Therapeutic Drug Monitoring of 6 New-Generation Antiseizure Medications Using a Mass Spectrometry Method: Analysis of 2-Year Experience in a Large Cohort of Korean Epilepsy Patients.

CONTEXT.­: New-generation antiseizure medications (ASMs) are increasingly prescribed, and therapeutic drug monitoring (TDM) has been proposed to improve clinical outcome. However, clinical TDM data on new-generation ASMs are scarce. OBJECTIVE.­: To develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for therapeutic drug monitoring (TDM) of 6 new-generation ASMs in serum and analyze the clinical TDM data from a large cohort of Korean patients with epilepsy. DESIGN.­: Stable isotope-labeled internal standards were added to protein precipitations of serum. One microliter of sample was separated on Agilent Poroshell EC-C18 column, and lacosamide, perampanel, gabapentin, pregabalin, vigabatrin, and rufinamide were simultaneously quantified by Agilent 6460 triple-quad mass spectrometer in multiple-reaction monitoring mode. Linearity, sensitivity, precision, accuracy, specificity, carryover, extraction recovery, and matrix effect were evaluated. TDM data of 458 samples from 363 Korean epilepsy patients were analyzed. RESULTS.­: The method was linear with limit of detection less than 0.05 µg/mL in all analytes. Intraassay and interassay imprecisions were less than 5% coefficient of variation. Accuracy was within ±15% bias. Extraction recovery ranged from 85.9% to 98.8%. A total of 88% (403 of 458) were on polypharmacy, with 29% (118 of 403) using concomitant enzyme inducers. Only 38% (175 of 458) of the concentrations were therapeutic, with 53% (244 of 458) being subtherapeutic. Drug concentration and concentration-to-dose ratio were highly variable among individuals in all 6 ASMs. CONCLUSIONS.­: A simple and rapid LC-MS/MS method for TDM of 6 ASMs was developed and successfully applied to clinical practice. This large-scale TDM data could help establish an effective monitoring strategy for these drugs.

Deposition of secondary organic aerosol in human lung model: Effect of photochemically aged aerosol on human respiratory system.

Ultrafine particles (UFP) of Secondary Organic Aerosol (SOA) penetrate deep into the human respiratory system and exert fatal effects on human health. However, there is little data on the potential deposited doses of UFP-generated SOA in the human respiratory tract. This study is to estimate the fraction of aerosol deposition using a multiple-path-particle-dosimetry (MPPD) model. For relevancy of real life, the model employed measured concentrations of toluene-derived fresh and aged SOA produced within serially connected smog chamber and PAM-OFR (Potential Aerosol Mass-Oxidation Flow Reactor) under atmospheric environmental conditions (NOx and relative humidity). The number concentrations and chemical composition of fresh and aged aerosols produced within the chambers were measured using Scanning Mobility Particle Sizer (SMPS) and High-Resolution Time-of-Flight Aerosol Mass Spectrometer (HR-ToF-AMS), while the morphology of individual particles was analyzed using Scanning Electron Microscopy (SEM). The number concentration of aged SOA-w/s was more than double compared to that of fresh SOA-w/s (maximum reached after 10 h) with its size less than 100 nm. The O:C ratio for aged SOA-w/s were 0.96 and 1.15 depending on RH (0.96 at 3% RH and 1.15 at 50% RH), and individual spherical particles containing water were present in agglomerates with its size of less than 1 µm. In all inhalable fresh and aged SOA produced in the two chambers, 5-22% of aerosol is deposited in the Head airways, 4-8% in the tracheobronchial, and 8-34% in the alveolar regions. The predominant deposition of the aged aerosol occurred in the alveoli (in the generation 20th lobe), and the deposition faction in the alveoli was 2-3 times higher in the children group than the adults group. This study presented a quantitative exposure assessment of SOA generated under a realistic simulation and suggested the possibility of evaluating long-term exposure to SOA and potential health effects by determining the potential inhalable aerosol doses and the fraction of deposition in the human respiratory system.

Characterization of Silver Nanowire-Based Transparent Electrodes Obtained Using Different Drying Methods.

