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Young Bae Choi,1,&ast; Hyun Joo Jung,1,&ast; Hae-Rim Kim,2 Soo In Jeong1 1Department of Pediatrics, Ajou University School of Medicine, Ajou University Hospital, Suwon, Korea; 2College of Natural Science, School of Statistics, University of Seoul, Seoul, Korea&ast;These authors contributed equally to this workCorrespondence: Soo In Jeong, Department of Pediatrics, Ajou University School of Medicine, Ajou University Hospital, 164, World Cup-Ro, Yeongtong-Gu, Suwon, 16499, Korea, Tel +82-31-219-5160, Fax +82-31-219-5169, Email sooinjeong@aumc.or.krPurpose: We investigated whether nonpharmaceutical interventions (NPI) to reduce the spread of coronavirus disease 2019 (COVID-19) was associated with a change in the incidence of immune thrombocytopenia (ITP).Patients and Methods: Using the Korean Health Insurance Review and Assessment Services (HIRA) database, individuals newly diagnosed with ITP between January 2015 and December 2020 were identified. The NPI period was defined as February 2020 to December 2020. The ITP incidence in the NPI period was compared with the mean annual incidence during the same months in the pre-NPI period and the incidence predicted by the autoregressive integrated moving average model.Results: In total, 25,723 patients were identified, and the overall annual incidence of ITP was 8.28 per 100,000 persons ([95% confidence interval (CI): 8.18– 8.39]. The ITP incidence in the NPI period was 6.60 per 100,000 person-years (95% CI: 6.37– 6.85), 0.77 times (95% CI: 0.74– 0.80) lower than that during the pre-NPI period [8.62/100,000 (95% CI: 8.50− 8.74)]. With the exception for patients aged ≥ 70 years, the ITP incidence was significantly lower in the NPI period than in the pre-NPI period. The most significant decline in the ITP incidence during the NPI period was observed in the 0– 9 years age group [25.76/100,000 vs 14.01/100,000, P < 0.001; incidence rate ratio (IRR): 0.54 (95% CI: 0.51– 0.58)]. The intravenous immunoglobulin-treated ITP incidence in the NPI period was 1.69/100,000 (95% CI: 1.58– 1.81), 0.79 times (95% CI: 0.73– 0.85) lower than that in the pre-NPI period 2.15/100,000 (95% CI: 2.09− 2.21)]. The incidence of steroid-treated ITP was lower in the NPI period than in the pre-NPI period (2.73/100,000 vs 2.2/100,000, P < 0.001), with an IRR of 0.80 (95% CI: 0.76– 0.83).Conclusion: This nationwide study revealed a significant decrease in ITP incidence, particularly among children, after the implementation of NPI.Keywords: purpura, thrombocytopenic, idiopathic, COVID-19, incidence, pandemic

Gopal Lamichhane,1,2,&ast; Grinsun Sharma,1,3,&ast; Biswash Sapkota,1,4,&ast; Mahendra Adhikari,1,5,&ast; Sandhaya Ghimire,1,&ast; Prakash Poudel,1,6 Hyun-Ju Jung2 1School of Health and Allied Sciences, Faculty of Health Sciences, Pokhara University, Pokhara, 33700, Nepal; 2Department of Oriental Pharmacy and Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeollabuk-do, 570-749, South Korea; 3Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, 570-749, South Korea; 4Department of Pharmacy and Clinical Pharmacology, Madan Bhandari Academy of Health Sciences, Hetauda, 44107, Nepal; 5Department of Pharmacy, Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University Düsseldorf, Düsseldorf, 40225, Germany; 6Pharmacy Program, Gandaki University, Pokhara, 33700, Nepal&ast;These authors contributed equally to this workCorrespondence: Prakash Poudel; Hyun Ju Jung, Email poudelprakesh@gmail.com; hyun104@wku.ac.krIntroduction: Herbal products have been widely used for the treatment of diseases throughout the ages. In this research, we investigated antioxidant, antibacterial, anti-adipogenic, and anti-inflammatory activities of methanolic extracts of five ethnomedicinally important plants; namely, Alnus nepalensis, Dryopteris sparsa, Artocarpus lacucha, Litsea monopetala, and Lyonia ovalifolia.Methods: We investigated the DPPH free radical scavenging potential, sensitivity