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Background: Physical activities are widely implemented for non-pharmacological intervention to alleviate depressive symptoms. However, there is little evidence supporting their genotype-specific effectiveness in reducing the risk of self-harm in patients with depression., Aims: To assess the associations between physical activity and self-harm behaviour and determine the recommended level of physical activity across the genotypes., Method: We developed the bidirectional analytical model to investigate the genotype-specific effectiveness on UK Biobank. After the genetic stratification of the depression phenotype cohort using hierarchical clustering, multivariable logistic regression models and Cox proportional hazards models were built to investigate the associations between physical activity and the risk of self-harm behaviour., Results: A total of 28 923 subjects with depression phenotypes were included in the study. In retrospective cohort analysis, the moderate and highly active groups were at lower risk of self-harm behaviour. In the followed prospective cohort analysis, light-intensity physical activity was associated with a lower risk of hospitalisations due to self-harm behaviour in one genetic cluster (adjusted hazard ratio, 0.28 [95% CI, 0.08-0.96]), which was distinguished by three genetic variants: rs1432639, rs4543289 and rs11209948. Compliance with the guideline-level moderate-to-vigorous physical activities was not significantly related to the risk of self-harm behaviour., Conclusions: A genotype-specific dose of light-intensity physical activity reduces the risk of self-harm by around a fourth in depressive patients.

Background: Resting Heart Rate (RHR) is commonly viewed as a reflection of underlying co-morbidities and not an independent risk factor. Here we compared whether high RHR (80-99 beats/min) and hypertension (blood pressure, BP ≥140/90 mmHg) independently predict all-cause mortality in 692,217 adults from Asia and Europe., Methods: Taiwan MJ cohort constituted of 636,064 adults (1994-2017) and the HUNT cohort of 56,153 Norwegian adults (1995-1997). Both cohorts were followed for about 25 years. We report adjusted hazard ratios (HRs) for all-cause mortality, and life expectancy were calculated., Results: The prevalence of high RHR changed little between those aged 20-29 years (21.2 %) and ≥ 70 years (25.2 %, ns.), whereas hypertension prevalence increased from 4.5 % to 57.3 %, respectively. We observed similar all-cause mortality among those with a high RHR and a normal BP and those with hypertension and normal RHR of 60-69 beats/min. We observed higher all-cause mortality among those with normal BP (≤120/80 mmHg) but high RHR than among those with hypertension and normal RHR. All-cause mortality risk associated with hypertension was not significant for those <40 years of age, whereas risk associated with high RHR remained significant across all age groups. Reductions in life expectancy was larger among individuals with normal BP, but high RHR (10.29 years, 95 % CI 8.09-12.49) compared with those with hypertension but normal RHR (5.53 years, 95 % CI 3.57-7.59)., Conclusions: Our data clearly demonstrate that elevated RHR should be considered as an independent risk factor for all-cause mortality. The observation that elevated RHR in young adulthood to middle age (20-50 years of age) served as better predictor of all-cause mortality than hypertension calls for a paradigm shift particularly among these age groups, and we suggest it is time that RHR should be regarded as a vital clinical sign measured and evaluated at all clinical visits., Competing Interests: Declaration of competing interest All authors report no conflict of interest., (Copyright © 2025. Published by Elsevier Inc.)

Introduction: Patient attitude to death is associated with outcomes in hospice care settings. This Korean study investigated the association between terminal cancer patient death acceptance and symptom control and quality of care (QoC) as perceived by family caregivers (FCs)., Methods: A multicenter cross-sectional survey was conducted in nine inpatient hospice care units, and the data of 108 dyads (terminal cancer patients who responded to the revised Death Attitude Profile and their primary FCs) were analyzed. Dyads were dichotomized into high and low groups by death-acceptance level. Multivariate regression models were used to examine the association between death acceptance and symptom severity/QoC as perceived by FCs., Results: Patients in the high acceptance group were younger, educated to a higher level, more religious, and had better-functioning families. Patients with severe shortness of breath were less likely to accept the inevitability of death. FCs of patients with high acceptance of death were more satisfied with QoC, particularly in domains of individualized care and family relationships. In addition, the positive association between patient acceptance and FC satisfaction with care was significant in dyads of young or female patients, patients with a low education level, and patients not cared for by a spouse., Conclusion: Terminal cancer patient death acceptance is associated with symptom control and FC perceived QoC., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The association between preoperative diabetes mellitus (DM) duration and outcomes of coronary artery bypass grafting (CABG) remains unclear. This study aimed to investigate the relationship between DM duration at the time of CABG and long-term outcomes, particularly patients with acute myocardial infarction (AMI)., Methods: Using data from South Korea's National Health Insurance Service database, the study included adult patients who underwent first-time isolated CABG with an AMI diagnosis between 2005 and 2021. DM patients were categorized based on whether their diagnosis occurred within 5 years before CABG. Patients with impaired fasting glucose were also classified. The primary outcome was all-cause overall mortality. The secondary outcome was repeat revascularization., Results: A total of 21,957 patients (median age, 65.0 years) were categorized into four groups: without DM, impaired fasting glucose, DM diagnosed within 5 years, and DM diagnosed more than 5 years before CABG. Patients with DM for less than 5 years had a higher overall mortality rate (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.08-1.24), and those with DM for more than 5 years had an even higher rate (HR, 1.36; 95% CI, 1.27-1.46) compared to those without DM. The incidence rate of repeat revascularization was significantly higher in those with DM for more than 5 years (HR, 2.07; 95% CI, 1.89-2.28)., Conclusions: The duration of DM prior to CABG is correlated with worse clinical outcomes. A prolonged period of DM before CABG may be a significant risk factor for poorer long-term outcomes in AMI patients., (Copyright © 2025. Published by Elsevier Inc.)

Background: Artificial intelligence (AI) models analyzing embryo time-lapse images have been developed to predict the likelihood of pregnancy following in vitro fertilization (IVF). However, limited research exists on methods ensuring AI consistency and reliability in clinical settings during its development and validation process. We present a methodology for developing and validating an AI model across multiple datasets to demonstrate reliable performance in evaluating blastocyst-stage embryos., Methods: This multicenter analysis utilizes time-lapse images, pregnancy outcomes, and morphologic annotations from embryos collected at 10 IVF clinics across 9 countries between 2018 and 2022. The four-step methodology for developing and evaluating the AI model include: (I) curating annotated datasets that represent the intended clinical use case; (II) developing and optimizing the AI model; (III) evaluating the AI's performance by assessing its discriminative power and associations with pregnancy probability across variable data; and (IV) ensuring interpretability and explainability by correlating AI scores with relevant morphologic features of embryo quality. Three datasets were used: the training and validation dataset (n = 16,935 embryos), the blind test dataset (n = 1,708 embryos; 3 clinics), and the independent dataset (n = 7,445 embryos; 7 clinics) derived from previously unseen clinic cohorts., Results: The AI was designed as a deep learning classifier ranking embryos by score according to their likelihood of clinical pregnancy. Higher AI score brackets were associated with increased fetal heartbeat (FH) likelihood across all evaluated datasets, showing a trend of increasing odds ratios (OR). The highest OR was observed in the top G4 bracket (test dataset G4 score ≥ 7.5: OR 3.84; independent dataset G4 score ≥ 7.5: OR 4.01), while the lowest was in the G1 bracket (test dataset G1 score < 4.0: OR 0.40; independent dataset G1 score < 4.0: OR 0.45). AI score brackets G2, G3, and G4 displayed OR values above 1.0 (P < 0.05), indicating linear associations with FH likelihood. Average AI scores were consistently higher for FH-positive than for FH-negative embryos within each age subgroup. Positive correlations were also observed between AI scores and key morphologic parameters used to predict embryo quality., Conclusions: Strong AI performance across multiple datasets demonstrates the value of our four-step methodology in developing and validating the AI as a reliable adjunct to embryo evaluation., Competing Interests: Declarations. Ethics approval and consent to participate: All collected data were de-identified and retrospectively collected prior to data analysis. Agreement to share data was authorized in the Software Licensing Agreement between each participating clinic and AIVF. IRB Study approval was obtained from the local independent review boards of IVI Valencia (Spain) (ID number 1902-VLC-018-MM), Assuta Ramat Hachayal (Israel) (ID number ASMC 68 − 18), Embryolab (Greece) (ID number 05/2019) and Clevelend Clinic (USA) (ID number 20–766). In Portugal, Ireland, Germany, Korea, and the Czech Republic, the study was deemed negligible risk authorized under the terms of the signed licensing agreement. Consent to participate was not applicable. Consent for publication: Not applicable. Competing interests: D.G., M.S., Y.T., Y.A., and N.L. are paid employees of AIVF. D.G. and D.S.S. have stock and share ownership of AIVF. M.M. is a member of the AIVF scientific advisory board team. C.L.C. is on the editorial board for the Journal of Assisted Reproduction and Genetics., (© 2025. The Author(s).)

