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Tuan Hiep Tran,1 Thiruganesh Ramasamy,1 Ju Yeon Choi,1 Hanh Thuy Nguyen,1 Thanh Tung Pham,1 Jee-Heon Jeong,1 Sae Kwang Ku,2 Han-Gon Choi,3 Chul Soon Yong,1 Jong Oh Kim11College of Pharmacy, Yeungnam University, Dae-Dong, 2College of Korean Medicine, Daegu Haany University, Gyeongsan, 3College of Pharmacy, Hanyang University, Hanyangdaehak-ro, Sangnok-gu, Ansan, South KoreaAbstract: The attachment of polyethylene glycol (PEG) increases the circulation time of drug-containing nanoparticles; however, this also negatively affects cellular uptake. To overcome this problem, unique lipid polymer hybrid (LPH) nanoparticles were developed with a pH-responsive PEG layer that detached prior to cell uptake. Docetaxel (DTX) was incorporated into the lipid core of the nanoparticles, which was then shielded with the pH-responsive block co-polymer polyethylene glycol-b-polyaspartic acid (PEG-b-PAsp) using a modified emulsion method. The optimized LPH nanoparticles were ~200 nm and had a narrow size distribution. Drug release from DTX-loaded LPH (DTX-LPH) nanoparticles was pH-sensitive, which is beneficial for tumor targeting. More importantly, DTX-LPH nanoparticles were able to effectively induce apoptosis in cancer cells. The negative surface charge and PEG shell of vehicle remarkably enhanced the blood circulation and physiological activity of DTX-LPH nanoparticles compared with that of free DTX. The nanoparticles were also found to reduce the size of tumors in tumor-bearing xenograft mice. The in vivo anticancer effect of DTX-LPH nanoparticles was further confirmed by the elevated levels of caspase-3 and poly ADP ribose polymerase found in the tumors after treatment. Thus, the results suggest that this novel LPH system could be an effective new treatment for cancer.Keywords: docetaxel, polyaspartic acid, drug delivery systems, antitumor, pH-sensitive

OBJECTIVE: We investigated the anti-osteoporotic effects of Polycan, a beta-glucan from Aureobasidium pullulans, in ovariectomized mice at doses of 31.25, 62.5, and 125 mg/kg. METHODS: Polycan was administered orally once a day for 28 d to bilateral ovariectomized mice, beginning 4 wk after surgery. Changes in body weight, bone weight, bone mineral content, bone mineral density, failure load, histologic profiles, and histomorphometric analyses were determined, in addition to serum osteocalcin, calcium, and phosphorus levels. Alendronate was used as a reference drug. RESULTS: Polycan significantly and dose-dependently suppressed decreases in bone weight, bone mineral content, failure load, bone mineral density, and serum calcium and phosphorus levels and the increase in serum osteocalcin levels. In addition, Polycan significantly suppressed decreases in histomorphometric parameters such as volume, length, and thickness of trabecular bone and thickness of cortical bone and the increase in osteoclast cells in the femur and tibia. CONCLUSION: Although the effects of Polycan were generally modest and smaller than those of alendronate, the effects on cortical bone thickness were more favorable for Polycan than for alendronate. In addition, Polycan exhibited favorable effects on ovariectomy-induced osteoporosis. However, more long-term studies are needed to confirm the effects of Polycan on osteoporosis. [ABSTRACT FROM AUTHOR]

Needle retention, where acupuncture needles are left in the patient following treatment, is a serious adverse event that can lead to infections, bleeding, and tissue damage. While rare, its potential complications render it a critical concern in acupuncture practice. Current research suggests that inadequate procedural safeguards contribute to the incidence of needle retention, yet there is limited investigation into the role of standard operating procedures (SOPs) in reducing such events. This study aimed to evaluate and compare the effects of 2 different SOPs on the incidence of needle retention in acupuncture treatment. We developed a new acupuncture procedure based on SOPs for acupuncture commonly used in hospitals in Taiwan. The main advancements included replacing paper confirmation checklists with online instant messaging systems, staff meetings before treatment, and repeated confirmations after treatment. We implemented 2 SOPs for inpatients in Taipei City Hospital from 2018 to 2021. The incidence of needle retention was calculated, and a logistic regression model was applied to estimate the odds ratio (95% confidence interval) for needle retention risk between the acupuncture SOPs. This study included 13,920 acupuncture treatments, of which 7653 followed the original SOP and 6267 followed the new SOP. The incidence of needle retention was 6.8 versus 2.2 per thousand acupuncture treatments for the original versus new SOPs, respectively. Compared with the original SOP, the new version showed a 0.41 adjusted odds ratio (95% confidence interval, 0.15-0.72; P = .032) of needle retention after adjusting for age, gender, body mass index, Barthel scale, and acupuncture treatment times. Ameliorating the SOPs could reduce the risk of needle retention after acupuncture. This study showed that a new acupuncture SOP, incorporating technology and better communication, significantly reduced needle retention incidents, enhancing patient safety and care quality., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.)

An ultrahigh-intensity femtosecond laser can establish a longitudinal electric field stronger than 10 13  Vm -1 within a plasma, accelerating particles potentially to GeV over a sub-millimetre distance. Laser-accelerated protons with high brightness and picosecond duration are highly desired for applications including proton imaging and flash radiotherapy, while a major limitation is the relatively low proton energy achieved yet, primarily due to the lack of a controllable acceleration structure. Here, we report the generation of protons with a cutoff energy exceeding 110 MeV, achieved by irradiating a multi-petawatt femtosecond laser on a conduction-restricted nanometre polymer foil with a finite lateral size. The enduring obstacles in achieving ultrahigh laser contrast and excellent laser pointing accuracy were successfully overcome, allowing the effective utilization of size-reduced nanometre foils. A long acceleration structure could be maintained in such a quasi-isolated foil since the conduction of cold electrons was restricted and a strong Coulomb field was established by carbon ions. Our achievement paves the road to enhance proton energy further, well meeting the requirements for applications, through a controllable acceleration process using well-designed nano- or micro-structured targets., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) has recently been proposed to describe the hepatic steatosis associated with metabolic abnormalities. Substantial evidence has shown that hepatic steatosis may be linked with cognitive impairment and dementia. This study aimed to clarify the association between MAFLD and brain structural and cognitive changes., Materials and Methods: We analysed data from 2155 participants with both baseline and 4-year follow-up brain magnetic resonance images and neuropsychological measures from the Ansan cohort of the Korean Genome Epidemiology Study. The presence of hepatic steatosis was defined as a liver attenuation index (LAI) value <5 Hounsfield units using computed tomography., Results: Over a median follow-up of 4.1 years, MAFLD was associated with an increased risk of white matter hyperintensity (WMH) (RR 1.35; 95% CI 1.09-1.66, p = 0.006), but not with brain volume changes. When examined by individual components of MAFLD, the presence of hepatic steatosis was an independent factor associated with the risk of WMH regardless of metabolic derangements. Lower LAI values were linearly associated with greater executive function Z score decline (p = 0.007). This relationship was more evident in the non-obese group (body mass index <25 kg/m 2 , p for interaction = 0.003)., Conclusions: MAFLD was associated with an increased risk of WMH over 4.1 years in middle-aged adults. The hepatic steatosis itself was independently associated with an increased risk of WMH regardless of comorbid metabolic abnormalities. The degree of hepatic steatosis was associated with decreased executive function, especially in non-obese individuals., (© 2025 John Wiley & Sons Ltd.)

