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The poultry red mite (PRM), Dermanyssus gallinae, significantly impacts the health of egg-laying hens. Mites feed on the blood of infested chickens and have a great economic impact on the poultry industry. Chemical treatment of mites raises concerns about their resistance to miticides and residues in eggs and poultry. Biocontrol using entomopathogenic fungi is expected to be a chemical-free strategy for reducing PRM infestations. Therefore, the present study aimed to investigate the effects of various entomopathogenic fungal species collected in South Korea on the inhibition of PRM. Seventeen strains of six fungal species collected from various sources were used to evaluate acaricidal activity against PRM. The results showed that 16/17 strains had acaricidal properties against PRM, of which strains of Metarhizium anisopliae had the highest acaricidal activity. Mites treated with M. anisopliae CBNU 4-2 showed 100 % mortality 5 d after inoculation, followed by M. flavoviride var. pemphigi. The M. flavoviride var. pemphigi CBNU 1-1-1 showed 97.78 % mortality after 10 d of exposure to fungi. The mortality rate of PRM treated with other strains slowly increased and reached its highest value on the 14th day of inoculation. The results of this study provide information on the acaricidal activity of different entomopathogenic fungi against PRM. This information is important for the selection of fungal species for developing biocontrol methods for PRM treatment. These strains could be used for further evaluation of PRM treatment on chicken farms, or in combination with other methods, to increase PRM treatment efficiency., Competing Interests: Declaration of Competing Interest The authors report there are no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In Alzheimer's disease, chronic neuroinflammation is accompanied by amyloid and tau pathologies. Especially, aberrant microglial activation is known to precede the regional tau pathology development, but the mechanisms how microglia affect tau spread remain largely unknown. Here, we found that toll-like receptor 2 (TLR2) in microglia recognizes oligomeric tau as a pathogenic ligand and induces inflammatory responses. Knockout of TLR2 reduced tau pathology and microglial activation in rTg4510 tau transgenic mice. Treatment of oligomeric tau induced TLR2 activation and increased inflammatory responses in microglial cells. TLR2 further mediated the tau-induced microglial activation and promoted tau uptake into neurons in neuron-microglia co-culture system and in mouse hippocampus after intracranial tau injection. Importantly, treatment with anti-TLR2 monoclonal antibody Tomaralimab blocked TLR2 activation and inflammatory responses in a dose-dependent manner, and significantly reduced tau spread and memory loss in rTg4510 mice. These results suggest that TLR2 plays a crucial role in tau spread by causing aberrant microglial activation in response to pathological tau, and blocking TLR2 with immunotherapy may ameliorate tau pathogenesis in Alzheimer's disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Extensive research has been conducted on anti-biofouling or antibacterial surfaces, with nanostructured surfaces that mimic cicada and dragonfly wings emerging as promising candidates for mechano-bactericidal applications. These biomimetic nanostructured surfaces are capable of exerting a bactericidal effect by directly damaging the membranes of bacteria attached to nanostructures. Although research on bactericidal effect using various nanostructures have been conducted, no specific studies have yet reported on the antibacterial efficiency of the surface having nanoline array, especially regarding the spacing between nanolines. This study details the fabrication of nanoline array via ultraviolet (UV) molding with polyurethane acrylate (PUA), noted for its UV sensitivity and rapid curing, enabling the fabrication of precise and scalable nanoscale structures. Investigation into the nanoline array's antibacterial effects against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) reveals that nanoline spacing critically influences bacterial adherence and viability, with specific spacings enhancing antibacterial properties. Scanning electron microscopy (SEM) and confocal microscopy analyses show that surface topography significantly affects bacterial behavior, with specific spacings leading to varied bacterial responses, including membrane damage and altered attachment patterns. The study highlights the potential of nanoline array in fabricating surfaces with tailored antibacterial properties, emphasizing the importance of nanoscale design in influencing bacterial interaction and viability. We also confirm the relative mechanical rigidity of the nanoline array, which exhibits antibacterial effects, through both experimental observations and numerical analysis. This indicates our proposed nanoline-array surface could have potential future applications in mechanical anti-bacterial functions that require such structural robustness., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hyun-Ha Park reports financial support was provided by National Research Foundation of Korea. Young-Sam Cho reports financial support was provided by National Research Foundation of Korea. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aims: The incidence of gastric and duodenal neuroendocrine tumors (GNET and DNET, respectively) is increasing, however associated factors of these diseases are not well known. Here, we investigated the factors associated with GNET and DNET., Methods: Patients with GNET and DNET presenting at eight tertiary referral centers between 2001 and 2020 were included and compared with healthy controls who underwent upper endoscopic screening. Clinical factors and laboratory data were analyzed to determine associated factors of GNET and DNET., Results: Overall, 396 patients with GNET and 193 patients with DNET were included and compared with 1725 healthy controls. Multivariate analysis showed that age (odds ratio [OR] 0.98), diabetes (OR 1.72), hypertension (OR 1.97), low serum high-density lipoprotein cholesterol (HDL-C) levels (OR 2.54), and past/present H. pylori infection (OR 1.46) were significantly associated with GNET. In contrast, DNET was significantly associated with diabetes (OR 1.80), hypertension (OR 1.68), low serum HDL-C levels (OR 2.29), and past/present H. pylori infection (OR 5.42). In the sex-based subgroup analysis in GNET, current smoking was strongly associated in women (OR 9.85), but not in men., Conclusions: This study identified several common metabolic factors associated with GNET and DNET. Additionally, some factors had sex-specific associations., Competing Interests: Conflict of interest The authors have no conflict of interest regarding this article., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Purpose: A pressure of approximately 15-25 mmHg is used for effective compression therapy to prevent and treat hypertrophic scar formation in patients with burns. However, conventional facial compression garments present challenges owing to inadequate pressure distribution in curved areas such as the cheeks, around the mouth, and the slope of the nose. This study aimed to evaluate the utility of a custom-made 3D compression mask equipped with pressure sensors to treat facial burn scars., Methods: This single-blinded, prospective randomized controlled trial was conducted between May and October 2023, involving 48 burn scars in 12 inpatients with facial burns. We created the custom-made 3D compression mask equipped with pressure sensors, inner lined with biocompatible silicon, and a harness system using 3D printing technology, which can continuously monitor whether an appropriate pressure of 15-25 mmHg maintains. The biological scar properties, Vancouver Scar Scale (VSS), and Patient and Observer Scar Assessment Scale (POSAS) scores in patients with facial burns were assessed before applying the compression mask and garment and at 4 and 12 weeks after application., Results: Pre-application assessment of biological scar properties, VSS, and POSAS revealed no statistically significant differences between the 3D mask and control groups (p > 0.05 for all). Throughout the 12-week application, skin hydration and scar thickness significantly increased (p < 0.001) and reduced (p = 0.010), respectively, in the 3D mask group compared to the control group. Additionally, significant improvements in scar pliability (p = 0.004) and height (p = 0.009) of VSS, itching (p = 0.047), scar stiffness (p = 0.001), thickness (p = 0.011), and irregularity (p < 0.001) of POSAS-patient component, and scar thickness (p = 0.001), pliability (p = 0.012), and surface area (p = 0.027) of the POSAS-observer component were observed in 3D mask group throughout the 12-week application compared to the control group., Conclusion: The customized 3D compression mask equipped with pressure sensors significantly improved scar thickness, skin hydration, and various assessment scale parameters throughout the 12-week application., Competing Interests: Declaration of Competing Interest None. The funder played no role in the design of the study, collection, analyses, or interpretation of data, writing of the manuscript, or the decision to publish the results., (Copyright © 2024 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

