Alix-normalized exosomal programmed death-ligand 1 analysis in urine enables precision monitoring of urothelial cancer.

Anti-programmed death-ligand 1 (PD-L1) Ab-based therapies have demonstrated potential for treating metastatic urothelial cancer with high PD-L1 expression. Urinary exosomes are promising biomarkers for liquid biopsy, but urine's high variability requires normalization for accurate analysis. This study proposes using the PD-L1/Alix ratio to normalize exosomal PD-L1 signal intensity with Alix, an internal exosomal protein less susceptible to heterogeneity concerns than surface protein markers. Extracellular vesicles were isolated using ExoDisc and characterized using various methods, including ExoView to analyze tetraspanins, PD-L1, and Alix on individual exosomes. On-disc ELISA was used to evaluate PD-L1 and Alix-normalized PD-L1 in 15 urothelial cancer patients during the initial treatment cycle with Tecentriq. Results showed that Alix signal range was relatively uniform, whereas tetraspanin marker intensity varied for individual exosome particles. On-disc ELISA was more reliable for detecting exosomal PD-L1 expression than standard plate ELISA-based measurement. Using exosomal Alix expression for normalization is a more reliable approach than conventional methods for monitoring patient status. Overall, the study provides a practical and reliable method for detecting exosomal PD-L1 in urine samples from patients with urothelial cancer.

Fucosylation and galactosylation in N-glycans of bovine intestinal alkaline phosphatase and their role in its enzymatic activity.

Bovine intestinal alkaline phosphatase (biALP), a membrane-bound plasma metalloenzyme, maintains intestinal homeostasis, regulates duodenal surface pH, and protects against infections caused by pathogenic bacteria. The N-glycans of biALP regulate its enzymatic activity, protein folding, and thermostability, but their structures are not fully reported. In this study, the structures and quantities of the N-glycans of biALP were analyzed by liquid chromatography-electrospray ionization-high energy collision dissociation-tandem mass spectrometry. In total, 48 N-glycans were identified and quantified, comprising high-mannose [6 N-glycans, 33.1 % (sum of relative quantities of each N-glycan)], hybrid (6, 11.9 %), and complex (36, 55.0 %) structures [bi- (13, 26.1 %), tri- (16, 21.5 %), and tetra-antennary (7, 7.4 %)]. These included bisecting N-acetylglucosamine (33, 56.6 %), mono-to tri-fucosylation (32, 53.3 %), mono-to tri-α-galactosylation (16, 20.7 %), and mono-to tetra-ß-galactosylation (36, 58.5 %). No sialylation was identified. N-glycans with non-bisecting GlcNAc (9, 10.3 %), non-fucosylation (10, 13.6 %), non-α-galactosylation (26, 46.2 %), and non-ß-galactosylation (6, 8.4 %) were also identified. The activity (100 %) of biALP was reduced to 37.3 ± 0.2 % (by de-fucosylation), 32.7 ± 2.9 % (by de-α-galactosylation), and 0.2 ± 0.2 % (by de-ß-galactosylation), comparable to inhibition by 10-4 to 101 mM EDTA, a biALP inhibitor. These results indicate that fucosylated and galactosylated N-glycans, especially ß-galactosylation, affected the activity of biALP. This study is the first to identify 48 diverse N-glycan structures and quantities of bovine as well as human intestinal ALP and to demonstrate the importance of the role of fucosylation and galactosylation for maintaining the activity of biALP.

FBXW7-mediated stability regulation of signal transducer and activator of transcription 2 in melanoma formation.

In this study, we provide critical evidence that STAT2 stability regulation plays an essential role in melanoma cell proliferation and colony growth. We found that the interaction of FBXW7 and STAT2 induced STAT2 destabilization via a ubiquitination-mediated proteasomal degradation pathway. Notably, GSK3ß-mediated STAT2 phosphorylation facilitated STAT2-FBXW7 interactions via the DNA binding domain of STAT2 and domains 1, 2, 6, and 7 of FBXW7 WD40. Importantly, the inverse correlation between protein levels of STAT2 and FBXW7 were observed not only in human melanoma cells but also in a human skin cancer tissue array. The relationship between protein levels of STAT2 and FBXW7, cell proliferation, and colony growth were similarly observed in the melanoma cell lines SK-MEL-2, -5, and -28. Moreover, STAT2 knockdown in melanoma cells suppressed melanoma cell proliferation and colony formation. These data demonstrated that FBXW7-mediated STAT2 stability regulation plays an essential role in melanoma cell proliferation and cancer growth.