Objectives: Sepsis is a life-threatening medical emergency, with a profound healthcare burden globally. Its pathophysiology is complex, heterogeneous and temporally dynamic, making diagnosis challenging. Medical management is predicated on early diagnosis and timely intervention. Transcriptomics is one of the novel "-omics" technologies being evaluated for recognition of sepsis. Our objective was to evaluate the performance of host gene expression biosignatures for the diagnosis of all-cause sepsis in adults., Data Sources: PubMed/Ovid Medline, Ovid Embase, and Cochrane databases from inception to June 2023., Study Selection: We included studies evaluating the performance of host gene expression biosignatures in adults who were diagnosed with sepsis using existing clinical definitions. Controls where applicable were patients without clinical sepsis., Data Extraction: Data including population demographics, sample size, study design, tissue specimen, type of transcriptome, health status of comparator group, and performance of transcriptomic biomarkers were independently extracted by at least two reviewers., Data Synthesis: Meta-analysis to describe the performance of host gene expression biosignatures for the diagnosis of sepsis in adult patients was performed using the random-effects model. Risk of bias was assessed according to the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A total of 117 studies (n = 17,469), comprising 132 separate patient datasets, were included in our final analysis. Performance of transcriptomics for the diagnosis of sepsis against pooled controls showed area under the receiver operating characteristic curve (AUC, 0.86; 95% CI, 0.84-0.88). Studies using healthy controls showed AUC 0.87 (95% CI, 0.84-0.89), while studies using controls with systemic inflammatory response syndrome (SIRS) had AUC 0.84 (95% CI, 0.78-0.90). Transcripts with excellent discrimination against SIRS controls include UrSepsisModel, a 210 differentially expressed genes biosignature, microRNA-143, and Septicyte laboratory., Conclusions: Transcriptomics is a promising approach for the accurate diagnosis of sepsis in adults and demonstrates good discriminatory ability against both healthy and SIRS control subjects., Competing Interests: The authors have no potential conflicts of interest or financial disclosures to declare., (Copyright © 2025 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Single-cell RNA sequencing (scRNA-seq) has improved our ability to characterize rare cell populations. In practice, cells from different tissues or donors are simultaneously loaded onto the instrument (multiplexed) at the recommended (standard loading) or higher (superloading) numbers to save time and money. Although cost-effective, superloading can stymie computational analyses owing to high multiplet rates and sample complexity., Methods: We compared the effects of superloading on multiplexed single-cell gene expression and T cell receptor (TCR) data generated from human thymus and blood samples from different donors., Results: Minimal transcriptomic differences were observed between the data generated by either standard or superloading. Irrespective of the loading cell number, we found that over 50% of the T cells expressing multiple TCR chains were doublets., Conclusion: Multiple samples can be run simultaneously without compromising data quality and subsequent analyses. However, an additional doublet removal step based on TCR configuration may improve the accuracy of T cell analysis.

Photodynamic therapy (PDT) offers minimally invasive and repeatable cancer treatment options. Despite advancements in photosensitizer (PS) design, the optical control of PS activation remains unexplored. Here, we present the first photoswitchable PS based on a BOAHY-BODIPY dyad system. Inspired by BODIPY multimer structures and BOAHY's photoisomerization properties, we designed mono-(4 series) and bis-BOAHY-BODIPY (5 series) conjugates. These dyads primarily generate reactive oxygen species via a type-I process under white light. Notably, the 4 series compounds demonstrated effective photocytotoxicity and photoswitching properties in vitro. Building on these, we iodinated the monoconjugates to develop the highly efficient photoswitching PS, 6b, which exhibited enhanced intersystem crossing and type-II reactive oxygen species generation due to a reduced singlet-triplet energy gap. As the first demonstration of photoswitchable PDT agents, this strategy introduces a new approach with significant potential for selective cancer treatment and clinical applications.

Background: Although the presence of both obesity and reduced muscle mass presents a dual metabolic burden and additively has a negative effect on a variety of cardiometabolic parameters, data regarding the associations between their combined effects and left ventricular diastolic function are limited. This study investigated the association between the ratio of skeletal muscle mass to visceral fat area (SVR) and left ventricular diastolic dysfunction (LVDD) in patients with preserved ejection fraction using random forest machine learning., Methods: In total, 1,070 participants with preserved left ventricular ejection fraction who underwent comprehensive health examinations, including transthoracic echocardiography and bioimpedance body composition analysis, were enrolled. SVR was calculated as an index of sarcopenic obesity by dividing the appendicular skeletal muscle mass by the visceral fat area., Results: In the random forest model, age and SVR were the most powerful predictors of LVDD. Multivariate logistic regression analysis demonstrated that older age (adjusted odds ratio [OR], 1.11; 95% confidence interval [CI], 1.07 to 1.15) and lower SVR (adjusted OR, 0.08; 95% CI, 0.01 to 0.57) were independent risk factors for LVDD. SVR showed a significant improvement in predictive performance and fair predictability for LVDD, with the highest area under the curve noted in both men and women, with statistical significance. In non-obese and metabolically healthy individuals, the lowest SVR tertile was associated with a greater risk of LVDD compared to the highest SVR tertile., Conclusion: Decreased muscle mass and increased visceral fat were significantly associated with LVDD compared to obesity, body fat composition, and body muscle composition indices.

Cyclooxygenase-2 (Cox-2) is a well-studied enzyme and a significant medicinal target associated with various inflammatory disorders. However, its role in pathogen-induced inflammatory responses in fish remains poorly understood. This study characterized the structural and functional properties of a Cox-2 homolog from red-spotted grouper (Epinephelus akaara) (EaCox-2). The three-dimensional structure of EaCox-2 revealed a homodimer with two functional domains: a catalytic domain with two active sites and a membrane-binding domain. EaCox-2 transcripts were ubiquitously expressed in all tested tissues of E. akaara, with the highest expression in the gills, followed by the spleen. Immune stimulation with polyinosinic:polycytidylic acid (poly I:C), lipopolysaccharides (LPS), and nervous necrosis virus (NNV) led to significant upregulation in EaCox-2 transcripts 12 and 24 h post-injection in both gill and spleen tissues. EaCox-2 overexpression in murine macrophages triggered a pro-inflammatory response characterized by M1 macrophage polarization, upregulation of pro-inflammatory mediators such as TNF-α, IL-1β, and IL-6, and iNOS enzyme, enhanced production of reactive nitric oxide (NO), and mitochondrial depolarization. These findings highlight the crucial role of EaCox-2 in regulating immune and inflammatory responses in E. akaara, providing valuable insights into the molecular mechanisms underlying teleost immunity., (Copyright © 2025. Published by Elsevier Ltd.)

Objectives: This study aimed to evaluate the prognostic impact of permanent pacemaker (PPM) implantation within the first year after mitral valve (MV) surgery combined with the Cox-maze procedure, focusing on long-term outcomes, including overall mortality, infective endocarditis (IE), and ischaemic stroke., Methods: We conducted a retrospective cohort study using data from the National Health Insurance Service (NHIS) in South Korea, identifying 10,127 patients who underwent MV surgery with the Cox-maze procedure between 2005 and 2020. Patients were classified into the PPM and non-PPM groups based on PPM implantation within one year postoperatively. The primary outcome was overall mortality, and secondary outcomes included risk factors for overall mortality, IE and ischaemic stroke. Multivariable Cox proportional hazards regression and Fine-Gray competing risk models were utilized for statistical analysis., Results: Of the total cohort, 178 patients (1.76%) underwent PPM implantation. The overall mortality during the follow-up period was 20.5%, with no significant difference between the PPM and non-PPM groups. PPM implantation was not a significant risk factor for overall mortality (Hazard ratio [HR], 0.825; 95% confidence interval [CI], 0.598-1.140; p = 0.244) or ischaemic stroke. However, PPM implantation was associated with a significantly increased risk of IE (HR, 2.015; 95% CI, 1.179-3.442; p = 0.010)., Conclusions: PPM implantation within the first year after MV surgery with the Cox-maze procedure does not significantly impact long-term mortality or ischaemic stroke risk but is associated with an increased risk of IE. The Cox-maze procedure remains advisable for patients with atrial fibrillation undergoing MV surgery., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Developing cost-effective, highly efficient, and durable bifunctional electrocatalysts for water electrolysis remains a significant challenge. Nickel-based materials have shown promise as catalysts, but their efficiency in alkaline electrolytes is still lacking. Fascinatingly, Mott-Schottky catalysts can fine-tune electron density at interfaces, boosting intermediate adsorption and facilitating desorption to reduce the energy barrier. In this study, iridium-implanted Mott-Schottky Ni/Ni 2 P nanosheets (Ir SA -Ni/Ni 2 P) is introduced, which are delivered from the metal-organic framework and employ them as the bifunctional catalysts for water electrolysis devices. This catalyst requires a small 54 mV overpotential for hydrogen evolution reaction (HER) and 192 mV for oxygen evolution reaction (OER) to reach 10 mA·cm -2 in a 1.0 m KOH electrolyte. Density functional theory (DFT) calculations reveal that the incorporation of Ir atoms with enriched interfaces between Ni and Ni 2 P can promote the active sites and be favorable for the HER and OER. This discovery highlights the most likely reactive sites and offers a valuable blueprint for designing highly efficient and stable catalysts tailored for industrial-scale electrolysis. The Ir SA -Ni/Ni 2 P electrode exhibits exceptional current density and outstanding stability in a single-cell anion-exchange membrane electrolyzer., (© 2025 Wiley‐VCH GmbH.)

Background Context: Instrumentation failure, notably rod fracture (RF), may occur even after ideal spinal deformity correction in adult spinal deformity (ASD). As RF is the major reason behind a revision surgery, various risk factors of RF are reported in literature, including pedicle subtraction osteotomy (PSO) technique itself. However, whether hip and knee joint diseases serve as another risk factor for RF remains unexplored., Purpose: To investigate the effects of lower-extremity joint diseases on RF in ASD patients who underwent deformity correction through long-segment fixation with PSO., Study Design: Retrospective study PATIENT SAMPLE: 96 consecutive ASD patients (mean age, 71.2 years) who underwent deformity correction through PSO and long-segment fixation from T10 to S1 between 2008 and 2019 were included. Those with radiographic data less than 2 years were excluded., Outcome Measures: RF was confirmed on radiograph, computed tomography (CT) and bone scan or SPECT images. Coronal and sagittal spinopelvic parameters, lower-extremity osteoarthritis (OA) parameters and clinical outcomes (Oswestry Disability Index [ODI] and Visual Analog Scale [VAS]) were analyzed., Methods: Radiographic measurements were performed at preoperative, postoperative, and last follow-up visits. Patients were divided into two groups: non-RF (n = 60) and RF (n = 36). Radiographic factors were assessed, correlations between parameters were examined, and multivariate logistic regression analysis was performed to evaluate risk factors for RF., Results: Structural and functional leg length discrepancies (LLDs), pelvic obliquity (PO), and the differences of mechanical axis (MAD) between both extremities had significantly differed between the groups (P < 0.05). The between-knee differences in the extent of OA, clinically significant MAD and PO, and the incidences of both structural and functional LLD were significantly greater in the RF group than in the non-RF group (P<0.05). On correlation analysis, PO was not correlated with coronal radiographic parameters but was correlated with structural and functional LLDs and MAD (P<0.05). Logistic analysis revealed that the difference in OA grade between the knee joints, functional LLD, and preoperative lower extremity surgery were significantly associated with RF (P<0.05)., Conclusion: ASD in the elderly often presents alongside degenerative changes in the lower-extremities, and even with ideal spinal deformity correction, RF may still occur if pre-existing joint pathologies are not resolved. In the deformity correction of ASD, it is essential that we not only pursue the restoration of spinopelvic harmony, but also apply perioperative measures for lower-extremity degenerative joint diseases., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2025. Published by Elsevier Inc.)