Background: Obesity is known to increase overall disease burden but does obesity management actually help reduce disease burden?, Objectives: To investigate the effects of weight loss on disease burden in people with obesity using the National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) in Korea., Setting: Pure longitudinal observational study using Nationwide cohort database., Methods: Out of 514,866 NHIS-HEALS cohort, participants with class II obesity in Asia-Pacific region (30 ≤ body mass index [BMI] < 35) who underwent health check-up provided by NHIS during 2003-2004 (index date) were included. All final participants continued to receive a total of 5 biennial health check-ups over the next 10 years without missing. A group-based trajectory model (GBTM) was used to categorize subjects based on 10-year BMI change patterns. The changes of co-morbidities, healthcare resource utilization, and medical cost were analyzed., Results: The final study subjects (9857) were categorized into 3 trajectory clusters based on the pattern of BMI (kg/m 2 ) change: maintenance (57.35%) with an average change of -.02 ± .06, loss (38.65%) with -.04 ± .08, and substantial loss (4.0%) with -.10 ± .18. The annual increases in the number of co-morbidities per subject in each cluster were .18, .18, and .16 (all P < .001), respectively. The increase of healthcare resource utilization over time was lowest for the substantial loss compared to maintenance and loss. With each passing year, the average annual total healthcare cost increased by ₩21,200 ($16.48, P = .034) and ₩10,500 ($8.16, P = .498) in the maintenance and loss, respectively, but decreased by ₩62,500 ($48.59, P = .032) in the substantial loss., Conclusions: Weight loss in people with obesity was associated with a reduced burden of disease, as evidenced by lower co-morbidity, healthcare resource utilization rate, and decreased medical costs. This study highlights the potential positive long-term impact on Korean society when actively managing weight in individuals with obesity., (Copyright © 2024 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Biofilms formed owing to the attachment of bacteria to surfaces have caused various problems in industries such as marine transportation/logistics and medicine. In response, many studies have been conducted on bactericidal surfaces, and nanostructured surfaces mimicking cicada and dragonfly wings are emerging as candidates for mechano-bactericidal surfaces. In specific circumstances involving mechano-bactericidal activity, certain nanostructured surfaces could exhibit their bactericidal effects by directly deforming the membranes of bacteria that adhere to these nanostructures. Additionally, in most cases, debris of bacterial cells may accumulate on these nanostructured surfaces. Such accumulation poses a significant challenge: it diminishes the mechano-bactericidal effectiveness of the surface, as it hinders the direct interaction between the nanostructures and any new bacteria that attach subsequently. In specific circumstances involving mechano-bactericidal activity, certain nanostructured surfaces could exhibit their bactericidal effects by directly deforming the membranes of bacteria that adhere to these nanostructures. Additionally, in most cases, debris of bacterial cells may accumulate on these nanostructured surfaces. Such accumulation poses a significant challenge: it diminishes the mechano-bactericidal effectiveness of the surface, as it hinders the direct interaction between the nanostructures and any new bacteria that attach subsequently.In other words, there is a need for strategies to remove the accumulated bacterial debris in order to sustain the mechano-bactericidal effect of the nanostructured surface. In this study, hierarchical micro/nano-structured surface (echinoid-shaped nanotextures were formed on Al micro-particle's surfaces) was fabricated using a simple pressure-less sintering method, and effective bactericidal efficiency was shown against E. coli (97 ± 3.81%) and S. aureus (80 ± 9.34%). In addition, thermal cleaning at 500 °C effectively eliminated accumulated dead bacterial debris while maintaining the intact Al 2 O 3 nanostructure, resulting in significant mechano-bactericidal activity (E. coli: 89 ± 6.86%, S. aureus: 75 ± 8.31%). As a result, thermal cleaning maintains the intact nanostructure and allows the continuance of the mechano-bactericidal effect. This effect was consistently maintained even after five repetitive use (E. coli: 80 ± 16.26%, S. aureus: 76 ± 12.67%)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: This study aimed to determine the effect of combined treatment with non-ablative laser and human stem cell-conditioned medium (HSCM) on tissue regeneration after burn-induced hypertrophic scar (HTS) formation., Methods: Fourteen patients with HTSs on both sides of the same body part were subjected to three sessions of non-ablative laser treatment, with an interval of four weeks between each treatment. Following laser treatment, HSCM and normal saline were applied to the HTSs of the right (experimental) and left side (control), respectively. Over the next 6 days, HSCM and moisturizer were applied to experimental scars, while only moisturizer was applied to control scars. Skin characteristics were evaluated before laser treatment and on the seventh day after the third laser treatment., Results: No significant intergroup differences were noted in the initial evaluation (P > 0.05). We found significant differences between the pre- and post-treatment measurements of erythema (P < 0.001), trans-epidermal water loss (TEWL; P < 0.001), and Cutometer® parameters (all parameters; P <0 . 05) of experimental scars. Control scars also showed significant differences between pre- and post-treatment measurements of thickness (P = 0.01), erythema (P < 0.001), TEWL (P < 0.001), and Cutometer® parameters (all parameters; P < 0.05). Changes (pre- to post-treatment) in scar thickness between the experimental (-0.003 ± 0.09) and control scars (0.04 ± 0.12) were significant (P = 0.01)., Conclusion: These results suggest that HSCM has a positive effect on short-term results when applied after laser treatment of hypertrophic scars., Competing Interests: Declaration of Competing Interest The authors declare no potential conflict of interest., (Copyright © 2022 Elsevier Ltd and ISBI. All rights reserved.)

The mechanism of indomethacin toxicity at the systemic level is largely unknown. In this study, multi-specimen molecular characterization was conducted in rats treated with three doses of indomethacin (2.5, 5, and 10 mg/kg) for 1 week. Kidney, liver, urine, and serum samples were collected and analyzed using untargeted metabolomics. The kidney and liver transcriptomics data (10 mg indomethacin/kg and control) were subjected to a comprehensive omics-based analysis. Indomethacin exposure at 2.5 and 5 mg/kg doses did not cause significant metabolome changes, whereas considerable alterations in the metabolic profile compared to the control were induced by a dose of 10 mg/kg. Decreased levels of metabolites and an increased creatine level in the urine metabolome indicated injury to the kidney. The integrated omics analysis in both liver and kidney revealed an oxidant-antioxidant imbalance due to an excess of reactive oxygen species, likely originating from dysfunctional mitochondria. Specifically, indomethacin exposure induced changes in metabolites related to the citrate cycle, cell membrane composition, and DNA synthesis in the kidney. The dysregulation of genes related to ferroptosis and suppression of amino acid and fatty acid metabolism were evidence of indomethacin-induced nephrotoxicity. In conclusion, a multi-specimen omics investigation provided important insights into the mechanism of indomethacin toxicity. The identification of targets that ameliorate indomethacin toxicity will enhance the therapeutic utility of this drug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Hypertrophic scars that occur after burns are less flexible and less elastic than normal skin. Objective measurement tools are required to assess hypertrophic scars after thermal injury. Cutometer® MPA 580 has been widely used for evaluating the properties of hypertrophic scars. Ultrasonography can evaluate elasticity, stiffness, and structure of tissues simultaneously using elastography and B-mode. This study aimed to investigate the intra-rater reliability and validity of elastography to visualize hypertrophic scars., Methods: Sixteen participants with a total of 96 scars were evaluated. The measurement sequence was elastography, Cutometer®, and elastography every 10 min. We then analyzed the intra-rater reliability using intraclass correlation coefficients (ICC). The results measured using elastography on the hypertrophic scars and surrounding normal skin were compared. The relationships between the elastographic and Cutometer® measurements using the 2-and 8-mm probes were compared., Results: The intra-rater reliability of elastographic measurements was acceptable for clinical use in terms of strain ratio (SR), shear-wave elastography (SWE), shear-wave speed (SWS), and SWE ratio ( ICC = 0.913, ICC=0.933, ICC = 0.842, and ICC = 0.921). The average SWS and SWE in hypertrophic scars were significantly greater than that for normal skin ( p < 0.001 and p < 0.001). SWE showed correlations with the R0 (r = -0.32, p = 0.002) and R8 (r = -0.30, p = 0.003) measured with the 8-mm probe. The SWE ratio was correlated with the R7 (r = -0.34, p = 0.001) measured with the 2-mm probe. The thickness of hypertrophic scars showed correlations with the R5 (r = 0.33, p < 0.001), R6 (r = 0.44, p < 0.001) and R8 (r = -0.35, p < 0.001) measured with the 8-mm probe. R0-R9 measured with 2-mm Cutometer® probes were not correlated with scar thickness ( r < 0.30, P > 0.05). The total scores of mVSS showed correlations with the R0 (r = 0.35, p < 0.001), R1(r = 0.32., p = 0.001), R3 (r = 0.38, p < 0.001), R4 (r = 0.38, p < 0.001), R8 (r = 0.34, p = 0.001), and R9 (r = 0.34, p = 0.001) measured with the 2-mm probe. R0-R9 measured with 8-mm Cutometer® probes were not correlated with mVSS ( r < 0.30, P > 0.05). The thickness of hypertrophic scars showed correlations with the SWE (r = 0.38, p < 0.001) and SWE ratio (r = 0.35, p < 0.001). Elastographic findings were not correlated with mVSS ( r < 0.30, P > 0.05)., Conclusion: In this study, together with the Cutometer®, ultrasound was confirmed as an evaluation tool that can objectively compare and analyze the difference between normal skin and hypertrophic scars., Competing Interests: Declaration of Competing Interest The authors declare no potential conflict of interest., (Copyright © 2022 Elsevier Ltd and ISBI. All rights reserved.)