Background: Cerebral small vessel disease (cSVD) is a major pathologic substrate of vascular contribution to cognitive impairment. However, population based long-term longitudinal cognitive function data in relation to cSVD are rare. We investigated the relationship between cSVD and cognitive decline over time in middle-aged through elderly population., Methods: This prospective cohort study was conducted in a community-based adult population (avg. age 58.5 ± 6.4) who underwent both magnetic resonance imaging (MRI) and comprehensive neuropsychological tests at baseline (2011-2014). The participants were followed-up with the same neuropsychological test battery 4-yearly in two more cycles (in 2015-2018 and 2019-2022). A total of 2454 participants who were free of dementia and cerebrovascular disease at baseline with cognitive function testing at least 2 time points over the time were analyzed. Data analysis was performed from May 1, 2023 to January 31, 2024. SVD was defined by the presence of any of the visible MRI markers (age-related white matter change, lacunes and cerebral microbleeds) at baseline. The main outcomes were multivariable adjusted mean differences of cognitive test performances by cSVD groups over time. The neuropsychological assessment battery included verbal and visual memory, verbal fluency, Digit Symbol-coding, Trail Making Test-A, and Stroop Test. To examine the relationship between cSVD and cognitive function, we used linear mixed model for repeated measurements to compare the means (95% CIs) by cSVD groups., Findings: Of the total, 908 (37.0%) participants had cSVD on MRI reading at baseline. By location, cSVD were mostly found in the frontal lobe followed by basal ganglia area of the brain. None of the cognitive test scores, except Trail Making Test-A, were significantly different between the cSVD groups at baseline. At 8-year follow-up, participants without cSVD performed significantly better than participants with cSVD in Stroop-color reading [Mean difference 1.19 (95% CI: 0.02-2.36), p = 0.0451] and visual reproduction-recognition [Mean difference 0.11 (95% CI: 0.01-0.21), p = 0.0221]. While no other cognitive tests showed any differential changes by cSVD groups, logical memory (Story Recall Tests) increased and Stroop-word reading decreased over time in both cSVD groups almost identically., Interpretation: Silent cSVD was independently associated with decline in executive functioning over 8-year follow-up period in this Korean middle-aged through elderly general population. Future studies considering wider spectrum of cSVD and longer follow-up durations may help predict further cognitive outcomes., Funding: This study was funded by the Korea Centers for Disease Control and Prevention., Competing Interests: None declared., (© 2025 The Authors.)

Although the relationships between basic clinical parameters and white matter hyperintensity (WMH) have been studied, the associations between vascular factors and WMH volume in general populations remain unclear. We investigated the associations between clinical parameters including comprehensive vascular factors and WMH in two large general populations. This retrospective, cross-sectional study involved two populations: individuals who underwent general health examinations at the Asan Medical Center (AMC) and participants from a regional cohort, the Korean Genome and Epidemiology Study (KoGES). WMH volume was quantified using the deep learning model nnU-Net. The associations between vascular factors and WMH volume were analyzed using multivariate linear regression. Individuals in the AMC cohort (n = 7471) had a mean [SD] age of 58.0 [9.2] years, and the KoGES participants (n = 2511), 59.2 [6.8] years. The normalized and logit-transformed WMH volumes for the AMC and KoGES were - 8.5 [1.3] and - 7.9 [1.2], respectively. The presence of carotid plaque, brachial-ankle pulse wave velocity, Agaston score, and coronary artery stenosis were associated with WMH volume after adjustments (AMC: carotid plaque β 0.13; 95% CI, 0.06-0.20; p < 0.001, baPWV β 0.001; CI 0-0.001; p < 0.001, Agaston score β 0.0003; CI 0.0001-0.0005; p < 0.001, minimal-to-mild coronary artery stenosis β 0.20; CI 0.12-0.29; p < 0.001, moderate-to-severe coronary artery stenosis β 0.30; CI 0.15-0.44; p < 0.001, KoGES: carotid plaque β 0.15; CI 0.02-0.27; p = 0.02, baPWV β 0.0004; CI 0-0.001; p = 0.001). Vascular parameters, reflecting atherosclerotic changes in carotid and coronary arteries and arterial stiffness, were independently associated with WMH volume in the general population., Competing Interests: Declarations. Ethics Approval: This cross-sectional study was approved by the institutional review board at the AMC (IRB 2021–0682) and KoGES (IRB 2006AS0045). The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Consent to Participate: Written informed consent from participants was waived by the ethics committee at the AMC because of the retrospective nature of the study. For KoGES, written informed consent was obtained from all participants. Consent for Publication: This paper does not involve any identifiable individual data. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Background: Exhaled nitric oxide concentration (FENO) is a marker of airway inflammation. This study aimed to evaluate the association of air pollution exposure with FENO levels and asthma prevalence with respiratory symptoms in school children., Methods: We analyzed 4736 school children who reside in six townships near industrial areas in central Taiwan. We evaluated asthmatic symptoms, FENO, and conducted the environmental questionnaire. The personal exposure of PM 2.5 , NO, and SO 2 was estimated using land-use regression models data on children's school and home addresses., Results: Annual exposure to PM 2.5 was associated with increased odds of physician-diagnosed asthma (OR = 1.595), exercise-induced wheezing (OR = 1.726), itchy eyes (OR = 1.417), and current nasal problems (OR = 1.334) (P < 0.05). FENO levels in the absence of infection were positively correlated with age, previous wheezing, allergic rhinitis, atopic eczema, near the road, and for children with high exposure to PM 2.5 (P < 0.05). An increase of 1 μg/m 3 PM 2.5 exposure was significantly associated with a 1.0% increase in FENO levels for children after adjusting for potential confounding variables, including exposures to NO and SO 2 ., Conclusions: Long-term exposures to PM 2.5 posed a significant risk of asthma prevalence and airway inflammation in a community-based population of children., Impact: Annual exposure to PM 2.5 was associated with increased odds of physician-diagnosed asthma and nasal problems and itchy eyes. Long-term exposures to PM2.5 were significantly associated with FENO levels after adjusting for potential confounding variables. This is first study to assess the association between FENO levels and long-term air pollution exposures in children near coal-based power plants. An increase of 1 μg/m 3 annual PM 2.5 exposure was significantly associated with a 1.0% increase in FENO levels. Long-term exposures to PM2.5 posed a significant risk of asthma prevalence and airway inflammation in a community-based population of children., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Purpose: This study aims to develop and implement an economic evaluation using a micro-costing approach to provide a precise and transparent analysis of the direct costs of cystoscopic procedures in Korean hospitals. The study seeks to identify key cost components and evaluate whether current reimbursement rates accurately reflect these direct costs., Materials and Methods: Significant variations in cost items were identified across different studies. An economic evaluation was conducted using a micro-costing methodology for the cost analysis of cystoscopic procedures, developed through literature review, data collection from studies, and expert consultations., Results: Gangnam Severance Hospital (GSH) performed 2,188 cystoscopic procedures, including 1,847 cystoscopies and 341 JJ stent removals, with average costs of $100.8 and $110.6, respectively. At National Health Insurance Service Ilsan Hospital (NHIMC), 1,463 procedures were performed, including 1,167 cystoscopies and 296 JJ stent removals, with average costs of $119.2 and $125.3. Cystoscopy costs at GSH were driven by reprocessing ($45.8, 45.4%) and equipment ($33.1, 32.9%), while NHIMC's were $52.5 (44.0%) for equipment and $48.7 (40.8%) for reprocessing. Both hospitals incurred financial losses, with NHIS (National Health Insurance Service) covering only about 71.7% and 60.6% of costs for cystoscopy, and 71.0% and 62.7% for JJ stent removal., Conclusions: The significant discrepancy between HIRA (Health Insurance Review & Assessment Service)'s estimated costs and those identified here suggests that current fees for cystoscopic procedures may be underestimated and require reassessment. Given the results, reevaluating these rates is essential to ensure fair compensation for healthcare providers and to deliver optimal patient care., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association.)

