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Yun Seob Jung,1 Byung Hak Jin,2 Ju Eun Choi,2 Min Soo Park,2 Young-Woo Kim,3 Hyung Won Kang,4 Sunyoung Cho,5 Choon Ok Kim2 1Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; 2Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, Seoul, Korea; 3School of Korean Medicine, Dongguk University, Gyeongju, Korea; 4College of Korean Medicine, Wonkwang University, Iksan, Korea; 5IntegroMediLab Co., Ltd, Seoul, KoreaCorrespondence: Choon Ok Kim, Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, Seoul, Korea, Tel +82-2-2228-0455, Fax +82-2-2227-7890, Email delivery98@yuhs.acPurpose: Herbal medicines are occasionally used in combination with conventional antidepressants to mitigate various depression-associated symptoms. However, there is limited information on herb–antidepressant interactions. In this study, we investigated the pharmacokinetic (PK) effects of four herbal medicines (Gami-soyosan, Banhasasim-tang, Ojeok-san, and Bojungikgi-tang) on escitalopram, a commonly used antidepressant.Patients and Methods: In this open-label, fixed-sequence, three-period, crossover study, 18 participants were enrolled and divided into two groups. Each group received a 10 mg oral dose of escitalopram in period 1. Participants took escitalopram once daily and their assigned herbal medicines thrice a day for 7 d in periods 2 (group 1: Gami-soyosan, group 2: Ojeok-san) and 3 (group 1: Banhasasim-tang; group 2: Bojungikgi-tang). The primary endpoints were Cmax,ss and AUCtau,ss of escitalopram. Cmax,ss and AUCtau,ss in period 1 were obtained using nonparametric superposition from single-dose data. The PK endpoints were classified according to the CYP2C19 phenotype.Results: Of 18 participants, 16 completed the study. Systemic exposure to escitalopram resulted in a minor increase in the presence of each herbal medicine. The geometric mean ratios (GMRs, combination with herbal medicines/escitalopram monotherapy) and their 90% confidence intervals (CIs) for Cmax,ss and AUCtau,ss were as follows: Gamisoyosan– 1.1454 (0.9201, 1.4258) and 1.0749 (0.8084, 1.4291), Banhasasim-tang– 1.0470 (0.7779, 1.4092) and 1.0465 (0.7035, 1.5568), Ojeok-san– 1.1204 (0.8744, 1.4357) and 1.1267 (0.8466, 1.4996), and Bojungikgi-tang– 1.1264 (0.8594, 1.4762) and 1.1400 (0.8515, 1.5261), respectively. Furthermore, no significant differences in the GMRs of Cmax,ss and AUCtau,ss were observed across different CYP2C19 phenotypes in any of the groups.Conclusion: The co-administration of escitalopram with Gami-soyosan, Banhasasim-tang, Ojeok-san, or Bojungikgi-tang did not exert significant PK effects on escitalopram. These findings provide valuable insights into the safe use of herbal medicines along with escitalopram.Keywords: CYP2C19 phenotype, herb–drug interaction, antidepressant, geometric mean ratio

Chungam Choi,1 Byung Won Yoo,2 Choon Ok Kim,2 Taegon Hong,2 Byung Hak Jin,2 Kwang-Seok Seo,3 Ja Yun Jang,4 Min Soo Park2 1Department of Nuclear Medicine, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea; 2Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea; 3Biopharmaceutical Research Laboratories, Dong-A Socio R&D Center, Yongin-si, Republic of Korea; 4Product Development Division, Dong-A ST Co., Ltd, Seoul, Republic of Korea Purpose: Filgrastim, a granulocyte-colony stimulating factor, is used to treat patients with neutropenia, including neutropenic fever. Leucostim® is a recombinant filgrastim product tested for biosimilarity with its reference product, Neupogen®. We conducted a comparative clinical trial of the 2 products. Patients and methods: A randomized, open-label, 2-way crossover, single-dose Phase I study was conducted for 56 healthy subjects. After a 5 and 10 μg/kg single subcutaneous administration of test and reference product, pharmacokinetic and pharmacodynamic parameters (absolute neutrophil count and CD34+ cell count) were compared. During the study, safety tests and adverse event monitoring were performed. Results: The test and the reference products had a comparable pharmacokinetic, pharmacodynamic, and safety profile. In both 5 and 10 μg/kg dosing, the 90% CIs of the test to reference ratio for primary parameters (peak plasma concentration and area under the plasma concentration vs time curve from time 0 extrapolated to the infinite time for plasma filgrastim concentration; maximal effect and area under the time-effect curve from time 0 to time of the last quantifiable effect for absolute neutrophil count) were within the 0.8–1.25 range. In addition, safety profiles between the 2 products were similar without any serious adverse events. Conclusion: This study has provided firm clinical evidence that the test filgrastim product is similar to its reference filgrastim product. Keywords: bioequivalence, biosimilar, G-CSF, biologics

Background: Induction of labour has become an increasingly common procedure. Ripening methods, including mechanical devices and pharmacological agents, improve the success rate of labour induction.Objective: To compare the efficacy and safety of the double-balloon catheter with prostaglandin E2 agents used for labour induction.Search Strategy: We searched electronic sources from MEDLINE, Embase and Web of Science, the Cochrane Library Database of Systematic Reviews, and ClinicalTrials.gov website.Selection Criteria: Only randomised controlled trials comparing the PGE2 agents with the double-balloon catheter for cervical ripening and labour induction in women with unfavourable cervices were included in the analysis.Data Collection and Analysis: The main outcomes included the vaginal delivery rate within 24 hours and risk of caesarean section. We calculated relative risks and mean differences using fixed- and random-effects models.Main Results: Nine studies (1866 patients) were included in this systematic review. Both the double-balloon catheter and PGE2 agents were comparable with regard to rate of caesarean section (RR 0.92; 95% CI 0.79, 1.07), vaginal delivery within 24 hours (RR 0.95; 95% CI 0.78, 1.16) and maternal adverse events, but the risk of excessive uterine activity (RR 10.02; 95% CI 3.99, 25.17) and need for neonatal intensive care unit admissions (RR 1.31; 95% CI 1.01, 1.69) were significantly increased in women who received PGE2 agents.Conclusions: The double-balloon catheter demonstrated greater safety and cost-effectiveness than PGE2 agents for cervical ripening and labour induction. The efficacy profiles of both methods were similar.Tweetable Abstract: Double-balloon catheter versus prostaglandin E2 for cervical ripening and labour induction. [ABSTRACT FROM AUTHOR]

Granulocyte colony-stimulating factor (G-CSF) mobilizes peripheral blood (PB) progenitor cells from bone marrow (BM) into circulation for PB stem cell transplantation (PBSCT). This study aimed to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model of filgrastim in healthy subjects to optimize PB CD34 + cell collection. Plasma filgrastim concentrations and CD34 + cell count data were obtained from a clinical study involving healthy Korean subjects. A total of 1378 plasma concentration measurements and 982 CD34 + cell count data collected from 53 subjects were used in the PK-PD model. Filgrastim PKs were adequately described by a one-compartment linear disposition model with an additional transit compartment for absorption. Log-transformed body weight was the only significant covariate affecting the volume of distribution and clearance. CD34 + cell mobilization was best captured by a modified Friberg model, assuming continual entry of proliferating BM stem cells into PB via a single transit compartment. Simulation results suggested that the 5 μg/kg twice-daily dosing regimen may yield higher CD34 + cell counts compared to the 10 μg/kg once-daily regimen for achieving target CD34 + cell counts of 20/μL and 50/μL. We successfully developed a robust PK-PD model of G-CSF that optimizes the yield of CD34 + cells during allogeneic PBSCT. This model can guide the efficient determination of optimal G-CSF dosing regimens and CD34 + cell harvesting strategies., (© 2025 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Izuforant is a selective, and potent histamine H4 receptor (H4R) antagonist developed to treat atopic dermatitis (AD). There is an unmet medical need for therapeutic agents to control inflammation and pruritus. Izuforant is a strong candidate for this task based on the findings of non-clinical studies showing that inhibition of the histamine-mediated signaling pathway via H4R by izuforant results in decreased pruritus and inflammation. This study aimed to evaluate the clinical pharmacokinetic (PK) and pharmacodynamic (PD) profiles of izuforant. Dose-block-randomized, double-blind, placebo-controlled, single- and multiple ascending dose studies were conducted in 64 healthy volunteers. For the single ascending dose (SAD) study, 10-600 mg izuforant was administered to the designated groups. For the multiple ascending dose (MAD) study, 100-400 mg izuforant was administered to three groups. The clinical pharmacokinetic (PK) profile of izuforant was evaluated using plasma and urine concentrations. Blood sampling for the PD assay, which measured imetit-induced eosinophil shape changes (ESC), was also conducted. A one-compartment PK model described the distribution and elimination profiles of izuforant. An imetit-induced ESC inhibition test was established and validated for PD evaluation as a measure of the H4R antagonistic effect. ESC inhibition was observed even at doses as low as 10 mg; however, this inhibition became stronger and lasted longer as the dose increased. All izuforant doses were well tolerated, and no discontinuations due to adverse events (AE) or deaths were reported., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Alanine aminotransferase (ALT) is widely used to screen patients with hepatic diseases. However, the current reference ranges (< 50 U/L) were developed by laboratories and have not been validated in populations with a large number of healthy individuals., Methods: This study collected venous blood and anthropometric data from a total of 13,287 healthy children aged 3 months to 18 years who underwent routine physical examinations in the Department of Pediatric Healthcare. We applied the least mean square algorithm to establish age- and sex-related reference percentiles of serum levels of transaminases. For validation, we recruited 4276 children and adolescents with obesity/overweight who underwent evaluation and metabolic tests in the hospital. Using receiver operating characteristic curves, we determined age- and sex-specific upper limit percentiles of liver enzymes for fatty liver diseases., Results: This study revealed a significant correlation between serum transaminase levels and age and sex (P < 0.01). These transaminase levels exhibited age- and sex-specific patterns. Among individuals in the non-alcoholic fatty liver disease (NAFLD) cohort, elevated ALT levels displayed a positive association with clinical markers of disease severity, including homeostatic model assessment of insulin resistance, waist-hip ratio, and serum uric acid levels (P < 0.01). According to the receiver operating characteristic curves, ALT levels at the 92.58th percentile for boys and the 92.07th percentile for girls yielded the highest accuracy and specificity., Conclusions: This study provides age- and sex-specific reference ranges for ALT, aspartate aminotransferase, and γ-glutamyltransferase in Chinese children and adolescents, making it the largest population study to date. Furthermore, the study establishes a precise upper limit for ALT levels, facilitating their use in NAFLD screening. Video Abstract., (© 2024. Children's Hospital, Zhejiang University School of Medicine.)

