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Annular rupture is a rare but life-threatening complication of transcatheter aortic valve replacement (TAVR). Mortality rates are high if immediate intervention, most often necessitating surgical repair, is not performed. Herein, we describe an 87-year-old man who, after deployment of TAVR, experienced acute decompensation and required urgent conversion to a midline sternotomy to repair an aortic annular rupture. This case demonstrates an example of a rare but severe complication of TAVR. This report provides an in-depth description of the surgical approach to repair an aortic annular rupture and demonstrates the utility of performing minimally invasive procedures inside a hybrid operating room.

A highly effective magnetic nanocomposite alginate beads (PPy-NTs/PEI@Alg@NiFe 2 O 4 ) were synthesized using alginate as the encapsulation reagent and polypyrrole/polyethylene imine with nano NiFe 2 O 4 as a functional filler to remove toxic Zn 2+ and Pb 2+ from polluted water. A response surface methodology (RSM) was used to statistically assess the influences of pH and the adsorbent dose on the adsorption performance. PPy-NTs/PEI@Alg@NiFe 2 O 4 magnetic microbeads exhibited the optimal adsorption capacity q e (18.6 mg/g) at pH 6 and a 2 mg/L dose for Zn 2+ removal. In comparison, the optimal q e (32.6 mg/g) was reached at pH 4.5 with a 1.5 mg/L dose for Pb 2+ remediation. From batch experiments, maximal absorption capacities of 53.3 mg/g and 22 mg/g were achieved for Pb 2+ and Zn 2+ , respectively, at 313 K. The pseudo-second-order kinetic model fitted the results well, suggesting that the chemisorption process regulates adsorption. Isotherm models indicate the presence of homogeneous adsorption sites from the well-fitting to Langmuir isotherm. An investigation of the effects of temperature and thermodynamic considerations revealed the endothermic nature of Zn 2+ and Pb 2+ absorption. The Fourier transform infrared spectra showed that -NH, -NH 2 , and -COO - are the main groups in PPy-NTs/PEI@Alg@NiFe 2 O 4 composite beads that were responsible for Zn 2+ and Pb 2+ removal from polluted water., 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 © 2024. Published by Elsevier B.V.)

Background: The physical dependence on prescription opioids among cancer survivors remains an under-investigated area, with a scarcity of well-designed prospective studies., Methods: This single-arm, phase-2 clinical trial in Korea assessed the efficacy and safety of a transdermal buprenorphine patch (TBP) in managing physical dependence on prescription opioids in cancer survivors, as confirmed through the DSM-5 criteria or psychiatric consultation for opioid withdrawal. This study involved a 4-phase treatment protocol of screening, induction/stabilization, discontinuation, and monitoring. The primary outcome was the rate of successful opioid discontinuation, as measured by a negative urine-drug screening at 8 weeks. Key secondary outcomes included the resumption of prescribed opioids, changes in both the Clinical Opioid Withdrawal Scale (COWS) and morphine equivalent daily dose (MEDD), and assessments related to the psychological and physiological aspects of dependence and safety., Results: Thirty-one participants were enrolled. In the intention-to-treat population, the success rate of opioid discontinuation was 58%, with only 2 participants experiencing a resumption of prescribed opioids. Significant reductions were observed in MEDD, which decreased from 98 to 26 mg/day (P < .001), and COWS scores, which decreased from 5.5 to 2.8 (P < .001). Desire to use opioids reduced from 7.0 to 3.0 on a 10-point numeric rating scale (P < .001). Toxicities related to TBP were mild and manageable, without severe precipitated withdrawal symptoms., Conclusion: TBP may be considered as an alternative therapeutic option in cancer survivors physically dependent on prescription opioids, especially where sublingual formulations are unavailable., (© The Author(s) 2024. Published by Oxford University Press.)

The practical use of polymers of intrinsic microporosity (PIMs) in CO 2 separation is often hindered by their moderate selectivity, performance instability over time, and pressure constraints. To address these limitations, a straightforward approach is presented to enhance the CO 2 separation capability of PIM-1 by incorporating metal ions into uniformly hydrolyzed PIM-1 (cPIM). This dual linking strategy, achieved via ionic and coordination bonding of metal ions with the polymeric side chains including ─COOH and ─CONH 2 , restructures the polymer, disrupting hydrogen bonds between cPIM chains and creating active sites for CO 2 via π-complexation. This modification enhances gas permeability while maintaining high selectivity. The optimized zinc-coordinated membrane achieves an impressive CO 2 permeability of ≈2,500 Barrer with CO 2 /N 2 and CO 2 /CH 4 selectivities of 27.1 and 23, respectively, outperforming pristine cPIM (700 Barrer; CO 2 /N 2  = 27; CO 2 /CH 4  = 19). Notably, this performance surpasses the 2008 Robeson upper-bound limits for both gas pairs. Additionally, the metal-coordinated membranes exhibit remarkable long-term stability, resisting aging effects for up to 20 days and maintaining anti-plasticization properties at pressures up to 20 bar. These dual-crosslinked membranes demonstrate promising potential for mixed gas separation, indicating their suitability for real-world industrial applications., (© 2024 Wiley‐VCH GmbH.)