Aims: This study aimed to assess treatment patterns and the effectiveness of long-acting injectable antipsychotics (LAIs) in patients with bipolar disorder (BD) across various Asian countries. The study focused on comparing the choices of LAIs, other psychotropic medications, and their psychotropic drug load to explore real-world usage and evaluate the potential benefits of LAIs in BD treatment across different countries., Methods: A retrospective cohort study was conducted with BD patients diagnosed according to ICD-10-CM codes F31.0 to F31.9 across 13 Asian countries or regions. Data were collected through an online system covering prescriptions for all psychotropic medications including LAIs. The Anatomical Therapeutic Chemical (ATC) Classification System was used to compare medication dosage patterns., Results: The study analyzed 2029 prescription records for BD, including 103 cases involving LAIs. The highest LAI prescription rates were found in Sri Lanka and Malaysia, with no reported use in Myanmar, India, and Japan. Patients receiving LAIs were younger, more often male, and had higher BMI and drug loads compared to those on oral medications. South Korea and Indonesia showed the highest LAIs drug load. South Korea, Pakistan, and China exhibited the highest total psychotropic drug loads, while Malaysia had the lowest., Conclusions: This study is the first to examine LAIs use for BD across Asia. Cross-national differences in LAIs prescriptions and psychotropic drug load highlight variations in treatment practices and healthcare systems. These findings underscore the need for further research and the development of region-specific guidelines to improve BD treatment outcomes., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest in reporting this study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Mirodenafil is a phosphodiesterase 5 (PDE5) inhibitor with high specificity for its target and good blood-brain barrier permeability. The drug, which is currently used for treatment of erectile dysfunction, reduces Aβ and pTau levels and improves cognitive function in mouse models of Alzheimer's disease. In the present study, we investigated the effect of mirodenafil in the transient and permanent middle cerebral artery occlusion (tMCAO and pMCAO) models of stroke in rats. Starting 24 ​h after cerebral artery occlusion, mirodenafil was administered subcutaneously at doses of 0.5, 1, and 2 ​mg/kg per day for 9 days in the tMCAO model and for 28 days in the pMCAO model. Mirodenafil significantly increased sensorimotor and cognitive recovery of tMCAO and pMCAO rats compared to saline control rats, and significantly decreased the amount of degenerative cells and cleaved caspase-3 and cleaved PARP immunoreactive cells. Effects were seen in a dose-dependent manner up to 1 ​mg/kg mirodenafil. The benefits of mirodenafil treatment increased with longer treatment duration, and the largest improvements over control were typically observed on the last assessment day. There was no effect of mirodenafil on infarct volume in both tMCAO and pMCAO rats. In an experiment to determine the treatment window for mirodenafil effects, a protective effect was observed when treatment was delayed 72 ​h after MCAO, although the most improvement was observed with shorter treatment windows. Using pMCAO and tMCAO rat models of stroke, we determined that mirodenafil improves the recovery of sensorimotor and cognitive functions after MCAO and protects cortical cells from apoptosis and degeneration. Greater benefit was observed with longer duration of treatment, and improvement was seen even when treatment was delayed., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The roles of aryl hydrocarbon receptor (AhR), AhR -nuclear translocator (ARNT), and AhR repressor (AhRR) genes in the elevation of cord blood IgE (CbIgE) remained unclear. Our aims were to determine the polymorphisms of AhR, ARNT, and AhRR genes, cord blood AhR (CBAhR) level, and susceptibility to elevation of CbIgE. 206 infant-mother pairs with CbIgE>=0.35 IU/ml and 421 randomly selected controls recruited from our previous study. Genotyping was determined using TaqMan assays. Statistical analysis showed AhR rs2066853 (GG vs. AA+AG: adjusted OR (AOR)=1.5, 95%CI=1.10-2.31 and AOR=1.60, 95%CI=1.06-2.43, respectively) and the combination of AhR rs2066853 and maternal total IgE (mtIgE)>=100 IU/ml were significantly correlated with CbIgE>=0.35 IU/ml or CbIgE>=0.5 IU/ml. CBAhR in a random subsample and CbIgE levels were significantly higher in infants with rs2066853GG genotype. We suggest that infant AhR rs2066853 and their interactions with mtIgE>=100 IU/ml significantly correlate with elevated CbIgE, but AhRR and ARNT polymorphisms do not.

Burosumab is approved for the treatment of hypophosphatemia in persistent tumor-induced osteomalacia. This work exemplifies a model-informed drug development approach that evaluated burosumab pharmacokinetics and pharmacokinetic/pharmacodynamics in the ultrarare tumor-induced osteomalacia population to support adult and pediatric dosing. Data from tumor-induced osteomalacia participants were combined with data from X-linked hypophosphatemia to understand pharmacokinetic and pharmacokinetic/pharmacodynamic characteristics and covariates specific to tumor-induced osteomalacia. Pharmacokinetic and pharmacokinetic/pharmacodynamic simulations were performed using final models to support dosing recommendations for adults and extrapolation to pediatric patients. Burosumab pharmacokinetics were described using a one-compartment model with first-order absorption and body weight as a significant covariate. Pharmacokinetic/pharmacodynamic relationships were described using a sigmoidal Emax model with significant covariates of baseline fibroblast growth factor 23 on baseline fasting serum phosphate and potency of burosumab response and tumor-induced osteomalacia disease state resulting in a steep slope of response; however, the covariates are not clinically meaningful. Simulations demonstrated that, in pediatric patients, starting doses of burosumab 0.3 and 0.4 mg/kg every 2 weeks at steady state would achieve normal serum phosphate levels in ≥ 30% of patients with relatively low risk of hyperphosphatemia (< 3%). In adults, burosumab 0.3 and 0.5 mg/kg every 4 weeks achieves similar percentages of responders and a relative low risk of hyperphosphatemia (< 7%). Serum phosphate titration-based burosumab dosing increased the probability of achieving normal serum phosphate levels. The models supported a model-informed drug development approach for global approvals of titration-based burosumab dosing, guided by monitoring fasting serum phosphate levels., (© 2024 Kyowa Kirin, Inc. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Background: Parkinson's disease (PD) is a prevalent neurodegenerative condition characterized primarily by motor symptoms, often accompanied by non-motor manifestations such as insomnia. Acupuncture, an increasingly popular alternative therapy, has shown promise in the prevention and alleviation of PD motor symptoms. However, the specific impact of acupuncture on the risk of developing PD in insomnia patients remains uncertain., Methods: In this retrospective study, we identified and matched 152,585 newly diagnosed insomnia patients from Taiwan's National Health Insurance Research Database (NHIRD) from 2000 to 2010. Using a 1:1 propensity score matching method, we ensured the comparability of two groups: patients who received acupuncture treatment and those who did not. It resulted in a final cohort of 20,112 patients in both the acupuncture and non-acupuncture groups., Results: Our analysis revealed that insomnia patients who underwent acupuncture treatment exhibited a significantly reduced risk of developing PD. The adjusted hazard ratio (aHR) was 0.44 (95 % confidence interval = 0.39-0.50) compared to those who did not receive acupuncture. Furthermore, the cumulative incidence of PD in the acupuncture group was significantly lower, as evidenced by the log-rank test ( p < 0.001)., Conclusion: In conclusion, our study provides evidence suggesting that acupuncture treatment is associated with a decreased risk of PD in patients with insomnia. However, further research is warranted to strengthen the evidence supporting these findings., Competing Interests: The authors confirm that they conducted the research without commercial or financial associations that might be interpreted as potential conflicts of interest., (© 2024 Korea Institute of Oriental Medicine. Published by Elsevier B.V.)