of selected bacterial strains towards the extracts using a disc diffusion assay, anti-inflammatory activity in RAW-264.7 cells, and anti-adipogenic activity by the ORO assay in 3T3-L1 preadipocytes.Results and discussion: The extract of A. nepalensis showed significant antioxidant activity (IC50=4.838 μg/mL), followed by A. lacucha, L. monopetala, and L. ovalifolia, exhibiting comparable IC50 values to that of ascorbic acid (IC50=5.063 μg/mL). Alnus nepalensis also showed good antibacterial activity in disc diffusion methods, with remarkable zones of inhibition in A. baumannii (14.66 mm) and P. mirabilis (15.50 mm) bacterial species. In addition, A. nepalensis was found to increase adipogenesis in 3T3-L1 cells, evidenced by increased lipid deposition in differentiated 3T3-L1 cells. A similar pattern of increased adipogenesis was observed on treatment with L. ovalifolia extracts. On the other hand, A. lacucha effectively reduced lipid deposition in 3T3-L1 cells at 100 μg/mL (75.18± 6.42%) by inhibiting adipogenesis, showing its potential use in the management of obesity. Furthermore, A. lacucha 100 μg/mL (15.91± 0.277 μM) and L. monopetala 75 μg/mL (12.52± 0.05 μM) and 100 μg/mL (11.77± 0.33 μM) significantly inhibited LPS-induced nitric oxide production in RAW 264.7 cells. Also, A. nepalensis and L. ovalifolia inhibited NO production significantly, endorsing their anti-inflammatory potential.Conclusion: The findings from these in-vitro studies suggest that the selected five plants possess remarkable antioxidant, antibacterial, anti-adipogenic, and anti-inflammatory activities. This study opens the door to conduct further advanced in-vivo experiments to find possible lead compounds for the development of valuable therapeutic agents for common health problems.Keywords: Alnus nepalensis, Dryopteris sparsa, Artocarpus lacucha, Litsea monopetala, Lyonia ovalifolia

Soo In Jeong, Hyun Joo Jung Department of Pediatrics, Ajou University School of Medicine, Suwon, Republic of KoreaCorrespondence: Hyun Joo Jung, Department of Pediatrics, Ajou University School of Medicine, 164 World Cup-ro, Yeongtong-gu, Suwon, 16499, Korea, Tel +81 31 219 5160, Fax +81 31 219 5169, Email free1109@ajou.ac.krPurpose: The association between coronavirus disease 2019 (COVID-19) and Kawasaki disease (KD) remains controversial. Prior to the nationwide epidemic of COVID-19, there was a unique, large-scale, regional outbreak in Daegu and Gyeonsangbuk-do (DG) in Korea in the spring of 2020. We evaluated the impact of COVID-19 on KD by comparing the characteristics of KD incidence between epidemic and non-epidemic regions in Korea.Patients and Methods: We analyzed nationwide Health Insurance Review and Assessment (HIRA) data to estimate KD incidence from February 2019 to July 2020. Patients below 18 years who were admitted with KD and administered both intravenous immunoglobulin and aspirin (ICD-10 code M303 for KD) were included in the study. We compared the incidence of KD in DG and other regions by analyzing the period-specific incidence from February to May before and after the COVID-19 era.Results: A total of 4461 patients were identified to have KD nationwide from February 2019 to July 2020. The nationwide incidence of KD was significantly reduced during this period compared with the period from February 2018 to July 2019 (p < 0.001). In the DG region, within the 0– 4-years age group, there was no significant difference in the incidence of KD between periods (p = 0.714). In the 5– 9 years age group, a significant decrease in KD incidence was observed in the DG region and all other regions from February 2019 to July 2020.Conclusion: There was a significant decrease in nationwide KD incidence during and until 2 months after the local epidemic in Korea. However, no significant decrease in KD incidence was observed in the 0– 4 years age group in the DG region where the local COVID-19 outbreak occurred. A larger study is necessary to determine the correlation between KD in this age group and the COVID-19 outbreak.Keywords: mucocutaneous lymph node syndrome, seasonal incidence, SARS-COV-2, social distancing, Republic of Korea

