Pharmacokinetic and Pharmacodynamic Modeling Analysis of Delpazolid (LCB01-0371) in Adult Patients with Pulmonary Tuberculosis.

Delpazolid (LCB01-0371) is a novel oxazolidinone derivative with a good safety profile for treating gram-positive pathogenic infections such as Mycobacterium abscessus, a highly pathogenic drug-resistant Mycobacterium. In this study, we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of delpazolid after 14 days of multiple oral administration, using data from adult patients with pulmonary tuberculosis. 800 mg once a day, 400 mg twice a day, 800 mg twice a day, and 1200 mg once a day delpazolid for 14 days were tested in 63 patients with pulmonary tuberculosis. For PK blood collection, inpatient and outpatient scheduling were separately implemented. Plasma concentrations of delpazolid were measured at visits 2, 4, 6, and 8 in outpatients, and four sparse blood samples were measured in inpatients. PD models were sequentially fitted using individual PK parameter estimates obtained from PK compartmental models. For PK modeling, 180 plasma concentrations of delpazolid from 56 patients were included. A two-compartment mixed first- and zero-order absorption model best described the time course of plasma concentration. For the PD model, 448 bacterial titer data from 60 patients were used. The time course of bacterial titers (log10 CFU/mL) was described by a model that consists of the growth and killing rate of bacteria with the sigmoid Emax model. The PK-PD simulation suggested that the bacterial titers are the lowest on the 800 mg bid regimen among the four, consistent with observed data, as all regimens substantially decrease. In the dose-response relationship, the effectiveness of delpazolid was suggested.

Low concentration zinc oxide nanoparticles enrichment enhances bacterial and pro-inflammatory resistance of calcium silicate-based cements.

Calcium silicate-based cement (CSC) is a commonly used material in endodontic treatment. However, it has limited antibacterial activity, especially for cases involving primary infections. Zinc oxide nanoparticles (ZnO-NPs) are recognized for their potential in biomedical applications due to their antibacterial properties and ability to reduce inflammation. This study aims to optimize CSC by incorporating ZnO-NPs to maintain its physical properties, enhance its antibacterial activity, and reduce the production of pro-inflammatory cytokines. ZnO-NPs were integrated into a commercial CSC (Endocem MTA) at 1 wt% (CSZ1) or 3 wt% (CSZ3). Setting time, compressive strength, and X-ray diffraction were then measured. In addition, pH, calcium ion release, and zinc ion release were measured for 7 days. Antibacterial activity against Enterococcus faecalis and viability of murine macrophages (RAW264.7) were determined using colorimetric assays. Gene expression levels of pro-inflammatory cytokines in lipopolysaccharide induced RAW264.7 were evaluated using quantitative polymerase chain reaction. Results were compared to an unmodified CSC group. In the CSZ3 group, there was a significant increase of approximately 12% in setting time and a reduction of about 36.4% in compressive strength compared to the control and CSZ1 groups. The presence of ZnO-NPs was detected in both CSZ1 and CSZ3. Both CSC and CSZ1 groups maintained an alkaline pH and released calcium ions, while zinc ions were significantly released in the CSZ1 group. Additionally, CSZ1 showed a 1.8-fold reduction of bacterial activity and exhibited around 85% reduction in colony-forming units compared to the CSC group. Furthermore, the CSZ1 group showed a more than 39% reduction in pro-inflammatory cytokine levels compared to the CSC group. Thus, enriching CSC with 1 wt% ZnO-NPs can enhance its antibacterial activity and reduce pro-inflammatory cytokines without showing any tangible adverse effects on its physical properties.

Mechanical properties and sustainable bacterial resistance effect of strontium-modified phosphate-based glass microfiller in dental composite resins.