Purpose: This study investigates the role and effectiveness of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in oral cancer, focusing on the clinical relevance of EGFR and myeloid cell leukemia-1 (Mcl-1) in head and neck cancers (HNCs). It aims to explore the molecular mechanism of afatinib, a TKI, in treating human oral cancer., Methods: We conducted an in silico analysis using databases like The Cancer Genome Atlas, Gene Expression Omnibus, and Clinical Proteomic Tumor Analysis Consortium, along with immunohistochemistry staining, to study EGFR and Mcl-1 expression in HNCs. For investigating afatinib's anticancer properties, we performed various in vitro and in vivo analyses, including trypan blue exclusion assay, Western blotting, 4'-6-diamidino-2-phenylindole staining, flow cytometry, quantitative real-time PCR, Mitochondrial membrane potential assay, overexpression vector construction, transient transfection, and a tumor xenograft model., Results: Higher expression levels of EGFR and Mcl-1 were observed in HNC patient tissues compared to normal tissues, with their co-expression significantly linked to poor prognosis. There was a strong correlation between EGFR and Mcl-1 expressions in oral cancer patients. Afatinib treatment induced apoptosis and suppressed Mcl-1 in oral cancer cell lines without the EGFR T790M mutation. The mechanism of afatinib-induced apoptosis involved the EGFR/mTOR/Mcl-1 axis, as shown by the effects of mTOR activator MHY1485 and inhibitor rapamycin. Afatinib also increased Bim expression, mitochondrial membrane permeabilization, and cytochrome c release. It significantly lowered tumor volume without affecting body, liver, and kidney weights., Conclusion: Afatinib, targeting the EGFR/mTOR/Mcl-1 axis, shows promise as a therapeutic strategy for oral cancer, especially in patients with high EGFR and Mcl-1 expressions., (© 2024. The Author(s).)

Bepotastine, a second-generation antihistamine for allergic rhinitis and urticaria, is widely used in all age groups but lacks appropriate dosing guidelines for pediatric patients, leading to off-label prescriptions. We conducted this study to propose an optimal dosing regimen for pediatric patients based on population pharmacokinetic (popPK) and physiologically based pharmacokinetic (PBPK) models using data from two previous trials. A popPK model was built using NONMEM software. A one-compartment model with first-order absorption and absorption lag time described our data well, with body weight incorporated as the only covariate. A PBPK model was developed using PK-Sim software version 10, and the model well predicted the drug concentrations obtained from pediatric patients. Furthermore, the final PBPK model showed good concordance with the known properties of bepotastine. Appropriate pediatric doses for different weight and age groups were proposed based on the simulations. Discrepancies in recommended doses from the two models were likely due to the incorporation of age-dependent physiological factors in the PBPK model. In conclusion, our study is the first to suggest an optimal oral dosing regimen of bepotastine in pediatric patients using both approaches. This is expected to foster safer and more productive use of the drug.

Clopidogrel is an antiplatelet drug used to reduce the risk of acute coronary syndrome and stroke. It is converted by CYP2C19 to its active metabolite; therefore, poor metabolizers (PMs) of CYP2C19 exhibit diminished antiplatelet effects. Herein, we conducted a proof-of-concept study for using population pharmacokinetic-pharmacodynamic (PK-PD) modeling to recommend a personalized clopidogrel dosing regimen for individuals with varying CYP2C19 phenotypes and baseline P2Y12 reaction unit (PRU) levels. Data from a prospective phase I clinical trial involving 36 healthy male participants were used to develop the population PK-PD model predicting the concentrations of clopidogrel, clopidogrel H4, and clopidogrel carboxylic acid, and linking clopidogrel H4 concentrations to changes in PRU levels. A two-compartment model effectively described the PKs of both clopidogrel and clopidogrel carboxylic acid, and a one-compartment model of those of clopidogrel H4. The CYP2C19 phenotype was identified as a significant covariate influencing the metabolic conversion of the parent drug to its metabolites. A PD submodel of clopidogrel H4 that stimulated the fractional turnover rate of PRU levels showed the best performance. Monte Carlo simulations suggested that PMs require three to four times higher doses than extensive metabolizers to reach the target PRU level. Individuals within the top 20th percentile of baseline PRU levels were shown to require 2.5-3 times higher doses than those in the bottom 20th percentile. We successfully developed a population PK-PD model for clopidogrel considering the impact of CYP2C19 phenotypes and baseline PRU levels. Further studies are necessary to confirm actual dosing recommendations for clopidogrel., (© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: To evaluate the amount of dentin loss following immersion in or toothbrushing with whitening toothpaste (WT) containing hydrogen peroxide (HP) and citric acid (CA). Additionally, the amount of dentin loss after brushing with a WT alone or in combination with a conventional toothpaste was assessed, and the effects of HP and CA solutions on the dentin surface were investigated., Methods: Bovine dentin specimens (n= 350) were randomly assigned to seven solutions of various compositions as toothpaste: The specimens assigned to each solution were then further divided into five treatment groups (n=10 each) : Group A = 1-hour immersion in each solution (ES); Group B = 10,000 brushing in ES; Group C = 1-hour immersion in ES + 10,000 brushing in ES; Group D = 1-hour immersion in ES + 10,000 brushing in reference slurry (RS); Group E = 10,000 brushing in ES + 10,000 brushing in RS. The amount and pattern of dentin loss were determined, and the surfaces were observed using noncontact profilometry., Results: The WT (pH 5.0) caused lower dentin loss than RS after a single brushing cycle; however, the extent of dentin loss after 1 hour of immersion in the WT was significantly greater than that in the RS. Among the specimens treated with WT, a significant difference in dentin loss was observed between Group C and Groups D and E (P< 0.05) but not between Groups D and E. The surfaces exposed to CAS1, CAPB, and WT exhibited U-shaped patterns of dentin loss after brushing or immersion, whereas a wedge-shaped pattern was observed in those that underwent brushing with the RS., Clinical Significance: The effects (dentin abrasion) of a whitening toothpaste containing hydrogen peroxide and citric acid when used in combination with a conventional toothpaste were similar to those seen with the continuous use of a conventional toothpaste alone., Competing Interests: The authors declared no conflict of interest. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1l1A204851611)., (Copyright©American Journal of Dentistry.)

Recent developments in tissue clearing methods such as the passive clearing technique (PACT) have allowed three-dimensional analysis of biological structures in whole, intact tissues, thereby providing a greater understanding of spatial relationships and biological circuits. Nonetheless, the issues that remain in maintaining structural integrity and preventing tissue expansion/shrinkage with rapid clearing still inhibit the wide application of these techniques in hard bone tissues, such as femurs and tibias. Here, we present an optimized PACT-based bone-clearing method, Bone-mPACT+, that protects biological structures. Bone-mPACT+ and four different decalcifying procedures were tested for their ability to improve bone tissue clearing efficiency without sacrificing optical transparency; they rendered nearly all types of bone tissues transparent. Both mouse and rat bones were nearly transparent after the clearing process. We also present a further modification, the Bone-mPACT+ Advance protocol, which is specifically optimized for processing the largest and hardest rat bones for easy clearing and imaging using established tissue clearing methods., (© 2023. The Author(s).)