Metallothionein Family Proteins as Regulators of Zinc Ions Synergistically Enhance the Anticancer Effect of Cannabidiol in Human Colorectal Cancer Cells.

Cannabidiol (CBD) is a chemical obtained from Cannabis sativa; it has therapeutic effects on anxiety and cognition and anti-inflammatory properties. Although pharmacological applications of CBD in many types of tumors have recently been reported, the mechanism of action of CBD is not yet fully understood. In this study, we perform an mRNA-seq analysis to identify the target genes of CBD after determining the cytotoxic concentrations of CBD using an MTT assay. CBD treatment regulated the expression of genes related to DNA repair and cell division, with metallothionein (MT) family genes being identified as having highly increased expression levels induced by CBD. It was also found that the expression levels of MT family genes were decreased in colorectal cancer tissues compared to those in normal tissues, indicating that the downregulation of MT family genes might be highly associated with colorectal tumor progression. A qPCR experiment revealed that the expression levels of MT family genes were increased by CBD. Moreover, MT family genes were regulated by CBD or crude extract but not by other cannabinoids, suggesting that the expression of MT family genes was specifically induced by CBD. A synergistic effect between CBD and MT gene transfection or zinc ion treatment was found. In conclusion, MT family genes as novel target genes could synergistically increase the anticancer activity of CBD by regulating the zinc ions in human colorectal cancer cells.

Shift of switching threshold in low-dimensional semiconductor-based complementary inverters via inkjet printing.

MoS2crystals grown by chemical vapor deposition are suited for realization of practical 2D semiconductor-based electronics. In order to construct complementary circuits with n-type MoS2, another p-type semiconductor, whose performance can be adjusted corresponding to that of MoS2in the limited chip area, has to be sought. Herein, we present a method for tuning switching threshold voltages of complementary inverters simply via inkjet printing without changing their channel dimensions. Random networks of inkjet printed single-walled carbon nanotubes are formed as p-channels beside MoS2, and their density and thickness are controlled by varying the number of printed layers. As a result, p-type transistor characteristics as well as inverter characteristics are facilely tuned only by varying the number of printed layers.

Photoactive Antiviral Face Mask with Self-Sterilization and Reusability.

Since the emergence of the COVID-19 pandemic outbreak, the increasing demand and disposal of surgical masks has resulted in significant economic costs and environmental impacts. Here, we applied a dual-channel spray-assisted nanocoating hybrid of shellac/copper nanoparticles (CuNPs) to a nonwoven surgical mask, thereby increasing the hydrophobicity of the surface and repelling aqueous droplets. The resulting surface showed outstanding photoactivity (combined photocatalytic and photothermal properties) for antimicrobial action, conferring reusability and self-sterilizing ability to the masks. Under solar illumination, the temperature of this photoactive antiviral mask (PAM) rapidly increased to >70 °C, generating a high level of free radicals that disrupted the membrane of nanosized (∼100 nm) virus-like particles and made the masks self-cleaning and reusable. This PAM design can provide significant protection against the transmission of viral aerosols in the fight against the COVID-19 pandemic.

Sex differences in perceived discomfort during seated static posture holding.

