Fenofibrate to prevent amputation and reduce vascular complications in patients with diabetes: FENO-PREVENT.

BACKGROUND: The potential preventive effect of fenofibrate on lower extremity amputation (LEA) and peripheral arterial disease (PAD) in patients with type 2 diabetes (T2D) is not fully elucidated. METHODS: We selected adult patients ≥ 20 years of age with T2D from the Korean National Health Insurance Service Database (2009-2012). The fenofibrate users were matched in a 1:4 ratio with non-users using propensity scores (PS). The outcome variables were a composite of LEA and PAD and the individual components. The risks of outcomes were implemented as hazard ratio (HR) with 95% confidence intervals (CI). For safety issues, the risks of acute kidney injury, rhabdomyolysis and resulting hospitalization were analyzed. RESULTS: A total of 114,920 patients was included in the analysis with a median follow-up duration of 7.6 years (22,984 and 91,936 patients for the fenofibrate user and non-user groups, respectively). After PS matching, both groups were well balanced. The fenofibrate group was associated with significantly lower risks of composite outcome of LEA and PAD (HR 0.81; 95% CI 0.70-0.94), LEA (HR 0.76; 95% CI 0.60-0.96), and PAD (HR 0.81; 95% CI 0.68-0.96). The risk of acute kidney injury, rhabdomyolysis, or hospitalization for these events showed no significant difference between the two groups. Subgroup analyses revealed consistent benefits across age groups, genders, and baseline lipid profiles. CONCLUSIONS: This nationwide population-based retrospective observational study suggests that fenofibrate can prevent LEA and PAD in patients with T2D who are on statin therapy.

A New Paradigm on Waste-to-Energy Applying Hydrovoltaic Energy Harvesting Technology to Face Masks.

The widespread use of single-use face masks during the recent epidemic has led to significant environmental challenges due to waste pollution. This study explores an innovative approach to address this issue by repurposing discarded face masks for hydrovoltaic energy harvesting. By coating the face masks with carbon black (CB) to enhance their hydrophilic properties, we developed mask-based hydrovoltaic power generators (MHPGs). These MHPGs were evaluated for their hydrovoltaic performance, revealing that different mask configurations and sizes affect their efficiency. The study found that MHPGs with smaller, more structured areas exhibited better energy output, with maximum open-circuit voltages (VOC) reaching up to 0.39 V and short-circuit currents (ISC) up to 65.6 µA. The integration of CB improved water absorption and transport, enhancing the hydrovoltaic performance. More specifically, MHPG-1 to MHPG-4, which represented different sizes and features, presented mean VOC values of 0.32, 0.17, 0.19 and 0.05 V, as well as mean ISC values of 16.57, 15.59, 47.43 and 3.02 µA, respectively. The findings highlight the feasibility of utilizing discarded masks in energy harvesting systems, offering both environmental benefits and a novel method for renewable energy generation. Therefore, this work provides a new paradigm for waste-to-energy (WTE) technologies and inspires further research into the use of unconventional waste materials for energy production.

Microwave-assisted solvothermal synthesis of nanostructured Ga-Doped Li7La3Zr2O12 solid electrolyte with enhanced densification and Li-ion conductivity.

Garnet-type Li7La3Zr2O12 (LLZO) Li-ion solid electrolytes are promising candidates for safe, next-generation solid-state batteries. In this study, we synthesize Ga-doped LLZO (Ga-LLZO) electrolytes using a microwave-assisted solvothermal method followed by low-temperature heat treatment. The nanostructured precursor (<50 nm) produced by the microwave-assisted solvothermal process has a high surface energy, facilitating the reaction for preparing garnet-type Ga-LLZO powders (<800 nm) within a short time (<5 h) at a low calcination temperature (<700 °C). Additionally, the calcined nanostructured Ga-LLZO powder can be sintered to produce a high-density pellet with minimized grain boundaries under moderate sintering conditions (temperature: 1150 °C, duration: 10 h). The optimal doping concentration was determined to be 0.4 mol% Ga, which resulted significantly increased the ionic conductivity (1.04 × 10-3 S cm-1 at 25 °C) and stabilized the cycling performance over 1700 h at 0.4 mA cm-2. This approach demonstrates the potential to synthesize oxide-type solid electrolyte materials with improved properties for solid-state batteries.