Purpose: To evaluate the inhibitory effects of Streptococcus salivarius K12 and M18 strains on the growth of six oral pathogens as well as their release of volatile sulfur compounds (VSCs), and whether these probiotics can inhibit the expression of arginine-specific gingipain A (RgpA), a protease secreted by Porphyromonas gingivalis., Materials and Methods: After six halitogenic oral pathogens (P. gingivalis, Treponema denticola, Tannerella forsythia, Fusobacterium nucleatum, Parvimonas micra, and Eikenella corrodens) were cultured with or without S. salivarius K12 and M18, the concentration of two VSCs was measured. Moreover, the antimicrobial activity of S. salivarius K12 and M18 against these pathogens and the suppressive effect on RgpA release by P. gingivalis were assessed., Results: In the co-culture of S. salivarius K12 or M18 with oral pathogenic bacteria, the growth of all six oral pathogens was significantly inhibited (p < 0.01). Additionally, S. salivarius K12 and M18 had an inhibitory effect on the production of the halitogenic substances H2S and CH3SH (p < 0.01) as well as the expression of P. gingivalis RgpA. Finally, we demonstrated that the addition of only culture supernatants of the two strains K12/M18 to oral pathogen cultures was sufficient to mimic the effects of K12/M18 co-cultures upon VSCs production and protease expression., Conclusions: S. salivarius K12 and M18 inhibited VSC release by all six of the major oral pathogens that were assayed and reduced the expression of RgpA.

Evogliptin (EV) is a novel dipeptidyl peptidase-4 inhibitor (DPP4i) for glycemic control in patients with type 2 diabetes mellitus (T2DM). This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between EV and sodium glucose cotransporter-2 inhibitors (SGLT2i) in healthy volunteers since combination therapy of DPP4i and SGLT2i has been considered as an effective option for T2DM treatment. A randomized, open-label, multiple-dose, two-arm, three-period, three treatments, two-sequence crossover study was conducted in healthy Korean volunteers. In arm 1, subjects were administered 5 mg of EV once daily for 7 days, 25 mg of empagliflozin (EP) once daily for 5 days, and the combination once daily for 5 days (EV + EP). In arm 2, subjects were administered 5 mg of EV once daily for 7 days, 10 mg of dapagliflozin (DP) once daily for 5 days, and the combination once daily for 5 days (EV + DP). Serial blood samples were collected for PK analysis, and oral glucose tolerance tests were conducted for PD analysis. In each arm, a total of 18 subjects completed the study. All adverse events (AEs) were mild with no serious AEs. The geometric mean ratio and confidence interval of the main PK parameters (maximum concentration of the drug in plasma at steady state and area under the plasma drug concentration-time curve within a dosing interval at a steady state) between EV and either EP or DP alone were not significantly altered by co-administration. Administration of EV + EP or EV + DP did not result in significant PD changes, as determined by the glucose-lowering effect. Administration of EV + EP or EV + DP had no significant effects on the PK profiles of each drug. All treatments were well-tolerated., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Spinal intradural arachnoid cysts (SACs) account for approximately 10% of total arachnoid cysts, and iatrogenic attribution is rare. A 50-year-old male presented with low back pain and severe radiating pain in his right leg along the S1 dermatome. He had an interspinous device (ISD) inserted 10 years earlier. Plain radiographs showed breakage and angular movement of the ISD at L4/5. Magnetic resonance imaging (MRI) of the lumbosacral spine disclosed multiple intradural cystic tumors in the entire lumbar region. He underwent removal of the ISD, laminectomy, and resection of the intradural cyst. The pathologic finding of the cystic tumor was compatible with arachnoid cyst. Antibodies to parasites, including cysticercosis, were negative in both the serum and cerebrospinal fluid (CSF). The ventral surface of the implant was clearly broken.

Background: DWP16001, a sodium-glucose cotransporter-2 inhibitor, has shown promise for improving blood glucose control and facilitating weight loss. Co-administration with phentermine could enhance these effects. So, we aimed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions of DWP16001 and phentermine., Methods: We conducted a randomized, open-label, 3-treatment, 6-sequence, 3-period crossover study involving 24 healthy adults. Participants received either DWP16001 (2 mg), phentermine (37.5 mg), or a combination of both once daily for 7 days. Blood samples, urine samples, and body weights were collected to evaluate the PK and PD., Results: The PK of the combination was found to be similar to that of the monotherapy. The geometric mean ratio (GMR) of C max,ss , and AUC tau,ss were 0.98 and 1.00, respectively, for DWP16001, and 1.01 and 0.94, respectively, for phentermine. Co-administration did not significantly affect the 24-hour urinary glucose excretion compared to DWP16001 monotherapy, and the GMR was 0.90. Participants tended to experience greater weight loss in the combination therapy group, and all demonstrated good tolerance., Conclusions: Our findings indicate that there were no significant interactions during co-administration. These results suggest that the combination of DWP16001 and phentermine may be safe and effective for the treatment of obesity and diabetes., Clinical Trial Registration: NCT05321732.

Concomitant administration of lobeglitazone, empagliflozin, and metformin is expected to enhance blood glucose-lowering effects and improve medication compliance in patients with diabetes mellitus. In this study, we investigated the pharmacokinetic (PK) interactions and safety of lobeglitazone and co-administered empagliflozin and metformin, which are approved agents used in clinical settings. Two randomized, open-label, multiple-dose, 2-treatment, 2-period, 2-sequence crossover clinical trials (parts 1 and 2) were conducted independently. In part 1, lobeglitazone monotherapy or lobeglitazone, empagliflozin, and metformin triple therapy was administered for 5 days. In part 2, empagliflozin and metformin dual therapy or the abovementioned triple therapy were administered for 5 days. Serial blood samples were collected up to 24 hours after the last dose in each period for PK evaluation. The primary PK parameters (AUC tau,ss , C max,ss ) of treatment regimens in each study part were calculated and compared. For lobeglitazone, the geometric mean ratios (GMRs) with 90% confidence intervals (CI) for triple therapy over monotherapy were 1.08 (1.03-1.14) for C max,ss and 0.98 (0.90-1.07) for AUC tau,ss . For empagliflozin, the GMRs and 90% CIs for triple therapy over dual therapy were 0.87 (0.78-0.97) for C max,ss and 0.97 (0.93-1.00) for AUC tau,ss . For metformin, the GMRs and 90% CIs for triple therapy over dual therapy were 1.06 (0.95-1.17) for C max,ss and 1.04 (0.97-1.12) for AUC tau,ss . All reported adverse events were mild. The triple therapy consisting of lobeglitazone, empagliflozin, and metformin did not show any clinically relevant drug interactions in relation to the PKs and safety of each drug substance., Trial Registration: ClinicalTrials.gov Identifier: NCT04334213., Competing Interests: Conflict of Interest: - Authors: Nothing to declare - Reviewers: Nothing to declare - Editors: Nothing to declare, (Copyright © 2023 Translational and Clinical Pharmacology.)

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder prevalent in school-age children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein γ-8 (TARP γ-8, also known as calcium voltage-gated channel auxiliary subunit gamma 8 (CACNG8)) is an auxiliary AMPA receptor (AMPAR) subunit. Here, we report an association between TARP γ-8 and ADHD, whereby adolescent TARP γ-8 knockout (KO) mice exhibited ADHD-like behaviors, including hyperactivity, impulsivity, anxiety, impaired cognition, and memory deficits. Human single-nucleotide polymorphism (SNP) analysis also revealed strong associations between intronic alleles in CACNG8 genes and ADHD susceptibility. In addition, synaptosomal proteomic analysis revealed dysfunction of the AMPA glutamate receptor complex in the hippocampi of TARP γ-8 KO mice. Proteomic analysis also revealed dysregulation of dopaminergic and glutamatergic transmissions in the prefrontal cortices of TARP γ-8 KO mice. Methylphenidate (MPH), which is commonly used to treat ADHD, significantly rescued the major behavioral deficits and abnormal synaptosomal proteins in TARP γ-8 KO mice. Notably, MPH significantly reversed the up-regulation of Grik2 and Slc6a3 in the prefrontal cortex. MPH also significantly improved synaptic AMPAR complex function by up-regulating other AMPAR auxiliary proteins in hippocampal synaptosomes. Taken together, our results suggest that TARP γ-8 is involved in the development of ADHD in humans. This study provides a useful alternative animal model with ADHD-like phenotypes related to TARP γ-8 deficiency, which has great potential for the development of new therapies.