Background: Little is known about the effect of postnatal exposure to heavy metals on children's behavior problems. This study aimed to investigate the association between metal exposure during different stages of postnatal life and neurobehavioral outcomes in preschool children., Methods: Urinary concentrations of six metals (arsenic, cadmium, chromium, lead, manganese, and vanadium) were measured using inductively coupled plasma mass spectrometry in 220 participants at two time points: before 1 year and at 5 years of age. Mothers completed the Child Behavior Checklist when the children were 5 years old. Multivariable linear and logistic regression analyses were used to evaluate the association between metal concentrations and behavioral outcomes. We employed Bayesian kernel machine regression (BKMR) to assess possible joint effects and potential interactions between metal mixtures and behavioral outcomes., Results: Concentrations of urinary arsenic (As) in infants were associated with higher scores for anxious/shy behavior problems (β ranging from 0.03 to 0.23). Further analyses showed that As exposure increased the odds of scores falling into the borderline or clinical range on anxious/depressed, affective, and pervasive developmental problems (ORs: 2.45-3.40). Stratification by sex indicated significance in girls but not in boys. BKMR analysis showed that, among the metal mixtures, As displayed a major effect on behavior scores. Concentrations of urinary cadmium in infants were also associated with higher behavioral scores but did not increase the risk of clinical problems. A cross-sectional survey in 5-year-olds did not show a significant association between concurrent metal exposure and behavioral outcome., Conclusion: Our results showed that exposure to As and Cd during infancy was associated with emotional problems in children. The effect of arsenic exposure was more pronounced among female infants. We suggest reducing exposure to toxic metals during early postnatal life to prevent behavioral problems in children.", Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic kidney disease (CKD) is a global health problem characterized by progressive renal fibrosis and excessive extracellular matrix deposition. Oxidative stress and epigenetic regulation, particularly through microRNAs (miRNAs), play crucial roles in the pathogenesis of CKD. In this study, we investigated the role of urinary miR-144-3p, which is upregulated in rats with CKD induced by diabetes and hypertension, in renal fibrosis progression, particularly its regulation of the nuclear factor erythroid-2-related factor 2 (NRF2) pathway. Our findings revealed elevated miR-144-3p levels and reduced NRF2 and target gene levels in kidney tissues of streptozotocin-treated spontaneously hypertensive rats. In vitro experiments demonstrated that miR-144-3p directly binds to the 3'-untranslated region of nrf2, suppressing the NRF2 pathway in renal tubular epithelial cells. Additionally, the profibrogenic factor transforming growth factor (TGF)-β1 increased miR-144-3p expression. TGF-β1-induced NRF2 suppression and reactive oxygen species elevation were found to be mediated through miR-144-3p upregulation. In vivo, cilostazol, an antiplatelet drug with an NRF2-activating effect, ameliorated renal injury in diabetic hypertensive rats by decreasing TGF-β1 and miR-144-3p levels while increasing NRF2 and its target gene levels in the kidneys. These findings highlight the potential therapeutic value of targeting the miR-144-3p/NRF2 pathway to attenuate CKD progression in hypertensive diabetic conditions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The study was funded by the National Research Foundation of Korea, MSIT (MK Kwak, T Bae), The Catholic University of Korea (MK Kwak), and the Ministry of Education of Korea (SK Kim, GS Bae). The research funding from MSIT and the Ministry of Education of Korea supported meeting attendance and travel (MK Kwak, SK Kim, GS Bae, T Bae)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Falls among stroke patients pose a significant health concern, leading to injuries, reduced mobility, and functional limitations. Recent research has suggested the potential benefits of acupuncture in enhancing balance and motor function in stroke patients. However, large-scale, long-term studies on acupuncture's role in reducing the risk of accidental injuries are scarce. This study aimed to evaluate acupuncture's effectiveness in decreasing the risk of accidental injuries in stroke patients., Materials and Methods: This study employed a large-scale cohort design, utilizing data from the 2000 Longitudinal Generation Tracking Database (LGTD 2000) in Taiwan, covering two million individuals. The cohort comprised stroke patients hospitalized between 2001 and 2012, with follow-up periods of at least six years to estimate accidental injury incidence and risk. Acupuncture treatments during both inpatient and outpatient phases after stroke diagnosis were included. Accidental injury data, including vehicular accidents and falls, were extracted from specialized hospitalization records. Hazard ratios were calculated, adjusting for variables like comorbidities, hypnotic medication usage, and demographic factors., Result: A total of 108,196 newly diagnosed stroke patients were included in the final cohort, with 42,083 receiving acupuncture treatment and 66,113 not receiving acupuncture. The acupuncture group exhibited a significantly lower incidence rate of accidental injuries (10.2 per 1,000 person-years) compared to the non-acupuncture group (15.8 per 1,000 person-years). After adjusting for various covariates, the acupuncture group had a reduced risk of accidental injuries with an adjusted hazard ratio (aHR) of 0.74 (95 % CI: 0.51-0.92). Subgroup analyses revealed consistent protective effects of acupuncture across different patient profiles and treatment characteristics, including age, sex, comorbidities, and hypnotic medication usage., Conclusion: This study provides evidence supporting the potential of acupuncture as an adjunctive therapy to reduce the risk of accidental injuries among stroke patients. Regardless of stroke subtype, age, or comorbidity burden, acupuncture was associated with a lower risk of accidental injuries., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Lithium and mood stabilizers are considered effective augmentation agents of antidepressants for treatment-resistant depression. Thus, this study aimed to estimate the network structure of depression symptom criteria among unipolar depression patients with mood stabilizers, using data from the Research on Asian Psychotropic Prescription Patterns for mood stabilizers (REAP-MS). We estimated a network of the 9 depression symptom criteria among 411 unipolar depression patients in Asia. Each of the depression symptom criteria was considered to be a dichotomous categorical variable. Suicidality (suicidal ideation or attempt) was the most centrally situated within the network of depression symptoms, followed by depressed mood, loss of energy, anhedonia and weight loss or gain. Contrastingly, concentration problem was the least interconnected. The depression symptom criteria were organized into 4 clusters by the community detection method. The findings suggest that suicidality may be one of the significant therapeutic target symptoms in unipolar depression patients with mood stabilizers., Competing Interests: Declaration of Competing Interest Seon-Cheol Park, an editorial board member of the Asian Journal of Psychiatry, was not involved in the evaluation of or decision to publish this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The TP53 c.359A＞G mutation significantly disrupts the expression of the major TP53 transcript variant encoding p53 K120R by generating a new splice donor site. An antisense morpholino oligomer (AMO) targeting this mutation successfully restored normal splicing and the expression of the major TP53 variant. Given that p53 exerts its tumor suppressor function by regulating target genes responsible for growth arrest or apoptosis, the p53 K120R protein enhanced by AMO exhibits impaired transcriptional regulation of CDKN1A, a key growth arrest gene, while maintaining normal induction of the pro-apoptotic BBC3 gene. As a result, the mutant p53 K120R protein shows a defective cell growth arrest phenotype but retains apoptotic function, suggesting that it may still possess some tumor suppressor activity. Furthermore, lysine 120, known to provide a critical acetylation site for p53 activation, highlights the relevance of acetylation in tumor suppression through studies of the p53 K120R mutant. However, our findings demonstrate that targeting mutant TP53 mRNA with AMO is essential for restoring p53 function. In conclusion, this study emphasizes the potential of AMO-mediated splice correction as a therapeutic approach for TP53 mutations. [BMB Reports 2024; 57(11): 503-508].