Pharmacokinetics and Pharmacodynamics of a Fixed-Dose Combination of Esomeprazole and Magnesium Hydroxide Compared to the Enteric-Coated Esomeprazole.

PURPOSE: A fixed-dose combination (FDC) of proton pump inhibitors (PPIs) and antacid salts enables rapid acid suppression through the neutralizing effect of the antacid salt and the rapid absorption of PPIs. This study aimed to compare the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a recently formulated FDC of esomeprazole and magnesium hydroxide to the enteric-coated esomeprazole in healthy subjects. METHODS: A randomized, open-label, multiple-dose, two-treatment, two-way crossover design was conducted in healthy subjects. Forty-nine subjects were randomized to one of the two treatment sequences and received either the test drug (esomeprazole/magnesium hydroxide 40/350 mg) or reference drug (enteric-coated esomeprazole 40 mg) for 7 days in the first period and the alternative in the second period with a 14-day washout period. Blood samples were collected for up to 24 hours for PK assessment, and 24-hour gastric pH monitoring was conducted for PD assessment both before and after a single administration, as well as at a steady state after seven consecutive days of administration. The PK and PD parameters were compared between the two drugs. FINDINGS: After multiple administrations, the median value of time to reach maximum concentration was faster in the test drug than in the reference drug, with a difference of 1.68 hours. The overall systemic exposure of the test drug was similar to that of the reference drug, and the PK parameter fell within the equivalence criteria. The test drug demonstrated a shorter time to reach gastric pH ≥ 4 compared to the reference drug (P = 0.0463). A decrease from baseline in integrated gastric acidity over 24 hours, which represents the degree of inhibition of gastric acid secretion, was equivalent between the two drugs. IMPLICATIONS: The fixed-dose combination of esomeprazole and magnesium hydroxide showed rapid absorption and quicker gastric acid suppression than enteric-coated esomeprazole with comparable PK and PD properties. CLINICALTRIALS: gov identifier: NCT04324905 (https://classic. CLINICALTRIALS: gov/ct2/show/NCT04324905).

Machine-Learning-Based Prediction of Photobiomodulation Effects on Older Adults with Cognitive Decline Using Functional Near-Infrared Spectroscopy.

Transcranial photobiomodulation (tPBM) has been widely studied for its potential to enhance cognitive functions of the elderly. However, its efficacy varies, with some individuals exhibiting no significant response to the treatment. Considering these inconsistencies, we introduce a machine learning approach aimed at distinguishing between individuals that respond and do not respond to tPBM treatment based on functional near-infrared spectroscopy (fNIRS) acquired before the treatment. We measured nine cognitive scores and recorded fNIRS data from 62 older adults with cognitive decline (43 experimental and 19 control subjects). The experimental group underwent tPBM intervention over a span of 12 weeks. Based on the comparison of the global cognitive score (GCS), merging the nine cognitive scores into a single representation, acquired before and after tPBM treatment, we classified all participants as responders or non-responders to tPBM with a threshold for the GCS change. The fNIRS data were recorded during the resting state, recognition memory task (RMT), Stroop task, and verbal fluency task. A regularized support vector machine was utilized to classify the responders and non-responders to tPBM. The most promising performance of our machine learning model was observed when using the fNIRS data collected during the RMT, which yielded an accuracy of 0.8537, an F1-score of 0.8421, sensitivity of 0.7619, and specificity of 0.95. To the best of our knowledge, this is the first study to demonstrate the feasibility of predicting the tPBM efficacy. Our approach is expected to contribute to more efficient treatment planning by excluding ineffective treatment options.

All-cause and cause-specific mortality risks in individuals with diabetes living alone: A large-scale population-based cohort study.