This study investigated how sex modifies postural discomfort perception during a sagittally-symmetric, seated static posture holding (SPH) task. Ten male and 10 female participants performed SPH and conducted subjective discomfort ratings in a total of 108 task conditions. A regression analysis found that the impacts of the body joint reactive moments on perceived discomfort were larger for the female group than the male whereas that of the shoulder joint angle was more pronounced for the male than the female. Also, some of the 108 task conditions were found to be more uncomfortable for the male group, while some others, for the female. The observed sex impacts are thought to be due to the sex differences in physical work capacities (muscular strength and joint flexibility). The results suggest that new posture analysis tools allowing sex-specific analyses are needed as they would improve the accuracy and precision of ergonomics posture analyses. Practitioner summary: This study empirically investigated how sex modifies postural discomfort perception during a seated posture holding (SPH) task. Sex was found to modify the impacts of joint reactive moments and the shoulder joint angle. The study results seem to reflect the sex differences in muscular strength and joint flexibility.

Effect of nationwide concurrent drug utilization review program on drug-drug interactions and related health outcome.

BACKGROUND: A computerized drug utilization review (DUR) program has provided physicians and pharmacists with alerts on drug-drug interactions (DDIs), drug-age precautions and therapeutic duplication in Korea since 2010. OBJECTIVE: The purpose of this study was to evaluate the impact of the DUR program on health outcomes associated with DDIs. METHODS: An uncontrolled before-after study was performed to investigate the impact of the nationwide DUR program on DDIs and related health outcomes. The study population consisted of people who used two types of DDI pairs before DUR implementation (from January 2009 to December 2010) and post-DUR implementation (from January 2012 to December 2013); (i) benzodiazepines with concurrent use of metabolic enzyme inhibitors and (ii) QTc (heart-rate corrected QT interval) prolongation agents. The main outcome measures were all-cause and cause-specific hospitalization admissions or emergency department (ED) visits. RESULTS: This study included 107 874 people who used benzodiazepines with enzyme inhibitors and 8489 who received co-medication of QTc prolongation agents. For patients receiving a combination of benzodiazepines and enzyme inhibitors, both all-cause hospitalization and cause-specific hospitalization decreased after DUR implementation, from 43.2% to 41.7% and from 4.6% to 4.5% (adjusted odds ratio [OR] = 0.96; 95% confidence interval (CI), 0.93-0.98; OR = 0.89, 95% CI = 0.84-0.99, respectively). For patients receiving co-medication of QTc prolongation agents, all-cause hospitalization (54.2%) was lower than before (54.9%) (OR = 0.87, 95% CI = 0.79-0.96), but no significant change was found for cause-specific hospitalization and ED visits. CONCLUSION: Implementation of a DUR program may reduce the adverse health outcomes posed by DDIs in patients on combination of benzodiazepines and enzyme inhibitors potentially QTc-prolongation agents.

Factors Associated With Quality of Death in Korean ICUs As Perceived by Medical Staff: A Multicenter Cross-Sectional Survey.

OBJECTIVES: Facilitating a high quality of death is an important aspect of comfort care for patients in ICUs. The quality of death in ICUs has been rarely reported in Asian countries. Although Korea is currently in the early stage after the implementation of the "well-dying" law, this seems to have a considerable effect on practice. In this study, we aimed to understand the status of quality of death in Korean ICUs as perceived by medical staff, and to elucidate factors affecting patient quality of death. DESIGN: A multicenter cross-sectional survey study. SETTING: Medical ICUs of two tertiary-care teaching hospitals and two secondary-care hospitals. PATIENTS: Deceased patients from June 2016 to May 2017. INTERVENTIONS: Relevant medical staff were asked to complete a translated Quality of Dying and Death questionnaire within 48 hours after a patient's death. A higher Quality of Dying and Death score (ranged from 0 to 100) corresponded to a better quality of death. MEASUREMENTS AND MAIN RESULTS: A total of 416 completed questionnaires were obtained from 177 medical staff (66 doctors and 111 nurses) of 255 patients. All 20 items of the Quality of Dying and Death received low scores. Quality of death perceived by nurses was better than that perceived by doctors (33.1 ± 18.4 vs 29.7 ± 15.3; p = 0.042). Performing cardiopulmonary resuscitation and using inotropes within 24 hours before death were associated with poorer quality of death, whereas using analgesics was associated with better quality of death. CONCLUSIONS: The quality of death of patients in Korean ICUs was considerably poorer than reported in other countries. Provision of appropriate comfort care, avoidance of unnecessary life-sustaining care, and permission for more frequent visits from patients' families may correspond to better quality of death in Korean medical ICUs. It is also expected that the new legislation would positively affect the quality of death in Korean ICUs.