The purpose of this study was to investigate molecular epidemiology of Theileria spp. in ticks in Korea and assess their potential threat from wildlife animals to domestic animals. A total of 21152 hard ticks were collected from Chungcheong and Jeolla provinces of Korea from March to October 2021. Tick species were identified by microscopy and Theileria spp. were screened by nested PCR targeting 18S rRNA. Haemaphysalis spp. were the most abundant tick species, followed by H. longicornis, H. flava, Amblyomma testudinarium, and Ixodes nipponensis. Of the collected ticks, 6914 ticks (541 pools) were screened, and PCR showed 211 positive pools (39.0%; MIR: 3.05). The PCR and phylogenetic analysis identified two Theileria species, T. luwenshuni and Theileria sp., with T. luwenshuni (162/211, 76.78%; MIR: 2.34) being more abundant than Theileria sp. (36/211, 17.06%; MIR: 0.52); co-infection of the two species were noted (13/211, 6.16%; MIR: 0.19). Among the tick species, H. longicornis, especially nymphs, showed the highest prevalence. Regarding season, the highest prevalence was observed in May. Considering the tick and Theileria species identified in this study, H. longicornis nymph and cervine play a critical role in maintaining Theileria spp. in Korea and could be a potential threat to domestic animals, including deer and goats. In addition, there are significant correlations among tick distribution, region, season, and prevalence of Theileria., Competing Interests: Declaration of Competing Interest Not applicable., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Emergency department (ED) clinicians may misdiagnose renal infarction (RI) as urolithiasis because RI is a rare disease with presenting symptoms similar to the symptoms of urolithiasis. However, earlier diagnosis of RI can improve patient prognosis., Objectives: We investigated potential predictors for distinguishing RI from urolithiasis based on clinical findings and laboratory results., Methods: This randomly matched retrospective case-control study included patients who had been diagnosed with acute RI or acute urolithiasis between January 2016 and March 2020. Patients were excluded if they were aged under 18 years, had a history of trauma, or had incomplete medical records. Using a matching ratio of 1:4, RI patients were randomly matched to urolithiasis patients. Multivariable logistic regression was performed to identify factors that could distinguish RI from urolithiasis., Results: In total, 48 patients were included in the RI group and 192 patients were included in the urolithiasis group. Multivariable logistic regression showed that age ≥ 65 years (odds ratio [OR] 6.155; p = 0.022), atrial fibrillation (OR 18.472; p = 0.045), current smoking (OR 17.070; p = 0.001), costovertebral angle tenderness (OR 0.179; p = 0.037), aspartate aminotransferase level ≥ 27.5 U/L (OR 6.932; p = 0.009), sodium level ≥ 138.5 mEq/L (OR 0.079; p = 0.004), and hematuria (OR 0.042; p = 0.001) were significant predictors that could distinguish RI from urolithiasis. Based on these results, a nomogram was constructed., Conclusion: Age ≥ 65 years, atrial fibrillation, current smoking, absence of costovertebral angle tenderness, aspartate aminotransferase level ≥ 27.5 U/L, sodium level < 138.5 mEq/L, and absence of hematuria were predictors that can distinguish between RI and urolithiasis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Information on the type of vesicular glutamate transporter (VGLUT) that is expressed in the Piezo2-positive (Piezo2+) neurons in the trigeminal ganglion (TG) and on the type of Piezo2+ axons and their distribution in the dental pulp is important for understanding dental pain elicited by mechanical stimuli and developing new therapeutic strategies., Methods: We examined the expression of Piezo2 and its coexpression with VGLUT1 and VGLUT2 in rat TG, the sensory root, and human dental pulp using light and electron microscopic immunohistochemistry and quantitative analysis., Results: VGLUT1 and VGLUT2 were expressed in the TG neurons. Piezo2 was expressed in axons of all types but primarily in small myelinated (Aδ) axons in the sensory root. In the dental pulp, Piezo2 was expressed densely in the numerous axons that form a plexus in the peripheral pulp. Piezo2+ axons in the peripheral pulp were mostly unmyelinated, and Piezo2 immunoreactivity was often concentrated near the axolemma, suggesting that it may represent functional receptors., Conclusions: These findings suggest that VGLUT1 and VGLUT2 are involved in the glutamate signaling in Piezo2+ neurons, Piezo2 may be primarily activated by noxious mechanical stimuli, and Piezo2-mediated dental mechanotransduction may be primarily elicited in the peripheral pulp., (Copyright © 2022 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Background: Chronic refractory cough significantly impairs the psychological and social aspects of quality of life. Loss of inhibitory control is suggested as a potential central neurobiological mechanism underlying chronic refractory cough., Research Question: Do structural and functional changes related to chronic cough occur in higher cortical brain regions?, Study Design and Methods: The structural and resting-state functional alterations in the brains of 15 patients with chronic refractory cough and 15 age- and sex-matched healthy control participants were evaluated. Gray matter volumes of the whole brain were measured using voxel-based morphometry based on T1-weighted MRI. Intrinsic functional connectivity within large-scale brain networks was examined on resting-state functional MRI. Correlation analyses were performed to examine the relationships of these brain changes with duration, severity, and impact of cough., Results: Compared with healthy control participants, patients with chronic refractory cough demonstrated a lower gray matter volume in the left frontal cluster and enhanced functional connectivity within the left frontoparietal network, which were associated with greater cough scores. Furthermore, enhanced functional connectivity within the left frontoparietal network was associated with a greater psychological and social impact of coughing. Lower left frontal gray matter volume was associated with longer cough duration., Interpretation: Structural and functional alterations in the left frontal brain regions may be implicated in the psychological and social impact and disease duration of chronic refractory cough. Our findings provide new perspectives on developing interventional approaches targeting the cognitive modulation of chronic coughing., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Drug-induced nephrotoxicity is frequently reported. However, the mechanisms underlying nephrotoxic medications and their overlapping molecular events, which might have therapeutic value, are unclear. We performed a genome-wide analysis of gene expression and a gene set enrichment analysis to identify common and unique pathways associated with the toxicity of colistin, ifosfamide, indomethacin, and puromycin. Rats were randomly allocated into the treatment or control group. The treatment group received a toxic dose once daily of each investigated drug for 1 week. Differentially expressed genes were found in the drug-treated kidney and liver compared to the control, except for colistin in the liver. Upregulated pathways were mainly related to cell death, cell cycle, protein synthesis, and immune response modulation in the kidney. Cell cycle was upregulated by all drugs. Downregulated pathways were associated with carbon metabolism, amino acid metabolism, and fatty acid metabolism. Indomethacin, colistin, and puromycin shared the most altered pathways in the kidney. Ifosfamide and indomethacin affected molecular processes greatly in the liver. Our findings provide insight into the mechanisms underlying the renal and hepatic adverse effects of the four drugs. Further investigation should explore the combinatory drug therapies that attenuate the toxic effects and maximize the effectiveness of nephrotoxic drugs., (Copyright © 2022. Published by Elsevier Inc.)