Diabetes management is often complicated by comorbidities, requiring complex medication regimens that increase the risk of drug-drug interactions (DDIs), potentially compromising treatment outcomes or causing toxicity. Although machine learning (ML) models have made strides in DDI prediction, existing approaches lack specificity for oral diabetes medications and face challenges in interpretability. To address these limitations, we propose a novel ML-based framework utilizing the Simplified Molecular Input Line Entry System (SMILES) to encode structural information of oral diabetes drugs. Using this representation, we developed an XGBoost model, selecting molecular features through LASSO. Our dataset, sourced from DrugBank, included 42 oral diabetes drugs and 1,884 interacting drugs, divided into training, validation, and testing sets. The model identified 606 optimal features, achieving an F1-score of 0.8182. SHAP analysis was employed for feature interpretation, enhancing model transparency and clinical relevance. By predicting adverse DDIs, our model offers a valuable tool for clinical decision-making, aiding safer prescription practices. The 606 critical features provide insights into atomic-level interactions, linking computational predictions with biological experiments. We present a classification model specifically designed for predicting DDIs associated with oral diabetes medications, with an openly accessible web application to support diabetes management in multi-drug regimens and comorbidity settings., 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 © 2024 Elsevier Inc. All rights reserved.)

Background: The effects of long-term care insurance (LTCI) in reducing medical costs and utilization among older adults have been reported. This study aims to investigate the mortality in patients with Parkinson's disease (PD) requiring LTCI and its relationships with economic status., Methods: This study was conducted using the database of the Korean National Health Insurance Service (NHIS)-Senior Cohort between 2008 and 2019. A total of 5937 patients with PD were included. Hazard ratios (HRs) of mortality associated with LTCI were estimated using a Cox regression model. Potential confounders such as demographics and comorbidities were adjusted., Results: Out of 5937 PD patients, 821 required LTCI, and 5116 did not. Compared to PD patients without LTCI, PD patients with LTCI were older and exhibited a higher comorbidity burden. The overall incidence rate of mortality was 18.63 per 100 person-years in PD patients with LTCI. PD patients requiring LTCI were associated with an increased HR of 3.61 (95 % CI = 3.13-4.16) for mortality compared to PD patients not eligible for LTCI. Low-income status with LTCI was associated with the highest mortality risk (HR = 4.54, 95 % CI = 3.38-6.09), compared to middle-income status (HR = 3.47, 95 % CI = 2.64-4.61) and high-income status (HR = 3.53, 95 % CI = 2.91-4.91)., Conclusions: Our study suggests that older PD patients requiring LTCI with low economic status have a higher risk of death. Continuous policy efforts to reduce the mortality risk in this group are needed., 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 © 2024 Elsevier Ltd. All rights reserved.)

Objective: The aim of the study is to evaluate the muscle thickness and walking test in people with hemophilia A and their correlation to joint health and functional impairments., Design: This is a cross-sectional study., Results: Twenty-nine severe/moderate people with hemophilia A were enrolled. Muscle thickness of quadriceps and medial gastrocnemius was measured using ultrasound. Joint health and functional capacity were assessed using Hemophilia Joint Health Score, Hemophilia Early Arthropathy Detection with Ultrasound, 6-Minute Walking test, Hemophilia Quality of Life Questionnaire for Adults, and Hemophilia Activities List. Quadriceps muscle thickness significantly correlated with Hemophilia Joint Health Score knee, Hemophilia Early Arthropathy Detection with Ultrasound knee, and Hemophilia Activities List. Calf muscle thickness significantly correlated with the Hemophilia Joint Health Score ankle. After adjusted age and body mass index, calf muscle thickness was inversely associated with the Hemophilia Joint Health Score ankle. Six-Minute Walking test was found to significantly correlate with Hemophilia Joint Health Score total, Hemophilia Early Arthropathy Detection with Ultrasound total, Hemophilia Quality of Life Questionnaire for Adults, and Hemophilia Activities List., Conclusions: Muscle thickness and the distance of 6-Minute Walking Test were linked to assessment of joint health, quality of life, and activity participation in people with hemophilia A. Ultrasound measurement of muscle thickness and walking test seem to be useful tools for the assessment of joint health and functional status in people with hemophilia A., Competing Interests: Conflict of interest statement: Dr. Jiunn-Horng Kang received research funding from Bayer and Sanofi, and honoraria from Sanofi; Dr. Chia-Yau Chang received research funding from Bayer and Sanofi, honoraria from Bay, Sanofi, Novo Nordisk, Takeda, Chugai, and Pfizer, and participated in advisory boards for Sanofi, Novo Nordisk, Bayer, and Chugai. The other authors state that they had no interests, which might be perceived as posing a conflict or bias. All the authors acknowledge the funding support for the study. Other coauthors stated that they had no interests, which might be perceived as posing a conflict or bias., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Polygenic risk scores (PRSs) likely predict risk and prognosis of glaucoma. We compared the PRS performance for primary open-angle glaucoma (POAG), defined using International Classification of Diseases (ICD) codes vs manual medical record review., Design: Retrospective cohort study., Methods: We identified POAG cases in the Mount Sinai BioMe and Mass General Brigham (MGB) biobanks using ICD codes. We confirmed POAG based on optical coherence tomograms and visual fields. In a separate 5% sample, the absence of POAG was confirmed with intraocular pressure and cup-disc ratio criteria. We used genotype data and either self-reported glaucoma diagnoses or ICD-10 codes for glaucoma diagnoses from the UK Biobank and the lassosum method to compute a genome-wide POAG PRS. We compared the area under the curve (AUC) for POAG prediction based on ICD codes vs medical records., Results: We reviewed 804 of 996 BioMe and 367 of 1006 MGB ICD-identified cases. In BioMe and MGB, respectively, positive predictive value was 53% and 55%; negative predictive value was 96% and 97%; sensitivity was 97% and 97%; and specificity was 44% and 53%. Adjusted PRS AUCs for POAG using ICD codes vs manual record review in BioMe were not statistically different (P ≥.21) by ancestry: 0.77 vs 0.75 for African, 0.80 vs 0.80 for Hispanic, and 0.81 vs 0.81 for European. Results were similar in MGB (P ≥.18): 0.72 vs 0.80 for African, 0.83 vs 0.86 for Hispanic, and 0.74 vs 0.73 for European., Conclusions: A POAG PRS performed similarly using either manual review or ICD codes in 2 electronic health record-linked biobanks; manual assessment of glaucoma status might not be necessary for some PRS studies. However, caution should be exercised when using ICD codes for glaucoma diagnosis given their low specificity (44%-53%) for manually confirmed cases of glaucoma., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Laparoscopic colon surgery is now commonly used for colorectal cancer (CRC) resection. The objective of this study was to compare the oncologic outcomes between open conversion and laparoscopic surgery, and to identify risk factors for open conversion., Methods: We retrospectively reviewed the medical records of patients who underwent curative resection for stage 0-III CRC at five Hallym University-affiliated hospitals between January 2011 and June 2021. The patients were divided into the conversion and laparoscopic groups according to whether laparoscopic surgery was completed., Results: Out of 2231 patients, laparoscopic surgery was completed in 2131 patients and 100 (4.5 %) converted to open surgery. The operation time (P = 0.028) and postoperative hospital stay (P = 0.036) were longer in the conversion group than in the laparoscopic group. Overall (P = 0.022) and severe (Clavien-Dindo classification grade ≥3) (P = 0.048) complications were more frequent in the conversion group than in the laparoscopic group. The 5-year recurrence-free survival (RFS) rate was worse in the conversion group than in the laparoscopic group (P = 0.002). In the multivariable analysis, open conversion was not a prognostic factor for RFS (P = 0.082). Abdominal surgery history (P = 0.021), obstruction (P < 0.001), and T4 stage (P < 0.001) were independently associated with open conversion., Conclusion: The conversion group had worse perioperative and oncologic outcomes. History of abdominal surgery, obstruction, and T4 stage were associated with open conversion. However, conversion itself was not associated with RFS., Competing Interests: Declarations of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Catheter-associated urinary tract infections (CAUTIs) increase clinical burdens. Identifying the high-risk patients is crucial. We aimed to develop and externally validate an explainable, prognostic prediction model of CAUTIs among hospitalized individuals receiving urinary catheterization., Methods: A retrospective cohort paradigm was applied for model development and validation using data from two hospitals and used the third hospital's data for external validation. Machine learning algorithms were applied for predictive modeling. We evaluated the calibration, clinical utility, and discrimination ability to choose the best model by the validation set. The best model was assessed for the explainability., Results: We included 122,417 instances from 20-to-75-year-old subjects. Fourteen predictors were selected from 20 candidates. The best model was the RF for prediction within 6 days. It detected 97.63% (95% confidence interval [CI]: ±0.06%) CAUTI positive, and 97.36% (95% CI: ±0.07%) of individuals that were predicted to be CAUTI negative were true negatives. Among those predicted to be CAUTI positives, we expected 22.85% (95% CI: ±0.07%) of them to truly be high-risk individuals. We provide a web-based application and a paper-based nomogram for using this model., Conclusions: Our prediction model accurately detected most CAUTI positive cases, while most predicted negative individuals were correctly ruled out., (Copyright © 2024. Published by Elsevier Inc.)