Background and Aim: Existing hepatocellular carcinoma (HCC) prediction models for the general population without traditional risk factors for chronic liver disease are limited. This study aimed to develop an HCC prediction model for individuals lacking these traditional risk factors., Methods: The total of 138 452 adult participants without chronic viral hepatitis or significant alcohol intake who underwent regular health checkup at a tertiary hospital in South Korea were followed up for the development of HCC. Risk factors for HCC development were analyzed using Cox regression analysis, and prediction model was developed using the risk factors., Results: Significant predictors of HCC development included older age, male sex, higher body mass index, presence of diabetes mellitus, and levels of aspartate aminotransferase, total cholesterol, and platelet count. A new HCC prediction model using these variables was developed. Harrell's concordance index and Heagerty's integrated area under the receiver operating characteristics (AUROC) curve of the model were 0.88 (95% confidence interval [CI] 0.85-0.91) and 0.89 (95% CI 0.86-0.91), respectively. The 5- and 10-year AUROC were 0.89 (95% CI 0.88-0.89) and 0.87 (95% CI 0.87-0.88), respectively. This model significantly outperformed the FIB-4 scoring model in predicting HCC and effectively stratified individuals into low-, intermediate-, and high-risk groups with significantly different cumulative incidences of HCC., Conclusions: The new model, based on clinical parameters, provides a valuable tool for clinicians to stratify HCC risk in the general population without risk factors for chronic liver disease., (© 2025 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Study Design: A systematic literature review and consensus using Delphi method., Objective: The aim was to formulate consensus recommendations regarding the natural history, diagnosis, classification and optimal treatment of Os Odontoideum with global applicability., Summary of Background: Os odontoideum (OO) is a rare anomaly of the cranio-vertebral junction (CVJ). Due to the paucity of literature, there is still considerable debate about the clinical management of OO., Material and Method: Using PubMed, the authors reviewed the literature on OO published from 2011 to 2022. Using the Delphi method, a panel expert spine surgeons and members of the WFNS Spine Committee analyzed the strength of the published literature, elaborated and voted statements concerning diagnosis and management., Result: The diagnosis may be established incidentally. Symptoms may manifest as neck discomfort or encompass occipital-cervical pain, myelopathy, or vertebrobasilar ischemia. Diagnosis is usually made with plain radiographs and CT can. Dynamic x-rays identify C1-C2 instability whereas MRI assess spinal cord integrity and compression. Asymptomatic cases lacking radiologic instability are generally handled through regular observation and serial imaging, until predictors of neurological deterioration necessitate surgical intervention. In the event of atlantoaxial instability or neurological dysfunction, surgical intervention with instrumentation and fusion is required to maintain stability. In irreducible cases, C1-2 joint manipulation and distraction permits re-alignment and deformity correction avoiding decompression, either from anterior or posterior., Conclusion: The management guidelines for asymptomatic OO are still a grey zone as our understanding of the natural history is still vague. Therefore, we need more large-center studies to investigate this condition further. Whenever symptomatic, unstable or asymptomatic presenting with risk factors, OO is better managed with atlanto-axial fusion avoiding occipital inclusion in the construct. In irreducible OO, C1-2 joint manipulation and distraction is preferred to decompression., Competing Interests: Conflict of Interest: The authors have nothing to disclose., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Nanoplastics (NPs) and microplastics (MPs) have become a global concern in recent years. Most current research on the impact of plastics on obstetrics has focused on their accumulation in specific tissues in animal models and the disease-causing potential of MPs. However, there is a relative lack of research on the cellular changes caused by the accumulation of MPs. In this study, we aimed to establish a proper in vitro exposure protocol for polystyrene (PS)-NPs and MPs and to investigate possible cytotoxic effects of PS-NPs and MPs on human endometrial stromal cells (ESCs) using different plastic sizes and concentrations. The results showed that smaller plastics, specifically 100 nm PS-NPs and 1 μm PS-MPs, had a higher cellular uptake propensity than larger particles, such as 5 μm PS-MPs, with significant morphological changes and cell death observed at concentrations above 100 μg/mL a 24-h period. In addition, confocal microscopy and real-time imaging confirmed the accumulation of these particles in the nucleus and cytoplasm, with internalization rates correlating with particle size. Also, 100 nm PS-NPs reduced cell proliferation and induced apoptosis. In conclusion, this study demonstrates that exposure to 100 nm PS-NPs and 1 μm PS-MPs leads to dynamic accumulation in ESCs, resulting in cell death or decreased proliferation at specific concentrations, which highlights the potential cellular toxicity of NPs or MPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

Solar-powered electrochemical NH 3 synthesis offers the benefits of sustainability and absence of CO 2 emissions but suffers from a poor solar-to-ammonia yield rate (SAY) due to a low NH 3 selectivity, large bias caused by the sluggish oxygen evolution reaction, and low photocurrent in the corresponding photovoltaics. Herein, a highly efficient photovoltaic-electrocatalytic system enabling high-rate solar-driven NH 3 synthesis was developed. A high-performance Ru-doped Co nanotube catalyst was used to selectively promote the nitrite reduction reaction (NO 2 RR), exhibiting a faradaic efficiency of 99.6% and half-cell energy efficiency of 52.3% at 0.15 V vs the reversible hydrogen electrode, delivering a high NO 2 RR selectivity even in electrolytes with high NO 3 - and low NO 2 - concentrations. Thus, the promoted NO 2 RR was coupled with the ethylene glycol oxidation reaction and a perovskite photovoltaic cell to achieve the highest SAY reported to date (146 ± 1 μmol h -1 cm -2 ) and stable operation.

Aim: We aimed to investigate the prevalence and factors associated with C-reactive protein (CRP) and procalcitonin (PCT) discordance in febrile infants with serious bacterial infections (SBIs)., Methods: We performed a retrospective review of febrile infants ≤ 90 days old presenting to the emergency department between December 2018 and June 2023. We compared conservative and pragmatic thresholds for PCT (< 0.5 ng/mL and < 1.7 ng/mL) and CRP (< 10 mg/L and < 20 mg/L). Discordance was defined as normal CRP with abnormal PCT and vice versa. Performance was presented using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)., Results: Among 3459 infants, 426 infants (12.3%) had SBIs, among whom 355 (83.3%) had both CRP and PCT performed. Overall, a conservative CRP threshold had the highest sensitivity (74.1%, 95% CI 69.2%-78.6%) and NPV (95.6%, 95% CI 94.6%-96.4%). Among those with SBIs, 148/355 (41.7%) had a normal PCT (< 1.7 ng/mL) and an abnormal CRP (≥ 20 mg/L), while 16/355 (4.5%) had a normal CRP (< 20 mg/L) and an abnormal PCT (≥ 1.7 ng/mL). An increased discordance, specifically abnormal CRP with normal PCT, was found in males, infants 29-90 days old, and those with urinary tract infections., Conclusion: SBI clinical decision rules should consider CRP-PCT discordance in specific patient populations., (© 2025 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

This study aimed to establish the optimal cut-off values for urinary cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)to determine smoking status in Korean women over 20 years of age and to assess the correlation of these biomarkers with reproductive health, particularly menopausal age, in postmenopausal women. Utilizing data from the 7th edition of the Korea National Health and Nutrition Examination Survey (2016- 2018), researchers included postmenopausal women aged 40-60 years who were within 5 years of menopause. Self-reported smoking status was aligned with biomarkers levels to calculate optimal cut-off values, classifying a total of 503 postmenopausal women into four groups: never smokers (cotinine <0.738ng/mL, NNAL <1.595pg/mL), secondhand smokers (SHSrs; cotinine 0.738-37.7ng/mL, NNAL 1.595-12.35pg/mL), light current smokers (cotinine 37.7-837ng/mL, NNAL 12.35-91.55pg/mg), and heavy current smokers (cotinine >837ng/mL, NNAL >91.55pg/mL). Differences in menopausal age were analyzed using Kaplan-Meier curves and log-rank tests. The results indicated significant differences in menopausal age between never smokers and heavy smokers (51.4±3.9 vs. 49.6±3.0 years, p=0.001) as well as SHSrs and heavy smokers (51.4±3.3 vs. 49.6±3.0 years, p=0.001) when applying urinary cotinine cutoff values. However, no significant differences in menopausal age were observed based on NNAL cutoffs. These findings suggest urinary cotinine levels correlated more strongly with menopausal age than using urine NNAL levels for defining smoking status among postmenopausal Korean women. Heavy current smokers, as identified by urinary cotinine levels, experienced menopause at an earlier age compared to never smokers and SHSrs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