Despite the advancements in precision medicine, regenerative medicine, and smart healthcare, traditional Chinese medicine (TCM) remains vital in Taiwan, reflecting its cultural and historical heritage. TCM is commonly used in conjunction with or as an alternative to conventional medicine and is reimbursed by Taiwan's National Health Insurance, enabling the Taiwanese people to integrate traditional and modern treatments for comprehensive healthcare. This article explores the critical role of specialization in TCM amid evolving healthcare challenges. This highlights the need for specialized knowledge among TCM physicians to manage iatrogenic risks, such as drug-herb interactions, and to improve healthcare outcomes, particularly when integrating TCM with Western medicine. Specialization enhances treatment precision, patient outcomes, and clinical research quality. Drawing on South Korea's experience in establishing a specialist physician system for traditional Korean medicine, Taiwan's Ministry of Health and Welfare's initiatives to advance systematic TCM training and regulatory frameworks were examined, showcasing the development and implementation of a TCM specialist physician training program. In conclusion, specialized physician training in TCM improves patient care, optimizes healthcare utilization, and promotes long-term sustainability of the health insurance system by aligning TCM practices with modern healthcare needs., Competing Interests: Declaration of Competing interest The authors of the manuscript titled “Enhancing Taiwan's Traditional Chinese Medicine Healthcare System Following the COVID-19 Pandemic Through Specialization in TCM” declare that there are no financial or non-financial conflicts of interest that could have influenced the work reported in this manuscript. Financial Conflicts of Interest: None. Non-Financial Conflicts of Interest: None. The authors affirm that the research findings are presented as objectively as possible, ensuring that the results and discussion are evidence-based and free from any potential bias., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Lycii Radicis Cortex (LRC), the dried root bark of Lycium chinese Mill., has traditionally been used as a medicinal herb in East Asia to treat fever and hyperhidrosis. In the present study, we investigated the effects of LRC extract on ligation-induced experimental periodontitis and associated alveolar bone loss in rats. Twenty-four hours after ligation placement, LRC was orally administered once daily for 10 days. Firstly, LRC administration inhibited anaerobic bacterial proliferation and inflammatory cell infiltration in gingival tissues. Additionally, LRC exhibited anti-inflammatory effects by reducing the expression of inflammatory mediators, including prostaglandin E 2 , interleukin-1β, and tumor necrosis factor-α. LRC treatment also downregulated mRNA expression of these inflammatory mediators in lipopolysaccharide-stimulated RAW 264.7 cells by inhibiting the mitogen-activated protein kinases and nuclear factor-κB (NF-κB) signaling pathways. Furthermore, LRC showed an antioxidant effect by decreasing the malondialdehyde level and inducible nitric oxide synthase activity in gingival tissues. Moreover, LRC effectively prevented the connective tissue degradation by inhibiting matrix metalloproteinase-8 expression and the loss of collagen-occupied areas in gingival tissues. LRC also decreased the receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) ratio, as well as the number and occupied areas of osteoclasts on the alveolar bone surface, thereby inhibiting alveolar bone loss. In summary, these findings suggest that LRC is a promising medicinal herb for alleviating periodontitis and related alveolar bone loss through its antimicrobial, anti-inflammatory, and antioxidant properties.

In this study, the impacts of laser irradiation on the surface morphology and hardness of copper (Cu) are investigated under various environments, including air, vacuum, and high-pressure gas flow through a supersonic nozzle. After irradiating Cu targets with laser pulses with energy of 30, 60, and 90 mJ/pulse, the surface structures of the targets are analyzed by scanning electron microscopy (SEM) and X-ray diffraction (XRD). The SEM analysis reveals diverse surface morphologies, including micro-cones, cavities, droplets, ripples, and island-like structures, depending on laser energy and environments. The XRD analysis provides insights into the structural changes induced by laser irradiation. The results indicate a significant enhancement in microhardness by a factor of 2.77, which is attributed to the surface and structural modifications incurred under various environments. In addition, the XRD analysis reveals a shift in the residual stress in the surface layers of copper from tensile before laser irradiation to compressive afterwards, highlighting the effectiveness of laser surface treatment in inducing favorable mechanical properties.

We demonstrated an inline synthesizer for generating ultrashort pulses in the ultraviolet (UV) range. The inline UV pulse synthesizer comprised three nonlinear crystals located in the propagation path of the fundamental driving laser pulse. Second-harmonic signals with central wavelengths of 420, 375, and 345 nm were generated in turn in the three BBO crystals, resulting in a synthesized UV pulse subsequent to the final nonlinear crystal. Its temporal amplitude and phase could be manipulated easily by changing the relative positions of the crystals, allowing for flexibility of the waveform. The minimum pulse duration of the synthesized UV pulse was 4.7 fs, which was close to the Fourier-transform-limited pulse duration. This ultrashort UV pulse with 19 μ J energy can be utilized in various applications such as high harmonic generation and frustrated tunneling ionization., (© 2024. The Author(s).)

While spray-drying has been widely utilized to improve the bioavailability of poorly water-soluble drugs, the outcomes often exhibit suboptimal particle size distribution and large particle sizes, limiting their effectiveness. In this study, we introduce electrostatic spraying as an advanced technology tailored for poorly water-soluble drugs, enabling the fabrication of nanoparticles with fine and uniform particle size distribution. Regorafenib (1 g), as a model drug, copovidone (5 g), and sodium dodecyl sulfate (0.1 g) were dissolved in 200 ml ethanol and subjected to conventional-spray-dryer and electrostatic spray dryer. The electrostatic spray-dried nanoparticles (ESDN) showed smaller particle sizes with better uniformity compared to conventional spray-dried nanoparticles (CSDN). ESDN demonstrated significantly enhanced solubility and rapid release in water. In vitro studies revealed that ESDN induced apoptosis in HCT-116 cells to a greater extent, exhibiting superior cytotoxicity compared to CSDN. Furthermore, ESDN substantially improved oral bioavailability and antitumor efficacy compared to CSDN. These findings suggest that ESD shows potential in developing enhanced drug delivery systems for poorly water-soluble drugs, effectively addressing the limitations associated with CSD methods., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

Background and Purpose: Only limited therapeutic agents have been developed for non-alcoholic steatohepatitis (NASH). Glabridin, a promising anti-obesity candidate, has only limited druggability due to its low in vivo chemical stability and bioavailability. Therefore, we developed vutiglabridin (VUTI), which is based on a glabridin backbone, and investigated its mechanism of action in treating NASH in animal models., Experimental Approach: Anti-NASH effects of VUTI were determined in in vitro fatty liver models, spheroids of primary human hepatocytes and L02 normal liver cell lines. To identify VUTI possible cellular target/s, biotin-labelled VUTI was synthesized and underwent chemical proteomic analysis. Further, the evaluation of VUTI therapeutic efficacy was carried out using an amylin-NASH and high-fat (HF) diet-induced obese (DIO) mouse models. This was carried out using transcriptomic, lipidomic and proteomic analyses of the livers from the amylin-NASH mouse model., Key Results: VUTI treatment markedly reduces hepatic steatosis, fibrosis and inflammation by promoting lipid catabolism, activating autophagy and improving mitochondrial dysfunction, all of which are hallmarks of effective NASH treatment. The cellular target of VUTI was identified as paraoxonase 2 (PON2), a newly proposed protein target for the treatment of NASH, VUTI enhanced PON2 activity. The results using PON2 knockdown cells demonstrated that PON2 is important for VUTI- activation of autophagy, promoting mitochondrial function, decreasing oxidative stress and alleviating lipid accumulation under lipotoxic condition., Conclusion and Implications: Our data demonstrated that VUTI is a promising therapeutic for NASH. Targeting PON2 may be important for improving liver function in various immune-metabolic diseases including NASH., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Herein, we reported novel docetaxel-decorated solid lipid nanoparticle (DCT-SLN)-loaded dual thermoreversible system (DCT-DRTS) for intramuscular administration with reduced burst effect, sustained release and improved antitumor efficacy. The optimized DCT-DRTs was subjected to in-vitro and in-vivo analyses. Antitumor evaluation of the DCT-DRTS was executed and compared with DCT-hydrogel, and DCT-suspension trailed by the histopathological and immune-histochemical analyses. The DCT-SLN gave a mean particle size of 157 nm and entrapment efficiency of 93 %. It was a solid at room temperature, and changed to liquid at physiological temperature due to its melting point of about 32 °C. Unlikely, poloxamer mixture remained liquefied at 25-27 °C, however converted to gel at physiological temperature. This behavior demonstrated opposed reversible property of the DCT-SLN and poloxamer hydrogel in DCT-DRTS system, making it ideal for intramuscular administration and quick gelation inside the body. The DCT-DRTS sustained the drugs release and unlike DCT-hydrogel, the preliminary plasma concentration of DCT-DRTS was significantly reduced, overcoming the burst release. A meaningfully enhanced antitumor efficacy and improved survival rate was observed from DCT-DRTS in tumor cell xenograft athymic nude mice. Additionally, increased apoptotic and reduced proliferation markers were observed in DCT-DRTS treated tumor masses. It was concluded that DCT-DRTS may be a suitable choice for intramuscular administration of DCT with sustained release, improved bioavailability, reduced toxicity and enhanced antitumor effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: The lateral spread response (LSR) is an important electrophysiological sign that predicts successful decompression in patients undergoing microvascular decompression (MVD) for hemifacial spasm (HFS). However, LSRs do not consistently correlate with clinical outcomes, and there are cases in which LSRs are absent. In this study, the authors identified a unique pattern on facial nerve electromyography (EMG) when the root exit zone (REZ) is touched. This distinctive EMG pattern, which the authors coined the "Sang-ku sign" (SKS), could aid in identifying the offending vessel on the REZ, even in the absence of LSRs., Methods: Between November 2022 and August 2023, the authors analyzed EMG findings from 185 patients undergoing MVD for HFS. Bipolar stimulation electrodes were placed at the marginal mandibular branch, and recordings were obtained from the frontalis and orbicularis oris muscles. Additionally, stimulation electrodes were placed at the temporal branch, and recordings were obtained from the oris and mentalis muscles. The authors statistically analyzed the presence of SKS and its association with demographic, surgical, clinical outcomes, and anatomical factors., Results: The authors observed a brief, burst-like wave pattern arising from all recorded muscle branches when Teflon felt was placed between the REZ and the facial nerve. This EMG pattern, the SKS, was found in 164 patients (88.6%). Among the factors analyzed, only patient age showed a significant association with the presence of the SKS in univariate analysis (p = 0.007). The presence of the SKS was significantly associated with predicting the disappearance of LSRs (p = 0.045). Clinical outcomes were favorable (99% at the last follow-up) in all cases; thus, no positive correlation was observed in the existence of the SKS and LSRs., Conclusions: The SKS could serve as an excellent guide for the facial nerve REZ during surgery. Given that HFS results from abnormal vascular contact on the REZ, this finding plays a crucial role in ensuring surgical success. Alongside LSRs, the SKS could provide valuable insights for neurosurgeons.