Dental composite resins are widely used in dental restorations. However, their clinical application is limited by the occurrence of secondary caries. Strontium-modified phosphate-based glass (Sr-PBG) is a material known to have a sustainable bacterial resistance effect. The mechanical properties (in particular, flexural strength, modulus of elasticity, and hardness) of dental materials determine their function. Therefore, this study aimed to investigate the mechanical and ion-releasing properties as well as the sustainable bacterial resistance effect of bioactive resin composites containing Sr-PBG. The data were analyzed by ANOVA and Tuckey's tests (p < 0.05). We incorporated a Sr-PBG microfiller at 3, 6, and 9 wt.% concentrations into a commercially available composite resin and investigated the mechanical properties (flexural strength, elastic modulus, and micro hardness), ion release characteristics, and color of the resultant resins. In addition, we examined the antibacterial effects of the composite resins against Streptococcus mutans (S. mutans). The mechanical properties of the Sr-PBG groups differed only slightly from those of the control group (p > 0.05). However, the optical density at 600 nm of S. mutans incubated on the experimental group was significantly lower compared to that observed with the control (p < 0.05) both before and after thermocycling between 5 and 55 â„ƒ for 850 cycles (dwell time: 45 s). Therefore, strontium-modified resin materials exhibited a sustainable bacterial resistance effect in vitro while maintaining some of the mechanical properties of ordinary acrylic resins.

A novel orthodontic adhesive containing zinc-doped phosphate-based glass for preventing white spot lesions.

OBJECTIVES: This study aimed at demonstrating the remineralization effect of the enamel around the brackets to aid reduction in white spot lesions (WSLs) with use of zinc-doped phosphate-based glass (Zn-PBG) containing orthodontic adhesives. METHODS: Zn-PBG powder was synthesized, and particle morphology, size, and density were evaluated. Orthodontic adhesives with increasing loading percentage of Zn-PBG powder were prepared: ZnPG3 (3 wt.%), ZnPG6 (6 wt.%), and ZnPG9 (9 wt.%). Brackets were bonded on the etched enamel surface and stored in distilled water (DW) for 1 h. Following, Shear bond strength (SBS) along with adhesive remnant index were analyzed. The release of calcium (Ca), phosphorus (P), and zinc (Zn) from adhesive specimens in DW was evaluated after 7, 15 and 30 days of immersion. The remineralization effect was confirmed by microhardness and surface morphology analysis with scanning electron microscopy. RESULTS: The SBS value was observed between 20 and 22 MPa on enamel surface. The concentration of Ca, P and Zn released in DW increased with loading percentage of Zn-PBG. The microhardness increased in the experimental groups after immersion in artificial saliva for 7 days. Apatite-like crystal formation was observed after 30 days in the ZnPG 9 group. CONCLUSIONS: The orthodontic adhesive containing Zn-PBG with an optimal SBS performance has an enamel remineralization effect, and therefore can aid in prevention of WSLs. CLINICAL SIGNIFICANCE: The orthodontic adhesive containing Zn-PBG is clinically advantageous as it can promote remineralization and resist the formation of WSLs that may occur during orthodontic therapy.

Effect of strontium substitution on functional activity of phosphate-based glass.

Phosphate-based glass (PBG) is a bioactive agent, composed of a glass network with phosphate as the primary component and can be substituted with various therapeutic ions for functional enhancement. Strontium (Sr) has been shown to stimulate osteogenic activity and inhibit pro-inflammatory responses. Despite this potential, there are limited studies that focus on the proportion of Sr substituted and its impact on the functional activity of resulting Sr-substituted PBG (PSr). In this study, focusing on the cellular biological response we synthesized and investigated the functional activity of PSr by characterizing its properties and comparing the effect of Sr substitution on cellular bioactivity. Moreover, we benchmarked the optimal composition against 45S5 bioactive glass (BG). Our results showed that PSr groups exhibited a glass structure and phosphate network like that of PBG. The release of Sr and P was most stable for PSr6, which showed favorable cell viability. Furthermore, PSr6 elicited excellent early osteogenic marker expression and inhibition of pro-inflammatory cytokine expression, which was significant compared to BG. In addition, compared to BG, PSr6 had markedly higher expression of osteopontin in immunocytochemistry, higher ALP expression in osteogenic media, and denser alizarin red staining in vitro. We also observed a comparable in vivo regenerative response in a 4-week rabbit calvaria defect model. Therefore, based on the results of this study, PSr6 could be identified as the functionally optimized composition with the potential to be applied as a valuable bioactive component of existing biomaterials used for bone regeneration.