Post-burn hypertrophic scars are characterized by excessive accumulation of extracellular matrix secreted by fibroblasts. Exosomes are membrane lipid extracellular vesicles that play a pivotal role in cellular communication. Previous studies revealed the role of stem cell-derived exosomes in repairing damaged tissues, and also showed that cancer cell-derived exosomes could affect the disease pathogenesis. However, the functional properties of exosomes derived from hypertrophic scar fibroblasts (HTSFs) have not yet been studied extensively. In this study, we aimed to investigate whether HTSFs-derived exosomes can change the fibrosis-related signaling pathways in human normal fibroblasts (HNFs). HTSFs and HNFs were isolated from human hypertrophic scar tissues. HTSFs-derived exosomes were extracted and treated to HNFs. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect mRNA and protein expression, respectively, and cell proliferation and mobility were also assessed. Exosome treatment markedly increased cell proliferation and migration, and induced small mother against decapentaplegic (SMAD) signaling by increasing the levels of phosphorylated SMAD2 and SMAD1/5/8. The levels of TAK1 signaling components were also increased after exosome treatment to HNFs, including phosphorylated TAK1, p38, ERK, and JNK. HTSFs-derived exosomes further induced the epithelial-mesenchymal transition by decreasing the expression level of E-cadherin and increasing the expression levels of N-cadherin and vimentin. Consequently, the expression levels of fibronectin, type Ⅰ collagen, and type Ⅲ collagen were increased. Our results demonstrate the fibrotic property of HTSFs-derived exosomes, which suggests a potential functional role in hypertrophic scar development and a new therapeutic target., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Due to its high polyunsaturated fatty acid content, acellular fish skin has emerged as a dermal substitute for the promotion of wound healing as it decreases scar formation while providing pain relief. However, various systematic studies on acellular fish skin, such as its biophysical analysis, in vitro activities, and clinical application, have not been sufficiently investigated. In this study, we conducted a comparative study to evaluate the wound-healing ability of acellular fish skin graft (Kerecis®) with that of the widely used bovine collagen skin graft (ProHeal®). The skin grafts were evaluated not only in terms of their biophysical properties, but also their in vitro cellular activities, using fibroblasts, keratinocytes, and human endothelial cells. The clinical study evaluated wound healing in 52 patients with acute burns who underwent skin grafting on donor sites from January 2019 to December 2020. The study was conducted with two groups; while only Kerecis® was tested in one group, Kerecis® and ProHeal® were compared in the other. In both groups, the application time of the dressing material was one to two days after split-thickness skin grafting to the donor sites. The Kerecis®-treatment group experienced faster healing than the other treatment group. In particular, the average wound healing time using the Kerecis® treatment and the ProHeal® treatment was 10.7 ± 1.5 days and 13.1 ± 1.4 days, respectively. We believe that the faster healing of the Kerecis® treatment, compared to that of the ProHeal® treatment, maybe due to the synergistic effect of the unique biophysical structure and the bioactive components of acellular fish skin., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: No population pharmacokinetics (PK) model of isoniazid (INH) has been reported for the Indonesian population with tuberculosis (TB). Therefore, we aimed to develop a population PK model to optimize pharmacotherapy of INH on the basis of therapeutic drug monitoring (TDM) implementation in Indonesian patients with TB., Materials and Methods: INH concentrations, N-acetyltransferase 2 (NAT2) genotypes, and clinical data were collected from Dr. Soetomo General Academic Hospital, Indonesia. A nonlinear mixed-effect model was used to develop and validate the population PK model., Results: A total of 107 patients with TB (with 153 samples) were involved in this study. A one-compartment model with allometric scaling for bodyweight effect described well the PK of INH. The NAT2 acetylator phenotype significantly affected INH clearance. The mean clearance rates for the rapid, intermediate, and slow NAT2 acetylator phenotypes were 55.9, 37.8, and 17.7 L/h, respectively. Our model was well-validated through visual predictive checks and bootstrapping., Conclusions: We established the population PK model for INH in Indonesian patients with TB using the NAT2 acetylator phenotype as a significant covariate. Our Bayesian forecasting model should enable optimization of TB treatment for INH in Indonesian patients with TB., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Optical diffraction tomography (ODT), an emerging imaging technique that does not require fluorescent staining, can measure the three-dimensional distribution of the refractive index (RI) of organelles. In this study, we used ODT to characterize the pathological characteristics of human eosinophils derived from asthma patients presenting with eosinophilia. In addition to morphological information about organelles appearing in eosinophils, including the cytoplasm, nucleus, and vacuole, we succeeded in imaging specific granules and quantifying the RI values of the granules. Interestingly, ODT analysis showed that the RI (i.e., molecular density) of granules was significantly different between eosinophils from asthma patients and healthy individuals without eosinophilia, and that vacuoles were frequently found in the cells of asthma patients. Our results suggest that the physicochemical properties of eosinophils derived from patients with asthma can be quantitatively distinguished from those of healthy individuals. The method will provide insight into efficient evaluation of the characteristics of eosinophils at the organelle level for various diseases with eosinophilia., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The current standard treatment for hypertrophic scars following burn injury is pressure garment therapy. The experimenters developed the novel portable pressure measuring device using silicon piezoresistive sensors. As PicoPress® is the most accurate (i.e., lowest variation and error) manometric sensor for pressure measurement, we sought to compare and examine the accuracy of the novel device regarding in vitro pressure measurements at the hypertrophic scar-pressure garment interface., Methods: The novel device was designed to operate in non-corrosive media, such as air. The device can use up to six pressure sensing points and was developed to adjust the number of pressure sensors according to the size of the scar. Pressure measurements were acquired through a readout circuit consisting of an analog-to-digital converter, a microprocessor, and a Bluetooth transmission module for wireless data transmission to an external device. All signals were converted into mean pressure expressed in millimeters of mercury (mmHg). The mean pressure values measured by the sensors were compared to those obtained from PicoPress®. 55 garment pressures recordings were obtained from the sensors over this study conducted in 2018-February 2020. We then analyzed the test-retest reliability using the intraclass correlation coefficients (ICC). PicoPress® was also employed in the same pressure garments for obtaining similar measurements. A two way random effects model ICC with 95% confidence intervals was used to compare the mean pressure values obtained from the silicon piezoresistive sensors to the PicoPress® measurements., Results: The test-retest reliability of the pressure sensors was close to the acceptable level for clinical use regarding stationary interface pressure measurement (ICC = 0.99, 95% CI 0.990-0.997). The mean pressure obtained from the silicon piezoresistive pressure sensors showed an accordance with the measurements from PicoPress® (ICC = 0.97, 95% CI 0.947-0.985)., Conclusion: The novel device may present a viable alternative to PicoPress® for garment pressure measurements. In addition, the novel device improves adaptability to the hypertrophic scar shape and size. Complementary characteristics such as wireless transmission to an external device may allow burn patients to continuously wear the device for real-time measurements during pressure garment therapy, thus improving existing devices including PicoPress®., (Copyright © 2021 Elsevier Ltd and ISBI. All rights reserved.)

Background: Personalized warfarin dosing is influenced by various factors including genetic and non-genetic factors. Multiple linear regression (LR) is known as a conventional method to develop predictive models. Recently, machine learning approaches have been extensively implemented for warfarin dosing due to the hypothesis of non-linear association between covariates and stable warfarin dose., Objective: To extend the multiple linear regression algorithm for personalized warfarin dosing in a Korean population and compare with a machine learning--based algorithm., Method: From this cohort study, we collected information on 650 patients taking warfarin who achieved steady state including demographic information, indications, comorbidities, comedications, habits, and genetic factors. The dataset was randomly split into training set (90%) and test set (10%). The LR and machine learning (gradient boosting machine [GBM]) models were developed on the training set and were evaluated on the test set., Result: LR and GBM models were comparable in terms of accuracy of ideal dose (75.38% and 73.85%), correlation (0.77 and 0.73), mean absolute error (0.58 mg/day and 0.64 mg/day), and root mean square error (0.82 mg/day and 0.9 mg/day), respectively. VKORC1 genotype, CYP2C9 genotype, age, and weight were the highest contributors and could obtain 80% of maximum performance in both models., Conclusion: This study shows that our LR and GMB models are satisfactory to predict warfarin dose in our dataset. Both models showed similar performance and feature contribution characteristics. LR may be the appropriate model due to its simplicity and interpretability., (© 2021 International Society on Thrombosis and Haemostasis.)