Bacterial Artificial chromosome (BAC) recombineering is a powerful genetic manipulation tool for the efficient development of recombinant genetic resources. Long homology arms of more than 150 kb composed of BAC constructs not only substantially enhance genetic recombination events, but also provide a variety of single nucleotide polymorphisms (SNPs) that are useful markers for accurately docking BAC constructs at target sites. Even if the BAC construct is homologous to the sequences of the target region, different variations may be distributed between various SNPs within the region and those within the BAC construct. Once the BAC construct carrying these variations was precisely replaced in the target region, the SNP profiles within the target genomic locus were directly replaced with those in the BAC. This alteration in SNP profiles ensured that the BAC construct accurately targeted the designated site. In this study, we introduced restriction fragment length polymorphism or single-strand conformation polymorphism analyses to validate and evaluate BAC recombination based on changes in SNP patterns. These methods provide a simple and economical solution to validation steps that can be cumbersome with large homologous sequences, facilitating access to the production of therapeutic resources or disease models based on BAC-mediated homologous recombination., Competing Interests: The author declares no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Background: The efficacy of postoperative tranexamic acid (TXA) administration in mitigating bleeding after primary laparoscopic Roux-en-Y gastric bypass (RYGB), a prevalent complication associated with significant morbidities and mortality, and the use of sequential laboratory parameter changes in bleeding screening and TXA impact tracking were investigated., Methods: This retrospective analysis included RYGB patients (aged 18-65 years, with a body mass index of 35-50 kg/m 2 ) over 5 years who were categorized into three groups by evolving treatment regimens: Group A (n = 42) received standard pre- and postoperative enoxaparin (30 mg) every 12 h; Group B (n = 160) received enoxaparin and postoperative TXA (250 mg every 6 h); and Group C (n = 73) received TXA alone. Postoperative bleeding-related adverse events, vital signs, and laboratory changes were compared., Results: Postoperative hemorrhage occurred in 3.6% (10/275) of patients, with no significant intergroup differences. Patients who experienced bleeding had greater decreases in hemoglobin (∆Hb) (2.1 vs. 1.4; p = 0.003), greater ∆Hb > 2 (50% vs. 15%; p = 0.013), and greater use of staples than did those who did not experience bleeding (8 vs. 7; p = 0.001). The ∆Hb values were lower in Groups B (1.4) and C (1.3) than in Group A (1.7, p = 0.011). No significant difference was noted between Groups C and B., Conclusion: This study emphasizes the potential of TXA to mitigate postoperative bleeding after RYGB, with no added benefit from excluding enoxaparin. Monitoring patients with a ∆Hb > 2 mg/dl and increased stapler usage is crucial. Further research is needed to validate routine TXA use across different procedures., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Recent research has established an association between insomnia and an elevated risk of stroke. Given the severe global impact of stroke on public health, exploring nonpharmacological interventions, such as acupuncture, that can mitigate stroke risk among individuals with insomnia is crucial., Methods: In this retrospective cohort study, we used data from the Taiwan National Health Insurance Database (NHIRD) to examine the relationship between acupuncture and the risk of stroke among individuals who received a diagnosis of insomnia between 2000 and 2017. The study participants were divided into two cohorts: the acupuncture group that received acupuncture and a matched control group that did not. The primary outcome was the occurrence of stroke., Results: Of the 217,356 patients included in the study, 3668 individuals in the acupuncture group and 4913 in the control group experienced stroke. The incidence rate of stroke was lower in the acupuncture group (4.51 per 1000 person-years) than in the control group (6.86 per 1000 person-years). After adjustment for various potential confounders, patients who received acupuncture exhibited a notably reduced risk of stroke, with an adjusted hazard ratio of 0.66 (95 % confidence interval [CI]: 0.63, 0.69). Furthermore, a dose-response relationship was evident, in that individuals who received 6-11 acupuncture sessions experienced a 24 % reduction in stroke risk, whereas those who received 12-17 sessions, 18-29 sessions, and ≥30 sessions exhibited reductions of 31 %, 34 %, and 42 %, respectively., Conclusion: Acupuncture treatment was significantly associated with a reduced risk of stroke among patients with insomnia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

Background: Natural anti-cytokine autoantibodies can regulate homeostasis of infectious and inflammatory diseases. The anti-cytokine autoantibody profile and relevance to the pathogenesis of asthma are unknown. We aim to identify key anti-cytokine autoantibodies in asthma patients, and reveal their immunological function and clinical significance., Methods: A Luciferase Immunoprecipitation System was used to screen serum autoantibodies against 11 key cytokines in patients with allergic asthma and healthy donors. The antigen-specificity, immunomodulatory functions and clinical significance of anti-cytokine autoantibodies were determined by ELISA, qPCR, neutralization assays and statistical analysis, respectively. Potential conditions for autoantibody induction were revealed by in vitro immunization., Results: Of 11 cytokines tested, only anti-IL-33 autoantibody was significantly increased in asthma, compare to healthy controls, and the proportion positive was higher in patients with mild-to-moderate than severe allergic asthma. In allergic asthma patients, the anti-IL-33 autoantibody level correlated negatively with serum concentration of pathogenic cytokines (e.g., IL-4, IL-13, IL-25 and IL-33), IgE, and blood eosinophil count, but positively with mid-expiratory flow FEF 25 - 75 %. The autoantibodies were predominantly IgG isotype, polyclonal and could neutralize IL-33-induced pathogenic responses in vitro and in vivo. The induction of the anti-IL-33 autoantibody in blood B-cells in vitro required peptide IL-33 antigen along with a stimulation cocktail of TLR9 agonist and cytokines IL-2, IL-4 or IL-21., Conclusions: Serum natural anti-IL-33 autoantibodies are selectively induced in some asthma patients. They ameliorate key asthma inflammatory responses, and may improve lung function of allergic asthma., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Blood concentrations of clozapine in Taiwanese patients appeared approximately 30-50 % higher than that from Caucasian patients, and women possessed a higher blood levels. Fluvoxamine was reported to increase the clozapine levels, reduce clozapine-related weight gain and metabolic disturbances, and improved general psychopathology. Clothiapine, a chemical structure analogue of clozapine, showed potential of benefitting patients who are unsuitable for clozapine treatment in Taiwan. Obsessive/compulsive symptom (OCS) is a common side effect of clozapine. Concentrations of clozapine were remarkably higher in patients with OCS than in those without. In conclusion, clozapine is a widely used in patients with schizophrenia in Taiwan., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Terahertz (THz) waves, known as non-ionizing radiation owing to their low photon energies, can actually ionize atoms and molecules when a sufficiently large number of THz photons are concentrated in time and space. Here, we demonstrate the generation of ionizing, multicycle, 15-THz waves emitted from large-area lithium niobate crystals via phase-matched optical rectification of 150-terawatt laser pulses. A complete characterization of the generated THz waves in energy, pulse duration, and focal spot size shows that the field strength can reach up to 260 megavolts per centimeter. In particular, a single-shot THz interferometer is employed to measure the THz pulse duration and spectrum with complementary numerical simulations. Such intense THz pulses are irradiated onto various solid targets to demonstrate THz-induced tunneling ionization and plasma formation. This study also discusses the potential of nonperturbative THz-driven ionization in gases, which will open up new opportunities, including nonlinear and relativistic THz physics in plasma., (© 2024. The Author(s).)