Asthma and Chronic Obstructive Pulmonary Disease (COPD) are major global health concerns, with inhalation therapy being a primary treatment method. Dry powder inhalers (DPIs) often face challenges related to particle aggregation, which can diminish drug delivery efficiency. This study investigates particle aggregation and aims to optimize the cohesion-adhesion balance to improve inhalation efficiency. Advanced techniques like atomic force microscopy and Raman imaging were used to analyze particle interactions, focusing on lactose ratios, particle morphology, and drug-drug interactions. The therapeutic efficacy of optimized formulations containing budesonide (BUD) and Arformoterol (AFT) was assessed using an asthma model, showing significant improvements in sRAW, neutrophil count, and tidal volume compared to the positive control, with p -values below 0.01. AFT exhibited comparable efficacy to Formoterol at half the dose. Additionally, pharmacokinetic studies demonstrated similar in vivo behavior between the drugs, confirming the therapeutic advantage of AFT, with p -values for AUC 0-t and Cmax of .646 and .153, respectively. The fine particle fractions for AFT and BUD were 39.4% and 50.6%, respectively, indicating improved drug delivery efficiency and potential for better clinical outcomes in asthma and COPD patients.

Contaminated sediments can adversely affect aquatic ecosystems, making the identification and management of pollutant sources extremely important. In this study, we proposed machine learning approaches to reveal sources and their influential distances for heavy metal contamination of downstream sediment. We employed classification models with artificial neural networks (ANN) and random forest (RF), respectively, to predict the heavy metal contamination of stream sediments using upland environmental variables as input features. A comprehensive Korean nationwide monitoring database containing 1546 datasets was used to train and test the models. These datasets encompass the concentrations of eight heavy metals (Ar, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) in sediment samples collected from 160 stream sites across the nation from 2014 to 2018. Model's prediction accuracy was evaluated for input feature sets from different influential upland areas defined by different buffer radii and the watershed boundary for each site. Although both ANN and RF models were unsatisfactory in predicting heavy metal quartile classes, RF-classifiers with adaptive synthetic oversampling (ORFC) showed reasonably well-predicted classes of the sediment samples based on the Canada's Sediment Quality Guidelines (accuracy ranged from 0.67 to 0.94). The best influential distance (i.e., buffer radius) was determined for each heavy metal based on the accuracy of ORFC. The results indicated that Cd, Cu and Pb had shorter influential distances (1.5-2.0 km) than the other heavy metals with little difference in accuracy for different influential distances. Feature importance calculation revealed that upland soil contamination was the primary factor for Hg and Ni, while residential areas and roads were significant features associated with Pb and Zn contamination. This approach offers information on major contamination sources and their influential areas to be prioritized for managing contaminated stream sediments., 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 © 2024 Elsevier B.V. All rights reserved.)