AIMS: The rise in one-person households is a global trend. We aimed to investigate mortality risk in individuals with diabetes living alone (IDLA) using a large-scale population-based database. METHODS: A total of 2,447,557 adults with type 2 diabetes were identified from the Korean National Health Information Database. One-person households were defined based on the number of registered family members. The risks of all-cause and cause-specific mortalities were estimated using a multivariable Cox proportional hazards regression model. RESULTS: During a median follow-up period of 6.0 years, 191,084 deaths (7.8 %) occurred. IDLA had a higher risk of mortality compared to those not living alone after adjusting for potential confounders (HR 1.20, 95 % CI: 1.18-1.22). This association was more prominent in younger individuals, men, and those with low income, and it was dependent on the duration of living alone. The risks of cause-specific mortality were all significantly higher in the IDLA group compared with the non-IDLA group. Adherence to favorable lifestyle behaviors was associated with a significant reduction in all-cause mortality, particularly in IDLA. CONCLUSIONS: The elevated risk of mortality in IDLA highlights the need for tailored medical interventions and social assistance, particularly for those with unhealthy lifestyles or low income.

Using Large Language Models to Detect Depression From User-Generated Diary Text Data as a Novel Approach in Digital Mental Health Screening: Instrument Validation Study.

BACKGROUND: Depressive disorders have substantial global implications, leading to various social consequences, including decreased occupational productivity and a high disability burden. Early detection and intervention for clinically significant depression have gained attention; however, the existing depression screening tools, such as the Center for Epidemiologic Studies Depression Scale, have limitations in objectivity and accuracy. Therefore, researchers are identifying objective indicators of depression, including image analysis, blood biomarkers, and ecological momentary assessments (EMAs). Among EMAs, user-generated text data, particularly from diary writing, have emerged as a clinically significant and analyzable source for detecting or diagnosing depression, leveraging advancements in large language models such as ChatGPT. OBJECTIVE: We aimed to detect depression based on user-generated diary text through an emotional diary writing app using a large language model (LLM). We aimed to validate the value of the semistructured diary text data as an EMA data source. METHODS: Participants were assessed for depression using the Patient Health Questionnaire and suicide risk was evaluated using the Beck Scale for Suicide Ideation before starting and after completing the 2-week diary writing period. The text data from the daily diaries were also used in the analysis. The performance of leading LLMs, such as ChatGPT with GPT-3.5 and GPT-4, was assessed with and without GPT-3.5 fine-tuning on the training data set. The model performance comparison involved the use of chain-of-thought and zero-shot prompting to analyze the text structure and content. RESULTS: We used 428 diaries from 91 participants; GPT-3.5 fine-tuning demonstrated superior performance in depression detection, achieving an accuracy of 0.902 and a specificity of 0.955. However, the balanced accuracy was the highest (0.844) for GPT-3.5 without fine-tuning and prompt techniques; it displayed a recall of 0.929. CONCLUSIONS: Both GPT-3.5 and GPT-4.0 demonstrated relatively reasonable performance in recognizing the risk of depression based on diaries. Our findings highlight the potential clinical usefulness of user-generated text data for detecting depression. In addition to measurable indicators, such as step count and physical activity, future research should increasingly emphasize qualitative digital expression.

Leveraging Input-Level Feature Deformation with Guided-Attention for Sulcal Labeling.

The identification of cortical sulci is key for understanding functional and structural development of the cortex. While large, consistent sulci (or primary/secondary sulci) receive significant attention in most studies, the exploration of smaller and more variable sulci (or putative tertiary sulci) remains relatively under-investigated. Despite its importance, automatic labeling of cortical sulci is challenging due to (1) the presence of substantial anatomical variability, (2) the relatively small size of the regions of interest (ROIs) compared to unlabeled regions, and (3) the scarcity of annotated labels. In this paper, we propose a novel end-to-end learning framework using a spherical convolutional neural network (CNN). Specifically, the proposed method learns to effectively warp geometric features in a direction that facilitates the labeling of sulci while mitigating the impact of anatomical variability. Moreover, we introduce a guided-attention mechanism that takes into account the extent of deformation induced by the learned warping. This extracts discriminative features that emphasize sulcal ROIs, while suppressing irrelevant information of unlabeled regions. In the experiments, we evaluate the proposed method on 8 sulci of the posterior medial cortex. Our method outperforms existing methods particularly in the putative tertiary sulci. The code is publicly available at https://github.com/Shape-Lab/DSPHARM-Net.