Effect of bacterial resistant zwitterionic derivative incorporation on the physical properties of resin-modified glass ionomer luting cement.

Biofilms induce microbial-mediated surface roughening and deterioration of cement. In this study, zwitterionic derivatives (ZD) of sulfobetaine methacrylate (SBMA) and 2-methacryloyloxyethyl phosphorylcholine, were added in concentrations of 0, 1, and 3% to three different types of commercially available resin-modified glass ionomer cement (RMGIC) (RMC-I: RelyX Luting 2, RMC-II: Nexus RMGI, and RMC-III: GC FujiCEM 2). The unmodified RMGICs served as the control group for comparison. The resistance of Streptococcus mutans to ZD-modified RMGIC was evaluated with a monoculture biofilm assay. The following physical properties of the ZD-modified RMGIC were assessed: wettability, film thickness, flexural strength, elastic modulus, shear bond strength, and failure mode. The ZD-modified RMGIC significantly inhibited biofilm formation, with at least a 30% reduction compared to the control group. The addition of ZD improved the wettability of RMGIC; however, only 3% of the SBMA group was statistically different (P < 0.05). The film thickness increased in proportion to the increasing ZD concentrations; there was no statistical difference within the RMC-I (P > 0.05). The experimental groups' flexural strength, elastic modulus, and shear bond strength showed an insignificant decrease from the control group; there was no statistical difference within the RMC-I (P > 0.05). The mode of failure differed slightly in each group, but all groups showed dominance in the adhesive and mixed failure. Thus, the addition of 1 wt.% ZD in RMGIC favorably enhanced the resistance to Streptococcus mutans without any tangible loss in flexural and shear bond strength.

Effects of once-weekly dulaglutide on juvenile type 2 diabetes mellitus and obesity in Korea: a pilot study.

PURPOSE: We sought to investigate the effects and side effects of once-weekly dulaglutide treatment for type 2 diabetes mellitus (T2DM) in patients <18 years of age in Korea. METHODS: : From the Eulji University Hospital database, we identified all patients <18 years of age diagnosed with T2DM and treated with dulaglutide from January 1, 2017, to July 31, 2022. RESULTS: We identified 5 patients <18 years of age treated with dulaglutide for T2DM management. Their mean (standard deviation [SD]) age was 16.6 (0.5) years. Four (80%) patients were female. The mean (SD) body mass index was 29.4 (5.1) kg/m2, and the mean (SD) age at diagnosis was 15.2 (1.6) years. Four patients had been treated previously with metformin alone or in combination with insulin. Four patients were treated with 1.5 mg of dulaglutide and one was treated with 0.75 mg of dulaglutide. The mean (SD) hemoglobin A1c concentrations at baseline, 3 months after treatment, and 1 year after treatment, respectively, were 10.0% (2.2%), 6.5% (1.5%), and 6.7% (1.4%), with significant differences. In addition, at baseline, 3 months after treatment, and 1 year after treatment, the mean (SD) body weight values were 79.7 (13.3) kg, 80.2 (14.0) kg, and 81.1 (15.3) kg, with no significant difference. CONCLUSION: Use of once-weekly dulaglutide for juvenile T2DM ensures very good glycemic control, with few side effects and good adherence, indicating its potential as a promising therapeutic agent in this age group. Nationwide studies are warranted to confirm our results.

Cerium oxide nanozymes confer a cytoprotective and bio-friendly surface micro-environment to methacrylate based oro-facial prostheses.