Giant water bugs (Hemiptera: Belostomatidae) are top predators in wetland ecosystems, serving as biological indicators of the health of lentic ecosystems and as effective biological control agents for freshwater snails and mosquitoes. This study aimed to predict the current and future distribution of two Korean giant water bugs, Appasus japonicus and Diplonychus esakii , under three climate change scenarios, contributing to the sustainable management of wetland ecosystems in South Korea. Using MaxEnt models, we employed seven climatic and three non-climatic variables to investigate the habitat preferences and distribution patterns of the species. The results revealed that A. japonicus is likely to experience a northward range contraction due to climate change, while D. esakii is predicted to expand its distribution northward without losing its current range. These responses may lead to occupancy turnover between the two species, potentially driving reassembly in aquatic organism community. Elevation was the primary factor influencing the distribution of A. japonicus , whereas annual mean temperature was the most informative variable for D. esakii , both factors derived under the current climate conditions. These findings suggest that both species are highly sensitive to climate change, with potential range shifts toward higher latitudes and elevations. This study provides insights into how climate change could impact two giant water bugs, thereby supporting future efforts to manage and conserve wetland ecosystems in this country.

Posttraumatic stress disorder (PTSD) is associated with mortality and increased risk of diseases of aging, but underlying mechanisms remain unclear. We examine associations of PTSD with one potential pathway, accelerated epigenetic aging. In a longitudinal cohort of trauma-exposed middle-aged women (n = 831, n observations = 1,516), we examined cross-sectional and longitudinal associations between PTSD, with and without comorbid depression, and epigenetic aging measured by six clocks at two time points approximately 13.5 years apart: Hannum, Horvath, PhenoAge, GrimAge, DunedinPoAM, and DunedinPACE. We further examined associations of 3 well-established predictors of aging and mortality also linked with PTSD, namely, body mass index (BMI), diet quality, and physical activity, with epigenetic aging. Cross-sectionally, across all six clocks, epigenetic aging in women with PTSD alone, depression alone, and co-occurring depression and PTSD did not differ from the reference group of women without PTSD or depression in analyses adjusted for age, self-reported race, cell proportions, and ancestry principal components. In longitudinal analyses, we similarly did not find any difference in change in epigenetic age over time by PTSD and depression status at baseline. Among the health factors, in cross-sectional analyses, higher BMI was significantly and consistently associated with greater epigenetic aging measured by the PhenoAge, GrimAge, DunedinPoAM, and DunedinPACE clocks, but not measured by the Hannum or Horvath clocks. Physical activity was not consistently associated with epigenetic aging measured by Hannum, Horvath, PhenoAge, or GrimAge. In analyses with the DunedinPoAm and DunedinPACE clocks, women who reported exercise equivalent to 1 or more hours/week walking had slower epigenetic aging than women with less exercise. Diet quality was not consistently associated with epigenetic aging measured by any of the clocks. Our data do not provide evidence that biological aging, as measured by any of the six epigenetic clocks, is a pathway linking PTSD with mortality and diseases of aging., 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 © 2024 Elsevier Inc. All rights reserved.)

Aquaculture products, such as clams, scallops, and oysters, are major vectors of fecal-derived pathogens. Male-specific and somatic coliphages are strongly correlated with human noroviruses, the major enteric viruses worldwide. Geographic information system with local land-use patterns can also provide valuable information for tracking sources of fecal-derived pathogens. We examined distributions of four fecal indicator microorganisms, i.e., male-specific and somatic coliphage, total coliform, and Escherichia coli ( E. coli ) in three river and seawater sampling sites located on the coast of Gomso Bay in the Republic of Korea during the sampling period (from March 2015 to January 2016). Geospatial analyses of fecal indicators and correlation between environmental parameters and fecal indicators or among fecal indicators were also performed. Overall, river water samples showed highest concentrations of both types of coliphage in summer (July 2015). High concentrations of both total coliform and E. coli were detected in river water during the period from July to September 2015. High concentrations of all fecal indicators were found at site GL02, located in the innermost part of Gomso Bay, which has high-density agriculture and residential areas. Environmental factors related to precipitation-cumulative precipitation on and from 3 days before the sampling day (Prep-0 and Prep-3, respectively)-and salinity were strongly correlated with concentrations of all fecal indicators. The present results suggest that investigations of multiple fecal indicators with a systemic geospatial information are necessary for precisely tracking fecal contaminations of aquaculture products.

