omPC patients undergoing cRP, high baseline PSA independently predicted biochemical recurrence. Nodal involvement was associated with more aggressive disease features and worse outcomes within the population. An exploratory subgroup analysis suggested that node-positive patients may be associated with improved outcomes after LND; however, this finding was limited by a very small sample size and requires prospective validation.
Historic data on inguinal hernia repair recurrences have been mixed, with some reports demonstrating higher recurrences after laparoscopic (laparoscopic IHR) and robotic inguinal hernia repair (robotic IHR) as compared with open inguinal hernia repair (open IHR). We evaluated the contemporary, real-world recurrence requiring reoperation (RRR) rates among open IHR, laparoscopic IHR, and robotic IHR. This population-based study utilized New York and Florida state databases between October 2015 and December 2021 to identify adult patients who underwent uncomplicated IHR using ICD-10 codes and categorized them into open IHR, laparoscopic IHR, or robotic IHR. RRR was defined as time to a second ipsilateral IHR. Among 265,955 patients, 134,348 underwent open IHR, 106,425 laparoscopic IHR, and 25,182 robotic IHR. Open IHR decreased from 61.8% in 2015 to 40.0% in 2021, while laparoscopic IHR and robotic IHR increased from 36.2 and 2.0% in 2015 to 40.0 and 16.9% in 2021, respectively (all p < 0.001). In 2015, RRR rates were similar for L‑IHR and O‑IHR (1.6%) but higher for R‑IHR (3.7%); by 2021, the RRR rate after R‑IHR declined to match the others. Multilevel Cox regression analysis demonstrated that laparoscopic IHR (HR 0.5 (0.4-0.7), p < 0.001) and robotic IHR (HR 0.4 (0.2-0.9), p = 0.04) were associated with lower risk of RRR in high laparoscopic inguinal hernia case volume institutions. Older age, White race, chronic obstruction pulmonary disease, obesity, hypertension, and tobacco use were independently associated with higher RRR. In contemporary times, RRR rates after laparoscopic IHR and open IHR were similar. While the RRR rate after robotic IHR was higher than both open IHR and laparoscopic IHR in earlier years, it has since declined to equivalent rates in recent years.
Retinal vein occlusion (RVO) is a chronic retinal vascular disease that often requires repeated anti-VEGF injections and long-term follow-up. However, predicting treatment responses across different follow-up timepoints remains clinically challenging. To address this issue, we developed an AI system integrating generative adversarial networks (GANs), UNet + +, and ResNet-101 to generate post-treatment OCT and fundus images and support clinical decision-making. A total of 2304 OCT and 576 fundus images from 576 RVO patients were collected at baseline and at weeks 4, 12, and 24 after treatment. The generated images demonstrated favorable visual quality, as evaluated by mean absolute error (MAE), peak signal-to-noise ratio (PSNR), and structural similarity index measure (SSIM). The system further quantified lesion areas and predicted retreatment needs, achieving average AUCs of 0.854 and 0.744 across six models in the internal and external test datasets, respectively. In the reader study, the AI system achieved higher predictive accuracy than retinal specialists while substantially reducing image interpretation time. Clinicians' predictive performance also improved with AI assistance.