AdCLD-CoV19-1, a chimeric adenovirus-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine, was previously reported to elicit robust antibody responses in mice and non-human primates after a single dose. In this study, we conducted a systems serology analysis to investigate changes in humoral immune responses induced by varying doses of the AdCLD-CoV19-1 vaccine in a phase I clinical trial. Serum samples from participants receiving either a low or a high dose of the vaccine were analyzed for antibody features against prototype SARS-CoV-2 spike (S) domains (full-length S, S1, S2, and receptor binding domain), as well as Fc receptor binding and effector functions. While both low- and high-dose vaccines induced robust humoral immune responses following vaccination, the quality of antibody features differed between the dose groups. Notably, while no significant difference was observed between the groups in the induction of most S1-specific antibody features, the high-dose group exhibited higher levels of antibodies and a stronger Fc receptor binding response specific to the S2 antigen. Moreover, univariate and multivariate analyses revealed that the high-dose vaccine induced higher levels of S2-specific antibodies binding to FcγR2A and FcγR3B, closely associated with antibody-dependent neutrophil phagocytosis (ADNP). Further analysis using the Omicron BA.2 variant demonstrated that the high-dose group maintained significantly higher levels of IgG and FcγR3B binding to the S2 antigen and exhibited a significantly higher ADNP response for the S2 antigen compared with the low-dose group. These findings underscore the importance of considering diverse humoral immune responses when evaluating vaccine efficacy and provide insights for optimizing adenovirus vector-based SARS-CoV-2 vaccine doses.IMPORTANCEOptimization of vaccine dose is crucial for eliciting effective immune responses. In addition to neutralizing antibodies, non-neutralizing antibodies that mediate Fc-dependent effector functions play a key role in protection against various infectious diseases, including coronavirus disease 2019. Using a systems serology approach, we demonstrated significant dose-dependent differences in the humoral immune responses induced by the AdCLD-CoV19-1 chimeric adenovirus-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine, particularly against the SARS-CoV-2 spike 2 domain. These findings highlight the importance of assessing not only neutralizing antibody titers but also the quality and functionality of antibody responses when evaluating vaccine efficacy., Competing Interests: The authors declare no conflict of interest.

Abstract: DNMT3A and TET2 are epigenetic regulator genes commonly mutated in age-related clonal hematopoiesis (CH). Despite having opposed epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematologic neoplasms. Although individual impacts on the epigenome have been described using different model systems, the phenotypic complexity in humans remains to be elucidated. Here, we make use of a natural inflammatory response occurring during coronavirus disease 2019 (COVID-19), to understand the association of these mutations with inflammatory morbidity (acute respiratory distress syndrome [ARDS]) and mortality. We demonstrate the age-independent, negative impact of DNMT3A mutant (DNMT3Amt) CH on COVID-19-related ARDS and mortality. Using single-cell proteogenomics we show that DNMT3A mutations involve myeloid and lymphoid lineage cells. Using single-cell multiomics sequencing, we identify cell-specific gene expression changes associated with DNMT3A mutations, along with significant epigenomic deregulation affecting enhancer accessibility, resulting in overexpression of interleukin-32 (IL-32), a proinflammatory cytokine that can result in inflammasome activation in monocytes and macrophages. Finally, we show with single-cell resolution that the loss of function of DNMT3A is directly associated with increased chromatin accessibility in mutant cells. Hence, we demonstrate the negative prognostic impact of DNMT3Amt CH on COVID-19-related ARDS and mortality. DNMT3Amt CH in the context of COVID-19, was associated with inflammatory transcriptional priming, resulting in overexpression of IL32. This overexpression was secondary to increased chromatic accessibility, specific to DNMT3Amt CH cells. DNMT3Amt CH can thus serve as a potential biomarker for adverse outcomes in COVID-19., (© 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Aim: Merkel Cell Carcinoma (MCC) is a rare skin cancer with a rising incidence worldwide. Anti-programmed death-1/ligand-1 (anti-PD-(L)1) therapies are effective for the treatment of advanced MCC. This study examines patterns of response / progression of advanced MCC to anti-PD-(L)1 therapies and describes subsequent management., Method: This is a multi-centre international retrospective cohort study with data collected up to May 2023 from 17 centres across 6 countries. Outcomes included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) for anti-PD-(L)1 and subsequent therapy., Results: One-hundred and eighty-five advanced MCC patients received anti-PD-(L)1 therapy. At median follow-up of 28.7 months (95 % CI: 21.4-38.3), ORR was 57.3 %, median DOR was 42.8 months (95 % CI, 25.8 - not reached (NR)), median PFS was 14 months (95 % CI, 8.1- 19.8), and median OS was 42.8 months (95 % CI, 30.3 - NR). One-hundred and eight patients (59 %) experienced progressive disease; 50 % (n = 54/108) with primary resistance and 26 % (n = 28/108) with secondary resistance. Fifty patients (27 %; n = 50/185) received subsequent systemic therapies (+/- local therapy) with response data; 18 (36 %; n = 18/50) received doublet platinum chemotherapy (ORR 67 %, DOR 5.0 months [95 % CI; 3.7 - NR]) and 16 (32 %; n = 16/50) were rechallenged with anti-PD-(L)1 (ORR 56 %, DOR 20.2 months [95 % CI; 8.3 - NR])., Conclusion: The most common subsequent treatment for patients with primary resistance was chemotherapy, while those with secondary resistance most frequently underwent further anti-PD-(L)1 therapy in combination with other therapies. Despite both therapies demonstrating promising ORR, doublet platinum chemotherapy had a poorer DOR compared to anti-PD-(L)1 rechallenge., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Georgina Venetia Long is supported by a National Health And Medical Research Council Investigator grant and the University of Sydney Medical Foundation. Inês Pires da Silva is supported by early career Cancer Institute New South Wales fellowship. Jeremy Mo has received travel support from Novartis, and honoraria from AstraZeneca. Caroline Gaudy-Marqueste has served as consultant and has received honoraria from Bristol-Myers Squibb, Merck Sharpe & Dohme, Pierre Fabre, and Sunpharma and travel support from Bristol-Myers Squibb, Merck Sharpe & Dohme,Pierre Fabre, and Janssen. Andrisha-Jade Inderjeeth has received honoraria from Bristol-Myers Squibb, Pfizer and Astellas. Alexander van Akkooi has served on advisory boards or as a consultant and has received honoraria from: 4SC AG, Amgen, Bristol-Myers Squibb, Merck Serono-Pfizer, MSD-Merck, Neracare, Novartis, Pierre Fabre, Sanofi, Sirius Medical, SkylineDX and Research Grants from Amgen, Merck Serono-Pfizer, SkylineDX. Anne Zaremba has received travel support from Novartis, Sanofi Grenzyme, and Bristol-Myers Squibb. Jenny H Lee has received honoraria from MSD, AstraZeneca and travel support from Novartis, Pfizer and MSD. Jenny H Lee has served on advisory boards for MSD and Sanofi. Jenny H Lee has received a research grant from MSD. Wen Xu has served on advisory boards for Merck, MSD, BMS and Novartis and has received honorarium from Merck, MSD, BMS, AstraZeneca, and Limbic. Wen Xu has received educational support from Merck, MSD, BMS, AstraZeneca, Daiichi-Sankyo, and Eli Lilly. Wen Xu has received research funding from Merck. Celeste Lebbe has served as a consultant and has received honoraria from BMS, MSD, Peirre Fabre, Erasca and Immunocore. Celeste Lebbe has received travel support from BMS, MSD, and Pierre Fabre. Shahneen Sandhu is supported by a National Health And Medical Research Council Investigator grant and a Peter MacCallum Cancer Centre Foundation Grant. Shahneen Sandhu has served on advisory boards for Bristol Myers Squibb, Merck Sharp and Dohme, AstraZeneca, Novartis, and Merck Serono (funds go to a research fund at Peter MacCallum Cancer Centre). Shahneen Sandhu has received institutional research grants for an investigator-initiated trial from Novartis, Genentech, Amgen, AstraZeneca, Merck Serono, Merck Sharp and Dohme, Pfizer and Senwha (funds go to a research fund at Peter MacCallum Cancer Centre). Serigne Lo has received fees for professional servces from SkylineDx BV and has received honoraria for editorial duties with The British Association of Dermatologists. Lisa Zimmer has served as consultant and has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sanofi, Sunpharma and Novartis. Matteo S Carlino has served on advisory boards or as a consultant for: Amgen, Bristol-Myers Squibb, Eisai, Ideaya, Merck Sharpe & Dohme, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi, and received honoraria from Bristol-Myers Squibb, Merck Sharpe & Dohme, and Novartis. Georgina Venetia Long is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer HealthCare Pharmaceuticals Inc, BioNTech SE, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IOBiotech, Immunocore Ireland Limited, Innovent Biologics USA Inc, Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec Medical Australia, PHMR Limited, Pierre Fabre, Regeneron Pharmaceuticals, Scancell Limited, SkylineDX B.V. Inês Pires da Silva declares honoraria speaker fees or advisory roles for Pierre Fabre, Merck Sharpe & Dohme, Roche, Novartis, and Bristol Myers Squibb and has served as consultant on advisory boards for MSD and Regeneron. All remaining authors have declared no conflicts of interest, (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Background: Concurrent exercise (CE), an emerging exercise modality characterized by sequential bouts of aerobic (AE) and resistance exercise (RE), has demonstrated acute benefits on executive functions (EFs) and neuroelectric P3 amplitude. However, the effect of acute CE on inhibitory control, a sub-component of EFs, and P3 amplitude remains inconclusive. Moreover, exploring the mechanisms underlying the effects of acute exercise on EFs contributes to scientific comprehension, with lactate recognized as a crucial candidate positively correlated with EFs. Therefore, this study aimed to determine the effects of acute CE on inhibitory control via behavioral and event-related potential approaches and to examine its potential mediational role on lactate., Methods: Seventy-eight adults (mean age = 22.95, SD = 1.75 years) were randomly assigned to either a CE, AE, or control (CON) group. Participants in the CE group engaged in 12-min of AE (40-59% of heart rate reserve [HRR]) coupled with 13-min of RE (1 set, with 75% of 10-repetition maximum, and 12 repetitions of 8 movements). The AE group participated in 25 min of AE (40-59% HRR). Prior to and following exercise onset, participants in both the CE and AE groups completed a 5-min warm-up and cool-down. Participants in the CON group read books for 35 min. Lactate concentrations were measured at timepoints of 0-, 17-, and 30-min relative to the treatment onset. Response time (RT) and accuracy in the Stroop test, as well as P3 amplitude, were assessed before and after the treatment., Results: The results revealed that both the CE and AE groups had significantly shorter RTs compared to the CON group, with no significant differences in accuracy among groups. A decrease in P3 amplitude was observed for the CE group compared to the AE and CON groups. The mediating effects of lactate between acute exercise and inhibitory control were insignificant., Conclusions: The findings suggest that both CE and AE improve inhibitory control and CE potentially enhances the efficient allocation of attention resources. The lack of a significant mediating effect of lactate warrants further investigation., Trial Registration: ClinicalTrials.gov, NCT06370286. Registered 12 April 2024-Retrospectively registered, https://clinicaltrials.gov/study/NCT06370286 ., Competing Interests: Declarations. Ethics approval and Consent to participate: The study received ethical approval from the Research Ethics Committee of National Taiwan Normal University (Approval No. 202101HM005), and all participants obtained written informed consent. Consent for Publication: Not applicable. Competing Interests: Ruei-Hong Li, Tai-Rui Chen, Nicholas D. Gilson, Marius Brazaitis, Yi-Ting Cheng, Hui-Fang Wu, Ji-Hang Lee, and Yu-Kai Chang declare that they have no competing interests., (© 2025. The Author(s).)