Objective: To analyze the trends of overweight and obesity prevalence in Chinese children, aged from 6 to 15 years old among 4 provinces and cities from 2009 to 2019. Methods: Reviewed the national multi-center epidemiological survey data of children from the National Key Technology R&D Program of China during the Eleventh Five-Year Plan (2009 to 2010) and the National Key Research and Development Program of China during the Thirteenth Five-Year Plan (2017 to 2019). The participants' data were selected from four provinces,municipalities and autonomous region,including Beijing, Tianjin (Northern region), Zhejiang (Eastern region), and Guangxi (Southern region). Totally 14 597 pairs of 6-15 year-old children were surveyed. According to the body mass index (BMI) and standard deviation score (SDS) of children among different genders, ages, and regions, t test or chi-square test was used to evaluate the changes in overweight and obesity over a 10-year span. Results: Totally 7 721 pairs of boys and 6 876 pairs of girls were collectted in this study, whose mean age was (10.7±2.5) years. In the past 10 years, the overall BMISDS were 0.39±1.24 and 0.36±1.31 and the overall obesity rate were 11.8% ( n =1 773) anel 12.5% ( n =1 813) of children in the 4 administrative regions did not have statistically significant differences (all P >0.05). However, the overall overweight rate rose from 17.1% ( n =2 496) to 19.1% ( n =2 781) (χ²=18.657, P <0.01), and the average annual growth rate was 0.20%. The BMISDS in the Eastern region increased from 0.10±1.07 to 0.19±1.22 ( t =-4.095, P <0.01), and the overweight rate and obesity rate increased by 3.8% ( n =202) and 3.1% ( n =169) respectively (both P <0.01); the BMISDS in the Northern region and the obesity rate did not have statistically significant differences(all P >0.05), but the overweight rate rose from 20.5% ( n= 1 233) to 22.8% ( n =1 365) significantly (χ²=7.431, P <0.01); BMISDS in the Southern region was significantly decreased from 0.30±1.19 to 0.09±1.25 ( t =1.426, P <0.01), and the rate of obesity decreased from 9.8% ( n =315) to7.9% ( n =256) (χ²=6.46, P <0.05), the overweight rate was not stafistically significant ( P =0.10), respectively. The obesity rate of boys had risen from 16.4% ( n =1 265) to 18.2% (1 407) (χ²=8.997, P <0.01) in the past 10 years, and the overweight rate had risen from 18.0% ( n =1 393) to 20.5% ( n =1 579) (χ²=14.26, P <0.01). The overweight+obesity rate rose from 34.4% ( n =2 658) to 38.7% ( n =2 986) (χ²=29.859, P <0.01), and the weight problem in the age group of 8 to 11 years was particularly severe (all P <0.01). The obesity rate of girls dropped from 6.8% ( n =468) to 5.9% ( n =406) (χ²=4.546, P <0.05), the overweight rate rose from 16.0% ( n =1 103) to 17.5% ( n =1 202) (χ²=5.006, P <0.05), and the overall overweight+obesity rate rose from 22.8% ( n =1 571) to 23.4% ( n =1 608) (χ²=0.53, P >0.05). Conclusions: The growth rate of obesity among children in China had slowed down from 2009 to 2019, but the overweight rate was still on the rise. The overall base of overweight and obesity population continued to expand. The weight problem of peri-adolescent boys was particularly prominent. The current status of obesity epidemics in different regions, ages, and genders are significantly different and had their own characteristics. It is necessary to establish a personalized prevention and control strategy.

Objective: In this study, we investigate about relationship between postoperative global sagittal imbalance and occurrence of mechanical complications after adult spinal deformity (ASD) surgery. In global sagittal balance parameters, odontoid-hip axis (OD-HA) angle and T1 pelvic angle (TPA) were analyzed., Methods: Between January 2009 and December 2016, 199 consecutive patients (26 males and 173 females) with ASD underwent corrective fusion of more than 4 levels and were followed up for more than 2 years. Immediate postoperative and postoperative 2 years whole spine x-rays were checked for evaluating immediate postoperative OD-HA, TPA, and other parameters. In clinical outcomes, back and leg pain visual analogue scale, Scoliosis Research Society-22 spinal deformity questionnaire (SRS-22), Oswestry Disability Index (ODI), 36- item Short Form Health Survey (SF-36) were evaluated., Results: Based on the occurrence of mechanical complications, a comparative analysis was performed for each parameter. In univariable analysis, mechanical complications were significantly much more occurred in OD-HA abnormal group (odds ratio [OR], 3.296; p < 0.001; area under the curve [AUC] = 0.645). In multivariable analysis, the result was much more related (OR, 2.924; p = 0.001; AUC = 0.727). In contrast, there was no significant difference between normal and the occurrence of mechanical complications in TPA. In clinical outcomes (normal vs. abnormal), the differences of SRS-22 (0.88 ± 0.73 vs. 0.68 ± 0.64, p = 0.042), ODI (-24.72 ± 20.16 vs. -19.01 ± 19.95, p = 0.046), SF-36 physical composite score (19.33 ± 18.55 vs. 12.90 ± 16.73, p = 0.011) were significantly improved in OD-HA normal group., Conclusion: The goal of ASD surgery is to improve patient life quality through correction. In our study, TPA was associated with spinopelvic parameter and OD-HA angle was associated with health-related quality of life and complications. OD-HA angle is predictable factor for mechanical complications after ASD surgery.

Study Design: Retrospective study., Objectives: Unilateral biportal endoscopic surgery (UBES) is a popular surgical method used to treat degenerative spinal diseases because of its merits, such as reduced tissue damage and outstanding visual capacity. However, dural injury is the most common complication of UBES with an incidence rate of 1.9% to 5.8%. The purpose of this study was to analyze the pattern of dural injury during UBES and to report the clinical course., Methods: We retrospectively reviewed the medical and radiographic records of surgically treated patients who underwent UBES at a single institute between January 2018 and December 2019., Results: Fifty-three patients, representing 67 segments, underwent UBES. Seven dural injuries occurred, and the incidence rate was 13.2%. Among 16 far lateral approaches, 2 dural injuries of the exiting roots occurred and were treated with fibrin sealant reinforcement. Among 51 median approaches, dural injury occurred at the thecal sac (n = 3) and traversing root (n = 2). A dural injury of the shoulder of the traversing root was treated with a fibrin sealant; however, a defect in the thecal sac required a revision for reconstruction. The other 2 thecal sac injuries were directly repaired via microscopic surgery., Conclusions: Dural injury during UBES can occur because of the various anatomical features of the meningo-vertebral ligaments. Direct repair of the central dural defect should be considered under microscopic vision. A linear tear in the lateral dura or root can be controlled with a simple patchy reinforcement under endoscopic vision.

Aims: Evogliptin is a potent and selective dipeptidyl peptidase-4 inhibitor for glycaemic control in patients with type 2 diabetes mellitus. Since evogliptin is mainly eliminated through hepatic metabolism, we investigated the pharmacokinetics (PKs) and safety characteristics of evogliptin in Korean patients with mild or moderate hepatic impairment., Methods: An open-label, parallel-group study was conducted in patients with mild or moderate hepatic impairment and healthy control subjects matched to each patient for sex, age and body mass index. A single dose (5 mg) of evogliptin was administered orally, and serial blood samples were collected over 120 h to assess the PK profile of evogliptin and its main metabolites (M7 and M8)., Results: Patients with mild hepatic impairment and their matched healthy controls showed similar maximum concentration (C max ) and area under the concentration-time curve values from 0 to 120 h (AUC last ); the geometric mean ratio (GMR) and 90% confidence interval (CI) were 1.04 (0.80, 1.35) and 1.01 (0.90, 1.14), respectively. Exposure to evogliptin (C max and AUC last ) was increased by about 40% in patients with moderate hepatic impairment-the GMR and 90% CI were 1.37 (1.09, 1.72) and 1.44 (1.18, 1.75), respectively. The metabolic ratios of M7 and M8 were lower in patients with moderate hepatic impairment than in matched healthy controls. Evogliptin was well tolerated by both patients and healthy subjects., Conclusion: Although evogliptin exposure was increased in patients with moderate hepatic impairment, the increase is unlikely to affect safety and efficacy adversely, and no dose adjustment is warranted., (© 2020 British Pharmacological Society.)

This study aimed to compare the change of surface roughness (Ra) and gloss units (GU) of five dental composites (Filtek Z250, Filtek Z350XT, Metafil CX, Ceram X one, and Venus Diamond) polished with three systems (Sof-Lex XT, Enhance/Pogo, and Sof-Lex Diamond) before/after simulated brushings and to determine the amount of time required to achieve maximum gloss. Ninety rectangular specimens (n=18 per composite) were prepared. Six specimens of each composite were assigned to one of the polishing systems. The Ra and GU of each specimen were measured after each polishing step. Five polished specimens per composite were brushed with a toothbrush machine, and the Ra and GU values were determined. Filtek Z350XT exhibited the most stable and lowest Ra during the brushing cycles regardless of polishing system. When using the Sof-Lex Diamond and Enhance/Pogo systems, the highest gloss and the smoothest surfaces were achieved after polishing and brushing.

(1) Background : To analyze the association between periodontal health status and daily oral health activities including lingual and palatal site toothbrushing. (2) Methods : One hundred and fifty Korean elderly people aged >65 years participated in the study. Clinical examination regarding oral health status, including periodontal health status, was evaluated, and data on the oral health activities, socio-demographic factors, and systemic health-related factors were obtained using a questionnaire. Statistical analyses assessed the differences of periodontal health status according to daily oral health activities, including lingual and palatal site toothbrushing. (3) Results : Oral health activities including lingual and palatal site toothbrushing, frequency of toothbrushing, use of an interdental toothbrush, dietary patterns, and activity dependence correlated with bleeding on probing (BOP) and periodontitis. After adjusting for covariates, the prevalence of periodontitis was lower in the group where the inner surfaces of the teeth were partially or wholly cleaned than in the group without such cleaning. High BOP was significantly associated with the brushing of the inner surfaces of teeth. (4) Conclusions : Lingual and palatal site toothbrushing was associated with good periodontal health status in the elderly; the importance of brushing the inner surfaces of teeth should be emphasized for them and their caregivers.