Purpose: This study aimed to investigate the regeneration effect of extracorporeal shock wave therapy (ESWT) on hypertrophic scar regeneration using objective measurements., Methods: This was a double-blinded, randomized, controlled trial of 48 participants who had undergone autologous split-thickness skin grafting (STSG) with same artificial dermis. The ESWT group (n=25) received shock waves with low-energy flux density (0.05-0.30mJ/mm 2 ). The interval between treatments is a 1-week. The ESWT group also received recommended treatment. The control group (n=23) only received standard treatment. We measured skin characteristics before treatment and after 6 weeks for both groups., Results: No significant intergroup difference was noted at the initial evaluations (p>0.05). The pre- to post-treatment change in the scar thickness (p=0.03) and erythema (p=0.03), greater reduction was found in the ESWT group than control group. The pre- to post-treatment change in the sebum level (p=0.02), more increase was found in the ESWT group. We found no significant differences in the change measurements between the two groups for melanin levels (p=0.62) and transepidermal water loss (TEWL) (p=0.94). The changes (skin distensibility, biological skin elasticity, gross skin elasticity, and skin viscoelasticity) measured with the Cutometer showed no significant differences between the two groups (p=0.87, p=0.32, p=0.37, and p=0.29, respectively)., Conclusion: This is the first report of ESWT on hypertrophic scar after burn using objective tools (melanin, erythema, sebum, TEWL, elasticity and thickness). ESWT has objective beneficial effects on burn-associated scar characteristics., (Copyright © 2020 Elsevier Ltd and ISBI. All rights reserved.)

Increased burdens of rare coding variants in genes related to lysosomal storage disease or mitochondrial pathways were reported to be associated with idiopathic Parkinson's disease. Under a hypothesis that the burden of damaging rare coding variants is increased in causative genes for hereditary parkinsonism, we analyzed the burdens of rare coding variants with a case-control design. Two cohorts of whole-exome sequencing data and a cohort of genome-wide genotyping data of clinically validated idiopathic Parkinson's disease cases and controls, which were open to the public, were used. The sequence kernel association test-optimal was used to analyze the burden of rare variants in the hereditary parkinsonism gene set, which was constructed from the Online Mendelian Inheritance in Man database through manual curation. The hereditary parkinsonism gene set consisted of 17 genes with a locus symbol prefix for familial Parkinson's disease and 75 hereditary atypical parkinsonism genes. We detected a significant association of enriched burdens of predicted damaging rare coding variants in hereditary parkinsonism genes in all three datasets. Meta-analyses of the rare variant burden test in a subgroup of gene sets revealed an association between burdens of rare damaging variants with PD in a hereditary atypical parkinsonism gene set, but not in a subgroup gene set with a locus symbol prefix for familial Parkinson's disease. Our results highlight the roles of rare damaging variants in causative genes for hereditary atypical parkinsonian disorders. We propose that Mendelian genes associated with hereditary disorders accompanying parkinsonism are involved in Parkinson's disease-related genetic networks., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: It is important to prevent the development of delayed neuropsychiatric sequelae (DNS) in acute carbon monoxide (CO) intoxication, but no effective treatment has been clearly identified. Hyperbaric oxygen (HBO) therapy is one of the treatment options in acute CO poisoning; however, whether it can prevent the development of DNS is controversial., Objectives: The purpose of this study is to compare the effectiveness of normobaric oxygen (NBO) and HBO in preventing DNS., Methods: This prospective observational study was conducted on all patients with CO poisoning admitted to the emergency department of a tertiary hospital from 2016 to 2019. We followed-up patients to determine whether symptoms of DNS occurred at ≤6 months. We matched the propensity score to an equivalent distribution of potential covariates., Results: A total of 224 patients with CO poisoning were enrolled in this study. NBO was used for 26 patients and HBO for 198 patients. DNS occurred in 40 patients. There were significant differences between the NBO and HBO groups in terms of carboxyhemoglobin, loss of consciousness, dizziness, chest pain, hospitalization, and length of hospital stay. The incidence of DNS was 19.2% in the HBO group, which was higher than the 7.7% observed in the NBO group, but the difference was not significant (p = 0.18). After propensity score matching, the incidence of DNS did not differ between the NBO and HBO groups (8.3% vs. 10.4%, p > 0.99)., Conclusion: There was no difference in the incidence of DNS between groups receiving HBO and NBO in acute CO intoxication., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aquaporins (AQPs) are a family of channel proteins that facilitate the transport of water and small solutes across biological membranes. They are widely distributed throughout the organism, having a number of key functions, some of them unexpected, both in health and disease. Among the various diseases in which AQPs are involved, infertility has been overlooked. According to the World Health Organization (WHO) infertility is a global public health problem with one third of the couples suffering from subfertility or even infertility due to male or female factors alone or combined. Thus, there is an urgent need to unveil the molecular mechanisms that control gametes production, maturation and fertilization-related events, to more specifically determine infertility causes. In addition, as more couples seek for fertility treatment through assisted reproductive technologies (ART), it is pivotal to understand how these techniques can be improved. AQPs are heterogeneously expressed throughout the male and female reproductive tracts, highlighting a possible regulatory role for these proteins in conception. In fact, their function, far beyond water transport, highlights potential intervention points to enhance ART. In this review we discuss AQPs distribution and structural organization, functions, and modulation throughout the male and female reproductive tracts and their relevance to the reproductive success. We also highlight the most recent advances and research trends regarding how the different AQPs are involved and regulated in specific mechanisms underlying (in)fertility. Finally, we discuss the involvement of AQPs in ART-related processes and how their handling can lead to improvement of infertility treatment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Neovascular age-related macular degeneration (nAMD) is a common cause of irreversible vision loss in the elderly. Anti-vascular endothelial growth factor has been effective in treating pathological ocular neovascularization, but it has limitations including the need for repeated intraocular injections for the maintenance of therapeutic effects in most patients and poor or non-response to this agent in some patients. in vitro cellular studies were conducted using retinal pigment epithelial cell lines (ARPE-19 and hTERT-RPE1), human umbilical vein endothelial cells (HUVECs), and human umbilical vein smooth muscle cells (HUVSMCs). in vivo efficacy of ilimaquinone (IQ) was tested in laser-induced choroidal neovascularization mouse and rabbit models. Tissue distribution study was performed in male C57BL6/J mice. IQ, 4,9-friedodrimane-type sesquiterpenoid isolated from the marine sponge, repressed the expression of angiogenic/inflammatory factors and restored the expression of E-cadherin in retinal pigment epithelial cells by inhibiting the Wnt/β-catenin pathway. In addition, it selectively inhibited proliferation and tube formation of HUVECs by activating the p53 pathway. Topical and intraperitoneal administration of IQ significantly reduced choroidal neovascularization in rabbits and mice with laser-induced choroidal neovascularization. Notably, IQ by the oral route of exposure was highly permeable to the eyes and suppressed abnormal vascular leakage by downregulation of β-catenin and stabilization of p53 in vivo. Our findings demonstrate that IQ functions through regulation of p53 and Wnt/β-catenin pathways with conceivable advantages over existing cytokine-targeted anti-angiogenic therapies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

There is a lack of comprehensive studies on the seroprevalence of tick-borne pathogens in the Republic of Korea. Therefore, the aim of this study was to investigate the seroprevalences of Anaplasma spp. (A. phagocytophilum/A. platys), Borrelia burgdorferi sensu lato, Babesia gibsoni, Ehrlichia spp. (E. canis/E. ewingii), and Ehrlichia chaffeensis in dogs across the Republic of Korea in 2017 and 2018. A total of 2215 serum samples collected from 938 companion dogs, 969 shelter dogs, and 308 military working dogs were examined using commercial enzyme-linked immunosorbent assay (ELISA) and indirect fluorescence immunoassay (IFA) kits. Data collected for each animal, including breed, sex, age, region, season, and dog type, were used for statistical analysis. The overall seroprevalence was highest for Anaplasma spp. (15.1 %), followed by Ehrlichia spp. (10.3 %), B. burgdorferi sensu lato (6.4 %), E. chaffeensis (2.3 %), and B. gibsoni (1.7 %). One hundred and sixty-one dogs had antibodies against two or three different pathogens. The most common combinations were Anaplasma spp. - Ehrlichia spp. (2.1 %), Anaplasma spp. - E. chaffeensis (1.4 %), and Anaplasma spp. - B. burgdorferi sensu lato (1.2 %). Season was significantly associated with the seroprevalences of B. burgdorferi sensu lato and Ehrlichia spp., with dogs presenting the highest percentage of positive results during summer. Anaplasma spp. and B. gibsoni were significantly more prevalent in the northern and southern regions, respectively. The seroprevalences of Anaplasma spp., B. burgdorferi sensu lato, and Ehrlichia spp. were significantly higher in military working dogs, while the seroprevalence of E. chaffeensis was higher in companion dogs. The current findings are important for future surveillance of canine tick-borne pathogens and designing appropriate approaches for the diagnosis and control of these pathogens in the Republic of Korea., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: The association between oxidized low-density lipoprotein (OxLDL) and plaque instability in coronary and carotid artery disease is well established. However, the association between OxLDL and the histologic changes of plaque in peripheral artery disease has not been clearly elucidated. This study aims to investigate the association between plasma OxLDL and histologic plaque instability in patients with peripheral artery disease., Methods: Prospectively obtained plaques from 48 patients who underwent endovascular atherectomy (n = 20), surgical endarterectomy (n = 9), or bypass surgery (n = 19) for treatment of atherosclerotic femoropopliteal artery disease were