Poly-(methyl methacrylate) (PMMA) is the preferred biomaterial for orofacial prostheses used for the rehabilitation of naso-palatal defects. However, conventional PMMA has limitations determined by the complexity of the local microbiota and the friability of oral mucosa adjacent to these defects. Our purpose was to develop a new type of PMMA, i-PMMA, with good biocompatibility and better biological effects such as higher resistance to microbial adhesion of multiple species and enhanced antioxidant effect. The addition of cerium oxide nanoparticles to PMMA using a mesoporous nano-silica carrier and polybetaine conditioning, resulted in an increased release of cerium ions and enzyme mimetic activity, without tangible loss of mechanical properties. Ex vivo experiments confirmed these observations. In stressed human gingival fibroblasts, i-PMMA reduced the levels of reactive oxygen species and increased the expression of homeostasis-related proteins (PPARg, ATG5, LCI/III). Furthermore, i-PMMA increased the levels of expression of superoxide dismutase and mitogen-activated protein kinases (ERK and Akt), and cellular migration. Lastly, we demonstrated the biosafety of i-PMMA using two in vivo models: skin sensitization assay and oral mucosa irritation test, respectively. Therefore, i-PMMA offers a cytoprotective interface that prevents microbial adhesion and attenuates oxidative stress, thus supporting physiological recovery of the oral mucosa.

Prevalence and trends in obesity and severe obesity in Korean children and adolescents, 2007-2020: A population-based study.

BACKGROUND: The age-adjusted prevalence of child and adolescent obesity has been stabilized in the Korean population, although severe obesity has increased with adverse health effects. In this study, we detailed the prevalence of and trends in overweight, obesity, and severe obesity in Korean children and adolescents by age group and sex from a nationally representative sample, using a new, 2017 age- and sex-specific reference for body mass index. METHODS: We collected Korea National Health and Nutrition Examination Survey data from the years 2007-2020. A total of 23,595 subjects (11,210 females) aged 2-18 years were included in this study. We calculated the recent prevalence of overweight and obesity, including severe obesity, by weighted data from 2019 and 2020. RESULTS: The prevalence of overweight and obesity (class II and class III obesity) was 23.5% and 14.2% (2.5% and 0.5%), respectively. Males showed a higher prevalence of overweight and obesity. Adolescents aged 13-15 years showed the highest prevalence of severe obesity. A positive linear trend was significant for overweight (p = 0.025), class I obesity (p < 0.001), and class II obesity (p = 0.002) for both sexes and all ages combined. However, the trend of obesity prevalence was different in each subgroup. Comparing pre- and post- COVID-19 pandemic, obesity prevalence seemed to increase, but not significantly. CONCLUSIONS: Despite previous reports that obesity in children and adolescents has remained stable, we found that the prevalence of overweight, obesity, and severe obesity has increased in Korean children and adolescents. The effects of COVID-19 on this trend require further evaluation.

Changes in mechanical and bacterial properties of denture base resin following nanoceria incorporation with and without SBA-15 carriers.

Poly (methyl methacrylate) (PMMA) is a commonly used material for the fabrication of biomedical appliances. Although PMMA has several advantages, it is susceptible to microbial insults with practical use. Therefore, different bioactive nanomaterials, such as nanoceria (CeN), have been proposed to enhance the properties of PMMA. In this study, we investigated the effect of the incorporation of CeN into PMMA with and without the use of mesoporous silica nanoparticle (SBA-15) carriers. The unmodified PMMA specimens (control, CTRL) were compared to groups containing SBA-15, CeN, and the synthesized SBA-15 impregnated with CeN (SBA-15@CeN) at different loading percentages. The mechanical and physical properties of the different SBA-15@CeN groups and their effects on cell viability were investigated, and the optimal CeN concentration was identified accordingly. Our results revealed that flexural strength was significantly (P < 0.01) reduced in the SBA-15@CeN3× group (containing 3-fold the CeN wt. %). Although the surface microhardness increased with the increase in the wt. % of SBA-15@CeN, cell viability was significantly reduced (P < 0.001). The SBA-15@CeN1× group had the optimal concentration and displayed significant resistance to single-and multispecies microbial colonization. Finally, the enzymatic activity of CeN was significantly high in the SBA-15@CeN1× group. The proinflammatory markers (IL-6, IL-1ß, TNF-α, CD80, and CD86) showed a significant (P < 0.001) multifold reduction in lipopolysaccharide-induced RAW cells treated with a 5-day eluate of the SBA-15@CeN1× group. These results indicate that the addition of SBA-15@CeN at 1.5 wt % improves the biological response of PMMA without compromising its mechanical properties.

Polybetaine-enhanced hybrid ionomer cement shows improved total biological effect with bacterial resistance and cellular stimulation.