Metal-based transparent top electrodes allow electronic devices to achieve transparency, thereby expanding their application range. Silver nanowire (AgNW)-based transparent electrodes can function as transparent top electrodes, owing to their excellent conductivity and transmittance. However, they require a high-temperature drying process, which damages the bottom functional layers. Here, we fabricated two types of AgNW-based electrodes using the following three drying methods: thermal, room-temperature, and vacuum. Thereafter, we investigated the variation in their morphological, electrical, and optical characteristics as a function of the drying method and duration. When the AgNW-exposed electrode was dried at room temperature, it exhibited a high surface roughness and low conductivity, owing to the slow solvent evaporation. However, under vacuum, it exhibited a similar electrical conductivity to that achieved by thermal drying because of the decreased solvent boiling point and fast solvent evaporation. Conversely, the AgNW-embedded electrodes exhibited similar roughness values and electrical conductivities regardless of the drying method applied. This was because the polymer shrinkage during the AgNW embedding process generated capillary force and improved the interconnectivity between the nanowires. The AgNW-based electrodes exhibited similar optical properties regardless of the drying method and electrode type. This study reveals that vacuum drying can afford transparent top electrodes without damaging functional layers.

Exposure to long-range transported particulate matter and modeling age-related particle deposition.

Exposure to particulate matter (PM) is known to cause cardiovascular disease and increase mortality and morbidity. Asian dust (AD) is a meteorological phenomenon which affects much of East Asia year-round but especially during the spring months. Here, we have characterized concentrations of PM10 and classified synoptic air flow trajectories using HYSPLIT model for Asian dust events (from March to April) in Jeju island, Korea. The ADE is a phenomenon in which sand and dust in the deserts of China or Mongolia rise mainly in spring and are blown away by western winds and gradually subside. The calculated inhaled PM10 doses from specific microenvironments (home, work or school, and transportation) were from 5.28 to 101.48 µg depending on age group and different microenvironments while the calculated PM10 inhaled doses for ADE ranged within 67.92 -769.27 µg. Also, we have evaluated the contribution of specific microenvironments to the exposure for different age groups using time-activity patterns and calculated inhaled PM10 doses and deposited mass/mass flux so as to estimate exposure using multiple-path particle dosimetry (MPPD) model. The monthly average outdoor PM10 concentration range was 29.3-65.4 µg/m3, whereas the monthly PM10 concentration for ADE was 127.0-342.0 µg/m3. Air masses from clusters 1 and 2 were 24% and 29% (in 2017), clusters 2 and 3 were 24% and 32% (in 2018), and clusters 1 and 3 were 28% and 26% (in 2019) for ADE. In the aerosol deposition based on MPPD model, the corresponding values for daily particle deposited mass for two age groups ranged from 8.64 ×10-5 µg (age 8) to 8.64 ×10-4 µg (age 21). We assessed the PM2.5 exposure considering time-activity patterns, age groups, and ADE exposure evaluation caused by long-range transport airflow; this could be helpful for assessing PM10 exposure-related health evaluation.

Application of an LC-MS/MS Method for the Simultaneous Quantification of Homovanillic Acid and Vanillylmandelic Acid for the Diagnosis and Follow-Up of Neuroblastoma in 357 Patients.

Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are end-stage metabolites of catecholamine and are clinical biomarkers for the diagnosis of neuroblastoma. For the first time in Korea, we implemented and validated a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay to measure urinary concentrations of HVA and VMA according to Clinical and Laboratory Standards Institute guidelines. Our LC-MS/MS assay with minimal sample preparation was validated for linearity, lower limit of detection (LOD), lower limit of quantification (LLOQ), precision, accuracy, extraction recovery, carryover, matrix effect, and method comparison. A total of 1209 measurements was performed to measure HVA and VMA in spot urine between October 2019 and September 2020. The relationship between the two urinary markers, HVA and VMA, was analyzed and exhibited high agreement (89.1% agreement, kappa's k = 0.6) and a strong correlation (Pearson's r = 0.73). To our knowledge, this is the first study to utilize LC-MS/MS for simultaneous quantitation of spot urinary HVA and VMA and analyze the clinical application of both markers on a large scale for neuroblastoma patients.

Personality Traits in Individuals with the Dual Diagnosis of Psychosis and Substance Use Disorders: A Comprehensive Review and Meta-Analysis.