Fire blight, a devastating bacterial disease affecting rosaceous plants such as apples and pears, is caused by Erwinia amylovora . The disease, known for its rapid spread and destructive potential, can lead to severe symptoms and often result in the death of infected plants. In Korea, the observation of E. amylovora was first recorded in 2015, and subsequent dissemination has been noted across the peninsula. We previously determined the genomic characteristics of five Korean E. amylovora strains isolated in 2015, demonstrating a close phylogenetic relationship to a North American lineage. Based on these results, we have now sequenced a collection of 92 E. amylovora genomes from various fire blight cases in Korea spanning from 2016 to 2018. Through the population genomic approach, we explored the genetic diversity among the isolates. Our comprehensive genomic assessment facilitated the reconstruction of phylogenetic relationships, the correlation of genetic and spatial distances, and the inference of the most recent common ancestor of Korean E. amylovora . We conclude that E. amylovora was introduced to Korea several years before the first disease outbreak. Genomic insights obtained from our investigation will be invaluable for understanding the genetic characteristics, geographic spread and evolutionary dynamics of Korean E. amylovora .

Background: Recently developed artificial intelligence-based coronary angiography (AI-QCA, fully automated) provides real-time, objective, and reproducible quantitative analysis of coronary angiography without requiring additional time or labor., Objectives: This study aimed to evaluate the efficacy of AI-QCA-assisted percutaneous coronary intervention (PCI) compared to optical coherence tomography (OCT)-guided PCI in terms of post-PCI results., Methods: This trial enrolled 400 patients with significant coronary artery disease undergoing PCI from 13 participating centers in South Korea. Patients were randomized in a 1:1 ratio to either AI-QCA-assisted or OCT-guided PCI. The primary endpoint was the post-PCI minimal stent area (MSA) assessed by OCT. The noninferiority of AI-QCA-assisted PCI to OCT-guided PCI regarding the post-PCI MSA was tested with a noninferiority margin of 0.8 mm 2 ., Results: A total of 395 patients (199 in the AI-QCA group and 196 in the OCT group) were included in the primary endpoint analysis. The post-PCI MSA was 6.3 ± 2.2 mm 2 in the AI-QCA group and 6.2 ± 2.2 mm 2 in the OCT group (difference, -0.16; 95% CI: -0.59 to 0.28; P for noninferiority < 0.001). Other OCT-defined endpoints, such as stent underexpansion (50.8% [101/199] vs 54.6% [107/196]; P = 0.48), dissection (15.6% [31/199] vs 12.8% [25/196]; P = 0.42), and untreated reference segment disease (15.1% [30/199] vs 13.3% [26/196]; P = 0.61), were not significantly different between groups, except for a higher incidence of stent malapposition in the AI-QCA group (13.6% [27/199] vs 5.6 [11/196]; P = 0.007)., Conclusions: This study demonstrated the noninferiority of AI-QCA-assisted PCI to OCT-guided PCI in achieving MSA with comparable OCT-defined endpoints. (Fully Automated Quantitative Coronary Angiography Versus Optical Coherence Tomography Guidance for Coronary Stent Implantation [FLASH]; NCT05388357)., Competing Interests: Funding Support and Author Disclosures This work was supported by the Korea Medical Device Development Fund grant funded by the Korean government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health and Welfare, and the Ministry of Food and Drug Safety) (Project Number: 1711179379, RS-2022-00141289) and Medipixel, Inc. Dr Kang has received consulting fees from Medipixel, Inc; and owns stock options of Medipixel, Inc. Dr Kweon has received consulting fees and research grant support from Medipixel, Inc. Dr Y-H Kim has received consulting fees from Medipixel, Inc. Dr Ahn has received consulting fees from Medipixel, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

This study proposes fluorenylmethoxycarbonyl (Fmoc)-protected single amino acids (Fmoc-AAs) as a minimalistic model system to investigate liquid-liquid phase separation (LLPS) and the elusive liquid-to-solid transition of condensates. We demonstrated that Fmoc-AAs exhibit LLPS depending on the pH and ionic strength, primarily driven by hydrophobic interactions. Systematic examination of the conditions under which each Fmoc-AA undergoes LLPS revealed distinct residue-dependent trends in the critical concentrations and phase behavior. Importantly, we elucidated the liquid-to-solid transition process, suggesting that it may be driven by a molecular mechanism different from that of LLPS. Fmoc-AA condensates showed promise for biomolecular enrichment and catalytic applications. This work provides significant insights into the molecular mechanisms of LLPS and the subsequent liquid-to-solid transition, offering a robust platform for future studies related to protocells and protein aggregation diseases.

A protective vaccine against HIV will likely need to induce broadly neutralizing antibodies (bnAbs) that engage relatively conserved epitopes on the HIV envelope glycoprotein (Env) trimer. Nearly all vaccine strategies to induce bnAbs require the use of relatively complex immunization regimens involving a series of different immunogens, most of which are Env trimers. Producing protein-based clinical material to evaluate such relatively complex regimens in humans presents major challenges in cost and time. Furthermore, immunization with HIV trimers as soluble proteins induces strong non-neutralizing responses to the trimer base, which is normally occluded on the virion. These base responses could potentially detract from the induction of nAbs and the eventual induction of bnAbs. mRNA vaccine platforms offer potential advantages over protein delivery for HIV vaccine development, including increased production speed, reduced cost, and the ability to deliver membrane-bound trimers that might facilitate improved immuno-focusing to non-base epitopes. We report the design of mRNA-delivered soluble and membrane-bound forms of a stabilized native-like Env trimer (BG505 MD39.3), initial immunogenicity evaluation in rabbits that triggered clinical evaluation, and more comprehensive evaluation of B cell, T cell, and antibody responses in non-human primates. mRNA-encoded membrane-bound Env immunization elicited reduced off-target base-directed Env responses and stronger neutralizing antibody responses, compared with mRNA-encoded soluble Env. Overall, mRNA delivery of membrane-bound Env appears promising for enhancing B cell responses to subdominant epitopes and facilitating rapid translation to clinical testing, which should assist HIV vaccine development., One Sentence Summary: HIV envelope trimer mRNA enables membrane-bound expression and represents a functional immunogen in pre-clinical mammalian models.

Purpose: Reduction and intraoperative maintenance of fracture fragments during minimally invasive plate osteosynthesis (MIPO) pose technical difficulties, particularly when the interposed fragment is angulated, prompting surgeons to attempt reduction due to concerns about nonunion or malunion. We aimed to compare the clinical and radiological outcomes of MIPO for mid-shaft clavicular fractures based on the reduced status of the interposed fragments., Method: Fifty-seven patients who underwent MIPO for acute mid-shaft Robinson type 2B clavicular fractures were divided into two groups based on the alignment of the interposed fracture fragment. A vertical fracture fragment was defined as one tilted by >45° relative to the long axis of the proximal clavicular shaft. Radiological outcomes were evaluated using time to union, clavicle thickness, and length ratio after union compared with the healthy side. Clinical outcomes were assessed using the visual analog scale (VAS); the Korean Shoulder Score (KSS); Disability of the Arm, Shoulder, and Hand (DASH) score; and shoulder range of motion (ROM). Continuous variables were analyzed using Student's t-test or Mann-Whitney U test, based on data distribution., Result: The vertical fragment group comprised 21 patients, and the nonvertical fragment group comprised 36. The mean time to union was similar between the vertical (4.48 ± 1.20 months) and nonvertical group (4.64 ± 1.17 months, p = 0.162). The groups showed comparable clavicular length and thickness ratios: 0.992 ± 0.040 vs. 1.076 ± 0.045 (p = 0.175), 1.189 ± 0.102 vs. 1.186 ± 0.271 (AP view, p = 0.165), and 1.121 ± 0.238 vs. 1.112 ± 0.230 (Lordotic view, p = 0.655), respectively. At 12 months, no significant differences were observed in VAS (0.3 ± 0.7 vs. 0.8 ± 0.8, p = 0.667), KSS (97.10 ± 6.30 vs. 96.75 ± 6.77, p = 0.940), and DASH (1.44 ± 3.64 vs. 2.00 ± 4.05, p = 0.501), or in ROM forward flexion (165.24 ± 9.28 vs. 162.78 ± 12.56, p = 0.464) and external rotation (60.95 ± 13.00 vs. 60.00 ± 13.47, p = 0.965)., Conclusion: Favorable radiological and clinical outcomes were achieved in all patients who underwent MIPO for mid-shaft clavicular fractures, regardless of whether the interposed fracture fragment after reduction was vertical., Competing Interests: Declaration of competing interest The authors have no conflict of interest related to this study., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the measurement of main pancreatic duct (MPD) diameter on MRI for predicting MPD involvement in intraductal papillary mucinous neoplasms (IPMN)., Methods: This retrospective study included 595 patients with surgically confirmed IPMN who underwent preoperative MRI from 2015 to 2022. Three independent readers measured the maximum MPD diameter on two-dimensional axial and coronal T2-weighted imaging. Inter-plane and inter-reader agreements were assessed using the intraclass correlation coefficient (ICC). Multivariable logistic regression identified clinical and radiological factors associated with MPD involvement. Accuracy, sensitivity, and specificity of MPD diameter cutoffs, including the 5-mm threshold from the 2024 International Consensus Guidelines, were calculated., Results: Of the 595 patients (mean age: 64.6 years ± 8.6, 394 men), 423 (71.1%) had IPMN with MPD involvement, whereas 172 (28.9%) did not have MPD involvement. The mean maximum MPD diameter was 7.9 ± 5.1 mm. Inter-plane agreement was excellent (ICC = 0.977-0.988), as was inter-reader agreement (ICC = 0.963). Only a large MPD diameter on MRI was independently associated with MPD involvement (odds ratio = 1.29 [95% confidence interval; 1.14-1.47], p <.01). Use of a maximum MPD diameter cutoff of ≥ 5 mm for MPD involvement yielded accuracy, sensitivity, and specificity of 76.0%, 79.2%, and 68.0%, respectively., Conclusion: Despite excellent inter-plane and inter-reader agreement, the MRI-based prediction of MPD involvement in IPMN has limitations., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Primary cholangiocarcinoma is a rare bile duct epithelial neoplasm that can present with atypical clinical manifestations, complicating its diagnosis. A 62-year-old male showed symptoms suggestive of a complicated hepatic cyst that was later identified as intrahepatic cholangiocarcinoma. The patient presented with abdominal discomfort without fever. Imaging revealed a large cystic lesion in the liver. Despite the initial treatment for a presumed abscess, a biopsy confirmed cholangiocarcinoma. This case highlights the diagnostic challenge of distinguishing between benign complicated hepatic cysts and malignancies, particularly when typical markers of infection are absent. Early biopsy and vigilant assessments are crucial in such presentations to avoid a delayed diagnosis and initiate appropriate treatment.