RSK2-Mediated ELK3 Activation Enhances Cell Transformation and Breast Cancer Cell Growth by Regulation of c-fos Promoter Activity.

Ribosomal S6 kinase 2 (RSK2), regulated by Ras/Raf/MEKs/ERKs, transmits upstream activation signals to downstream substrates including kinases and transcription and epigenetic factors. We observed that ELK members, including ELK1, 3, and 4, highly interacted with RSK2. We further observed that the RSK2-ELK3 interaction was mediated by N-terminal kinase and linker domains of RSK2, and the D and C domains of ELK3, resulting in the phosphorylation of ELK3. Importantly, RSK2-mediated ELK3 enhanced c-fos promoter activity. Notably, chemical inhibition of RSK2 signaling using kaempferol (a RSK2 inhibitor) or U0126 (a selective MEK inhibitor) suppressed EGF-induced c-fos promoter activity. Moreover, functional deletion of RSK2 by knockdown or knockout showed that RSK2 deficiency suppressed EGF-induced c-fos promoter activity, resulting in inhibition of AP-1 transactivation activity and Ras-mediated foci formation in NIH3T3 cells. Immunocytofluorescence assay demonstrated that RSK2 deficiency reduced ELK3 localization in the nucleus. In MDA-MB-231 breast cancer cells, knockdown of RSK2 or ELK3 suppressed cell proliferation with accumulation at the G1 cell cycle phase, resulting in inhibition of foci formation and anchorage-independent cancer colony growth in soft agar. Taken together, these results indicate that a novel RSK2/ELK3 signaling axis, by enhancing c-Fos-mediated AP-1 transactivation activity, has an essential role in cancer cell proliferation and colony growth.

Cloaked Exosomes: Biocompatible, Durable, and Degradable Encapsulation.

Exosomes-nanosized extracellular vesicles (EVs) naturally secreted from cells-have emerged as promising biomarkers and potential therapeutic vehicles, but methods to manipulate them for engineering purposes remain elusive. Among the technical obstacles are the small size and surface complexity of exosomes and the complex processing steps required, which reduce the biocompatibility of currently available methods. The encapsulation of exosomes with a nanofilm of supramolecular complexes of ferric ions (Fe3+ ) and tannic acid is demonstrated here. The resulting natural polyphenol, ≈10 nm thick, protects exosomes from external aggressors such as UV-C irradiation or heat and is controllably degraded on demand. Furthermore, gold nanoparticles can be covalently attached for single-exosome level visualization. To fully exploit their therapeutic potential, chemotherapeutic drug-loaded EVs are functionalized to achieve the targeted, selective killing of cancer cells preferentially over normal cells. This nanofilm not only preserves the native size and chemical makeup of the intrinsic exosomes, but also confers new capabilities for efficient tumor targeting and pH-controlled release of drugs. Demonstrating a scalable method to produce biocompatible, durable, on-demand degradable, and chemically controllable shields for exosome modification and functionalization, the methods introduced here are expected to bring the potential of exosome-based nanomedicine applications closer to reality.

Potentially inappropriate medication and hospitalization/emergency department visits among the elderly in Korea.