Hybrid ionomer cements (HICs) are aesthetic polyelectrolyte cements that have been modified with a resin. The setting of HICs occurs by both monomer polymerization and an acid-base reaction. In addition, HICs contain a resin, which is substituted for water. Thus, the competition between the setting reactions and reduced water content inherently limits polysalt formation and, consequently the bioactive interactions. In this study, we explored the effects of polybetaine zwitterionic derivatives (mZMs) on the augmentation of the bioactive response of HICs. The polybetaines were homogenized into an HIC in different proportions (α, ß, and γ) at 3% w/v. Following basic characterization, the bioactive response of human dental pulp stem cells (hDPSCs) was evaluated. The augmented release of the principal constituent ions (strontium, silica, and fluoride) from the HIC was observed with the addition of the mZMs. Modification with α-mZM elicited the most favorable bioactive response, namely, increased ion elution, in vitro calcium phosphate precipitation, and excellent biofouling resistance, which deterred the growth of the bridging species of Veillonella. Moreover, α-mZM resulted in a significant increase in the hDPSC response, as confirmed by a significant increase (p < 0.05) in alizarin red staining. The results of mRNA expression tests, performed using periodically refreshed media, showed increased and early peak expression levels for RUNX2, OCN, and OPN in the case of α-mZM. Based on the results of the in vitro experiments, it can be concluded that modification of HICs with polybetaine α-mZM can augment the overall biological response.

Zinc-modified phosphate-based glass micro-filler improves Candida albicans resistance of auto-polymerized acrylic resin without altering mechanical performance.

Colonization of auto-polymerized acrylic resin by pathogenic Candida albicans is a common problem for denture users. In this study, zinc-modified phosphate-based glass was introduced into an auto-polymerized acrylic resin at concentrations of 3, 5, and 7 wt.%. The mechanical or physical properties (flexural strength, elastic modulus, microhardness, and contact angle), surface morphology of the resultant materials, and the antimicrobial effect on C. albicans were investigated. There were no statistical differences in the mechanical properties between the control and the zinc-modified phosphate-based glass samples (p > 0.05); however, the number of C. albicans colony-forming units was significantly lower in the control group (p < 0.05). Scanning electron microscopy revealed that C. albicans tended not to adhere to the zinc-modified-phosphate-based glass samples. Thus, the zinc-modified materials retained the advantageous mechanical properties of unaltered acrylic resins, while simultaneously exhibiting a strong antimicrobial effect in vitro.

Molecular weight tuning optimizes poly(2-methoxyethyl acrylate) dispersion to enhance the aging resistance and anti-fouling behavior of denture base resin.

Poly(methyl methacrylate) (PMMA)-based denture base resins easily develop oral bacterial and fungal biofilms, which may constitute a significant health risk. Conventional bacterial-resistant additives and coatings often cause undesirable changes in the resin. Reduced bacterial resistance over time in the harsh oral environment is a major challenge in resin development. Poly(2-methoxyethyl acrylate) (PMEA) has anti-fouling properties; however, due to the oily/rubbery state of this polymer, and its surface aggregation tendency in a resin mixture, its direct use as a resin additive is limited. This study aimed to optimize the use of PMEA in dental resins. Acrylic resins containing a series of PMEA polymers with various molecular weights (MWs) at different concentrations were prepared, and the mechanical properties, surface gloss, direct transmittance, and cytotoxicity were evaluated, along with the distribution of PMEA in the resin. Resins with low-MW PMEA (2000 g mol-1) (PMEA-1) at low concentrations satisfied the clinical requirements for denture resins, and the PMEA was homogeneously distributed. The anti-fouling performance of the resin was evaluated for protein adsorption, bacterial and fungal attachment, and saliva-derived biofilm formation. The PMEA-1 resin most effectively inhibited biofilm formation (∼50% reduction in biofilm mass and thickness compared to those of the control). Post-aged resins maintained their mechanical properties and anti-fouling activity, and polished surfaces had the same anti-biofilm behavior. Based on wettability and tribological results, we propose that the PMEA additive creates a non-stick surface to inhibit biofilm formation. This study demonstrated that PMEA additives can provide a stable and biocompatible anti-fouling surface, without sacrificing the mechanical properties and aesthetics of denture resins.