Dicarboxylate cellulose nanofibrils-supported silver nanoparticles as a novel, green, efficient and recyclable catalyst for 4-nitrophenol and dyes reduction.

This study reports dicarboxylate cellulose nanofibrils (DCNF) as a novel reducing and supporting agent for producing silver nanoparticles (AgNPs) with high efficiency (63.82 % reduction) and loading (6.88 %) using UV light. Unlike previous research, AgNPs formation with DCNF doesn't involve cellulose oxidation. Instead, it appears to involve a loss of carboxyl groups from DCNF. In comparative studies, pristine CNF (PCNF) and TEMPO-oxidized CNF (TOCNF) were also examined for AgNPs production. The resulting AgNPs from DCNF exhibited a significantly smaller average size (3.9 ± 0.7 nm) compared to those from PCNF (26.9 ± 10.9 nm) and TOCNF (13.5 ± 4.5 nm). Catalytic activity evaluation by the 4-nitrophenol (4-NP) reduction reaction revealed a high rate constant of 8.47× 10-3 s-1 by AgNPs/DCNF, which surpassed AgNPs/TOCNF (1.79 × 10-3 s-1) and AgNPs/PCNF (0.63 × 10-3 s-1) by 4.7 and 13.4 times, respectively. Besides 4-NP, AgNPs/DCNF aerogels were also applied for methyl orange and Rhodamine B dyes reduction. The aerogels showed excellent reusability, maintaining over 95 % conversion even after five cycles and also effective in treating real samples and mixed dye solutions. This study opens the door for future research exploring DCNF as a support material for various metal, metal oxide, and carbon nanoparticles.

Population pharmacokinetic analysis of zastaprazan (JP-1366), a novel potassium-competitive acid blocker, in patients and healthy volunteers.

Zastaprazan (JP-1366) is a novel potassium-competitive acid blocker for the treatment of acid-related disorders. We aimed to establish a population pharmacokinetic (PK) model of zastaprazan, thereby characterizing the PK of zastaprazan in patients with gastroesophageal reflux disease (GERD) as well as evaluating the impact of various covariates, including CYP2C19 phenotypes, on zastaprazan PK. This population PK analysis included zastaprazan plasma concentration-time data from 92 patients with erosive GERD and 68 healthy volunteers without any gastrointestinal disorders and was performed using nonlinear mixed-effect modeling. Simulations were conducted to predict zastaprazan PK under various dosing regimens in patients with GERD. The plasma PK of zastaprazan was adequately described by a two-compartment model with Erlang-type absorption (six sequential compartments) and first-order elimination. CYP2C19 phenotypes had no significant effect on zastaprazan PK. The disease status was identified as a significant covariate on apparent clearance of zastaprazan, showing lower values in patients with GERD compared to healthy volunteers. However, the model-based simulation indicated that the impact of disease status on zastaprazan exposure was not clinically meaningful. Overall, the current population PK model successfully characterized the observed zastaprazan PK in both patients with GERD and healthy volunteers.

Different Associations between Lipid Levels and Risk for Heart Failure according to Diabetes Progression.

Background: The relationship between circulating lipid levels and the risk for heart failure (HF) is controversial. We aimed to examine this association, and whether it is modified by the duration of diabetes or treatment regimens in people with type 2 diabetes mellitus. Methods: Individuals (n=2,439,978) who underwent health examinations in 2015 to 2016 were identified from the Korean National Health Information Database. Subjects were categorized according to the duration of diabetes (new-onset, <5, 5-10, or ≥10 years) and number of antidiabetic medications. Incident HF was defined according to the International Classification of Diseases, 10th Revision (ICD-10) code I50 as the primary diagnosis during hospitalization. The risk for HF was estimated using multivariate Cox proportional hazard analysis. Results: During a median follow-up of 4.0 years, 151,624 cases of HF occurred. An inverse association between low-density lipoprotein cholesterol (LDL-C) levels and incident HF was observed in the new-onset diabetes group, with an approximately 25% lower risk in those with LDL-C levels of 100-129, 130-159, and ≥160 mg/dL, compared to those with levels <70 mg/dL. However, J-shaped associations were noted in the long-standing diabetes group, with a 16% higher risk in those with LDL-C level ≥160 mg/dL, compared to those with levels <70 mg/dL. Similar patterns were observed in the relationship between total cholesterol or non-high-density lipoprotein cholesterol and the risk for HF, and when subjects were grouped according to the number of antidiabetic medications instead of diabetes duration. Conclusion: Different associations between lipid levels and the risk for HF were noted according to disease progression status among individuals with diabetes.