OBJECTIVE: To investigate the association between potentially inappropriate medicine (PIM) use, defined using the American Geriatric Society (AGS) 2012 Beers criteria, and the risk of hospitalization or emergency department (ED) visits in elderly patients, and to examine the most frequently used PIMs among patients with adverse outcomes. DESIGN/SETTING: This was a retrospective study using National Health Insurance claims data from 2010 to 2012. INTERVENTION(S): Elderly patients who took PIMs are compared to those who were not taking PIMs. STUDY PARTICIPANTS: Elderly patients (n = 79 552) who visited medical institutions in Jeju Island during 2011. MAIN OUTCOME MEASURE: Hospitalization and ED visits were evaluated according to whether the patients took PIMs during the study period. The most frequent medications used by the PIM group were also investigated. RESULTS: The likelihood of hospitalization was higher in older patients who took at least one PIM than in those who were not taking PIMs during the study period (odds ratio 2.25, 95% confidence interval 2.09-2.44). Patients taking PIMs were more likely to visit EDs (odds ratio 1.59, 95% confidence interval 1.50-1.67). Among patients who were hospitalized or visited EDs, 45.5% had taken at least one PIM on that day. The most commonly used PIMs included chlorpheniramine maleate, diazepam, metoclopramide HCl and diclofenac sodium. CONCLUSION: Our findings indicate that PIM use can lead to negative health consequences, providing further evidence of the inappropriateness of these medications. Thus, pharmaceutical policies regarding PIM use may need to be implemented for elderly adults in Korea.

FAST: Size-Selective, Clog-Free Isolation of Rare Cancer Cells from Whole Blood at a Liquid-Liquid Interface.

Circulating tumor cells (CTCs) have great potential to provide minimally invasive ways for the early detection of cancer metastasis and for the response monitoring of various cancer treatments. Despite the clinical importance and progress of CTC-based cancer diagnostics, most of the current methods of enriching CTCs are difficult to implement in general hospital settings due to complex and time-consuming protocols. Among existing technologies, size-based isolation methods provide antibody-independent, relatively simple, and high throughput protocols. However, the clogging issues and lower than desired recovery rates and purity are the key challenges. In this work, inspired by antifouling membranes with liquid-filled pores in nature, clog-free, highly sensitive (95.9 ± 3.1% recovery rate), selective (>2.5 log depletion of white blood cells), rapid (>3 mL/min), and label-free isolation of viable CTCs from whole blood without prior sample treatment is achieved using a stand-alone lab-on-a-disc system equipped with fluid-assisted separation technology (FAST). Numerical simulation and experiments show that this method provides uniform, clog-free, ultrafast cell enrichment with pressure drops much less than in conventional size-based filtration, at 1 kPa. We demonstrate the clinical utility of the point-of-care detection of CTCs with samples taken from 142 patients suffering from breast, stomach, or lung cancer.

Fully integrated lab-on-a-disc for nucleic acid analysis of food-borne pathogens.

This paper describes a micro total analysis system for molecular analysis of Salmonella, a major food-borne pathogen. We developed a centrifugal microfluidic device, which integrated the three main steps of pathogen detection, DNA extraction, isothermal recombinase polymerase amplification (RPA), and detection, onto a single disc. A single laser diode was utilized for wireless control of valve actuation, cell lysis, and noncontact heating in the isothermal amplification step, thereby yielding a compact and miniaturized system. To achieve high detection sensitivity, rare cells in large volumes of phosphate-buffered saline (PBS) and milk samples were enriched before loading onto the disc by using antibody-coated magnetic beads. The entire procedure, from DNA extraction through to detection, was completed within 30 min in a fully automated fashion. The final detection was carried out using lateral flow strips by direct visual observation; detection limit was 10 cfu/mL and 10(2) cfu/mL in PBS and milk, respectively. Our device allows rapid molecular diagnostic analysis and does not require specially trained personnel or expensive equipment. Thus, we expect that it would have an array of potential applications, including in the detection of food-borne pathogens, environmental monitoring, and molecular diagnostics in resource-limited settings.

All-in-one centrifugal microfluidic device for size-selective circulating tumor cell isolation with high purity.