With the development of the Korean economy, demand for high-quality beef, specifically Hanwoo beef, is escalating, with marbling traits-measured by the widely used marbling score-being a key contributor to meat palatability. The differences between the high-quality and the lower-quality meat, according to the satisfaction of the customers, are not the result from only the degree of marbling but also from the delicacy of the marbling flecks distribution. Using the computer marbling analysis technique, an index for quantifying marbling fineness of 256 sirloin cuts at 12th- 13th thoracic vertebra named F7 index was developed in this study. F7 index is defined as the standard deviation of the ratios of marbling particles area to the tile area, was developed in this study. At the optimal step size of 70 tiles per axis, F7 index discriminated dramatically the finely marbled and coarsely marbled sirloin with Beef Marbling Score from 6 to 9, with P value = 1.340 × 10-27 < 0.05 of. Although the efficiency of computer image analysis procedure with the F7 index is still being optimized, the F7 index shows great potential to enhance the accuracy of Hanwoo beef quality grading alongside marbling score and support the development of improved breeding strategies for the Hanwoo cattle population in Korea., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Radiotherapy (RTx) is a highly effective treatment for head and neck cancer that can cause concurrent damage to surrounding healthy tissues. In cases of nasopharyngeal carcinoma (NPC), the auditory apparatus is inevitably exposed to radiation fields and sustains considerable damage, resulting in dysfunction. To date, little research has been conducted on the changes induced by RTx in the middle ear and the underlying mechanisms involved. Dexamethasone (DEX) is widely used in clinical practice because of its immunosuppressive and anti-inflammatory properties. The present study investigated the effects and underlying mechanisms of DEX delivered via intratympanic administration on RTx-induced damage to the middle ear and human middle ear epithelial (HMEE) cells. Sprague-Dawley (SD) rats were exposed to fractionated RTx (6.6 Gy/day for 5 days), and middle ear samples were collected at 1 and 4 months. Rats that received RTx presented a significant increase in the thickness of the submucosal layer in the middle ear and disorganization of the ciliated epithelium in the Eustachian tube (ET) mucosa. Importantly, intratympanic administration of DEX 30 min before RTx resulted in a lower degree of damage than that in the control group. Furthermore, DEX pretreatment downregulated the expression of cell death pathway markers in HMEE cells. Our collective results potentially support the use of DEX to reduce radiation-induced damage in the middle ear and may contribute to the development of future studies., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: If the animal was dead before the set end point due to individual variation, the experiment would be terminated humanely by euthanasia with CO2 upon that time. We confirmed that all experiments in this study were performed in accordance with the relevant guidelines and regulations. All the procedure of the study is followed by the ARRIVE guidelines., (© 2025. The Author(s).)

Background: The degenerative spondylosis can cause the difficulty in maintaining sagittal and coronal alignment of spine, and X-ray parameters are the gold standard to analyze the malalignment. This study aimed to develop a new 3D full body scanner to analyze the spinal balance and compare it to X-ray parameters., Methods: Ninety-seven adult participants who suffer degenerative spondylosis underwent 3D full body scanning, whole spine X-rays, clinical questionnaires and body composition analyses. The 5 inflection points (ear, shoulder, hip, knee, ankle) of the 3D scanner in the sagittal plane were automatically labeled by an AI algorithm. Three concepts are created including "the angle between two points with respect to the plumb line", "the horizontal distances between two points in the sagittal plane" and "the angle between three points". For the coronal plane, the shoulder gradient was analyzed. X-ray parameters of cervical, thoracolumbar and whole spine sagittal balance and coronal balances were compared. The body composition data and clinical questionnaire scores were compared to x-ray and 3D scanner parameters., Results: The correlation coefficient (C.C.) of dAB&#95;hor (horizontal distance between ear and shoulder in the sagittal plane) and C2-C7 SVA was 0.478 (p-value < 0.001). The C.C. of aAC&#95;sag (sagittal angle of ear-hip from the plumb line) and ODHA was 0.336 (p < 0.001). About coronal balance, the C.C. of shoulder gradient and clavicle angle from x-ray was 0.373 (p < 0.001). The C.C.s were merely affected by body composition data. But in multiple regression analysis, BMI affected 3D scanner data. Clinical symptoms showed correlations with aBCD(shoulder-hip-knee) and aCDE(hip-knee-ankle angle), which may reflect a compensatory pelvic retroversion and knee flexion for positive sagittal imbalance., Conclusions: This new 3D scanner has some strengths like radiation-free methods, correlation with x-ray parameters and clinical symptoms, independence to body composition data, and possibility of analyzing dynamic spine balance., Competing Interests: Declarations. Ethics approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the institutional review board (IRB) at the Seoul National University BRM Medical center (IRB No. 30–2022-68). Consent to participate: All persons gave their informed consent prior to their inclusion in the study. Details that might disclose the identity of the subjects under study were omitted. Consent for publication: Not applicable as all personal information is anonymized and the submission does not include images that may identify patients. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