Hyun Joo Jung,1 Il Jae Lee,2 Seung-Hyun Yoon3 1Department of Pediatrics, Ajou University Hospital, Ajou University School of Medicine, Suwon, Gyeonggi-do, South Korea; 2Department of Plastic Surgery, Ajou University Hospital, Ajou University School of Medicine, Suwon, Gyeonggi-do, South Korea; 3Department of Physical Medicine and Rehabilitation, Ajou University Hospital, Ajou University School of Medicine, Suwon, Gyeonggi-do, South KoreaCorrespondence: Seung-Hyun Yoon Tel +82 31 219 5279Fax +82 31 219 5209Email yoonsh.md@gmail.comPurpose: Kikuchi disease (KD) is typically a benign disease. Recent studies reporting recurrence or serious cases suggest a possible association of KD with systemic autoimmune disorders. We performed a long-term analysis of the characteristics of KD in patients of all ages and assessed KD recurrence or progress to systemic autoimmune disorders.Patients and Methods: Electronic medical records of patients diagnosed with KD between April 1995 and May 2017 were reviewed for clinical and laboratory manifestations.Results: In total, 480 patients were confirmed to have KD based on histopathology findings. The mean age at KD diagnosis was 24.4 years. Recurrence occurred in 11.3% of patients; 2.7% developed autoimmune diseases after KD diagnosis. Patients who experienced recurrence had more extranodal symptoms, lymphopenia, and a longer lymphopenia-recovery duration. Patients who developed autoimmune diseases after KD were more likely to have extranodal symptoms, KD recurrence, and anti-nuclear antibody positivity.Conclusion: KD patients with risk factors need to be followed-up for KD recurrence and the development of systemic autoimmune diseases.Keywords: Kikuchi disease, histiocytic necrotizing lymphadenitis, recurrence, autoimmune disorders

Sooyoung Shin,1,2 Hyun Joo Jung,3 Sang-Min Jeon,1 Young-Joon Park,1 Jung-Woo Chae,2 Hwi-Yeol Yun2 1College of Pharmacy, Ajou University, Suwon, Gyeonggi-do 16499, Republic of Korea; 2College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea; 3Department of Pediatrics, Ajou University Hospital, Suwon, Gyeonggi-do 16499, Republic of KoreaCorrespondence: Hwi-Yeol Yun; Jung-Woo Chae Tel +82 42 821 5941; +82 42 821 5929Fax +82 42 823 6566Email hyyun@cnu.ac.kr; jwchae@cnu.ac.krAim: The aim of this study was to evaluate whether vancomycin trough concentrations at initial steady state are associated with clinical and microbiological outcomes along with vancomycin-related nephrotoxicity in pediatric patients with Gram-positive bacterial (GPB) infections.Methods: A retrospective cohort study of pediatric patients who received vancomycin for ≥ 72 hours during 2008– 2016 was conducted. Study patients were divided into three cohorts in accordance with their first trough levels at steady state: < 5 mg/L (lower-trough), 5– 10 mg/L (low-trough), and > 10 mg/L (high-trough; reference) cohorts.Results: Of the 201 patients eligible for study inclusion, 60 patients in the lower- and low-trough cohorts, respectively, were idect 3ntified via propensity score matching and analyzed against 30 high-trough patients in each comparison pair (neonates were excluded due to small sample size). Lower-trough patients were at a greater risk for prolonged therapy, retreatment, and dose adjustment than high-trough patients. Final steady-state troughs remained substantially lower in both the lower- and low-trough cohorts (p< 0.001 and p=0.005, respectively), despite greater dose up-titration in the lower-trough cohort and percent change in daily dose in both the lower- and low-trough cohorts than in the high-trough cohort (p< 0.001 for all). Clinical cure and death risk, along with the risks of isolation of resistant strains and renal events, were not significantly different between cohorts in both comparison pairs.Conclusion: Vancomycin troughs of < 5 mg/L at initial steady state were associated with significantly compromised clinical outcomes in terms of risk of therapy prolongation, retreatment, and aggressive dose up-titration, compared to > 10 mg/L troughs in pediatric patients with GPB infections.Keywords: pediatrics, vancomycin, drug monitoring, Gram-positive bacterial infection