evaluated for histologic fibrosis, sclerosis, calcification, necrosis, cholesterol cleft, and foamy macrophages using hematoxylin and eosin, oil red O, and immunohistochemical staining. Unstable plaques were defined as plaques that were positive for foamy macrophages and with lipid content of more than 10% of the total plaque area. Plasma OxLDL levels were measured using an enzyme-linked immunosorbent assay (Mercodia AB, Uppsala, Sweden)., Results: Of the 48 patients, 26 (54%) had unstable plaques. The unstable plaque group was younger, had fewer angiographic total occlusions, less calcification, and more CD68-positive and LOX-1-positive cells than the stable plaque group. Plasma OxLDL levels were significantly higher in the unstable plaque group than in the stable plaque group (57.4 ± 13.9 vs. 47.2 ± 13.6 U/L, P = 0.014). Multivariate analysis revealed that plasma OxLDL level, smoking, angiographic nontotal occlusion, and statin nonuse were independent predictors of unstable plaque., Conclusions: Among patients with peripheral artery disease, the histologic instability of femoropopliteal plaque was independently associated with high plasma OxLDL, smoking, nontotal occlusion, and statin nonuse. Further large-scale studies are necessary to evaluate the role of noninvasive OxLDL measurement for predicting plaque instability and future adverse vascular event., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Pancreatic cancer is a fatal disorder which originates in pancreas. Its mortality rate is increasing with time. Some studies also reported that pancreatic cancer would be ranked 2nd by the year 2030. Codon usage bias (CUB) arises when synonymous codons for each amino acid are not used randomly in the coding sequences of genes. We used bioinformatic methods to analyze the compositional properties, codon context and codon usage trend of the genes associated with pancreatic cancer as no work was reported yet. From the base composition analysis, the pancreatic cancer genes were found to be GC-rich and at the 3rd codon position the G/C ending codons were more preferred to A/T ending ones. The CUB was low in genes associated with pancreatic cancer. Correspondence analysis proposed that other than base constraints, CUB might also be affected by some other factors such as natural selection. Moreover, results of correlation analysis indicated that CUB and various GC contents i.e. GC, GC1, GC2, GC3 played important role in the release of free energy by transcripts of the genes associated with pancreatic cancer. The low compAI values of coding sequences suggested a low translation rate of the genes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to culturally adapt the Intensive Care Experience Questionnaire (ICEQ) for Korean patients and evaluate its validity and reliability., Methods: This cross-sectional study comprised two phases. The first phase involved the cultural adaptation of the ICEQ. In the second phase, the psychometric properties of the adapted measure were evaluated. Cultural adaptation was conducted in accordance with the World Health Organization's process. The adapted questionnaire was administered to 200 Korean patients who had received treatment in an intensive care unit within the past six months. Model fit was assessed through confirmatory factor analysis, and convergent validity and discriminant validity of the items were assessed. Known-groups validity was evaluated using the t test and Cohen's effect size. Cronbach's α was used to examine internal consistency reliability., Results: The Korean version of the ICEQ (K-ICEQ) consists of 26 items and four subscales: Frightening Experiences, Awareness of Surroundings, Satisfaction with Care, and Recall of Experiences. The model fit indices, convergent validity, and discriminant validity of the K-ICEQ were all satisfactory. According to the results of the test of known-groups validity, intensive care unit (ICU) experience varied according to gender, planned ICU admission, mechanical ventilation, and restraints application. Cronbach's α of the K-ICEQ subscales ranged from .74 to .93., Conclusion: The validity and reliability of the K-ICEQ reflecting the characteristics of Korean ICU patients were satisfactory. The K-ICEQ can be used to evaluate the experience of Korean ICU patients and contribute to the development of interventions to improve the ICU experience., Competing Interests: Declaration of Competing Interest The authors declare there are no conflicts of interest with respect to the research, authorship, and publication of this article., (Copyright © 2020. Published by Elsevier B.V.)

Post-burn hypertrophic scar (HTS) is a form of excessive dermal fibrosis characterized by cutaneous scarring, which is common in patients following burn injury. Moreover, at least 50% of HTS are accompanied by inflammation. Cytoplasmic polyadenylation element binding (CPEB) proteins are key mRNA-binding proteins that control the translation of several mRNAs. However, their potential roles in treating dermal fibrosis and scarring remain unknown. Therefore, in this study, we aimed to investigate the effects of small interfering RNA (siRNA)-mediated knockdown of CPEB1 or CPEB4 in human THP-1 macrophages and dermal fibroblasts treated with LPS and TGF-β1. We found significantly increased CPEB1 and CPEB4 mRNA and protein levels in LPS-treated THP-1 cells and TGF-β1-treated fibroblasts. CPEB1 and CPEB4 knockdowns suppressed LPS-activated TAK1 signaling cascades by reducing the levels of TNF-α and phosphorylated TAK1, p38, ERK, JNK, and NF-κB-p65 in THP-1 cells. CPEB1 and CPEB4 knockdowns also attenuated TGF-β1-activated Smad-dependent and -independent signaling cascades by reducing the levels of TAK1, p38, ERK, JNK, and phosphorylated Smad 2 and Smad 1/5/8 in fibroblasts. Furthermore, CPEB1 or CPEB4 knockdown markedly decreased the levels of fibrosis markers, including α-SMA, type I collagen, and fibronectin in fibroblasts. Our findings indicate that CPEB1 and CPEB4 are involved in the regulation of the TAK1 and Smad signalings in human macrophages and dermal fibroblasts. These activities may play a role in cutaneous scarring responses., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Clinical characteristics of the international population with severe asthma are unknown. Intercountry comparisons are hindered by variable data collection within regional and national severe asthma registries. We aimed to describe demographic and clinical characteristics of patients treated in severe asthma services in the United States, Europe, and the Asia-Pacific region., Methods: The International Severe Asthma Registry retrospectively and prospectively collected data in patients with severe asthma (≥ 18 years old), receiving Global Initiative for Asthma (GINA) Step 5 treatment or with severe asthma remaining uncontrolled at GINA Step 4. Baseline demographic and clinical data were collected from the United States, United Kingdom, South Korea, Italy, and the Severe Asthma Web-based Database registry (including Australia, Singapore, and New Zealand) from December 2014 to December 2017., Results: We included 4,990 patients. Mean (SD) age was 55.0 (15.9) years, and mean (SD) age at asthma onset was 30.7 (17.7) years. Patients were predominantly female (59.3%) and white (72.6%), had never smoked (60.5%), and were overweight or obese (70.4%); 34.9% were at GINA Step 5; and 57.2% had poorly controlled disease. A total of 51.1% of patients were receiving regular intermittent oral corticosteroids, and 25.4% were receiving biologics (72.6% for those at GINA Step 5). Mean (SD) exacerbation rate was 1.7 (2.7) per year. Intercountry variation was observed in clinical characteristics, prescribed treatments, and biomarker profiles., Conclusions: Using a common data set and definitions, this study describes severe asthma characteristics of a large patient cohort included in multiple severe asthma registries and identifies country differences. Whether these are related to underlying epidemiological factors, environmental factors, phenotypes, asthma management systems, treatment access, and/or cultural factors requires further study., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Selenium (Se) plays a vital role in reactive oxygen species (ROS) homeostasis and redox regulation in intracellular signaling via selenocysteine (Sec), known as the 21st proteinogenic amino acid, but its specific biological functions in development and disease remain undiscovered. In this study, we explored the role of selenophosphate synthetase 1 (SEPHS1) in the pluripotency maintenance and reprogramming. We found that high level of SEPHS1 is retained in undifferentiated embryonic stem cells (ESCs), which is decreased during their differentiation. SEPHS1 knockdown significantly reduced reprogramming efficiency, proving that SEPHS1 is required for acquisition of pluripotency. However, SEPHS1 knockdown did not affect the expression of significant pluripotency genes, suggesting that SEPHS1 may be involved in the survival of pluripotent stem cells rather than in the regulation of pluripotency genes. Transcriptome analysis revealed altered expression of the gene set related to the ROS pathway and apoptosis in SEPHS1-knockdown cells. We also demonstrated the role of SEPHS1 in human ESC clonogenicity, and we found improved single-cell survival of hESCs by selenium treatment in a concentration-dependent manner. Our study implies that hSEPHS1 is a regulator of selenium-mediated redox-signaling in human pluripotent stem cells and plays a role in their survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background & Aims: Poor outcomes can result from inadequate energy intake. We aimed to investigate the reliability of resting energy expenditure (REE) measured by indirect calorimetry (IC) with REE calculated using predictive equations for nutritional support in patients with major burns., Methods: REE was measured using IC and compared with predictive equations in 215 adult severe burns patients from Jan 2011 to Jun 2015. Agreement between IC and predictive equations was assessed using Bland-Altman methods., Results: All predictive equations, including newly developed Hangang equation, were compared with REE measured using IC. The mean measured REE was 1712 kcal/d. Bland-Altman analysis showed that 1.2 times HBE, Thumb 25, and Ireton-Jones equations had higher accuracy and reliability. The concordance correlation coefficient was higher (0.49) in the Ireton-Jones equation, and root mean square error (RMSE) was lowest (471.5) in the Thumb 25 equation. The proportion of patients with predicted REE within ±10% of measured REE was highest with Thumb 25 (52.5%). In the validation set, the Hangang equation showed the highest Lin's concordance correlation coefficient (0.67) and the lowest RMSE (311.4). Other equations for burns patients had higher mean bias and overestimated REE when compared with IC results., Conclusions: This study suggests that Thumb 25 can be used as an alternative method for estimating energy requirements of patients with major burns when IC is not available or applicable. However, for these patients with significant variation in metabolism over time, an alternative equation is the new Hangang equation., (Copyright © 2018. Published by Elsevier Ltd.)