Deep seawater (DS), obtained from a depth over 200 m, has health benefits due to its rich nutrients and minerals, and intake of DS has shown diverse immunomodulatory effects in allergies and cancer. Therefore, the immunostimulatory effects of Korean mineral-rich seawaters were examined in a cyclophosphamide (CPA)-induced immunosuppression model. Three samples of Korean seawater, namely DS from the East Sea off the coasts of Pohang (PDS) and Uljin (UDS), and seawater from the West Sea off the coast of Boryeong (BS), were collected. The seawaters were abundant in several minerals (calcium, iron, zinc, selenium, etc.). Mice were orally administered the seawaters for 42 days, followed by CPA-induced immunosuppression. The CPA induction reduced the weight of the spleen and lymph nodes; however, the administration of seawaters increased the weight of the lymphoid organs, accompanied by stimulation of natural killer cells' activity and NF-kB-mediated cytokine production (IFNγ, TNFα, IL1β, IL6, and IL12). The mouse-derived splenocytes showed lymphoproliferation without cytotoxicity in the seawater groups. Histopathological analysis revealed that the seawaters improved the CPA-induced atrophic changes by promoting lymphoproliferation in the spleen and lymph nodes. These results provide useful information for the use of Korean mineral-rich seawaters, particularly PDS and UDS, as alternative immunostimulants under immunosuppressive conditions.

Objective: Exposure to ambient PM 2.5 and its bound metals poses a risk to health and disease, via, in part, oxidative stress response. A variety of oxidative stress markers have been used as markers of response, but their relevance to environmental exposure remains to be established. We evaluated, longitudinally, a battery of oxidative stress markers and their relationship with the exposure of PM 2.5 and its bound metals in a panel of healthy participants., Material and Methods: Levels of residence- and personal-based ambient air PM 2.5 and its bound metals, as well as of lung function parameters, were assessed in a total of 58 questionnaire-administered healthy never smoker participants (male, 39.7%). Levels of urinary oxidative stress markers, including Nε-(hexanoyl)-lysine (HEL; an early lipid peroxidation product), 4-hydroxynonenal (4-HNE), N7-methylguanine (N7-meG), and 8-hydroxy-2-deoxyguanosine (8-OHdG), plasma antioxidants [superoxide dismutase (SOD) and glutathione peroxidase (GPx), and urinary metals were measured by ELISA, LC-MS, and ICP-MS, respectively. The results of three repeated measurements at two-month intervals were analyzed using the Generalized Estimating Equation (GEE)., Results: After adjusting for confounders, residence- and personal-based PM 2.5 levels were positively associated with HEL (β = 0.22 and 0.18) and N7-meG (β = 0.39 and 0.13). Significant correlations were observed between personal air PM 2.5 -Pb and urinary Pb with HEL (β = 0.08 and 0.26). While FVC, FEV 1 , FEV 1 /FVC, MMF, and PEFR predicted% were normal, a negative interaction (pollutant*time, P < 0.05) was noted for PM 2.5 -V, Mn, Co, Ni, Zn, As, and Pb. Additionally, a negative interaction was found for N7-meG (β = -21.35, -18.77, -23.86) and SOD (β = -26.56, -26.18, -16.48) with FEV 1 , FVC, and PEFR predicted%, respectively., Conclusion: These findings emphasize potential links between environmental exposure, internal dose, and health effects, thereby offering valuable markers for future research on metal exposure, oxidative stress, and health outcomes., Competing Interests: Declaration of competing interest All authors declare no conflict of interest in relation to this work., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are "non-atopic", lacking a clear etiology., Methods: In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman's rank correlation coefficients, multiple logistic regression, and multinomial logistic regression., Results: Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified., Conclusion: The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies., (© 2024. The Author(s).)

Therapeutic antibodies that block vascular endothelial growth factor (VEGF) show clinical benefits in treating nonsmall cell lung cancers (NSCLCs) by inhibiting tumor angiogenesis. Nonetheless, the therapeutic effects of systemically administered anti-VEGF antibodies are often hindered in NSCLCs because of their limited distribution in the lungs and their adverse effects on normal tissues. These challenges can be overcome by delivering therapeutic antibodies in their mRNA form to lung endothelial cells, a primary target of VEGF-mediated pulmonary angiogenesis, to suppress the NSCLCs. In this study, we synthesized derivatives of poly(β-amino esters) (PBAEs) and prepared nanoparticles to encapsulate the synthetic mRNA encoding bevacizumab, an anti-VEGF antibody used in the clinic. Optimization of nanoparticle formulations resulted in a selective lung transfection after intravenous administration. Notably, the optimized PBAE nanoparticles were distributed in lung endothelial cells, resulting in the secretion of bevacizumab. We analyzed the protein corona on the lung- and spleen-targeting nanoparticles using proteomics and found distinctive features potentially contributing to their organ-selectivity. Lastly, bevacizumab mRNA delivered by the lung-targeting PBAE nanoparticles more significantly inhibited tumor proliferation and angiogenesis than recombinant bevacizumab protein in orthotopic NSCLC mouse models, supporting the therapeutic potential of bevacizumab mRNA therapy and its selective delivery through lung-targeting nanoparticles. Our proof-of-principle results highlight the clinical benefits of nanoparticle-mediated mRNA therapy in anticancer antibody treatment in preclinical models.

Purpose: To assess the role of the interleukin (IL)-17 A/IL-17 receptor A (IL-17RA) in Kawasaki disease (KD)-related coronary arteritis (CA)., Methods: In human study, the plasma levels of IL-17 A and coronary arteries were concurrently examined in acute KD patients. In vitro responses of human coronary endothelial cells to plasma stimulation were investigated with and without IL-17RA neutralization. A murine model of Lactobacillus casei cell-wall extract (LCWE)-induced CA using wild-type Balb/c and Il17ra-deficient mice were also inspected., Results: The plasma levels of IL-17 A were significantly higher in KD patients before intravenous immunoglobulin therapy, especially in those with coronary artery lesion. The pre-IVIG IL-17 A levels positively correlated with maximal z scores of coronary diameters and plasma-induced endothelial mRNA levels of chemokine (C-X-C motif) ligand-1, IL-8, and IL-17RA. IL-17RA blockade significantly reduced such endothelial upregulations of aforementioned three genes and inducible nitric oxide synthase, and neutrophil transmigration. IL-17RA expression was enhanced on peripheral blood mononuclear cells in pre-IVIG KD patients, and in the aortic rings and spleens of the LCWE-stimulated mice. LCWE-induced CA composed of dual-positive Ly6G- and IL-17 A-stained infiltrates. Il17ra-deficient mice showed reduced CA severity with the fewer number of neutrophils and lower early inducible nitric oxide synthase and chemokine (C-X-C motif) ligand-1 mRNA expressions than Il17ra +/+ littermates, and absent IL-17RA upregulation at aortic roots., Conclusion: IL-17 A/IL-17RA axis may play a role in mediating aortic neutrophil chemoattraction, thus contributory to the severity of CA in both humans and mice. These findings may help to develop a new therapeutic strategy toward ameliorating KD-related CA., (© 2024. The Author(s).)