Recent developments in tissue clearing methods have significantly advanced the three-dimensional analysis of biological structures in whole, intact tissue, providing a greater understanding of spatial relationships and biological circuits. Nonetheless, studies have reported issues with maintaining structural integrity and preventing tissue disintegration, limiting the wide application of these techniques to fragile tissues such as developing embryos. Here, we present an optimized passive tissue clearing technique (PACT)-based embryo clearing method, initial embedding PACT (IMPACT)-Basic, that improves tissue rigidity without compromising optical transparency. We also present IMPACT-Advance, which is specifically optimized for thin slices of mouse embryos past E13.5. We demonstrate proof-of-concept by investigating the expression of two relatively understudied PR domain (PRDM) proteins, PRDM10 and PRDM13, in intact cleared mouse embryos at various stages of development. We observed strong PRDM10 and PRDM13 expression in the developing nervous system and skeletal cartilage, suggesting a functional role for these proteins in these tissues throughout embryogenesis.

Objective: To explore the role of long intergenic non-coding ribonucleic acid 483 (LINC00483) in the development of breast cancer (BC) and its possible mechanism of action., Patients and Methods: LINC00483 expression level in BC tissues and cell lines was detected via quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR). The association between LINC00483 expression and survival rate of BC patients was analyzed using Kaplan-Meier survival analysis. The binding relation between LINC00483 and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was verified via RNA immunoprecipitation (RIP) and RNA pull-down assays. The expression of IGF2BP1 in BC patients was determined using qRT-PCR. Moreover, the role of LINC00483 on the proliferative ability of BC cells was detected via cell counting kit-8 (CCK8) and 5-Ethynyl-2'-deoxyuridine (EdU) assays. Whether LINC00483 exerts its effects under the regulation of IGF2BP1 was verified via reversal assay., Results: The results of qRT-PCR showed that LINC00483 had a significantly high expression in BC tissues and corresponding cell lines, and it rose with the increase in tumor stage, which was higher in patients with metastasis. CCK8/EdU assay revealed that the proliferative ability of MDA-MB-231 and MCF-7 cell lines was enhanced by overexpression of LINC00483. It was confirmed by RIP and pull-down assays that IGF2BP1 could bind to LINC00483, and the expression of LINC00483 was significantly promoted after up-regulation of IGF2BP1. It was found via qRT-PCR that the expression of IGF2BP1 evidently rose in BC patients, which was positively related with the expression level of LINC00483. The results of reversal assay manifested that the function of LINC00483 on cell proliferation was regulated by IGF2BP1., Conclusions: LINC00483 has a significantly higher expression in BC tissues than that in para-carcinoma tissues, and its effect of promoting proliferation of BC cells may be regulated by IGF2BP1.

Objective: To analyze the epidemiological characteristics of imported COVID-19 cases in early phase in Shanghai, introduce measures and provide reference for prevention and control of imported COVID-19 cases. Methods: Data of imported COVID-19 cases in Shanghai reported as of 30 March, 2020 were obtained from National Notifiable Disease Report System of China CDC and field epidemiological investigation reports by CDCs in Shanghai. The information about measures of prevention and control was collected from official websites and platforms of the governments. Data cleaning and statistical analysis were performed with softwares of EpiData 3.1, Excel 2019 and SAS 9.4. Results: A total of 171 imported COVID-19 cases had been reported as of 30 March, 2020 in Shanghai, including 170 confirmed cases and 1 asymptomatic infection case. Among them, cases of Chinese nationality accounted for 71.3% (122/171) and cases of foreign nationality accounted for 28.7% (49/171). The median age of the cases was 23 years ( P(25) , P(75) : 18, 35 years), and the male to female ratio of the cases was 1.3∶1. Students accounted for 56.6% (97/171). About 45.6% (78/171) of the cases fell ill before arriving in Shanghai. The cases with mild or common clinical manifestation accounted for 96.5% (165/171) and no significant difference in clinical type was observed between overseas Chinese cases and foreign cases. The epidemic curve by diagnosis date reached peak on March 24, and the number of the cases gradually declined due to the closed-loop management process of joint port prevention and control mechanism. The 171 imported COVID-19 cases were mainly from 24 countries and regions, including the United Kingdom (64 cases, 37.3%), the United States (32 cases, 18.6%), France (19 cases, 11.0%) and Italy (16 cases, 9.4%). About 40.4% of the cases (69/171) planned to continue travelling to 21 other provinces and municipalities in China. Customs quarantine and community observation/detection points identified 43.9% (75/171) cases and 31.0% (53/171) cases, respectively. Conclusions: The imported COVID-19 cases in early phase in Shanghai were mainly young population and students accounted for high proportion. The imported risk of COVID-19 was consistent with the severity of the epidemic in foreign countries. The closed-loop management model of the joint port prevention and control mechanism plays an important role in the identification and management of the imported COVID-19 cases.

Purpose: The present study aimed to evaluate the clinical benefit of additional toothbrushing accompanying non-surgical periodontal treatment on oral and general health in patients with type 2 diabetes mellitus (T2DM)., Methods: We conducted a doubled-blind randomized controlled trial in 60 T2DM patients between June 2013 and June 2014. The patients were randomly assigned to the scaling and root planing (SRP) group; the scaling and root planing with additional toothbrushing (SRPAT) group, in which additional toothbrushing was performed by toothpick methods; or the control group. Microbiological and oral examinations were performed for up to 12 weeks following treatment. Non-surgical treatment was conducted in the experimental groups. The SRP group received scaling and root planing and the SRPAT group received additional toothbrushing with the Watanabe method once a week from the first visit through the fifth visit. The primary outcomes were changes in haemoglobin A1c (or glycated haemoglobin; HbA1c) levels, serum endotoxin levels, and interleukin-1 beta levels. Periodontal health status was measured by periodontal pocket depth, the calculus index, and bleeding on probing (BOP)., Results: Both the SRP and SRPAT groups showed improvements in periodontal health and HbA1c, but the SRPAT group showed significantly less BOP than the SRP group. Furthermore, only the SRPAT group showed a statistically significant decrease in serum endotoxin levels., Conclusions: Non-surgical periodontal treatment was effective in improving HbA1c and serum endotoxin levels in T2DM patients. Furthermore, non-surgical treatment with additional tooth brushing had a more favourable effect on gingival bleeding management.Trial RegistrationClinical Research Information Service Identifier: KCT000416., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2020. Korean Academy of Periodontology.)

Objective: To analyze the epidemiological characteristics of a cluster of 5 confirmed COVID⁃19 cases related with the transmission in incubation period of initial case, and find out the infection source and transmission chain.. Methods: According to "The Prevention and Control Protocol for Coronavirus Disease 2019 (Third Edition)" issued by the National Health Commission, a field epidemiological survey was conducted for the 5 cases in January 2020. Nasopharyngeal swabs and sputum samples were collected from them for the detection of 2019-nCoV by real time RT-PCR. Multi prevention and control measures were taken, such as tracking and screening close contacts, medical isolation observation, investigating the epidemiological link, analyzing transmission chain. Results: Case 1, who had common environmental exposure with other COVID⁃19 cases, got sick on 20 January, 2020 and was confirmed on 1 February. Case 2 became symptomatic on 22 January and was confirmed on 27 January. Case 3 got sick on 25 January and was confirmed on 30 January. Case 4 had illness onset on 20 January and was confirmed on 1 February. Case 5 got sick on 23 January and was confirmed on 31 January. Among the 5 cases, case 2 died and the illness of other cases were effectively controlled. After exclusion of other common exposure factors, case 1 had a 6-hour meeting with case 2 and case 3 on 19 January. Case 2 and case 3 might be infected by case 1 during the incubation period. It is the key point for epidemiological investigation. Conclusion: The epidemiological investigation indicates that the transmission might occur in the incubation period of COVID-19 case, close attention should be paid to it in future COVID-19 prevention and control.

Objective: To understand the status of child health services by primary medical institutions in less developed areas in Sichuan province and provide evidence for the development of health policy for poverty alleviation. Methods: Annual child health records in the primary medical institutions selected through multistage stratified sampling in 21 prefectures in Sichuan were extracted during 2014-2018. Field survey and telephone interview were used to evaluate the performance of child health services provided and the child guardian's satisfaction degree. Sample descriptive statistics, pair sample t -test, χ (2) test, trend χ (2) test, Pearson correlation analysis were used for statistical analysis. Results: Except child system management rate, the other indicators reflecting the status of child health service in less developed areas in Sichuan were on rise ( P <0.05), and close to average level of whole province in 2018. Except child system management rate, the other indicators reflecting the status of child health management in less developed counties were lower than those in developed counties in Sichuan, most differences were significant ( P <0.05). Except child health management rate of traditional Chinese medicine, the other indicators reflecting the status of child health management in less developed counties were higher than those in poverty-stricken counties in Sichuan, most differences were not significant ( P ≥0.05). Except child systematic management rate, the gap in indicators reflecting child health service status between less developed area and developed area was in reduction, some difference were significant ( P <0.05). The child guardian satisfaction degree was associated with true child health management rates ( r =0.947, P =0.015), and child health management rate of traditional Chinese medicine ( r =0.996, P <0.001). Conclusions: Some achievements have been made in child health services provided by primary medical institutions in less developed areas in Sichuan. To achieve the 2020 poverty alleviation goal, it is necessary to take measures to increase input and improve service level.