Hydrophobic, ultraviolet radiation-shielding, and antioxidant functionalities of TEMPO-oxidized cellulose nanofibril film coated with modified lignin nanoparticles.

In this study, lignin nanoparticles (LN) and octadecylamine-modified LN (LN-ODA) were utilized as coating materials to enhance the hydrophobic, antioxidant, and ultraviolet radiation-shielding (UV-shielding) properties of a TEMPO-oxidized nanocellulose film (TOCNF). The water contact angle (WCA) of the TOCNF was approximately 53° and remained stable for 1 min, while the modified LN-ODA-coated TOCNF reached over 130° and maintained approximately 85° for an hour. Pure TOCNF exhibited low antioxidant properties (4.7 %), which were significantly enhanced in TOCNF-LN (81.6 %) and modified LN-ODA (10.3 % to 27.5 %). Modified LN-ODA-coated TOCNF exhibited antioxidant properties two to six times higher than those of pure TOCNF. Modified LN-ODA exhibited thermal degradation max (Tmax) at 421 °C, while pure LN showed the main degradation temperature at approximately Tmax 330 °C. The thermal stability of TOCNF-LN-ODA-coated materials remained consistent with that of pure TOCNF, while the crystallinity index of the sample showed a slight decrease due to the amorphous nature of the lignin structure. The tensile strength of TOCNF was approximately 114.1 MPa and decreased to 80.1, 51.3, and 30.3 MPa for LN-ODA coating at 5, 10, and 15 g/m2, respectively.

A randomized study to evaluate the safety and immunogenicity of a pentavalent meningococcal vaccine.

A randomized, active-controlled, double-blind, first-in-human, phase 1 study was conducted in healthy Korean adults to evaluate the safety, tolerability, and immunogenicity of EuNmCV-5, a new pentavalent meningococcal vaccine targeting serogroups A, C, W, X, and Y. Sixty participants randomly received a single dose of either EuNmCV-5 or MenACWY-CRM, a quadrivalent vaccine containing serogroups A, C, W, and Y. Safety was assessed through monitoring anaphylactic reactions, adverse events for 28 days, and serious adverse events over 180 days. Immunogenicity was assessed via rabbit complement-dependent serum bactericidal antibody (rSBA) assay. EuNmCV-5 was safe, well-tolerated, and elicited a substantial antibody titer increase. The seroprotection rates exceeded 96.7%, and the seroconversion rates were over 85% for all the targeted serogroups. It showed higher seroconversion rates against serogroups A and C (p = 0.0016 and 0.0237, respectively) and elicited a substantial increase in GMT for all targeted serogroups compared to the MenACWY-CRM.ClinicalTrials.gov identifier: NCT05739292.

Highly Conductive and Stretchable Hydrogel Nanocomposite Using Whiskered Gold Nanosheets for Soft Bioelectronics.

The low electrical conductivity of conductive hydrogels limits their applications as soft conductors in bioelectronics. This low conductivity originates from the high water content of hydrogels, which impedes facile carrier transport between conductive fillers. This study presents a highly conductive and stretchable hydrogel nanocomposite comprising whiskered gold nanosheets. A dry network of whiskered gold nanosheets is fabricated and then incorporated into the wet hydrogel matrices. The whiskered gold nanosheets preserve their tight interconnection in hydrogels despite the high water content, providing a high-quality percolation network even under stretched states. Regardless of the type of hydrogel matrix, the gold-hydrogel nanocomposites exhibit a conductivity of ≈520 S cm-1 and a stretchability of ≈300% without requiring a dehydration process. The conductivity reaches a maximum of ≈3304 S cm-1 when the density of the dry gold network is controlled. A gold-adhesive hydrogel nanocomposite, which can achieve conformal adhesion to moving organ surfaces, is fabricated for bioelectronics demonstrations. The adhesive hydrogel electrode outperforms elastomer-based electrodes in in vivo epicardial electrogram recording, epicardial pacing, and sciatic nerve stimulation.