Circulating tumor cells (CTCs) have gained increasing attention owing to their roles in cancer recurrence and progression. Due to the rarity of CTCs in the bloodstream, an enrichment process is essential for effective target cell characterization. However, in a typical pressure-driven microfluidic system, the enrichment process generally requires complicated equipment and long processing times. Furthermore, the commonly used immunoaffinity-based positive selection method is limited, as its recovery rate relies on EpCAM expression of target CTCs, which shows heterogeneity among cell types. Here, we propose a centrifugal-force-based size-selective CTC isolation platform that can isolate and enumerate CTCs from whole blood within 30 s with high purity. The device was validated using the MCF-7 breast cancer cell line spiked in phosphate-buffered saline and whole blood, and an average capture efficiency of 61% was achieved, which is typical for size-based filtration. The capture efficiency for whole blood samples varied from 44% to 84% under various flow conditions and dilution factors. Under the optimized operating conditions, a few hundred white blood cells per 1 mL of whole blood were captured, representing a 20-fold decrease compared to those obtained using a commercialized size-based CTC isolation device. In clinical validation, normalized CTC counts varied from 10 to 60 per 7.5 mL of blood from gastric and lung cancer patients, yielding a detection rate of 50% and 38%, respectively. Overall, our CTC isolation device enables rapid and label-free isolation of CTCs with high purity, which should greatly improve downstream molecular analyses of captured CTCs.

Prognostic value of central venous oxygen saturation and blood lactate levels measured simultaneously in the same patients with severe systemic inflammatory response syndrome and severe sepsis.

BACKGROUND: Blood lactate levels and central venous oxygen saturation (ScvO(2)) are known to be useful indicators of global tissue hypoxia. However, it is unclear whether ScvO(2) correlates with lactate levels when measured simultaneously and whether changes in ScvO(2) or lactate levels in serial measurements have prognostic value. We investigated the correlation between ScvO(2) and lactate levels measured simultaneously and their association with clinical outcomes. METHODS: We performed a prospective observational study of patients with severe systemic inflammatory response syndrome (SIRS) and severe sepsis who were admitted to the medical intensive care unit. ScvO(2) and lactate levels were measured simultaneously at the time of study enrollment, every 6 h for 24 h, and then every 24 h until the goal was reached. RESULTS: Twenty-five patients were enrolled in the study; 13 have died and 12 have survived. There was no correlation between lactate levels and ScvO(2). Neither lactate levels nor ScvO(2) at the time of admission differed between nonsurvivors and survivors. Normalization of lactate levels within 48 h was significantly associated with survival. CONCLUSIONS: In patients with severe SIRS and severe sepsis, simultaneously measured ScvO(2) and lactate levels showed no correlation, and normalization of lactate levels within 48 h was a predictive factor for survival.

An update on the sample preparation and analytical methods for synthetic food colorants in food products.

Colorants, especially synthetic colorants, play a crucial role in enhancing the aesthetic qualities of food owing to their cost-effectiveness and stability against environmental factors. Ensuring the safe and regulated use of colorants is essential for maintaining consumer trust in food safety. Various preparation and analytical technologies, which are continuously undergoing improvement, are currently used to quantify of synthetic colorants in food products. This paper reviews recent developments in analytical techniques for synthetic food colorants, detection and compares the operational principles, advantages, and disadvantages of each technology. Additionally, it also explores advancements in these technologies, discussing several invaluable tools of analysis, such as high-performance liquid chromatography, liquid chromatography-tandem mass spectrometry, electrochemical sensors, digital image analysis, near-infrared spectroscopy, and surface-enhanced Raman spectroscopy. This comprehensive overview aims to provide valuable insights into current progress and research in the field of food colorant analysis.

Tonicity-induced cargo loading into extracellular vesicles.

The current challenge in using extracellular vesicles (EVs) as drug delivery vehicles is to precisely control their membrane permeability, specifically in the ability to switch between permeable and impermeable states without compromising their integrity and functionality. Here, we introduce a rapid, efficient, and gentle loading method for EVs based on tonicity control (TC) using a lab-on-a-disc platform. In this technique, a hypotonic solution was used for temporarily permeabilizing a membrane ("on" state), allowing the influx of molecules into EVs. The subsequent isotonic washing led to an impermeable membrane ("off" state). This loading cycle enables the loading of different cargos into EVs, such as doxorubicin hydrochloride (Dox), ssDNA, and miRNA. The TC approach was shown to be more effective than traditional methods such as sonication or extrusion, with loading yields that were 4.3-fold and 7.2-fold greater, respectively. Finally, the intracellular assessments of miRNA-497-loaded EVs and doxorubicin-loaded EVs confirmed the superior performance of TC-prepared formulations and demonstrated the impact of encapsulation heterogeneity on the therapeutic outcome, signifying potential opportunities for developing novel exosome-based therapeutic systems for clinical applications.