Our previous work indicates the lymphatic network and perivascular spaces or tissues might be involved in the facial intradermal brain-targeted delivery of Evans blue (EB). In this article, we presented the detailed involvement of both, and the linkage between lymphatic network and perivascular spaces or tissues. The in-vivo imaging, the trigeminal transection and immunohistochemistry were used. In-vivo imaging indicated intradermal injection in the mystacial pad (i.d.) delivered EB into the brain at 2-, 6- and 24 h, while intranasal injection (i.n.) delivered EB into the rostral head and intravenous injection (i.v.) diffused EB weakly into the brain. Trigeminal perineurial and epineurial EB occurred along the perivascular spaces or tissues and along brain vessels. EB diffused into the lymphatic vessels and submandibular lymph nodes. Moreover, perineurial and epineurial EB co-located or overlaid with Lyve1 immuno-reactivity and VEGF antibody, and lymphatic network connected with perivascular spaces or tissues, suggesting lymphatic system-perivascular spaces might involve in the EB delivery with i.d. The trigeminal transection reduced the trigeminal epineurial and perineurial EB and brain EB along vessels. EB diffused in the fasciculus and the perineurium, blood and lymphatic vessels in the mystacial pad, mystacial EB overlaid VEGF or Lyve1 antibody. In summary, the dermal-trigeminal-brain perivascular spaces or tissues and the linkage to the lymphatic network mediated the intradermal brain-targeted delivery.

Background: Transdural disc herniation (TDH) is a rare event accounting for 0.3-1.5% of all disc herniation cases. Considering the risk of leakage of the cerebrospinal fluid from the dural defect after removal of TDH or incomplete removal, it is very important to recognize TDH before surgery. This study is a retrospective case analysis to analyze the imaging findings of seven cases and to construct a preoperative prediction model for TDH., Methods: Retrospective radiographic examination was performed among patients operated for TDH in two institutions from 2008 to 2018. The radiographic images were analyzed according to the following eight signs: including absence of dural tent, complete block of spinal canal, hawk-beak sign, double-layered lesion, increased distance between the dura and cauda equina, rim enhancement, dural tent enhancement, and epidural gas. To clarify the predictive ability of these radiographic signs, consecutive 131 surgically confirmed epidural disc herniation (EDH) patients for the last 2 years were set as a control group for TDH. The sum of radiographic findings was compared between TDH and EDH patients to determine the cutoff value., Results: There were 1 thoracic and 6 lumbar TDHs among 75 thoracic and 6674 lumbar disc herniation cases with an incidence of 1.33% and 0.09%, respectively. Dural tent (p = 0.000, odds ratio = 106.67), double-layered lesion (p = 0.000, odds ratio = 22.69), and distance between the dura and cauda equina (p = 0.007, odds ratio = 52.00) were statistically significantly different between TDH and EDH. According to the receiver operating characteristic curve, the cutoff value of 1.5 had 85.7% sensitivity and 90.8% specificity., Conclusion: Preoperative imaging can be useful for TDH diagnosis. It is safe to consider the possibility of TDH in patients with more than two findings in the preoperative images.

Study Design: Retrospective case analysis., Objective: This study was conducted to investigate the course of ossification of the posterior longitudinal ligament (OPLL) progression after laminoplasty (LP) or laminectomy with posterior fixation (PF)., Summary of Background Data: LP is now recognized as a standard technique for the treatment of cervical multisegment OPLL; however, PF is beneficial for patients with severe stenosis. In recent years, there has been increasing interest in mechanical stress in OPLL, which is assumed to significantly impact progression., Methods: The progression of OPLL was assessed using midline sagittal computed tomography images of the cervical spine at various follow-up points. Radiographic parameters including the C2-C7 Cobb angle, C2-C7 range of motion (ROM), and adjacent cranial and caudal segmental ROMs were measured. Postoperative changes and differences between the LP and PF groups in the radiographic parameters were calculated to assess biomechanical stress. Logistic regression analysis was used to analyze the risk factors affecting the progression rate., Results: The authors included 14 PF and 36 LP patients, with a mean follow-up period of 28.9±20.8 and 37.6±16.8 months, respectively (P=0.069). After surgical treatment, both groups showed loss of cervical lordosis (9.2±6.9 vs. 5.3±8.2 degrees, P=0.220) and C2-C7 ROM (14.6± 13.5 vs. 13.1±12.2 degrees, P=0.861). The decrease of ROM in the cranial adjacent segment was larger in the LP group than in the PF group (0.7±4.1 vs. 1.4±5.5 degrees, P=0.453). The ROM in the caudal adjacent segment decreased in the LP group but increased in the PF group (-1.4±6.2 vs. 2.6±5.1 degrees, P=0.041). The progression rate was 2.15±1.31 mm/mo in the PF group and 1.53±1.04 mm/mo in the LP group (P=0.041). PF showed an odds ratio of 12.917 for a higher progression rate (95% confidence interval, 1.397-119.443; P=0.024)., Conclusion: The rate of progression of cervical OPLL was significantly higher after PF than after LP.Level III-a retrospective analysis.

Objective: This study aimed to assess the dental caries status of Nepali students and describe correlated modifiable factors., Basic Research Design: Cross-sectional analytic study., Participants: 730 grade two to four (6-14 years old) students from 23 different government schools in seven different districts in Nepal from December 2014 to February 2015. The schools were located in areas of low socioeconomic status without access to fluoridated water., Method: A trained, calibrated dentist performed visual examination using WHO criteria. Data on demographic variables, oral health behaviors, the number of shops (including sugary snacks) around each school and the distance from Dhulikhel city (where many medical and dental facilities are available) to each school were collected. Multivariable logistic regression was used to identify factors associated with dental caries., Results: Of the participants, 53.7% and 14.4% had decayed, missing and filled teeth (dmft) in the primary and permanent dentition, respectively. The mean number of primary decayed teeth (dt) was found to be 1.69, and the permanent DT was 0.22; mean dmft was 1.74 in primary dentition and 0.22 in permanent dentition. The number of markets near a school and the distance to the Dhulikhel city were associated with permanent (odds ratio [OR]: 1.67) and primary dmft (OR: 0.62), respectively, after adjusting for the related covariates., Conclusions: Most dental caries remains untreated. Students with more shops near their school and who attended schools closer to the city were more likely to have dental caries., (Copyright© 2019 Dennis Barber Ltd.)

Background: Sufentanil is commonly used for analgesia and sedation during extracorporeal membrane oxygenation (ECMO). Both ECMO and the pathophysiological changes derived from critical illness have significant effects on the pharmacokinetics (PK) of drugs, yet reports of ECMO and sufentanil PK are scarce. Here, we aimed to develop a population PK model of sufentanil in ECMO patients and to suggest dosing recommendations., Methods: This prospective cohort PK study included 20 patients who received sufentanil during venoarterial ECMO (VA-ECMO). Blood samples were collected for 96 h during infusion and 72 h after cessation of sufentanil. A population PK model was developed using nonlinear mixed effects modelling. Monte Carlo simulations were performed using the final PK parameters with two typical doses., Results: A two-compartment model best described the PK of sufentanil. In our final model, increased volume of distribution and decreased values for clearance were reported compared with previous PK data from non-ECMO patients. Covariate analysis showed that body temperature and total plasma protein level correlated positively with systemic clearance (CL) and peripheral volume of distribution (V2), respectively, and improved the model. The parameter estimates of the final model were as follows: CL = 37.8 × EXP (0.207 × (temperature - 36.9)) L h -1 , central volume of distribution (V1) = 229 L, V2 = 1640 × (total plasma protein/4.5) 2.46  L, and intercompartmental clearance (Q) = 41 L h -1 . Based on Monte Carlo simulation results, an infusion of 17.5 μg h -1 seems to reach target sufentanil concentration (0.3-0.6 μg L -1 ) in most ECMO patients except hypothermic patients (33 °C). In hypothermic patients, over-sedation, which could induce respiratory depression, needs to be monitored especially when their total plasma protein level is low., Conclusions: This is the first report on a population PK model of sufentanil in ECMO patients. Our results suggest that close monitoring of the body temperature and total plasma protein level is crucial in ECMO patients who receive sufentanil to provide effective analgesia and sedation and promote recovery., Trial Registration: Clinicaltrials.gov NCT02581280 , December 1st, 2014.