Hyo-Jung Kim,1 Joo-Young Lee,1 Eun-Song Lee,1 Hyo-Jung Jung,2 Hyung-Joon Ahn,2 Baek-Il Kim11Department of Preventive Dentistry & Public Oral Health, Brain Korea 21 PLUS Project, Yonsei University College of Dentistry, Seoul, Republic of Korea; 2Department of Orofacial pain & Oral medicine, Yonsei University College of Dentistry, Seoul, Republic of KoreaPurpose: Conventional oral exercises in previous studies are considered impractical for continuous use in the elderly because of the extended duration needed for effective outcomes. Therefore, in the present study, a simple oral exercise (SOE) was developed to reduce performance time, focusing on improvements in mastication, salivation, and swallowing functions. The aim of this study was to determine the short-term effects of the SOE with respect to improving mastication, salivation, and swallowing function in elderly subjects ≥65 years of age.Patients and methods: The study included 84 subjects, all of whom performed the SOE 2 times per day for 1 week. Masticatory performance was assessed using the mixing ability index (MAI). Unstimulated saliva and the degree of moisture of the tongue/buccal mucosa were evaluated, and the repetitive saliva swallowing test was performed. On the basis of each of these four measurements, subjects were dichotomized into two groups with high (good) and low (poor) conditions. The same evaluations were conducted before and immediately after intervention, as well as after 1 week of intervention. A subjective evaluation with questionnaires was performed after 1 week of intervention. The changes were analyzed using repeated-measures ANOVA, Cochran’s Q test, and McNemar’s test.Results: The mean MAI increased by 6% immediately after the intervention, and by 16% in the poor-chewing group. Similarly, the amount of unstimulated saliva increased by 0.1 ml/min immediately after the SOE, and by 29% in the poor-salivation group. The degree of tongue moisture increased by 3% and was maintained. In the poor-swallowing group, 25% and 40% of the subjects were upgraded to the good-swallowing group immediately after intervention, as well as after 1 week of intervention, respectively. The subjects experienced less discomfort as their oral function improved.Conclusion: The SOE was effective in immediately improving oral functions, and improvement was maintained for 1 week.Keywords: deglutition disorders, elderly, mastication, oral exercise, salivation, xerostomia

Dae Ro Lee,1 Myoung Jin Ho,1 Hyuck Jun Jung,1 Ha Ra Cho,1 Jun Seo Park,1 Suk-Hyun Yoon,2 Yong Seok Choi,1 Young Wook Choi,3 Chung-Hun Oh,2,4,5 Myung Joo Kang1 1College of Pharmacy, 2Department of Medical Laser, Graduate School, Dankook University, Dongnam-gu, Choenan, Chungnam, 3College of Pharmacy, Chung-Ang University, Dongjak-gu, Seoul, 4Department of Oral Physiology, College of Dentistry, Dankook University, 5Abel Medi-Tech Inc., Dongnam-gu, Cheonan, Chungnam, Korea Abstract: A new Soluplus (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer)-based supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to enhance oral absorption of tacrolimus (FK506) with minimal use of oil, surfactant, and cosurfactant. A high payload supersaturable system (S-SEDDS) was prepared by incorporating Soluplus, as a precipitation inhibitor, to SEDDS consisting of Capmul MCM, Cremophor EL, and Transcutol (FK506:vehicle:Soluplus =1:15:1). In vitro dissolution profile and in vitro pharmacokinetic aspect of S-SEDDS in rats were comparatively evaluated with those of conventional SEDDS formulas containing four times greater content of vehicle components (FK506:vehicle =1:60). Both formulations formed