OBJECTIVE: Substance abuse comorbidity is highly prevalent and is linked to detrimental outcomes in individuals with psychotic disorder, but the role of personality traits as the underlying mechanism is being increasingly underscored. This study aimed to profile temperamental risks of comorbid substance use disorder in psychotic disorders by performing meta-analyses on personality trait differences between psychotic disorders with comorbidity (dual diagnosis; DD) and without it (psychotic disorders; PSD). Methods: A systematic review of English articles using PubMed, MEDLINE, Scopus, Google Scholar, and ProQuest Dissertation and Theses. Only original empirical studies including participants with diagnosis of psychotic disorders based on structured diagnostic interviews, with and without substance use disorder evaluated with reliable and valid tests were included. Articles were independently extracted by two authors using predefined data fields, including study quality indicators. All pooled analyses were based on random-effect models. Thirteen studies (N = 885) met our inclusion criteria. All effect-size estimates were calculated based on means and standard deviations of included measures. Separate effect size estimates were obtained for four traits in the UPPS model (negative urgency, low premeditation, low perseverance, sensation seeking), four traits in the HS model (unconscientious disinhibition, negative affect, disagreeable disinhibition, positive affect) and trait anhedonia. Results: Negative urgency (four studies with 262 participants; ES = 0.59; 95% confidence interval [CI] [0.34, 0.84]), low premeditation (five studies with 349 participants; ES = 0.60; 95% CI [0.39, 0.80]), sensation seeking (seven studies with 550 participants; ES = 0.63; 95% CI [0.17, 1.09]) and unconscientious disinhibition (five studies with 291 participants; ES = 0.36; 95% CI [0.13, 0.59]) were elevated in DD than PSD. Heterogeneity of sensation seeking was significant (I2 = 86.2%). Conclusions: The findings of the current meta-analysis highlight a unique profile of impulsive and externalizing trait personality domains pertaining to DD. The study emphasizes the importance of emotion regulation interventions targeting impulsivity or negative affect (i.e. negative urgency, low premeditation) in substance abuse comorbidity patients.

A Sensitive and Specific Liquid Chromatography-Tandem Mass Spectrometry Assay for Simultaneous Quantification of Salivary Melatonin and Cortisol: Development and Comparison With Immunoassays.

Melatonin and cortisol are clinically important for diagnosing sleep and mood disorders. We developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for simultaneous measurement of salivary melatonin and cortisol concentrations according to the Clinical and Laboratory Standards Institute guidelines. Additionally, we compared the LC-MS/MS assay with immunoassays, ELISA (Direct Salivary Melatonin Elisa EK-DSM, Bühlmann Laboratories AG, Schönenbuch, Switzerland) and electrochemiluminescence immunoassay (Cortisol II, Roche, Mannheim, Germany), using 121 saliva samples. The LC-MS/MS assay exhibited good performance in terms of linearity, precision, accuracy, limit of detection, lower limit of quantification, extraction recovery, carry-over, and matrix effect. The LC-MS/MS assay and immunoassays showed strong correlation (Pearson's r=0.910 for melatonin, r=0.955 for cortisol), but demonstrated a significant mean bias of 23.2% (range 54.0-143.7%) for melatonin and 48.9% (range 59.7-184.7%) for cortisol. Our LC-MS/MS assay provided more sensitive and reliable salivary melatonin and cortisol quantification results compared with immunoassays.

Characterization of optical manipulation using microlens arrays depending on the materials and sizes in organic photovoltaics.

Various physical structures have improved light-harvesting and power-conversion efficiency in organic photovoltaic devices, and optical simulations have supported the improvement of device characteristics. Herein, we experimentally investigated how microlens arrays manipulate light propagation in microlens films and material stacks for organic photovoltaics to understand the influence of the constituent materials and sizes of the microlens. As materials to fabricate a microlens array, poly(dimethylsiloxane) and Norland Optical Adhesive 63 were adopted. The poly(dimethylsiloxane) microlens array exhibited higher total transmittance and higher diffuse transmittance, further enhancing the effective optical path and light extinction in material stacks for organic photovoltaics. This resulted in more current generation in an organic photovoltaic device with a poly(dimethylsiloxane) microlens array than in a Norland Optical Adhesive 63 microlens array. The sizes of the microlenses were controlled from 0.5 to 10 µm. The optical characteristics of microlens array films and material stacks with microlenses generally increased with size of the microlens, leading to a 10.6% and 16.0% improvement in the light extinction and power-conversion efficiency, respectively. In addition, electron and current generation in material stacks for organic photovoltaics were calculated from light extinction. The theoretical current generation matched well with experimental values derived from organic photovoltaic devices. Thus, the optical characterization of physical structures helps to predict how much more current can be generated in organic photovoltaic cells with a certain physical structure; it can also be used for screening the physical structures of organic photovoltaic cells.