Objectives: Obstructive sleep apnea is associated with alterations in slow-wave activity during sleep, potentially increasing the risk of Alzheimer's disease. This study investigated the associations between obstructive sleep apnea manifestations such as respiratory events, hypoxia, arousal, slow-wave patterns, and neurochemical biomarker levels., Methods: Individuals with suspected obstructive sleep apnea underwent polysomnography. Sleep disorder indices, oxygen metrics, and slow-wave activity data were obtained from the polysomnography, and blood samples were taken the following morning to determine the plasma levels of total tau (T-Tau) and amyloid beta-peptide 42 (Aβ 42 ) by using an ultrasensitive immunomagnetic reduction assay. Subsequently, the participants were categorized into groups with low and high Alzheimer's disease risk on the basis of their computed product Aβ 42 × T-Tau. Intergroup differences and the associations and mediation effects between sleep-related parameters and neurochemical biomarkers were analyzed., Results: Forty-two participants were enrolled, with 21 assigned to each of the low- and high-risk groups. High-risk individuals had a higher apnea-hypopnea index, oxygen desaturation index (≥3%, ODI-3%), fraction of total sleep time with oxygen desaturation (SpO 2- 90% TST ), and arousal index and greater peak-to-peak amplitude and slope in slow-wave activity, with a correspondingly shorter duration, than did low-risk individuals. Furthermore, indices such as the apnea-hypopnea index, ODI-3% and SpO 2- 90% TST were found to indirectly affect slow-wave activity, thereby raising the Aβ 42 × T-Tau level., Conclusions: Obstructive sleep apnea manifestations, such as respiratory events and hypoxia, may influence slow-wave sleep activity (functioning as intermediaries) and may be linked to elevated neurochemical biomarker levels. However, a longitudinal study is necessary to determine causal relationships among these factors., Statement of Significance: This research aims to bridge gaps in understanding how obstructive sleep apnea is associated with an elevated risk of Alzheimer's disease, providing valuable knowledge for sleep and cognitive health., Competing Interests: Declaration of conflicts of interest The authors declare that they have no competing interests., (Copyright © 2024 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC), the most aggressive subtype, presents a critical challenge due to the absence of approved targeted therapies. Hence, there is an urgent need to identify effective therapeutic targets for this condition. While epidermal growth factor receptor (EGFR) is prominently expressed in TNBC and recognized as a therapeutic target, anti-EGFR therapies have yet to gain approval for breast cancer treatment due to their associated side effects and limited efficacy. Here, we discovered that intercellular adhesion molecule-1 (ICAM-1) exhibits elevated expression levels in metastatic breast cancer and serves as a pivotal binding adaptor for EGFR activation, playing a crucial role in malignant progression. The activation of EGFR by tumor-expressed ICAM-1 initiates biased signaling within the JAK1/STAT3 pathway, consequently driving epithelial-to-mesenchymal transition and facilitating heightened metastasis without influencing tumor growth. Remarkably, ICAM-1-neutralizing antibody treatment significantly suppressed cancer metastasis in a breast cancer orthotopic xenograft mouse model. In conclusion, our identification of ICAM-1 as a novel tumor intrinsic regulator of EGFR activation offers valuable insights for the development of TNBC-specific anti-EGFR therapies., (© 2024. The Author(s).)

Rationale: Recent studies have demonstrated the direct connections between the skull bone marrow, meninges, and brain. In an effort to explore these connections for the purpose of brain drug delivery, we previously proposed the direct application of CNS drugs into the diploic space between the outer and inner cortex of the skull, namely, intracalvariosseous administration (ICO). It was successfully demonstrated that small molecular to large colloidal drugs can readily reach the brain after ICO in mice and rabbits. Here, we report that a single ICO of donepezil microspheres protects cognitive impairment in Alzheimer mouse models over a month-long period. Methods: Donepezil-loaded long-acting microspheres (DPZ@LAM) were prepared with biodegradable poly(DL-lactide-co-glycolide) (PLGA). Pharmacokinetic study and behavioral test were performed to determine the brain exposure and therapeutic effects after ICO of DPZ@LAM in scopolamine-induced memory-deficient mice. Results: DPZ@LAM were capable of a month-long and precisely controlled drug release. After a single ICO of DPZ@LAM, DPZ concentration in brain sustained above the effective therapeutic levels for four weeks. The long-lasting brain exposure also led to significantly recovered cognitive function in scopolamine-induced memory-deficient mice, along with decreased acetylcholinesterase activity and increased brain-derived neurotrophic factor. Conclusions: ICO allows for BBB-bypassing brain drug delivery through the direct connection between the skull bone marrow and brain, providing an alternative approach for the treatment of neurodegenerative diseases with otherwise BBB impermeable CNS drugs., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Information and communications technology-based tailored management (TM) intervention is a novel automatic system in which a smartphone app for the management of patients with hypertension and diabetes, the provider web, and Bluetooth devices are linked. However, little evidence exists regarding the cost-effectiveness of the interventions using mobile apps., Objective: This study aimed to assess the cost-effectiveness of TM intervention for adult patients with hypertension or diabetes in primary care compared with usual care (UC)., Methods: Cost-effectiveness analysis using a Markov model was conducted from the Korean health care system perspective. Based on 6-month outcome data from an information and communications technology-based tailored chronic disease management (ICT-CM) trial, effectiveness over a lifetime beyond the trial periods was extrapolated using a cardiovascular disease risk prediction model. Costs were estimated using ICT-CM trial data and national health insurance claims data. Health utility weights were obtained from the Korea National Health and Nutrition Examination Survey., Results: In the base-case analysis, compared with UC, TM was more costly (US $23,157 for TM vs US $22,391 for UC) and more effective (12.006 quality-adjusted life-years [QALYs] for TM vs 11.868 QALYs for UC). The incremental cost-effectiveness ratio was US $5556 per QALY gained. Probabilistic sensitivity analysis showed that the probability of TM being cost-effective compared with UC was approximately 97% at an incremental cost-effectiveness ratio threshold of US $26,515 (KRW 35 million) per QALY gained., Conclusions: Compared with UC, TM intervention is a cost-effective option for patients with hypertension or diabetes in primary care settings. The study results can assist policy makers in making evidence-based decisions when implementing accessible chronic disease management services., (©Sung-Hee Oh, Jae-Heon Kang, Jin-Won Kwon. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 11.10.2024.)