The forensic analysis of bloodstains on various substrates plays a crucial role in criminal investigations. This study presents a novel approach for analyzing bloodstains using Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) in combination with machine learning. ATR-FTIR offers non-destructive and non-invasive advantages, requiring minimal sample preparation. By detecting specific chemical bonds in blood components, it enables the differentiation of various body fluids. However, the subjective interpretation of the spectra poses challenges in distinguishing different fluids. To address this, we employ machine learning techniques. Machine learning is extensively used in chemometrics to analyze chemical data, build models, and extract useful information. This includes both unsupervised learning and supervised learning methods, which provide objective characterization and differentiation. The focus of this study was to identify human and porcine blood on substrates using ATR-FTIR spectroscopy. The substrates included paper, plastic, cloth, and wood. Data preprocessing was performed using Principal Component Analysis (PCA) to reduce dimensionality and analyze latent variables. Subsequently, six machine learning algorithms were used to build classification models and compare their performance. These algorithms comprise Partial Least Squares Discriminant Analysis (PLS-DA), Decision Trees (DT), Logistic Regression (LR), Naive Bayes Classifier (NBC), Support Vector Machine (SVM), and Neural Network (NN). The results indicate that the PCA-NN model provides the optimal solution on most substrates. Although ATR-FTIR spectroscopy combined with machine learning effectively identifies bloodstains on substrates, the performance of different identification models still varies based on the type of substrate. The integration of these disciplines enables researchers to harness the power of data-driven approaches for solving complex forensic problems. The objective differentiation of bloodstains using machine learning holds significant implications for criminal investigations. This technique offers a non-destructive, simple, selective, and rapid approach for forensic analysis, thereby assisting forensic scientists and investigators in determining crucial evidence related to bloodstains., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Achilles tendon is composed of dense connective tissue and is one of the largest tendons in the body. In veterinary medicine, acute ruptures are associated with impact injury or sharp trauma. Healing of the ruptured tendon is challenging because of poor blood and nerve supply as well as the residual cell population. Platelet-rich plasma (PRP) contains numerous bioactive agents and growth factors and has been utilized to promote healing in bone, soft tissue, and tendons., Objective: The purpose of this study was to evaluate the healing effect of PRP injected into the surrounding fascia of the Achilles tendon after allograft in rabbits., Methods: Donor rabbits (n = 8) were anesthetized and 16 lateral gastrocnemius tendons were fully transected bilaterally. Transected tendons were decellularized and stored at -80°C prior to allograft. The allograft was placed on the partially transected medial gastrocnemius tendon in the left hindlimb of 16 rabbits. The allograft PRP group (n = 8) had 0.3 mL of PRP administered in the tendon and the allograft control group (n = 8) did not receive any treatment. After 8 weeks, rabbits were euthanatized and allograft tendons were transected for macroscopic, biomechanical, and histological assessment., Results: The allograft PRP group exhibited superior macroscopic assessment scores, greater tensile strength, and a histologically enhanced healing process compared to those in the allograft control group., Conclusions: Our results suggest administration of PRP on an allograft tendon has a positive effect on the healing process in a ruptured Achilles tendon., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Korean Society of Veterinary Science.)

Background: As clinical practices with lithium salts for patients diagnosed with bipolar disorder (BD) are poorly documented in Asia, we studied the prevalence and clinical correlates of lithium use there to support international comparisons., Methods: We conducted a cross-sectional study of use and dosing of lithium salts for BD patients across 13 Asian sites and evaluated bivariate relationships of lithium treatment with clinical correlates followed by multivariate logistic regression modeling., Results: In a total of 2139 BD participants (52.3% women) of mean age 42.4 years, lithium salts were prescribed in 27.3% of cases overall, varying among regions from 3.20% to 59.5%. Associated with lithium treatment were male sex, presence of euthymia or mild depression, and a history of seasonal mood change. Other mood stabilizers usually were given with lithium, often at relatively high doses. Lithium use was associated with newly emerging and dose-dependent risk of tremors as well as risk of hypothyroidism. We found no significant differences in rates of clinical remission or of suicidal behavior if treatment included lithium or not., Conclusions: Study findings clarify current prevalence, dosing, and clinical correlates of lithium treatment for BD in Asia. This information should support clinical decision-making regarding treatment of BD patients and international comparisons of therapeutic practices., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Vutiglabridin, which affects the pharmacokinetics (PKs) of food, is currently under clinical development for the treatment of obesity. This study aimed to evaluate the effects of low- and high-fat meals on PKs of vutiglabridin in healthy male subjects. A randomized, open-label, single-dose, three-period, six-sequence crossover study was conducted. The subjects received a single oral dose of vutiglabridin 480 mg in a fasted state, 30 min after the intake of a low-fat meal (total 500-600 kcal, fat content 100-125 kcal) and high-fat meal (total 800-1000 kcal, fat content 500-600 kcal), with a 21-day washout period. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum plasma concentration (C max ) and area under the plasma concentration-time curve to the last measurable timepoint (AUC last ) were calculated. After intake of low- and high-fat meals, systemic exposure to vutiglabridin was increased, and the time to reach C max (T max ) was delayed compared to that in the fasted state. The GMRs (90% CIs) of low-fat meal to fasted state for C max and AUC last were 2.14 (1.76-2.60) and 2.15 (1.92-2.42), respectively, and those of high-fat meal to fasted state were 3.07 (2.53-3.72) and 3.00 (2.67-3.37), respectively. The median T max was delayed by 1.5 h in both fed states compared with that in the fasted state. The study drug was well-tolerated after administration in both the fed and fasted states. Food ingestion substantially increased the extent of oral vutiglabridin absorption in healthy subjects, and this enhancement increased with the fat content of the meal., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: Acupuncture, a widely employed traditional therapeutic modality known for its efficacy in pain alleviation and diverse condition management, may inadvertently result in mechanical nerve injury due to its invasive nature. This research aimed to ascertain the incidence of nerve injuries post-acupuncture, identify associated risk factors, and map the distribution of nerve injury sites., Methods: A case-control study nested in the National Health Insurance Research Database (NHIRD) 2000-2018 two million cohort was conducted. Patients previously diagnosed with nerve injury, surgery, or degeneration before acupuncture were excluded. Cases were defined as patients receiving acupuncture and seeking medical attention for nerve injury (ICD9-CM code 950-957) within 14 days post-procedure, while control groups comprised patients undergoing acupuncture without subsequent adverse events. Invasive treatments prior to adverse events and adverse events occurring more than 14 days post-acupuncture were excluded. To ensure case-control comparability, factors such as age, gender, socioeconomic status, and medical facility environment were controlled using propensity score matching., Results: The study encompassed 14,507,847 acupuncture treatments administered to 886,753 patients, with 8361 instances of post-acupuncture nerve injury identified, representing an incidence rate of approximately 5.76 per 10,000 procedures. Age emerged as a significant risk factor, with the adjusted odds ratios escalating with age. Several comorbidities including diabetes, hypothyroidism, liver cirrhosis, chronic kidney disease, herpes zoster, hepatitis virus, rheumatoid arthritis, systemic lupus erythematosus, dementia, and cerebrovascular accidents were associated with an elevated risk of nerve injury post-acupuncture., Conclusion: This study underscores the importance of meticulous patient profiling and cautious therapeutic approach in acupuncture, considering the evident influence of various demographic, systemic, and treatment-related factors on the incidence of nerve injuries., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)