Objective: Identifying collaterals from external carotid artery (ECA) is necessary before treatment of ophthalmic artery (OphA) aneurysm. We present a manual carotid compression test to verify collaterals in ophthalmic artery aneurysms, and evaluate its usefulness., Materials and Methods: From March 2013 to December 2017, endovascular coiling was performed 19 consecutive patients with 20 OphA aneurysms. We performed manual carotid compression test for patients who had aneurysms incorporating entry of OphA. Clinical and angiographic outcomes were investigated., Results: Of 13 cases underwent manual carotid compression test, 12 cases were confirmed collateral flow from ECA to OphA. During the coil embolization, we tried to maintain the original OphA flow even if it has a collateral anastomosis. Among them, OphA occlusion occurred in one patient during coiling. Recurrence of aneurysm was occurred in a ruptured case and additional embolization was required., Conclusions: The manual carotid compression test is useful method to identify the collaterals from ECA in patients with OphA aneurysm. This test can be used as a screening test for confirming collateral flow in OphA aneurysms or as an alternative for patients who are difficult to perform BTO., Competing Interests: Disclosure: The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper., (© 2019 Journal of Cerebrovascular and Endovascular Neurosurgery.)

Background: We compared the outcomes of endovascular embolization and surgery and investigated the factors affecting the clinical outcomes of spinal intradural dorsal arteriovenous fistulas (SIDAVFs)., Methods: The medical records of 26 patients who had undergone endovascular embolization or surgery for SIDAVFs from 2004 to 2014 were retrospectively reviewed. The recurrence rate and clinical outcomes for each treatment modality were compared. Multivariate analysis was used to identify significant factors influencing the clinical outcomes using the Aminoff and Logue (AL) score., Results: Of the 26 patients, 14 (56%) had undergone endovascular embolization and 11 (44%) had undergone surgery as the initial treatment. Embolization was applied as the primary treatment for most patients. Surgery was chosen for patients with difficult superselection (n = 5), multiple feeders (n = 2), or easy surgical accessibility (n = 4). Of the 14 patients who had undergone embolization as initial treatment, 5 (36%) had developed a recurrence within an average of 29.6 months (range, 2-87). One patient with recurrent SIDAVF was treated with repeat embolization and four with surgery. None of patients in the surgical group developed recurrence. Embolization as the initial treatment resulted in significantly greater recurrence compared with surgery (odds ratio, 2.222; 95% confidence interval, 1.369-3.608; P = 0.046). Surgery resulted in better clinical outcomes than embolization (P = 0.021). The final AL score was also strongly affected by the preoperative AL score, micturition score, and recurrence (P = 0.000, P = 0.000, and P = 0.011, respectively)., Conclusions: Our results have shown that surgery results in a low recurrence rate and superior clinical outcomes. A multidisciplinary and ordered decision is crucial for the treatment choice to ensure better outcomes, especially for patients with a definite neurologic deficit at diagnosis., (Copyright © 2018. Published by Elsevier Inc.)

Background: There are many types of disabilities, and each type has a variety related to socioeconomic factors. Such factors affect to many health problems of the disabled. However, surveys of the oral health status of the disabled in Korea are rare., Objective: The purpose of this study was to estimate oral health disparity through comparing oral health status of the disabled to the non-disabled, adjusted for the net effect of the disability on oral health status., Methods: A cross-sectional study was conducted among the disabled in urban and suburban areas in Korea from June to September 2016. People with physical, mental, and multiple disabilities took part in this survey. The clinical examinations were carried out by trained dentists. Statistical analysis was performed to quantify the association between oral health and socioeconomic status after restricting the analysis using a propensity score matching method., Results: The disabled had more DMFT, DT, and MT, fewer FT, and fewer teeth than the non-disabled based on entire groups (P<0.01). No difference in the ratio of periodontitis was observed. The subjects with mental disabilities (MD) scored 3.09 (95% CI, 1.07-8.97), and those with multiple disabilities scored 4.37 (95% CI, 1.16-16.37) for edentulous status. The MD had an odds ratio of 1.34 (95% CI, 1.03-1.74), and those with multiple disabilities had an odds ratio of 1.75 (95% CI, 1.11-2.76) for the DMFT index., Conclusions: These results represent poor oral health status of the disabled compared to the non-disabled. Consequentially, we can verify that not only the existence of disability but also the type of disability has a decisive effect on oral health condition. This comparison is necessary to widen our approach to evaluate the actual status condition of the disabled., Competing Interests: The authors have declared that no competing interests exist.

Currently, combination drug therapy is one of the most effective approaches to glioma treatment. However, due to the inherent dissimilar pharmacokinetics of individual drugs and blood brain barriers, it was difficult for the concomitant drugs to simultaneously be delivered to glioma in an optimal dose ratio manner. Herein, a cationic micellar core (Cur-M) was first prepared from d-α-tocopherol-grafted-ε-polylysine polymer to encapsulate the hydrophobic curcumin, followed by dopamine-modified-poly-γ-glutamic acid polymer further deposited on its surface as a anion shell through pH-sensitive linkage to encapsulate the hydrophilic doxorubicin (DOX) hydrochloride. By controlling the combinational Cur/DOX molar ratio at 3:1, a pH-sensitive core-shell nanoparticle (PDCP-NP) was constructed to simultaneously target the cancer stem cells (CSCs) and the differentiated tumor cells. PDCP-NP exhibited a dynamic diameter of 160.8 nm and a zeta-potential of -30.5 mV, while its core-shell structure was further confirmed by XPS and TEM. The ratiometric delivery capability of PDCP-NP was confirmed by in vitro and in vivo studies, in comparison with the cocktail Cur/DOX solution. Meanwhile, the percentage of CSCs in tumors was significantly decreased from 4.16% to 0.95% after treatment with PDCP-NP. Overall, PDCP-NP may be a promising carrier for the combination therapy with drug candidates having dissimilar physicochemical properties.

Purpose: Ilaprazole, the latest proton pump inhibitor, can be used with clarithromycin and amoxicillin as a triple therapy regimen for eradicating Helicobacter pylori. The aim of this study was to evaluate pharmacokinetic drug interactions and safety profiles after coadministration of clarithromycin, amoxicillin, and ilaprazole., Methods: A randomised, open-label, one-way crossover, two parallel sequences study was conducted in 32 healthy subjects. In part 1, the subjects received a single dose of ilaprazole 10 mg in period 1 and clarithromycin 500 mg and amoxicillin 1000 mg twice daily for 6 days in period 2. In part 2, the subjects received clarithromycin 500 mg and amoxicillin 1000 mg once in period 1 and ilaprazole 10 mg twice daily for 6 days in period 2. In both sequences, the three drugs were coadministrated once on day 5 in period 2. Pharmacokinetic evaluations of ilaprazole (part 1), and clarithromycin and amoxicillin (part 2) were conducted., Results: Twenty-eight subjects completed the study. For ilaprazole, the peak concentration (C max ) slightly decreased from 479 (ilaprazole alone) to 446 ng/mL (triple therapy) [Geometric least square mean ratio (90% confidence interval), 0.93 (0.70-1.22)]. The area under the concentration-time curve from 0 h to the last measurable concentration (AUC last ) slightly increased from 3301 to 3538 μg·h/mL [1.07 (0.85-1.35)]. For clarithromycin, the C max slightly decreased from 1.87 to 1.72 μg/mL [0.90 (0.70-1.15)], and AUC last slightly increased from 14.6 to 16.5 μg·h/mL [1.09 (0.87-1.37)]. For amoxicillin, the C max slightly decreased from 9.37 to 8.14 μg/mL [0.86 (0.74-1.01)], and AUC last slightly decreased from 27.9 to 26.7 μg·h/mL [0.98 (0.83-1.16)]. These changes in the PK parameters of each drug were not statistically significant., Conclusions: The coadministration of ilaprazole, clarithromycin, and amoxicillin was tolerable and did not cause a significant PK drug interaction. Thus, a triple therapy regimen comprising ilaprazole, clarithromycin, and amoxicillin may be an option for the eradication of H. pylori. Clinicaltrials.gov number: NCT02998437.

Objective: To compare the nutritional factors and oral status of elders living alone and elders living with their families in Korea., Background: Numerous studies have found that the presence of fewer remaining teeth is associated with decreased nutrient intake; however, there is no study comparing the nutritional status and oral status of elders living alone with that of elders living with family based on a nationally representative sample., Methods: A sample of 2904 individuals who participated in the sixth Korean National Health and Nutrition Examination Survey was reviewed (65-84 years of age). Living status was defined according to the participants' self-reported questionnaire, and a nutrient intake questionnaire was designed as an open questionnaire and used during the face-to-face interviews. The number of existing teeth was used to determine oral status. A complex-sample general linear analysis and multivariate logistic regression analysis were used to evaluate the association between the number of teeth and nutrient intake among elders living with family and elders living alone after adjusting for confounders., Results: Elders living alone were significantly older and tended to have the following characteristics: women, lower household income, lower educational level, poor perceived health status, non-smokers, non-drinkers and lack of physical activity. Elders living alone had a poorer perceived oral health status, had not received an oral examination in the past year, had chewing problems and had fewer existing teeth (P < .05). Elders living with family showed better oral health and nutrient intake status. Participants who had many existing teeth had higher nutrient intake than the participants who had fewer existing teeth., Conclusions: For healthy lives at old age, family support or additional social support for elders living alone should be considered., (© 2018 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd.)