Mesozooplankton communities have been used extensively as reliable climate change indicators, mainly because of their rapid growth and sensitivity to environmental changes. This study explored the modifications in the taxonomic composition of the mesozooplankton community and the associated physical changes of transport-driven, eddy-driven, and marine heatwaves in the summers of the last 14 years (2009-2022) within the mixed layer of the Ulleung Basin in the East Sea/Japan Sea, where surface waters have rapidly warmed in recent decades. A slight increase was observed in the abundance of mesozooplankton from 2009 (3709 inds.m -3 ) to 2022 (4231 inds.m -3 ), with two notable peaks in 2015 (11,377 inds.m -3 ) and 2020 (11,184 inds.m -3 ), which was mainly attributed to the prevalence of Noctiluca scintillans. The first peak in 2015 showed thaliaceans to be the next dominant taxa, in which the southward direction of meandering in East Korea Warm Current (EKWC), presence of the Ulleung warm eddy, lower volume of the Western Channel (V-west) of the Korea Strait, and marine heatwaves (MHWs) did not occur. In contrast to the first peak, the second peak in 2020 showed Pyrocystis pseudonoctiluca to be the next dominant species, which may have been transported and advected by the strong V-west and eastward direction of the EKWC and the occurrence of MHWs that allowed the persistence of the subtropical species P. pseudonoctiluca. Overall, the significant increases in the second dominant mesozooplankton taxa appeared to be affected by physical changes, including transport or eddy-driven changes, along with the occurrence of strong V-west, the direction of the EKWC, and the occurrence of MHWs, which may synergistically influence the increase in the second dominant taxa during summer. This study highlights the complex interplay between notable variations in mesozooplankton communities and environmental factors, highlighting the potential consequences of different physical changes (transport-driven and eddy-driven) in this regional ocean., 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 © 2024 Elsevier B.V. All rights reserved.)

Polygenic risk score (PRS) and rare monogenic variant screening are valuable tools for predicting cancer risk and identifying individuals at high risk. Integrating both common and rare genetic variants is crucial for accurate risk assessment. However, estimating the impacts of rare variants on cancer and combining them with PRS remains challenging. Here, we analyze 454,711 exome sequencing and 487,409 array UK Biobank samples, focusing on breast and prostate cancers. We introduce an expanded PRS (EPRS) approach, yielding a systematic model for more effective risk stratification. By prioritizing and clustering genes with cancer-specific rare variants based on odds ratios and population-attributable fraction, we refine risk stratification by combining both monogenic and polygenic effects. Individuals in high-PRS groups with rare high-impact gene variants show up to 15- and 22-fold higher risk for breast and prostate cancers, respectively, compared to those in the intermediate-PRS groups without rare variants. Combined risk profiles vary across distinct rare variant clusters within the same PRS group for both cancers. Our EPRS approach enhances risk stratification for breast and prostate cancers, offering important insights for future research and potential applications to other cancer types., (© 2024. The Author(s).)

Purpose: Staphylococcus aureus is a Gram-positive bacterium that most frequently acquires antibiotic resistance. As an opportunistic pathogen, it can cause conditions such as bacteremia, sepsis, and myocarditis. Due to the social need for a vaccine against methicillin-resistant Staphylococcus aureus (MRSA), many research groups have been designing and studying vaccines for decades. In this study, we developed a multivalent vaccine and evaluated its efficacy by applying a novel adjuvant, β-glucan., Materials and Methods: A vaccine composed of four pore-forming toxins from S. aureus was administered to rabbits 3 times, after which they were challenged with S. aureus USA 300 LAC strain. We measured changes in the rabbits' body weight to monitor systemic adverse reactions and analyzed the total immunoglobulin G antibody titer against the four antigens using enzyme-linked immunosorbent assay. For each rabbit, the number of abscesses and colony-forming units (CFU) in the kidneys were measured., Results: In all vaccinated groups, strong antibody responses against the four antigens were observed. After challenging with MRSA, the vaccinated groups showed less weight change compared to the non-vaccinated groups (average 5.7% versus 13.5%). Additionally, the number of renal abscesses was significantly lower in the vaccinated groups, with three individuals in group 1 (four antigens adjuvanted with β-glucan&#95;PK1) showing no abscess formation. The number of bacteria identified in the kidneys was also statistically significantly lower in the vaccinated group compared to the non-vaccinated group., Conclusion: We demonstrated that the four toxoid antigens we selected can protect against S. aureus infection in a rabbit model and that β-glucan could be used as an immune enhancer. Overall, our study shows that new antigen combinations can induce protective immunity in animal models and that a toxin-based vaccine can help control bacterial colonization., Competing Interests: No potential conflict of interest relevant to this article was reported., (© Korean Vaccine Society.)