Potential consumer exposure to respirable particles and TiO2 due to the use of eyebrow powders.

BACKGROUND: Cosmetic powders contain numerous components, including titanium dioxide (TiO2), which is classified as possibly carcinogenic to humans (Group 2B). However, little is known about potential inhalation exposures to particles that are released during cosmetic powder applications. METHODS: We realistically simulated the application of five different eyebrow powders using a mannequin and then determined concentrations of total suspended particles (TSP), PM10, and PM4 fractions of particles that would be inhaled during powder application. We determined the size and shape of particles in the original powders and released particles, as well as their TiO2 concentrations and Ti content of individual particles. RESULTS: The application of eyebrow powders resulted in the release and inhalation of airborne particles at concentrations ranging from 21.2 to 277.3 µg/m3, depending on the particle fraction and the powder. The concentrations of TiO2 in PM4 and PM10 samples reached 2.7 µg/m3 and 9.3 µg/m3, respectively. The concentration of TiO2 in airborne particle fractions was proportional to the presence of TiO2 in the bulk powder. CONCLUSION: The application of eyebrow powders results in user exposures to respirable PM4 and PM10 particles, including those containing TiO2. This information should be of interest to stakeholders concerned about inhalation exposure to TiO2.

Effect of Low-Pressure Plasma Treatment Parameters on Wrinkle Features.

Wrinkles attract significant attention due to their ability to enhance the mechanical and optical characteristics of various optoelectronic devices. We report the effect of the plasma gas type, power, flow rate, and treatment time on the wrinkle features. When an optical adhesive was treated using a low-pressure plasma of oxygen, argon, and nitrogen, the oxygen and argon plasma generated wrinkles with the lowest and highest wavelengths, respectively. The increase in the power of the nitrogen and oxygen plasma increased the wavelengths and heights of the wrinkles; however, the increase in the power of the argon plasma increased the wavelengths and decreased the heights of the wrinkles. Argon molecules are heavier and smaller than nitrogen and oxygen molecules that have similar weights and sizes; moreover, the argon plasma comprises positive ions while the oxygen and nitrogen plasma comprise negative ions. This resulted in differences in the wrinkle features. It was concluded that a combination of different plasma gases could achieve exclusive control over either the wavelength or the height and allow a thorough analysis of the correlation between the wrinkle features and the characteristics of the electronic devices.

Human Inhalation Exposure to Aerosol and Health Effect: Aerosol Monitoring and Modelling Regional Deposited Doses.

Since poor air quality affects human health in the short and long term, much research has been performed on indoor and outdoor aerosol exposure; however, there is a lack of specific data on the exposure and health risks of inhalable aerosols that contain bioaerosol in different environments of human life. To investigate the potential exposure to inhalable aerosols (in the monitoring of particulate matter (PM) based on R modeling, variations of PM depend on the ventilation system and bioaerosols based on size distribution) in various environments, the special viability and culturability of bioaerosols and their deposition doses in the respiratory system were evaluated. We conducted exposure assessments on inhalable aerosols in various indoor environments (childcare facilities, schools, commercial buildings, elderly and homes). The fractions of PM (PM10, PM4 and PM2.5) were investigated and, for the bioaerosol, the viability, culturability, inhalation daily dose and the deposited dose of the aerosol in the respiratory system were calculated to evaluate the human health effects. For two years, the distribution of the indoor PM concentration was high in all PM fractions in schools and commercial buildings, and low in the elderly and at homes. For airborne bacteria, the highest concentrations were shown in the childcare facility during the four seasons, while airborne fungi showed high concentrations in the buildings during the spring and summer, which showed significant differences from other investigated environments (between the buildings and elderly and homes: p < 0.05). The viability and culturability for the bioaerosol showed no significant difference in all environments, and the correlation between inhalable PM and bioaerosol obtained from the six-stage impactor showed that the coefficient of determination (R2) between coarse particles (PM10-2.5, the size of stage 2-3) and cultivable airborne bacteria ranged from 0.70 (elderly and homes) to 0.84 (school) during the summer season.