Irilin D suppresses RANKL-induced osteoclastogenesis and prevents inflammation-induced bone loss by disrupting the NF-κB and MAPK signaling pathways.

Excessive activity of osteoclasts(OCs) lead to bone resorption in chronic inflammatory conditions. The use of natural compounds to target OCs offers significant promise in the treatment or prevention of OC-associated diseases. Irilin D (IRD), a natural isoflavone derived from Belamcanda chinensis (L.) DC., has potential effects on OC differentiation both in vitro and in vivo that have yet to be thoroughly explored. In our study, we found that IRD inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced OC differentiation, actin ring formation, and bone resorption in vitro without compromising cell viability. However, IRD did not exhibit anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated macrophages. Furthermore, IRD reduced LPS-induced inflammatory bone loss by blocking osteoclastogenesis in a mouse model. Mechanistically, IRD disrupted RANKL-induced activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB), leading to the inhibition of c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) activation. We also demonstrated that IRD inhibited RANKL-induced osteoclastic NFATc1 target genes, including DC-STAMP, ACP5, and CtsK. Our results indicate that IRD mitigates LPS-induced inflammatory bone resorption in mice by inhibiting RANKL-activated MAPKs and NF-κB signaling pathways, suggesting its potential as a natural isoflavone for preventing or treating OC-associated diseases.

A Deep Learning-Based Approach for Prediction of Vancomycin Treatment Monitoring: Retrospective Study Among Patients With Critical Illness.

BACKGROUND: Vancomycin pharmacokinetics are highly variable in patients with critical illnesses, and clinicians commonly use population pharmacokinetic (PPK) models based on a Bayesian approach to dose. However, these models are population-dependent, may only sometimes meet the needs of individual patients, and are only used by experienced clinicians as a reference for making treatment decisions. To assist real-world clinicians, we developed a deep learning-based decision-making system that predicts vancomycin therapeutic drug monitoring (TDM) levels in patients in intensive care unit. OBJECTIVE: This study aimed to establish joint multilayer perceptron (JointMLP), a new deep-learning model for predicting vancomycin TDM levels, and compare its performance with the PPK models, extreme gradient boosting (XGBoost), and TabNet. METHODS: We used a 977-case data set split into training and testing groups in a 9:1 ratio. We performed external validation of the model using 1429 cases from Kangwon National University Hospital and 2394 cases from the Medical Information Mart for Intensive Care-IV (MIMIC-IV). In addition, we performed 10-fold cross-validation on the internal training data set and calculated the 95% CIs using the metric. Finally, we evaluated the generalization ability of the JointMLP model using the MIMIC-IV data set. RESULTS: Our JointMLP model outperformed other models in predicting vancomycin TDM levels in internal and external data sets. Compared to PPK, the JointMLP model improved predictive power by up to 31% (mean absolute error [MAE] 6.68 vs 5.11) on the internal data set and 81% (MAE 11.87 vs 6.56) on the external data set. In addition, the JointMLP model significantly outperforms XGBoost and TabNet, with a 13% (MAE 5.75 vs 5.11) and 14% (MAE 5.85 vs 5.11) improvement in predictive accuracy on the inner data set, respectively. On both the internal and external data sets, our JointMLP model performed well compared to XGBoost and TabNet, achieving prediction accuracy improvements of 34% and 14%, respectively. Additionally, our JointMLP model showed higher robustness to outlier data than the other models, as evidenced by its higher root mean squared error performance across all data sets. The mean errors and variances of the JointMLP model were close to zero and smaller than those of the PPK model in internal and external data sets. CONCLUSIONS: Our JointMLP approach can help optimize treatment outcomes in patients with critical illnesses in an intensive care unit setting, reducing side effects associated with suboptimal vancomycin administration. These include increased risk of bacterial resistance, extended hospital stays, and increased health care costs. In addition, the superior performance of our model compared to existing models highlights its potential to help real-world clinicians.