Background: Next-generation sequencing (NGS) has become widely available but molecular profiling-guided therapy (MGT) had not been well established in the real world due to lack of available therapies and expertise to match treatment. Our study was designed to test the feasibility of a nationwide platform of NGS-guided MGT recommended by a central molecular tumor board (cMTB) for metastatic solid tumors., Patients and Methods: Patients with advanced or metastatic solid tumors with available NGS results and without standard treatment were enrolled. The cMTB interpreted the patients' NGS reports and recommended the following: (i) investigational medicinal products (IMPs) approved in other indications; (ii) alternative treatments; (iii) clinical trials. The primary variables were the proportion of patients with actionable genomic alterations and those receiving MGT as per cMTB recommendations. Others included treatment duration (TD), overall response rate (ORR), disease control rate (DCR), and safety., Results: From February 2021 to February 2022, 193 cases [99 (51.3%) men; median age 58 years (range 24-88 years); median line of previous treatment 3 (range 0-9)] from 29 sites were enrolled for 60 cMTB sessions. The median time from case submission to cMTB discussion was 7 days (range 2-20 days), and to IMP treatment initiation was 28 days (range 14-90 days). Actionable genetic alterations were found in 145 patients (75.1%). A total of 89 (46.1%) patients received actual dosing of IMPs, and 10 (5.2%) were enrolled in cMTB-recommended clinical trials, achieving an MGT rate of 51.3%. ORR and DCR of IMPs were 10.1% and 72.5%, respectively. The median TD was 3.5 months [95% confidence interval (CI) 2.8-5.5 months], and the 4-month TD rate was 44.9%. The median overall survival of patients who received IMPs was 6.9 months (95% CI 5.2-10.0 months)., Conclusion: KOSMOS confirmed the feasibility of MGT recommended by the cMTB, achieving a high MGT match rate and promising effectiveness in heavily pretreated advanced cancer patients., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Novel clinical trial designs are conducted in the precision medicine era. This study aimed to evaluate biomarker-driven, adaptive phase II trials in precision oncology, focusing on infrastructure, efficacy, and safety. We systematically reviewed and analyzed the target studies. EMBASE and PubMed searches from 2015 to 2023 generated 29 eligible trials. Data extraction included infrastructure, biomarker screening methodologies, efficacy, and safety profiles. Government agencies, cancer hospitals, and academic societies with accumulated experiences led investigator-initiated precision oncology clinical trials (IIPOCTs), which later guided sponsor-initiated precision oncology clinical trials (SIPOCTs). Most SIPOCTs were international studies with basket design. IIPOCTs primarily used the central laboratory for biomarker screening, but SIPOCTs used both central and local laboratories. Most of the studies adapted next-generation sequencing and/or immunohistochemistry for biomarker screening. Fifteen studies included an independent central review committee for outcome investigation. Efficacy assessments predominantly featured objective response rate as the primary endpoint, with varying results. Nine eligible studies contributed to the United States Food and Drug Administration's marketing authorization. Safety monitoring was rigorous, but reporting formats lacked uniformity. Health-related quality of life and patient-reported outcomes were described in some protocols but rarely reported. Our results reveal that precision oncology trials with adaptive design rapidly and efficiently evaluate anticancer drugs' efficacy and safety, particularly in specified biomarker-driven cohorts. The evolution from IIPOCT to SIPOCT has facilitated fast regulatory approval, providing valuable insights into the precision oncology landscape.

Bilateral communication between bones and muscles is essential for healing composite bone-muscle injuries from orthopedic surgeries and trauma. However, these injuries are often characterized by exaggerated inflammation, which can disrupt bone-muscle crosstalk, thereby seriously delaying the healing of either tissue. Existing approaches are largely effective at healing single tissues. However, simultaneous healing of multiple tissues remains challenging, with little research conducted to date. Here we introduce collagen patches that overcome this overlooked issue by harnessing the plasticity of macrophage phenotypes. Phosphatidylserine liposomes (PSLs) capable of shifting the macrophage phenotype from inflammatory M1 into anti-inflammatory/prohealing M2 were coated on collagen patches via a layer-by-layer method. Original collagen patches failed to improve tissue healing under inflammatory conditions coordinated by M1 macrophages. In contrast, PSL-coated collagen patches succeeded in accelerating bone and muscle healing by inducing a microenvironment dominated by M2 macrophages. In cell experiments, differentiation of preosteoblasts and myoblasts was completely inhibited by secretions of M1 macrophages but unaffected by those of M2 macrophages. RNA-seq analysis revealed that type I interferon and interleukin-6 signaling pathways were commonly upregulated in preosteoblasts and myoblasts upon stimulation with M1 macrophage secretions, thereby compromising their differentiation. This study demonstrates the benefit of PSL-mediated M1-to-M2 macrophage polarization for simultaneous bone and muscle healing, offering a potential strategy toward simultaneous regeneration of multiple tissues. STATEMENT OF SIGNIFICANCE: Existing approaches for tissue regeneration, which primarily utilize growth factors, have been largely effective at healing single tissues. However, simultaneous healing of multiple tissues remains challenging and has been little studied. Here we demonstrate that collagen patches releasing phosphatidylserine liposomes (PSLs) promote M1-to-M2 macrophage polarization and are effective for simultaneous healing of bone and muscle. Transcriptome analysis using next-generation sequencing reveals that differentiation of preosteoblasts and myoblasts is inhibited by the secretions of M1 macrophages but promoted by those of M2 macrophages, highlighting the importance of timely regulation of M1-to-M2 polarization in tissue regeneration. These findings provide new insight to tissue healing of multiple tissues., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Riki Toita received a research grant from NGK Spark Plug Co., Ltd. (currently Niterra Co., Ltd.) Masahiro Kitamura, Atsushi Kato, Hideto Yamada, Shogo Yamaguchi, and Shinjiro Kasahara are employees of Niterra Co., Ltd. The remaining authors declare no competing interests., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Importance: EGFR-variant non-small cell lung cancer (NSCLC) is associated with a high rate of central nervous system (CNS) metastases, even with treatment with first-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)., Objective: To investigate CNS activity with lazertinib, a third-generation EGFR TKI., Design, Setting, and Participants: This multicenter single-arm, phase 2 nonrandomized controlled trial was conducted in South Korea and included patients with EGFR-variant NSCLC who had asymptomatic or mildly symptomatic brain metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs. Data were collected from June 2021 to April 2022, with a data cutoff date of December 15, 2022., Exposure: Lazertinib, 240 mg, once daily., Main Outcomes and Measures: The primary end point was intracranial objective response rate (iORR) in the evaluable population according to the Response Evaluation Criteria in Solid Tumours version 1.1 assessed by the investigators. Secondary end points included intracranial progression-free survival (iPFS) and iORR in patients with T790M-negative disease and isolated CNS progression as well as overall ORR, duration of response, intracranial duration of response, disease control rate, overall survival, cerebrospinal fluid penetration of lazertinib, and safety., Results: Among 40 included patients, 25 (63%) were women, and the median (range) age was 63 (29-85) years. A total of 38 patients were evaluable for tumor response, including 12 patients with leptomeningeal metastases. At data cutoff, the median (range) follow-up was 13.6 (2.9-17.7) months. The iORR for the evaluable population was 55% (21 of 38; 95% CI, 38.3-71.4); for patients with T790M-positive disease, 80% (4 of 5; 95% CI, 28.4-99.5); for patients with T790M-negative disease, 43% (9 of 21; 95% CI, 21.8-66.0); and for patients with T790M-unknown disease, 67% (8 of 12; 95% CI, 34.9-90.1). The median iPFS was 15.8 months (95% CI, 15.2-not reached) for the evaluable population, 15.2 months (95% CI, 4.2-not reached) for the T790M-positive subgroup, 15.4 months (95% CI, 7.9-not reached) for the T790M-negative subgroup, and 18.0 months (95% CI, 3.9-not reached) for the T790M-unknown subgroup. The cerebrospinal fluid penetration rate of lazertinib was 46.2% (95% CI, 10.0-49.6), providing further support for its mechanism of intracranial response. Most adverse events were grade 1 or 2., Conclusions and Relevance: In this study, lazertinib had substantial CNS activity, regardless of T790M status, against the progression of intracranial metastases with or without leptomeningeal metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs in patients with metastatic EGFR-variant NSCLC. These results suggest that using lazertinib instead of brain local treatment could be a potential strategy in patients with EGFR-variant NSCLC whose CNS metastases progressed after prior EGFR TKI treatment., Trial Registration: ClinicalTrials.gov Identifier: NCT05326425.