With the in-depth and comprehensive research on probiotic Bacillus, it has become a hot topic in food science. However, the current status of research using bibliometric analysis to assess the application of probiotic Bacillus in food science has not been comprehensively reviewed. The Web of Science (WOS) database was used in this review's bibliometric analysis to determine the hotspots for research as well as the extent of completed experiments. Furthermore, a systematic review was conducted on the research hotspots of probiotic Bacillus in food science. The comprehensive analysis showed it was a growing and global research field. The keywords with high frequency mainly included "spore," "strain," and "production," which were research hot topics in the last decade. The application of the spore form or nutrient cells of probiotic Bacillus in industrialized food production through nutrient fortification, fermentation agents, and highly efficient synthesis of metabolites showed great development potential., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Stroke is globally recognized as the second leading cause of death, significantly impairing both motor and cognitive functions. Enhancing regeneration after stroke is crucial for restoring these functions and necessitates strategies to promote neuroregeneration to achieve better post-stroke outcomes. Brain-derived neurotrophic factor (BDNF) plays a key role in neuroregeneration by influencing motor ability, learning, memory, and rehabilitation after stroke. However, challenges such as the substantial protein size, short half-life of BDNF, and blood-brain barrier hinder its efficient delivery to the brain. In this study, LM22A-4, a BDNF mimetic, was utilized and delivered through a Smart Mesoporous Ball (SMB-3) system to target the ischemic injured brain and explore its potential therapeutic effects in a mouse ischemic stroke model. Treatment with LM22A-4-loaded SMB-3 (LM22A-4-SMB-3) markedly restored neurological, motor, and cognitive deficits following ischemic stroke compared to LM22A-4 alone. Additionally, administration of LM22A-4-SMB-3 reduced apoptotic cell death and glial activation, as evidenced by the TUNEL assay results, and decreased GFAP and Iba-1 expression levels. Furthermore, the phosphorylation of TrkB and Akt, but not that of Erk, was considerably increased in the LM22A-4-SMB-3-treated group. Treatment also enhanced the number of BrdU+/NeuN+ cells, with a marked reduction in post-stroke brain atrophy. These findings suggest that LM22A-4-SMB-3 can attenuate ischemic damage and recover neurological, motor, and cognitive functions by increasing p-TrkB and p-Akt levels and promoting neurogenesis. Therefore, SMB-3-mediated delivery of LM22A-4 presents a potentially applicable delivery system, and LM22A-4-SMB-3 use could be considered a novel therapeutic strategy to improve post-stroke outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: To evaluate the effectiveness and safety of radiofrequency ablation (RFA) for the treatment of symptomatic distant metastasis of differentiated thyroid carcinoma., Materials and Methods: The medical records of 12 patients who underwent RFA for the palliative treatment of 18 symptomatic distant metastases from thyroid cancer between January 2008 and December 2020 were analyzed. All patients were assessed for their degree of discomfort and underwent periodical evaluations as outpatients, including clinical examination, imaging, and serologic markers., Results: Among the 18 tumors treated, nine were soft tissue, and nine were bone metastases. The mean size of the treated tumors was 5.3 cm (range, 1.7-10.7 cm). All patients complained of pain, discomfort and/or bulging of the metastatic mass before RFA. After RFA, 11 out of the 18 patients with metastatic tumors (61.1%) reported a subjective improvement in symptoms. Nine out of 18 tumors decreased in size, with a mean size reduction ratio of 43% ± 22%. Although symptom improvement was achieved in 61.1% of the tumors, after a mean follow-up duration of 37.4 months, five patients experienced progression of the tumor, four patients had a stable tumor status, and three patients died from pneumonia. There were no major adverse events related to RFA during the treatment or follow-up period., Conclusion: RFA can be used as palliative therapy to relieve the symptoms caused by metastatic tumors; however, it has a limited role in improving the overall prognosis in patients with distant metastasis from thyroid cancer., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no relevant conflicts of interest to disclose., (© 2025. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Objective: Investigate whether deaf or hard of hearing (D/HH) patients with COVID-19 exhibited different hospitalisation outcomes compared with hearing patients with COVID-19., Design: Cohort study SETTING: Statewide Inpatient Databases for Florida, Maryland, New York and Washington, for the year 2020., Participants: Records of patients aged 18-64 years with COVID-19 PRIMARY OUTCOMES AND MEASURES: Differences in in-hospital death, 90-day readmission, length of stay, hospitalisation cost, hospitalisation cost per day, intensive care unit (ICU) or coronary care unit (CCU) utilisation and ventilation use were evaluated. Adjustment variables included patient basic characteristics, socioeconomic factors, and clinical factors., Results: The analyses included 347 D/HH patients and 72 882 non-D/HH patients. Multivariable log-transformed linear regression models found an association of patients' hearing loss status with longer length of stay (adjusted mean ratio (aMR) 1.15, 95% CI 1.04 to 1.27, p<0.01), higher hospitalisation cost (aMR 0.96, 95% CI 1.00 to 1.22, p=0.049) and lower hospitalisation cost per day (aMR 0.96, 95% CI 0.92 to 1.00, p=0.04). We did not detect any significant relationships with other outcomes., Conclusions: Our findings suggest that higher hospitalisation costs were attributed to prolonged stays rather than costly interventions, such as ICU care. Communication barriers between healthcare providers and D/HH patients, coupled with providers' cautious approach to discharging D/HH patients, may explain our findings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Acetabular subchondral cysts are commonly identified signs of joint degeneration and arthritis. This pathology is generally considered a relative contraindication for hip preservation surgery., Purpose: To investigate the effect of arthroscopic bone grafting for the treatment of acetabular subchondral cysts., Study Design: Cohort study (diagnosis); Level of evidence, 3., Methods: We completed a retrospective analysis of hip arthroscopies performed by the senior author between 2013 and 2021. Patients with radiologic evidence of acetabular cysts who underwent arthroscopic bone grafting, with or without subsequent periacetabular osteotomy (PAO) and/or derotational femoral osteotomy with a minimum of 2-year follow-up, were included in the analysis. Patients undergoing surgical treatment for diagnoses of slipped capital femoral epiphysis, Legg-Calves-Perthe disease, osteochondromatosis, or postdislocation syndrome, as well as patients who refused to participate in the study, were excluded. We compared the patient-reported outcomes (PROs) for patients who underwent arthroscopic bone grafting with a case-matched control group without acetabular cysts with the same surgical route (hip arthroscopy or hip arthroscopy followed by PAO). An "inside-out" arthroscopic bone grafting technique was utilized, which allowed for precise access to the cystic cavity through the articular side. We analyzed postoperative PROs at a minimum of 2 years postoperatively using the international Hip Outcome Tool (iHOT-12) and Nonarthritic Hip Score (NAHS)., Results: In total, there were 44 hips in the experimental group and 78 hips in the control group. The mean PRO interval in the experimental group was 3.4 years (range, 2-5 years postoperatively), with 20 patients reaching PROs 5 years postoperatively. The experimental group reported significant improvement of iHOT-12 and NAHS scores postoperatively (both P < .001). Postoperative iHOT-12 and NAHS scores did not significantly differ between groups over a 5-year follow-up interval ( P = .26 and .17, respectively). Radiographic evidence of cyst healing was achieved in all 7 patients who underwent postoperative magnetic resonance imaging, with 3 cases of complete resolution., Conclusion: Acetabular subchondral cysts treated with an inside-out method of arthroscopic bone grafting in the setting of hip preservation surgery with or without PAO was associated with a significant improvement in midterm PROs, comparable with a control group of patients without acetabular cysts who did not undergo bone grafting. Our results support the use of arthroscopic grafting in appropriately selected patients and suggest that hip preservation is not contraindicated in patients with acetabular subchondral cysts., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: A.N.M. holds stock or stock options in Pfizer and Roche and is a board or committee member for the Radiological Society of North America. O.M-D. owns stock or stock options in HeapSI and MITA, receives IP royalties from Stryker, and has received consulting fees from Stryker. J.H.L. has received hospitality payments from Smith+Nephew, Stryker, and Heraeus Medical and education payments from Gemini Mountain Medical. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. Ethical approval for this study was obtained from Colorado Multiple Institutional Review Board (IRB No. CRV006-1)., (© The Author(s) 2025.)

Background: Leptomeningeal metastasis (LM) is a devastating complication of cancer that is difficult to treat. Thus, early diagnosis is essential for LM patients. However, cerebrospinal fluid (CSF) cytology has low sensitivity, and imaging approaches are ineffective. We explored targeted CSF metabolic profiling to discriminate among LM and other conditions affecting the central nervous system (CNS)., Methods: We quantitatively measured amino acids, biogenic amines, hexoses, acylcarnitines (AC), cholesteryl esters (CE), glycerides, phosphatidylcholines (PC), lysophosphatidylcholines (LPC), sphingomyelins (SM), and ceramides (Cer) in 117 CSF samples from various groups of healthy controls (HC, n = 10), patients with LM (LM, n = 47), parenchymal brain tumor (PBT, n = 45), and inflammatory disease (ID, n = 13) with internal standards using the Absolute IDQ- p400 ® targeted mass spectrometry kit. Metabolites detected in > 90% of samples or showing a difference in proportional level between groups ≥ 75% were used in logistic regression models when there was no single metabolite with AUC = 1 for the groups of comparison., Results: PC and SM had higher levels in LM than in PBT or HC, whereas LPC had lower level in PBT than the other groups. Glycerides and Cer levels were higher in PBT and LM than in HC. Long-chain AC level in PBT was lower than in LM or HC. A regression model including Ala, PC (42:7), PC (30:3), PC (37:0), and Tyr achieved complete discrimination (AUC = 1.0) between LM and HC. In comparison of PBT and HC, twenty-six individual metabolites allowed complete discrimination between two groups, and between ID and HC fourty-six individual lipid metabolites allowed complete discrimination. Twenty-one individual metabolites (18 ACs and 3 PCs) allowed complete discrimination between LM and PBT., Conclusions: Using a commercial targeted liquid chromatography-mass spectrometry (LC-MS) metabolomics kit, we were able to differentiate LM from HC and PBT. Most of the discriminative metabolites among different diseases were lipid metabolites, for which their CNS distribution and quantification in different cell types are largely unknown, whereas amino acids, biogenic amines, and hexoses failed to show significant differences. Future validation studies with larger, controlled cohorts should be performed, and hopefully, the kit may expand its metabolite coverage for unique cancer cell glucose metabolism., Competing Interests: Declarations. Ethics approval and consent to participate: This study followed the Helsinki declaration. All participants signed an informed consent form and this study was approved by the Institutional Review Board of our institute (Registration number: NCC2014-0135). Consent for publication: All authors read and approved the final manuscript. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The tumor-specific efficacy of the most current anticancer therapeutic agents, including antibody-drug conjugates (ADCs), oligonucleotides, and photosensitizers, is constrained by limitations such as poor cell penetration and low drug delivery. In this study, we addressed these challenges by developing, a positively charged, amphiphilic Chlorin e6 (Ce6)-conjugated, cell-penetrating anti-PD-L1 peptide nanomedicine (CPPD1) with enhanced cell and tissue permeability. The CPPD1 molecule, a bioconjugate of a hydrophobic photosensitizer and strongly positively charged programmed cell death-ligand 1 (PD-L1) binding cell-penetrating peptide (CPP), is capable of self-assembling into nanoparticles with an average size of 199 nm in aqueous solution without the need for any carriers. These carrier-free nanoparticles possess the ability to penetrate the cell membrane of cancer cells and target tumors expressing PD-L1 on their surface. Notably, CPPD1 nanoparticles effectively blocked programmed cell death-1 (PD-1)/PD-L1 interactions and reduced PD-L1 expression via lysosomal degradation. They also demonstrated the responsiveness of CPPD1 nanoparticles in photodynamic therapy (PDT) to a 635 nm laser, leading to the generation of ROS, and induction of various immunogenic cell deaths (ICD). Highly penetrating CPPD1 nanoparticles could immunogenically modulate the microenvironment of CT26 cancer and were also effective in treating abscopal metastatic tumors, addressing major limitations of traditional PDT.