Efficacy and Safety of Lurasidone vs. Quetiapine XR in Acutely Psychotic Patients With Schizophrenia in Korea: A Randomized, Double-Blind, Active-Controlled Trial.

OBJECTIVE: This study was performed to evaluate the efficacy and safety of lurasidone (160 mg/day) compared to quetiapine XR (QXR; 600 mg/day) in the treatment of acutely psychotic patients with schizophrenia. METHODS: Patients were randomly assigned to 6 weeks of double-blind treatment with lurasidone 160 mg/day (n=105) or QXR 600 mg/day (n=105). Primary efficacy measure was the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions severity (CGI-S) score. Adverse events, body measurements, and laboratory parameters were assessed. RESULTS: Lurasidone demonstrated non-inferiority to QXR on the PANSS total score. Adjusted mean±standard error change at week 6 on the PANSS total score was -26.42±2.02 and -27.33±2.01 in the lurasidone and QXR group, respectively. The mean difference score was -0.91 (95% confidence interval -6.35-4.53). The lurasidone group showed a greater reduction in PANSS total and negative subscale on week 1 and a greater reduction in end-point CGI-S score compared to the QXR group. Body weight, body mass index, and waist circumference in the lurasidone group were reduced, with significantly lower mean change compared to QXR. Endpoint changes in glucose, cholesterol, triglycerides, and low-density lipoprotein levels were also significantly lower. The most common adverse drug reactions with lurasidone were akathisia and nausea. CONCLUSION: Lurasidone 160 mg/day was found to be non-inferior to QXR 600 mg/day in the treatment of schizophrenia with comparable efficacy and tolerability. Adverse effects of lurasidone were generally tolerable, and beneficial effects on metabolic parameters can be expected.

Exercise improves load bearing bone structural properties in female secreted protein acidic and rich in cysteine (SPARC) null mice but not in males.

Secreted protein acidic and rich in cysteine (SPARC) is the most abundant glycoprotein in bone and is thought to play a critical role in bone remodeling and homeostasis. However, the effect of SPARC in relation to gender and exercise on bone quality is not well understood. The purpose of this study was to quantify differences in the structural and biomechanical properties between calvarial and femoral bone from male and female wild-type (WT) and SPARC null (SPARC(-/-)) mice as well as the ability of exercise to rescue bone health. Male and female WT and transgenic SPARC(-/-) mice were given either a fixed or rotating running wheel for exercise. Bone structural, biomechanical, and morphological parameters were quantified using micro computed tomography, push out testing for the calvaria, three-point flexural testing for the femurs, histological and immunofluorescent staining. Similar reductions in structural and biomechanical strength were observed in both male and female SPARC(-/-) calvaria, most of which were not significantly affected by exercise. In femurs, SPARC(-/-) had a significant effect on structural parameters in both sexes, but was more pronounced in females with some properties being rescued with running. Interestingly, the effect of SPARC(-/-) on bone mineral density was only detected in female SPARC(-/-) mice, not males, and was subsequently rescued with exercise. This study emphasizes the differences between sexes in WT and SPARC(-/-) mice in regard to structural parameters and biomechanical properties. Research into gender differences can help inform and personalize treatment options to more accurately meet patient needs.

Evaluation of resazurin phenoxazine dye as a highly sensitive cell viability potency assay for natural killer cell-derived extracellular vesicle-based cancer biotherapeutics.