Exposure to inhalable aerosols and their chemical characteristics from different potential factors in urban office environments.

Indoor air quality (IAQ) is one of important issues in indoor environment due to exposure to inhalable aerosol which is affected by indoor and outdoor factors. To demonstrate the effect of indoor and outdoor to the IAQ, this study presents three fractions of particulate matter (PM) (PM2.5, PM4, PM10), characterization of I/O ratios for PM under potential indoor (average occupancy) and outdoor factors (Asian dust, rain, wind, and snow days) and evaluation of chemical components in aerosols. In the chemical characteristics of PM, organic carbon (OC), elemental carbon (EC), and trace elements were analyzed in indoors and outdoors. There was no significant difference of respirable aerosol (PM2.5 and PM4) concentration in different indoor environments. The concentration of OC in PM10 was lower in indoor than outdoor in summer and winter seasons, while the concentration of OC in PM2.5 was higher in indoor than outdoor. Also, the OC/EC ratios in PM2.5 were higher than those in PM10. Further, the ratios of trace elements in PM2.5 and PM10 were different at various locations within the building. This study demonstrated that the exposure to PM2.5 is greatly affected by outdoor environment. Although there was no difference in inhalable and respirable aerosol concentration at different locations within the building, the impact of outdoor factors is strongly supported by OC/EC ratios and PM2.5/PM10 ratios of trace elements. This study shows that chemical components through the HVAC system affected the exposure to the indoor respirable aerosol, which could lead to adverse effect on the indoor air quality.

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1.

Correct temporal and spatial control of actin dynamics is essential for the cytotoxic T cell effector function against tumor cells. However, little is known whether actin engineering in tumor-targeted T cells can enhance their antitumor responses, thereby potentiating the adoptive T cell therapy. Here, we report that TAGLN2, a 22-KDa actin-stabilizing protein which is physically associated with lymphocyte function-associated antigen-1 (LFA-1), potentiates the OTI TCR CD8+ T cells to kill the intercellular adhesion molecule-1 (ICAM-1)-positive/OVA-presenting E0771 cells, but not ICAM-1-negative OVA-B16F10 cells, suggesting an 'inside-out' activation of LFA-1, which causes more efficient immunological synapse formation between T cells and tumor cells. Notably, recombinant TAGLN2 fused with the protein transduction domain (TG2P) overcame the disadvantages of viral gene delivery, leading to a significant reduction in tumor growth in mice. TG2P also potentiated the CD19-targeted, chimeric antigen receptor (CAR)-modified T cells to kill Raji B-lymphoma cells. Our findings indicate that activating the TAGLN2-actin-LFA-1 axis is an effective strategy to potentiate the adoptive T-cell immunotherapy.

Clinical Utility of Beck Anxiety Inventory in Clinical and Nonclinical Korean Samples.

Despite the prominent use of the Beck Anxiety Inventory (BAI) in primary healthcare systems, few studies have confirmed its diagnostic utility and psychometric properties in non-Western countries. This study aims to clarify the clinical utility of the BAI as a screening tool for anxiety disorders according to DSM-IV criteria, based on blind recruitment and diagnostic interviews of both clinical and non-clinical participants in the Korean population. A total of 1,157 participants were involved in the final psychometric analysis, which included correlational analysis with other anxiety and depression self-report measures and mean score comparison with the Beck Depression Inventory (BDI). ROC analysis and calculation of positive and negative predictive values were conducted to examine diagnostic utility. The BAI was found to have high correlations with depression-related self-report measures (0.747-0.796) and moderate to high correlations with anxiety-related self-report measures (0.518-0.776). The ROC analysis failed to provide cutoff scores with adequate sensitivity and specificity for identifying participants with anxiety disorders (85.0% sensitivity, 88.1% specificity, and 92.8% AUC). The comparison of BAI and BDI mean scores for different diagnostic groups revealed that BAI and BDI scores were higher in the depressive or anxiety disorders group than in the non-clinical group. However, BAI mean score was not higher for the anxiety-only group than the depression-only group. Our data supports the BAI reliability and validity as a tool to measure the severity of general anxiety in clinical and non-clinical populations; however, it fails to capture the unique characteristics of anxiety disorders that distinguish them from depressive disorders. Further clinical implications of the BAI based on these results and some limitations of the study are discussed.