Multivalent network modifier upregulates bioactivity of multispecies biofilm-resistant polyalkenoate cement.

Polyalkenoate cement (PAC) is a promising material for regenerative hard tissue therapy. The ionically rich glass component of PAC encourages bioactive interaction via. the release of essential ions. However, PAC bioactivity is restricted owing to (i) structurally inherent cationic network formers and (ii) surface bacterial biofilm formation. These two factors cause a deficiency in ion release, further complicated by secondary infections and premature therapeutic failure. Here, a multivalent zwitterionic network modifier (mZM) is presented for upregulation of ionic exchange and bioactivity enhancement. By introducing a non-zero charged mZM into PACs, an increase in the proportion of non-bridging oxygen occurs. The network modification promotes ion channel formation, causing a multiple-fold increase in ion release and surface deposition of hydroxy-carbonate apatite (ca. 74%). Experiments ex vivo and animal models also demonstrate the efficient remineralization ability of the mZM. Furthermore, divalent cationic interaction results in bacterial biofilm reduction (ca. 68%) while also influencing a shift in the biofilm species composition, which favors commensal growth. Therefore, PAC modification with mZM offers a promising solution for upregulation of bioactivity, even aiding in customization by targeting site-specific regenerative therapy in future applications.

Does coronavirus disease 2019 affect body mass index of children and adolescents who visited a growth clinic in South Korea?: a single-center study.

PURPOSE: This study investigated the impact of coronavirus disease 2019 (COVID-19) on body mass index (BMI) of children and adolescents. METHODS: From May to July 2020, the obesity rate of children and adolescents was compared retrospectively to the corresponding rate in the same period in 2019. The change in height, weight, and BMI of the girls who received a gonadotropin releasing hormone agonist (GnRHa) for precocious puberty (n=53) and the controls (n=31) who visited a growth clinic for early breast budding but were not treated with GnRHa in the first half of 2020 were compared to the corresponding change in the first half of 2019 using a paired t-test. RESULTS: The rate of overweight or obesity in new outpatients (n=113, 83 girls, 30 boys) who visited growth clinics from May to July 2019 was 25.3% for girls and 23.3% for boys. The corresponding rate for the same period in 2020 (n=201, 153 girls, 48 boys) was 31.4% for girls and 45.8% for boys. There was a significant increase in the rate of overweight or obesity. The BMI of the GnRHa treatment group increased significantly from May to July 2019 than during the same period in 2020 (P<0.01). There was no significant difference in BMI between those periods in the control group. CONCLUSION: During the social distancing period, the incidence of obesity was higher in boys than in girls. The obesity rate in girls who visited the growth clinic for early breast budding during routine follow-ups did not increase.

Molecular basis of weak A subgroups in the Korean population: Identification of three novel subgroup-causing variants in the ABO regulatory regions.

BACKGROUND: Recent studies on Chinese and Japanese populations have shown that weak ABO subgroups could be caused by variants in the major regulatory regions of ABO, the proximal promoter, +5.8-kb site, and CCAAT-binding factor/NF-Y binding site. We investigated the molecular basis of weak A subgroups in the Korean population. STUDY DESIGN AND METHODS: This study included 11 samples suspected to have a weak A subgroup. These samples were subjected to sequencing analysis of ABO exons 6 and 7. If no subgroup-causing variants were detected in this region, exons 1-5 and three major regulatory regions were sequenced. RESULTS: Sequencing analysis of exons 6 and 7 detected two known subgroup alleles (ABO*AW.10, n = 5; ABO*AEL.02, n = 2). The remaining four samples contained a sequence variant in the proximal promoter (g.4944C>T, n = 1; g.4954G>T, n = 1) or +5.8-kb site (g.10843T>C, n = 1; g.10935C>T, n = 1). Notably, three of the four variants (g.4944C>T, g.4954G>T, and g.10843T>C) have not been reported previously in weak ABO subgroups. CONCLUSION: This study provides the first evidence that alterations in the proximal promoter and + 5.8-kb site could account for a substantial proportion of weak A subgroups in the Korean population.