Natural killer cell-derived extracellular vesicles (NK-EVs) are candidate biotherapeutics against various cancers. However, standardised potency assays are necessary for a reliable assessment of NK-EVs' cytotoxicity. This study aims to thoroughly evaluate a highly sensitive resazurin phenoxazine-based cell viability potency assay (measurement of the cellular redox metabolism) for quantifying the cytotoxicity of NK-EVs against leukaemia K562 cells (suspension model) and breast cancer MDA-MB-231 cells (adherent model) in vitro. The assay was evaluated based on common analytical parameters setforth by regulatory guidelines, including specificity, selectivity,accuracy, precision, linearity, range and stability. Our results revealed that this resazurin-based cell viability potency assay reliably and reproducibly measured a dose-response of NK-EVs' cytotoxic activity against both cancer models. The assay showed precision with 5% and 20% variation for intra-run and inter-run variability. The assay signal showed specificity and selectivity of NK-EVs against cancer target cells, as evidenced by the diminished viability of cancer cells following a 5-hour treatment with NK-EVs, without any detectable interference or background. The linearity analysis of target cancer cells revealed strong linearity for densities of 5000 K562 and 1000 MDA-MB-231 cells per test with a consistent range. Importantly, NK-EVs' dose-response for cytotoxicity showed a strong correlation (|ρ| ∼ 0.8) with the levels of known cytotoxic factors associated with the NK-EVs' corona (FasL, GNLY, GzmB, PFN and IFN-γ), thereby validating the accuracy of the assay. The assay also distinguished cytotoxicity changes in degraded NK-EVs, indicating the ability of the assay to detect the potential loss of sample integrity. Compared to other commonly reported bioassays (i.e., flow cytometry, cell counting, lactate dehydrogenase release assay, DNA-binding reporter assay and confluence assay), our results support this highly sensitive resazurin-based viability potency assay as a high-throughput and quantitative method for assessing NK-EVs' cytotoxicity against both suspension and adherent cancer models for evaluating NK-EVs' biotherapeutics.

Pharmacokinetic drug-drug interactions of JBPOS0101 mediated by cytochrome P450 3A4 and UDP-glucuronosyltransferases.

JBPOS0101 is a new antiepileptic drug and is a substrate of UDP-glucuronosyltransferases (UGTs) in in vitro test. In vitro experiments showed different results regarding whether JBPOS0101 induces (EC50 136 µM) or inhibits (IC50 95.4-386.5 µM) cytochrome P450 (CYP) 3A4. As co-medication of JBPOS0101 and carbamazepine (CBZ) is expected in clinical settings, drug-drug interactions (DDIs) between them should be determined. This study aimed to investigate pharmacokinetic (PK) interactions of JBPOS0101 influenced by CYP3A4 and UGTs using midazolam (MDZ) and CBZ. A two-cohort, open-label, fixed-sequence study was conducted in healthy Koreans. In cohort A, subjects received MDZ IV alone, and then JBPOS0101 were co-administered with MDZ after oral doses of JBPOS0101 for 7 days. In cohort B, multiple doses of JBPOS0101 and CBZ were administered respectively, and subjects received both together for 7 days. Serial blood samples were collected for PK analysis. When MDZ and JBPOS0101 were co-administered, the systemic exposure of MDZ decreased by 30%. Meanwhile, JBPOS0101 did not significantly changed the PK of CBZ. CBZ decreased the systemic exposure of JBPOS0101 at steady state by 40%, respectively. With IV administration of MDZ, JBPOS0101 acted as a weak inducer of hepatic CYP3A4 and decreased systemic exposure of MDZ. The ability of JBPOS0101 to similarly modulate gut CYP3A4 activity will require further evaluation. Co-administration of multiple doses of JBPOS0101 and CBZ did not significantly alter CBZ pharmacokinetics, but the clinical impact of decreased systemic exposure of JBPOS0101 by CBZ should be further considered.

Transcranial Electrical Stimulation: Clinical Implication and Practice for Treatment of Psychiatric Illness.

Brain electrical stimulation, particularly non-invasive brain stimulation (NIBS) techniques such as transcranial electrical stimulation (tES), have emerged as a promising treatment for various psychiatric disorders, including depression, anxiety, and post-traumatic stress disorder. tES techniques, such as transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS), are cost-effective and safe interventions that are designed to affect neuronal circuits in the brain using various modalities. Although tES has shown effectiveness in the treatment of psychiatric disorders, there is a lack of comprehensive papers that consider its clinical implications. Therefore, this review aims to evaluate the clinical implications of tES and provide practical guidance for the treatment of psychiatric illnesses. Moreover, this review provides an overview of tES techniques and their mechanisms of action and summarizes recent clinical studies that have examined the use of tES for psychiatric disorders.