Objectives: This study aimed to investigate clinical and coronary computed tomographic angiography (CTA) characteristics of lesions that progressed to chronic total occlusion (CTO)., Background: CTO is one of the most common reasons for referral to coronary artery bypass surgery. Prediction and adequate early management for future CTO lesions may be beneficial., Methods: The study evaluated patients with at least 1 vessel with a diameter stenosis of ≥70% on invasive coronary angiography (ICA) who underwent previous coronary CTA >12 months before ICA, from 2006 to 2015. The study compared the baseline clinical and coronary CTA characteristics of the patients with future CTO lesions with those of the patients with future non-CTO lesions (patient-level analysis) and compared coronary CTA findings between the future CTO lesion with the most stenotic non-CTO lesion in each CTO patient (lesion-level analysis)., Results: Among the 216 patients, 32 (14.8%) had a CTO lesion on ICA. In patient-level analysis, no significant differences in clinical characteristics were found, whereas the coronary CTA culprit lesions of the CTO group had a smaller minimal lumen diameter (MLD) with more adverse plaque characteristics. In lesion-level analysis, future CTO lesions had a smaller MLD, a smaller reference segment diameter (RD), and longer lesion length. These lesions were more likely to be noncalcified plaques with a noneccentric cross-sectional distribution, and had a higher remodeling index, lower mean plaque attenuation (MPA), and more napkin-ring signs. In multivariate analysis and receiver-operating characteristic curve analysis, MLD of <2.0 mm, RD of <3.2 mm, and MPA of <50 Hounsfield units were independent predictors of future CTO lesions. The risk of CTO development in lesions with triple risk factors was 14-fold higher than that of the lesions with no risk factors., Conclusions: Lesions that progressed to CTO had more severe baseline coronary CTA features than non-CTO lesions. A small MLD, small RD, and low MPA were independent predictors of progression to CTO., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: This cross-sectional study aimed to investigate whether adipose tissue loss and reduced vitamin D levels following severe burn injury are associated with pathologic scar formation and biomechanical scar properties., Methods: A total of 492 male subjects with hypertrophic burn scars were enrolled from January 2014 to July 2018 and analyzed. Body fat content was measured using dual-energy X-ray absorptiometry. Values of melanin, erythema, and trans-epidermal water loss (TEWL) and the distensibility and elasticity of hypertrophic scars were examined using pigment- and TEWL-measuring devices and a suction skin elasticity meter., Results: Burn patients with higher fat percentage tended to have higher 25(OH) vitamin D levels (P < 0.001). As body fat percentage increased, hypertrophic scars showed higher mean value of Uf (distensibility, P < 0.001) and lower mean value of Uv/Ue (viscoelasticity or interstitial fluid shifting, P < 0.001). Burn patients with higher 25(OH) vitamin D levels tended to have higher mean values of Uf (P < 0.001) and Ua/Uf (gross elasticity, P = 0.013) and lower mean value of Uv/Ue (P = 0.008)., Conclusion: Adipose tissue loss and decreased 25(OH) vitamin D levels following burn injury were related to scar rigidity and slow interstitial fluid shifting in hypertrophic scars., (Copyright © 2019 Elsevier Ltd and ISBI. All rights reserved.)

Background: Optimal stenting strategy for long femoropopliteal artery lesions still remains undefined. Longer stent length has been shown to be associated with increased risk of restenosis. We sought to compare the efficacy of spot versus long stenting in the treatment of femoropopliteal artery disease., Methods: This study was designed as a multicenter randomized controlled trial to compare immediate and mid-term outcomes of spot versus long primary stenting for femoropopliteal arterial lesions. A total of 125 patients were randomized 1:1 to spot stenting group (n = 59) or long stenting group (n = 66)., Results: All lesions were treated with self-expanding bare nitinol stents. Baseline clinical and lesion characteristics were similar between the 2 groups except for male gender and current smoker. The mean lesion length was 24.1 ± 8.8 cm. Technical success was achieved in all patients. The 1-year primary patency and TLR-free (target lesion revascularization) survival did not differ significantly between the 2 groups. However, the spot stenting group showed a trend toward higher primary patency (86.1% vs. 72.7%, P = 0.158) and TLR-free survival (94.2% vs. 82.5%, P = 0.120). The total stented length (hazard ratio [HR] 1.01, 95% confidence interval [CI] 1.00-1.01, P = 0.011) and age (HR 0.94, 95% CI 0.90-1.00, P = 0.035) were independent predictors of restenosis., Conclusions: The spot stenting appears to be more favorable than the long stenting in terms of primary patency and TLR-free survival, although the difference was not statistically significant. The stented length was an independent predictor of restenosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: The authors investigated the utility of noninvasive hemodynamic assessment in the identification of high-risk plaques that caused subsequent acute coronary syndrome (ACS)., Background: ACS is a critical event that impacts the prognosis of patients with coronary artery disease. However, the role of hemodynamic factors in the development of ACS is not well-known., Methods: Seventy-two patients with clearly documented ACS and available coronary computed tomographic angiography (CTA) acquired between 1 month and 2 years before the development of ACS were included. In 66 culprit and 150 nonculprit lesions as a case-control design, the presence of adverse plaque characteristics (APC) was assessed and hemodynamic parameters (fractional flow reserve derived by coronary computed tomographic angiography [FFR CT ], change in FFR CT across the lesion [△FFR CT ], wall shear stress [WSS], and axial plaque stress) were analyzed using computational fluid dynamics. The best cut-off values for FFR CT , △FFR CT , WSS, and axial plaque stress were used to define the presence of adverse hemodynamic characteristics (AHC). The incremental discriminant and reclassification abilities for ACS prediction were compared among 3 models (model 1: percent diameter stenosis [%DS] and lesion length, model 2: model 1 + APC, and model 3: model 2 + AHC)., Results: The culprit lesions showed higher %DS (55.5 ± 15.4% vs. 43.1 ± 15.0%; p < 0.001) and higher prevalence of APC (80.3% vs. 42.0%; p < 0.001) than nonculprit lesions. Regarding hemodynamic parameters, culprit lesions showed lower FFR CT and higher △FFR CT , WSS, and axial plaque stress than nonculprit lesions (all p values <0.01). Among the 3 models, model 3, which included hemodynamic parameters, showed the highest c-index, and better discrimination (concordance statistic [c-index] 0.789 vs. 0.747; p = 0.014) and reclassification abilities (category-free net reclassification index 0.287; p = 0.047; relative integrated discrimination improvement 0.368; p < 0.001) than model 2. Lesions with both APC and AHC showed significantly higher risk of the culprit for subsequent ACS than those with no APC/AHC (hazard ratio: 11.75; 95% confidence interval: 2.85 to 48.51; p = 0.001) and with either APC or AHC (hazard ratio: 3.22; 95% confidence interval: 1.86 to 5.55; p < 0.001)., Conclusions: Noninvasive hemodynamic assessment enhanced the identification of high-risk plaques that subsequently caused ACS. The integration of noninvasive hemodynamic assessments may improve the identification of culprit lesions for future ACS. (Exploring the Mechanism of Plaque Rupture in Acute Coronary Syndrome Using Coronary CT Angiography and Computational Fluid Dynamic [EMERALD]; NCT02374775)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In clinical conditions, the reconstructions performed in the complex and three-dimensional bone defects in the craniomaxillofacial (CMF) area are often limited in facial esthetics and jaw function. Furthermore, to regenerate a bone defect in the CMF area, the used scaffold should have unique features such as different mechanical strength or physical property suitable for complex