Verrucous carcinoma (VC) is a rare subtype of squamous cell carcinoma (SCC) characterized by its histological presentation as a low-grade tumor with no potential for metastasis, setting it apart from invasive SCC. However, distinguishing VC from its benign counterpart, verrucous hyperplasia (VH), is challenging due to their clinical and morphological similarities. Despite the importance of accurate diagnosis for determining treatment strategies, diagnosis of VH and VC relied only on lesion recurrence after resection. To address this challenge, we generated RNA profiling data from tissue samples of VH and VC patients to identify novel diagnostic markers. We analyzed differentially expressed (DE) mRNA and long non-coding RNA (lncRNA) in tissue samples from VH and VC patients. Additionally, ChIP-X Enrichment Analysis 3 (ChEA3) was conducted to identify the top five transcription factors potentially regulating the expression of DE mRNAs in VH and VC. Our analysis of mRNA and lncRNA expression profiles in VH and VC provides insights into the underlying molecular characteristics of these diseases and offers potential new diagnostic markers. The identification of specific DE genes and lncRNAs may enable clinicians to more accurately differentiate between VH and VC, leading to better treatment choices., Competing Interests: Declaration of competing interest No potential conflict of interest relevant to this article was reported., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Oxidative stress in skeletal muscle can lead to muscle atrophy through reactive oxygen species (ROS)-induced damage and cell death. tert -Butyl hydroperoxide (TBHP), an exogenous ROS generator, induces oxidative stress and cell death in various cells. Sinapine from cruciferous plants possesses beneficial effects, but its role in protecting skeletal muscle cells against ROS-induced cell death remains unclear. This study demonstrates that sinapine pretreatment significantly reduced TBHP-induced cell death and ROS accumulation in a dose-dependent manner. TBHP activated mitogen-activated protein kinase (MAPK) pathways including Akt, p38, and JNK, and triggered autophagy. Sinapine suppressed the phosphorylation of Akt, MEK3/6, p38, MEK4, and JNK, and modulated key autophagy markers. Notably, the co-treatment of MAPK inhibitors attenuated TBHP-induced cell death and LC3B-II accumulation. These findings suggest that sinapine is a promising phytochemical for mitigating oxidative stress-mediated muscle injury, offering potential therapeutic strategies for maintaining skeletal muscle homeostasis and addressing muscle-related pathologies., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© The Korean Society of Food Science and Technology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Aim: Various subcategories for steatotic liver disease (SLD) were proposed globally. Previous studies suggested a heightened risk of cardiovascular diseases (CVD) with prolonged antibiotic exposure and metabolic dysfunction-associated SLD (MASLD), respectively. This study investigates the impact of antibiotic usage on CVD in MASLD patients., Methods: From the Korean National Health Insurance Service database, 276 520 adults aged 40 and older were included. Antibiotic exposure was defined by the cumulative prescription days and the number of classes. Participants were categorized into no SLD and MASLD groups. Hepatic steatosis was defined by using the fatty liver index ≥60. From 2013 to 2019, 16 197 CVD cases were recorded. A multivariate Cox model, adjusting for covariates, assessed adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for CVD risk associated with MASLD and antibiotic prescriptions., Results: The group with ≥91 days of antibiotics prescribed and MASLD showed a significantly increased risk of CVD (aHR, 1.56; 95% CI, 1.39-1.74) compared with antibiotic non-users without SLD. Furthermore, the group with ≥4 classes of antibiotics prescribed and MASLD had an elevated risk of CVD (aHR, 1.49; 95% CI, 1.34-1.66) compared with antibiotic non-users without SLD. Consistent results were observed in several sensitivity analyses., Conclusions: Our study identified prolonged antibiotic exposure may be a factor that increases the risk of CVD in MASLD patients. These findings suggest an epidemiological basis for the therapeutic application of antibiotics in MASLD patients, and emphasize the need for further studies to deepen the understanding of these intricate relationships., (© 2024 Japan Society of Hepatology.)