Current Status of Cognitive Remediation for Psychiatric Disorders: A Review.

Cognition is an important factor that affects daily functioning and quality of life. Impairment in cognitive function is a common symptom present in various psychological disorders, which hinders patients from functioning normally. Given that cognitive impairment has devastating effects, enhancing this in patients should lead to improvements in compromised quality of life and functioning, including vocational functioning. Over the past 50 years, several attempts have been made to improve impaired cognition, and empirical evidence for cognitive remediation (CR) has accumulated that supports its efficacy for treating schizophrenia. More recently, CR has been successfully applied in the treatment of depressive disorders, bipolar disorders, attention deficit/hyperactivity disorder, and anorexia nervosa. This study critically reviews recent CR studies and suggests their future direction. This study aimed to provide a modern definition of CR, and examine the current status of empirical evidence and representative CR programs that are widely used around the world.

Characterization of particulate matter concentrations and bioaerosol on each floor at a building in Seoul, Korea.

Particulate matter (PM) in buildings are mostly sourced from the transport of outdoor particles through a heating, ventilation, and air conditioning (HVAC) system and generation of particle within the building itself. We investigated the concentrations and characteristic of indoor and outdoor particles and airborne bacteria concentrations across four floors of a building located in a high-traffic area. In all the floors we studied (first, second, fifth, and eighth), the average concentrations of particles less than 10 µm (PM10) in winter for were higher than those in summer. On average, a seasonal variation in the PM10 level was found for the first, fifth, and eighth floors, such that higher values occurred in the winter season, compared to the summer season. In addition, in winter, the indoor concentrations of PM10 on the first, fifth, and eighth floors were higher than those of the outdoor PM10. The maximum level of airborne bacteria concentration was found in a fifth floor office, which held a private academy school consisting of many students. Results indicated that the airborne bacteria remained at their highest concentration throughout the weekday period and varied by students' activity. The correlation coefficient (R (2)) and slope of linear approximation for the concentrations of particulate matter were used to evaluate the relationship between the indoor and outdoor particulate matter. These results can be used to predict both the indoor particle levels and the risk of personal exposure to airborne bacteria.

Gallstone analysis using Fourier transform infrared spectroscopy (FT-IR).

BACKGROUND: Gallstone analysis is important in determining the possible etiology of stone formation and the pathophysiology of cholelithiasis. Physical analysis using Fourier transform infrared spectroscopy (FT-IR), compared to chemical analysis, requires minimal sample volume, shows uniform sensitivity and specificity for all components and provides quantitative results with greater reproducibility. We studied the characteristics and distribution of gallstones using FT-IR in addition to the risk factors for gallstone formation in Korean patients. A better understanding of the mechanism underlying stone formation may help prevent gallstone development. METHODS: Physical analysis of gallstones in 490 patients who underwent cholecystectomy was carried out using the FT-IR system 2000 (Perkin-Elmer Co.) and Spectrum software (Perkin-Elmer Co.). Visual inspection of the size, color, consistency and surface of the stones was compared with the physical characteristics. Clinical, demographic and laboratory findings were evaluated and compared with the gallstone components. RESULTS: The FT-IR evaluation showed that most gallstones were composed of a single component (84.1%); cholesterol was the most commonly observed element among the major components (50%, 245/490). Morphological classification according to color, consistency and surface was different from the FT-IR composition analysis. There were significant differences in the components based on age, obesity, education level and the presence of diabetes mellitus. CONCLUSIONS: The results of this study show that physical analysis of gallstones with FT-IR provides important information on stone composition, distribution and risk factors. These study results will help improve our understanding of the pathophysiology of gallstone disease in the Korean population, where there is a high frequency of hepatobiliary disorders.