shape and function of the CMF bones. Therefore, a three-dimensional synthetic scaffold with a patient-customized structure and mechanical properties is more suitable for the regeneration. In this study, the customized kagome-structure scaffold with complex morphology was assessed in vivo. The customized 3D kagome-structure model for the defect region was designed according to data using 3D computed tomography. The kagome-structure scaffold and the conventional grid-structure scaffold (as a control group) were fabricated using a 3D printer with a precision extruding deposition head using poly(ε-caprolactone) (PCL). The two types of 3D printed scaffolds were implanted in the 8-shaped defect model on the rabbit calvarium. To evaluate the osteoconductivity of the implanted scaffolds, new bone formation, hematoxylin and eosin staining, immunohistochemistry, and Masson's trichrome staining were evaluated for 16 weeks after implantation of the scaffolds. To assess the mechanical robustness and stability of the kagome-structure scaffold, numerical analysis considering the 'elastic-perfectly plastic' material properties and deformation under self-contact condition was performed by finite element analysis. As a result, the kagome-structure scaffold fabricated using 3D printing technology showed excellent mechanical robustness and enhanced osteoconductivity than the control group. Therefore, the 3D printed kagome-structure scaffold can be a better option for bone regeneration in complex and large defects than the conventional grid-type 3D printed scaffold., (Copyright © 2019. Published by Elsevier B.V.)

Background: Low forced expiratory volume in 1 s (FEV 1 ) is a risk factor for asthma exacerbations (AEs). We aimed to determine if asthma control could reduce the future risk of AEs in patients with low FEV 1 . This study was conducted to evaluate the future risks of AEs within six months according to Asthma Control Test™ (ACT) score and FEV 1 ., Methods: A total of 565 patients with asthma were enrolled from the COREA cohort. The ACT score, lung function test, and number of AEs were assessed at baseline, three-month follow-up, and six-month follow-up with conventional asthma treatments by asthma specialists in real clinical settings., Results: Female sex, low ACT score, low FEV 1 , low FVC, and AE history in the previous three months were related with increased AEs within six months. AEs during six-month follow-up occurred in 24% of patients with ACT <20 and FEV 1 < 60% at baseline. Among patients with an ACT score ≥20, 3.4% of patients with an FEV 1 < 2.16 L and 9.8% of patients with FEV 1 ≥ 2.16 L had experienced AEs (P = 0.01), although no differences were observed in the presence of AEs within six months according to the predicted FEV 1 (FEV 1  ≥ 60% vs. FEV 1 < 60%, 5.66% vs. 8.51%, P = 0.65)., Conclusion: Patient with low FEV 1 seemed to show higher risk of AEs than those with near-normal FEV 1 despite ACT score ≥20 and asthma treatments. Therefore, treatment strategies that prevent AEs are needed in high-risk asthmatic patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We describe complete healing of an extensive cystic lesion by using a conservative approach: root canal treatment with concurrent surgical drainage. A silicone Foley catheter drain was modified into a surgical drainage stent, which was then used for 4 weeks. Disinfection of the root canal was achieved by the use of hand files and irrigation with 5.25% NaOCl for a minimum of 30 minutes. The irrigant changes were performed at 5-minute intervals, and no intracanal dressing was used. At subsequent follow-up examinations, cone-beam computed tomography and periapical radiographs confirmed that complete healing had occurred around the periapical and lateral areas of affected teeth. This case report indicates the potential for healing of large cystic lesions by nonsurgical root canal treatment., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Background: There have been limited and conflicting results regarding the prognostic impact of revascularization treatment on the long-term clinical outcomes of silent ischemia. The current study aimed to determine whether revascularization treatment compared with medical treatment (MT) alone reduces long-term risk of cardiac death of asymptomatic patients with objective evidence of inducible myocardial ischemia., Methods: A total of 1473 consecutive asymptomatic patients with evidence of inducible myocardial ischemia were selected from a prospective institutional registry. All patients showed at least 1 epicardial coronary stenosis with ≥50% diameter stenosis in coronary angiography. Patients were classified according to their treatment strategies. The primary outcome was cardiac death up to 10 years., Results: Among the total population, 709 patients (48.1%) received revascularization treatment including percutaneous coronary intervention (PCI, n = 558) or coronary artery bypass graft surgery (CABG, n = 151), with the remaining patients (764 patients, 51.9%) receiving MT alone. During the follow-up period, the revascularization treatment group showed a significantly lower risk of cardiac death compared with the MT alone group (25.4% vs. 33.7%, HR 0.624, 95%CI 0.498-0.781, p < 0.001). Among revascularized patients, patients with negative non-invasive stress test results after revascularization showed significantly lower risk of cardiac death compared to those with residual myocardial ischemia (8.9% vs. 18.7%, HR 0.406, 95% CI 0.175-0.942, p = 0.036)., Conclusions: In patients with silent myocardial ischemia, revascularization treatment was associated with significantly lower long-term risk of cardiac death compared with the MT alone group. The current results support contemporary practice of ischemia-directed revascularization, even in patients with silent myocardial ischemia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Microbial spoilage is a complex event to which different bacterial populations and metabolites can contribute depending on the storage conditions. This study explored the evolution of spoilage and related volatile organic compounds (VOCs) in chilled beef under air and vacuum packaging (VP). The results suggested that different storage conditions affected changes in bacterial communities and metabolites in beef and consequently affected the odor properties of the stored beef, thereby leading to spoilage. Bacterial species belonging to Pseudomonadaceae (Pseudomonas spp.) and lactic acid bacteria (Lactobacillus sp.) dominated the bacterial communities in beef stored under air and VP, respectively, with several VOCs associated with off-odors of the stored beef and most likely produced by both bacteria. Our results suggested several microbial VOCs that could be used as potential spoilage indicators, including acetic acid, butanoic acid, and 2-butanone in VP-stored beef and 3-methylbutan-1-ol, ethyl acetate, acetoin, 2-butanone, and diacetyl in air-stored beef. These findings might provide valuable information regarding the quality monitoring of beef during storage., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Tissue engineering aims to repair or replace damaged tissues or organs using biomedical scaffolds cultured with cells. The scaffolds composed of biomaterials should guide the cells to mature into functional tissues or organs. An ideal scaffold to regenerate hard tissues should have mechanical stability as well as biocompatibilities. It has been well known that gelatin can provide outstanding biological activities, but its low mechanical stability can be one of obstacles to be used in hard tissue regeneration. To overcome the issue, we used PVA, which can reinforce the low mechanical stability of the gelatin. The gelatin/PVA scaffolds have been fabricated using a low temperature 3D-printing process. By manipulating various weight fractions of PVA/gelatin, we can obtain the optimal mixture ratio in aspect of the physical and biological properties of the scaffolds. As a result, a weight fraction of 5:5 showed appropriate mechanical strength and enhanced cell activities, such as cell proliferation and differentiation. The gelatin/PVA scaffold showed potential for future application as biomedical scaffold in soft and hard tissue regeneration., (Copyright © 2018. Published by Elsevier B.V.)