Herein, a theranostic liposome (QSC-Lip) integrated with superparamagnetic iron oxide nanoparticles (SPIONs) and quantum dots (QDs) and cilengitide (CGT) into one platform is constructed to target glioma under magnetic targeting (MT) for guiding surgical resection of glioma. Transmission electron microscopy and X-ray photoelectron spectroscopy confirm the complete coencapsulation of SPIONs and QDs in liposome. Besides, CGT is also effectively encapsulated into the liposome with an encapsulation efficiency of ∼88.9%. QSC-Lip exhibits a diameter of 100 ± 1.24 nm, zeta potential of -17.10 ± 0.11 mV, and good stability in several mediums. Moreover, each cargo shows a biphasic release pattern from QSC-Lip, a rapid initial release within initial 10 h followed by a sustained release. Cellular uptake of QSC-Lip is significantly enhanced by C 6 cells under MT. In vivo dual-imaging studies show that QSC-Lip not only produces an obvious negative-contrast enhancement effect on glioma by magnetic resonance imaging but also makes tumor emitting fluorescence under MT. The dual-imaging of QSC-Lip guides the accurate resection of glioma by surgery. Besides, CGT is also specifically distributed to glioma after administration of QSC-Lip under MT, resulting in an effective inhibition of tumors. The integrated liposome may be a potential carrier for theranostics of tumor., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Nephropathy is one of the most severe complications of diabetic patients. The therapeutic strategies for diabetic patients should not only focus on the control of blood glucose but also pay attention to the occurrence of diabetic nephropathy (DN). Coenzyme Q10 (CoQ10) has great therapeutic potential for DN. However, the clinical application of CoQ10 has been limited because of its low water-solubility and non-specific distribution. Liposomes were supposed to be an effective way for delivering CoQ10 to kidney. CoQ10 was effectively encapsulated into the liposome (CoQ10-LIP) with a high entrapment efficiency of 86.15 %. The CoQ10-LIP exhibited a small hydrodynamic diameter (180 ± 2.1 nm) and negative zeta potential (-18.20 mV). Moreover, CoQ10-LIP was combined with ultrasound-mediated microbubble destruction (UTMD) to enhance specific distribution of CoQ10 in kidney. In early stage of diabetic mellitus (DM), rats were administrated with CoQ10-LIP followed by UTMD (CoQ10-LIP+UTMD) to prevent occurrence of DN. Results revealed that CoQ10-LIP+UTMD effectively prevented the renal morphology and function of diabetics rats from damage. The protective mechanism of CoQ10-LIP was highly associated with protecting podocyte, promoting vascular repair and inhibiting cell apoptosis. Conclusively, CoQ10-LIP in combination with UTMD might be a potential strategy to prevent occurrence of DN., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

A poor percutaneous penetration capability for most topical anti-inflammatory drugs is one of the main causes compromising their therapeutic effects on psoriatic skin. Even though curcumin has shown a remarkable efficacy in the treatment of psoriasis, its effective penetration through the stratum corneum is still a major challenge during transdermal delivery. The aim of our study was to design skin-permeating nanoparticles (NPs) to facilitate delivery of curcumin to the deeper layers of the skin. A novel amphiphilic polymer, RRR-α-tocopheryl succinate-grafted-ε-polylysine conjugate (VES-g-ε-PLL) was synthesized and self-assembled into polymeric nanoparticles. The nanoparticles of VES-g-ε-PLL exhibiting an ultra-small hydrodynamic diameter (24.4nm) and a positive Zeta potential (19.6mV) provided a strong skin-penetrating ability in vivo. Moreover, curcumin could effectively be encapsulated in the polymeric nanoparticles with a drug loading capacity of 3.49% and an encapsulating efficiency of 78.45%. In order to prolong the retention time of the ultra-small curcumin-loaded nanoparticles (CUR-NPs) in the skin, silk fibroin was used as a hydrogel-based matrix to further facilitate topical delivery of the model drug. In vitro studies showed that CUR-NPs incorporated in silk fibroin hydrogel (CUR-NPs-gel) exhibited a slower release profile of curcumin than the plain CUR-gel, without compromising the skin penetration ability of CUR-NPs. In vivo studies on miquimod-induced psoriatic mice showed that CUR-NPs-gel exhibited a higher therapeutic effect than CUR-NPs as the former demonstrated a more powerful skin-permeating capability and a more effective anti-keratinization process. CUR-NPs-gel was therefore able to inhibit the expression of inflammatory cytokines (TNF-α, NF-κB and IL-6) to a greater extent. In conclusion, the permeable nanoparticle-gel system may be a potential carrier for the topical delivery of lipophilic anti-psoriatic drugs., (Copyright © 2017. Published by Elsevier B.V.)

Atorvastatin and ezetimibe are frequently co-administered to treat patients with dyslipidemia for the purpose of low-density lipoprotein cholesterol control. However, pharmacokinetic (PK) drug interaction between atorvastatin and ezetimibe has not been evaluated in Korean population. The aim of this study was to investigate PK drug interaction between two drugs in healthy Korean volunteers. An open-label, randomized, multiple-dose, three-treatment, three-period, Williams design crossover study was conducted in 36 healthy male subjects. During each period, the subjects received one of the following three treatments for seven days: atorvastatin 40 mg, ezetimibe 10 mg, or a combination of both. Blood samples were collected up to 96 h after dosing, and PK parameters of atorvastatin, 2-hydroxyatorvastatin, total ezetimibe (free ezetimibe + ezetimibe-glucuronide), and free ezetimibe were estimated by non-compartmental analysis in 32 subjects who completed the study. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) of the maximum plasma concentration (C max,ss ) and the area under the curve within a dosing interval at steady state (AUC τ,ss ) of atorvastatin when administered with and without ezetimibe were 1.1087 (0.9799-1.2544) and 1.1154 (1.0079-1.2344), respectively. The corresponding values for total ezetimibe were 1.0005 (0.9227-1.0849) and 1.0176 (0.9465-1.0941). There was no clinically significant change in safety assessment related to either atorvastatin or ezetimibe. Co-administration of atorvastatin and ezetimibe showed similar PK and safety profile compared with each drug alone. The PK interaction between two drugs was not clinically significant in healthy Korean volunteers., Competing Interests: Conflicts of interests: -Authors: The authors have no conflict of interest to disclose. -Reviewers: Nothing to declare -Editors: Nothing to declare, (Copyright © 2017 Translational and Clinical Pharmacology.)

Extracorporeal membrane oxygenation (ECMO) is associated with pharmacokinetic (PK) changes of drugs. It presents considerable challenges to providing optimal dosing regimens for patients receiving ECMO. We aimed to describe the population PK of remifentanil in critically ill adult patients receiving venoartrial extracorporeal membrane oxygenation (VA-ECMO) and to identify determinants associated with altered remifentanil concentrations. The population PK model of remifentanil was developed using nonlinear mixed effects modelling (NONMEM). Fifteen adult patients who received a continuous infusion of remifentanil during VA-ECMO participated in the study. The PK of remifentanil was best described by a one-compartment model with additive and proportional residual errors. Remifentanil concentrations were affected by sex and ECMO pump speed. The final PK model included the effect of sex and ECMO pump speed on clearance is developed as followed: clearance (L/h) = 366 × 0.502 sex  × (ECMO pump speed/2350) 2.04 and volume (L) = 41. Remifentanil volume and clearance were increased in adult patients on VA-ECMO compared with previously reported patients not on ECMO. We suggest that clinicians should consider an increased remifentanil dosing to achieve the desired level of sedation and provide a dosing regimen according to sex and ECMO pump speed.

Endometrial injury usually results in intrauterine adhesion (IUA), which is an important cause of infertility and recurrent miscarriage in reproductive women. There is still lack of an effective therapeutic strategy to prevent occurrence of IUA. Keratinocyte growth factor (KGF) is a potent repair factor for epithelial tissues. Here, a temperature-sensitive heparin-modified poloxamer (HP) hydrogel with affinity to KGF (KGF-HP) was used as a support matrix to prevent IUA and deliver KGF. The rheology of KGF-HP hydrogel was carefully characterized. The cold KGF-HP solution was rapidly transited to hydrogel with suitable storage modulus (G') and loss modulus (G″) for the applications of uterus cavity at temperature of 33 °C. In vitro release demonstrated that KGF was released from HP hydrogels in sustained release manner for a long time. In vivo bioluminescence imaging showed that KGF-HP hydrogel was able to prolong the retention of the encapsulated KGF in injured uterus of rat model. Moreover, the morphology and function of the injured uterus were significantly recovered after administration of KGF-HP hydrogel, which were evaluated by two-dimensional ultrasound imaging and receptive fertility. Not only proliferation of endometrial glandular epithelial cells and luminal epithelial cells but also angiogenesis of injured uterus were observed by Ki67 and CD31 staining after 7 d of treatment with KGF-HP hydrogel. Finally, a close relatively relationship between autophagy and proliferation of endometrial epithelial cells (EEC) and angiogenesis was firstly confirmed by detecting expression of LC3-II and P62 after KGF treatment. Overall, KGF-HP may be used as a promising candidate for IUA treatment.