During the pandemic surge, including SARS-CoV-2 and influenza, pooling samples emerged as an efficient strategy to identify infected individuals in large groups. While pooling enhances RT-PCR throughput, reducing costs and resources, it dilutes positive samples with negative ones, lowering sensitivity and increasing false negatives. This study proposes a new method to address the trade-off between pool sizes and RT-PCR accuracy. This method integrates large-scale pooling with sample enrichment using a nano-hybrid membrane, preventing the pooling-induced decrease in viral concentration and maintaining cycle threshold (Ct) values close to individual positive samples. The nano-hybrid membrane, named SIMPLE (streamlined, simple, and inexpensive method for preconcentration, lysis, and nucleic acid extraction), comprises layered red blood cell membranes, polyethersulfone, and silica membranes. Using SIMPLE, a Ct value reduction to ≈2.6 is demonstrated in pooled COVID-19 samples with a pool size of 6 and found Ct values from larger pool sizes (8, 16, 32, 64, and 128) comparable to individual positive samples., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer with limited treatment options, often associated with Merkel cell polyomavirus (MCPyV) and marked by hypoxic tumor microenvironments that promote resistance to therapies. Belzutifan, an FDA-approved hypoxia-inducible factor-2α (HIF-2α) inhibitor, has shown promise in inhibiting tumor growth; however, its clinical efficacy is hindered by its low solubility, rapid clearance, and limited bioavailability. In this study, we present a strategy using porous silicon (pSi) microparticles and nanoparticles as carriers for the sustained delivery of benzoate to MCC cells. The pSi carriers were engineered to securely encapsulate and gradually release belzutifan, overcoming the limitations of free drug administration. Microparticles provided sustained extracellular release, while nanoparticles enabled efficient intracellular delivery, enhancing HIF-2α inhibition. Moreover, the use of biodegradable silicon particles enables long-term consistent release of belzutifan over 10 days in vitro with a single dose administration in the tumor microenvironment, while free belzutifan is rapidly deactivated within 1 day postadministration. In vitro studies demonstrated significant immunogenic cell death (ICD) in MCC cells, marked by the cytosolic localization of HMGB1 and elevated expression of pro-inflammatory cytokines as well as strong upregulation of TLR9. Particularly, the increased TLR9 expression in both MCC cell lines with pSi carrier treatment reinforces immune activation through toll-like receptor signaling, enhancing both innate and adaptive immune responses within the tumor microenvironment. These findings indicate that pSi carriers not only enhance belzutifan's stability and release profile but also amplify antitumor immune responses within the tumor microenvironment. Our results suggest that belzutifan-loaded pSi carriers offer a potent and targeted therapeutic strategy for MCC, potentially addressing key challenges in cancer immunotherapy by combining HIF-2α inhibition with robust immune activation. This platform highlights the universal utility of pSi-based delivery systems to advance MCC treatment with implications for broader cancer therapies.

Background: Graft selection is an important part of preoperative planning for anterior cruciate ligament reconstruction (ACLR). In addition, ACLR with the remnant preservation technique has recently gained attention due to potential benefit in bone-tendon healing, graft revascularization, and proprioceptive nerve remodeling. However, the ideal graft choice remains controversial, and there is limited research comparing autograft and allograft in ACLR with remnant preservation., Purpose: To compare knee muscle strength, neuromuscular control, and patient-reported outcomes between hamstring (HS) tendon autografts and tibialis anterior (TA) allografts in patients undergoing ACLR with remnant preservation through posterior transseptal portal for >1 year., Study Design: Cohort study; Level of evidence, 3., Methods: A total of 70 patients who underwent ACLR with remnant preservation between 2018 and 2021 using HS tendon autograft (n = 35) or TA allograft (n = 35) were analyzed at 3 different time points (preoperative, 6 months, and 12 months). Quadriceps and HS muscle strengths were measured with an isokinetic device. Proprioception was evaluated with reproduction of passive positioning for joint position sense and overall stability index (OSI) for dynamic postural stability. Patient-reported outcomes included the Lysholm score and the International Knee Documentation Committee score., Results: There were no significant differences in demographic information including age, body mass index, concomitant meniscal injuries, and sports activities ( P > .05) between HS tendon autograft and TA allograft groups. Quadriceps and HS strength in both groups, HS strength in deep knee flexion in both groups, and OSI in the HS tendon autograft group significantly improved at 12 months ( P < .05). Repeated-measures analysis of variance revealed significant interactions between time and grafts for OSI ( F [2, 136] = 5.08; P = .007). The subsequent independent t test demonstrated that the OSI was significantly higher in the TA allograft group (2.7 ± 1.0) than that of the HS tendon autograft group (2.1 ± 0.8) at 12 months ( P = .009), indicating better dynamic postural stability in the HS tendon autograft group., Conclusion: No significant differences were found in knee muscle strength or patient-reported outcomes between HS tendon autograft and TA allograft after ACLR with remnant preservation for up to 1 year except for dynamic postural stability favoring HS tendon autograft., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This work was supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (Project Number: 1475013503, RS-2023-00210209). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. Ethical approval for this study was obtained from Anam Hospital, Korea University (2018AN0261 / K2018-0444-003)., (© The Author(s) 2025.)

Dynamic communication between hepatocytes and the environment is critical in hepatocellular carcinoma (HCC) development. Clinical immunotherapy against HCC is currently unsatisfactory and needs more systemic considerations, including the identification of new biomarkers and immune checkpoints. Transmembrane 4 L six family member 5 (TM4SF5) is known to promote HCC, but it remains unclear how cancerous hepatocytes avoid immune surveillance and whether avoidance can be blocked. We investigated how TM4SF5-mediated hepatic tumorigenesis avoids surveillance by natural killer (NK) cells, which are prevalent in the liver, and whether the avoidance can be blocked by anti-TM4SF5 agents. We used comprehensive structure activity relationship analysis to identify TM4SF5-specific isoxazole (TSI)-based small molecules that inhibit TM4SF5-mediated effects. TM4SF5 expressed by hepatocytes reduced NK cell cytotoxicity by downregulating stimulatory ligands/receptors, including signaling lymphocytic activation molecule family member 7 (SLAMF7). TM4SF5 bound SLAMF7 depending on N-glycosylation and caused intracellular trafficking of SLAMF7 from the plasma membrane to lysosomes for degradation. TSI treatments in cell lines and animal models of HCC blocked this binding, intracellular trafficking, and downregulation, resulting in higher levels of stimulatory NK cell ligands. In mouse xenograft models, TSI treatment abrogated HCC development by increasing the abundance and dispersion of Slamf7-positive cells in liver tissues, recapitulating the phenotype of Tm4sf5-knockout mice and indicating TSI-mediated restoration of NK cell surveillance. These findings suggest that TSIs can inhibit TM4SF5-mediated liver carcinogenesis by increasing NK cell surveillance., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Microstructure optimization and high-performance material development are crucial for improving the electrochemical performance of all-solid-state batteries (ASSBs). Researchers frequently record numerous micro-scale or nano-scale electron micrographs for unbiased post-mortem analysis, performance evaluation, and improvement of ASSBs. However, these micrographs are often underutilized and typically analyzed qualitatively without ensuring an accurate representation of the experimental objectives. This study explores machine learning (ML)-based quantitative analysis techniques using electron microscopy images, combined with a stereology-driven linear-intercept concept method and semantic segmentation, to extract quantitative microstructural parameters for optimizing ASSB performance. The applicability of ML-assisted image analytics is demonstrated by employing composite cathodes in ASSBs to achieve unbiased automation and deep semantic segmentation during microstructural characterization. Furthermore, the ramifications of this ML-assisted method are discussed, along with its advantages and disadvantages in battery research., (© 2025 Wiley‐VCH GmbH.)

Macrophages encounter a myriad of biochemical and mechanical stimuli across various tissues and pathological contexts. Notably, matrix rigidity has emerged as a pivotal regulator of macrophage activation through mechanotransduction. However, the precise mechanisms underlying the interplay between mechanical and biochemical cues within the nuclear milieu remain elusive. Here We elucidate how the increased matrix rigidity drives macrophages to amplify alternatively-activated (M2 phenotype) signaling cooperatively with biochemical cues (e.g., IL4/13) through altered nuclear mechanics. We demonstrate that reconstructed podosome-like F-actins and contractility induce nucleus deformation, opening nuclear pores, which facilitates nuclear translocation of the key transcription factor STAT6. Furthermore, the altered nuclear mechanics increases chromatin accessibility induced by H3K9 methylation, particularly of M2-associated gene promoters. These cooperative events of the mechano-chemical signaling at the cytoskeletal-to-nuclear domains facilitate M2 transcriptional activation and cellular functions. We further evidence the rigidity-primed M2 macrophages are immunosuppressive and accumulated within stiffened tumors in patients. This study proposes a mechanism by which matrix mechanics crosstalks with biochemical signals to potentiate macrophage activation through nuclear mechanosensing and chromatin modifications, offering insights into macrophage mechanobiology and its therapeutic modulations., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background and Objectives: We propose the use of GPT-4 to facilitate initial history-taking in neurology and other medical specialties. A large language model (LLM) could be utilized as a digital twin which could enhance queryable electronic medical record (EMR) systems and provide healthcare conversational agents (HCAs) to replace waiting-room questionnaires., Methods: In this observational pilot study, we presented verbatim history of present illness (HPI) narratives from published case reports of headache, stroke, and neurodegenerative diseases. Three standard GPT-4 models were designated Models P : patient digital twin; N : neurologist to query Model P; and S : supervisor to synthesize the N-P dialogue into a derived HPI and formulate the differential diagnosis. Given the random variability of GPT-4 output, each case was presented five separate times to check consistency and reliability., Results: The study achieved an overall HPI content retrieval accuracy of 81%, with accuracies of 84% for headache, 82% for stroke, and 77% for neurodegenerative diseases. Retrieval accuracies for individual HPI components were as follows: 93% for chief complaints, 47% for associated symptoms and review of systems, 76% for relevant symptom details, and 94% for histories of past medical, surgical, allergies, social, and family factors. The ranking of case diagnoses in the differential diagnosis list averaged in the 89th percentile., Discussion: Our tripartite LLM model demonstrated accuracy in extracting essential information from published case reports. Further validation with EMR HPIs, and then with direct patient care will be needed to move toward adaptation of enhanced diagnostic digital twins that incorporate real-time data from health-monitoring devices and self-monitoring assessments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Lee, Choi, Angulo, McDougal and Lytton.)