spherical drug-loaded microemulsion 80% of accumulated dissolution rate for 24 hours, analogous to that from conventional SEDDS. Moreover, pharmacokinetic parameters of the maximum blood concentration and area under the curve from S-SEDDS formula in rats were not statistically different (P>0.05) than those of conventional SEDDS. The results suggest that the Soluplus-based supersaturable system can be an alternative to achieve a comparable in vitro dissolution profile and in vivo oral absorption with conventional SEDDS, with minimal use of vehicle ingredients. Keywords: tacrolimus, supersaturation, precipitation inhibitor, Soluplus, microemulsion, oral bioavailability

Backgrounds: The association between weight change in patients with diabetes, and the development of infective endocarditis (IE) has never been studied. Therefore, we evaluated the associations of weight changes in patients with diabetes with the development of IE., Methods: In this Korean population-based cohort study, we included patients with diabetes aged ≥20 years who underwent health screenings twice in a 2-year interval between 2009 and 2012. Patients were categorized into five groups according to the degree of weight change between the two health screenings and were followed up until December 2018. A patient with a weight change of ≤-10% was designated to the severe weight loss group, -10 to ≤-5% to the moderate weight loss group, -5 to ≤5% to the stable weight group, 5 to ≤10% to the moderate weight gain group, and ≥10% to the severe weight gain group. The primary outcome was the incidence of IE., Results: A total of 1,762,108 patients with diabetes were included. There were 67,580 (3.9%) individuals with severe weight loss, 247,969 (14.1%) with moderate weight loss, 1,267,849 (72.0%) with stable weight, 135,774 (7.7%) with moderate weight gain, 42,936 (2.4%) with severe weight gain. During the follow-up (median, 5.21 years), 828 cases of IE occurred. After adjusting for covariates, both weight loss (HR: 2.41, 95% CI: 1.87-3.12 for the severe weight loss group; HR: 1.28, 95% CI: 1.05-1.55 for the moderate weight loss group) and weight gain (HR: 1.17, 95% CI: 0.91-1.50 for the moderate weight gain group; HR: 1.59, 95% CI: 1.11-2.28 for the severe weight gain group) were associated with an increased risk of IE compared to those for the stable weight group., Conclusion: Both weight gain and weight loss are associated with an increased incidence of IE, and the greater the degree of weight change, the greater the risk., Competing Interests: Ethics approval and consent to participate: This study was approved by the institutional review board of Soongsil University (approval no. SSU-202003-HR-201–01). The requirement for informed consent was waived owing to the retrospective nature of the study. All methods in this study were performed in accordance with the relevant guidelines and regulations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Adiponectin (ADPN) exerts various cellular and metabolic functions by activating signaling pathways, including extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways, the protein kinase B (Akt) pathway, and the p38 mitogen-activated protein kinase (MAPK) pathway. However, generating functional recombinant human adiponectin (hADPN) in bacterial or mammalian cells is challenging. Although ADPN agonist peptides have been developed, problems like stability, solubility, and affinity for receptors remain. Recently, a genome-edited chicken bioreactor system was established, ensuring efficient ADPN production with optimal post-transcriptional modifications. We assessed the ability of egg white (EW)-derived hADPN, commercial hADPN, various ADPN agonist peptides, and globular ADPN on activation of the ERK1/2, Akt, and p38 MAPK pathways. EW-derived hADPN, abundant in hexamers and high molecular weight multimers, significantly phosphorylated ERK1/2 in serum-starved HEK293 cells after 15 min of treatment. Comparative analysis revealed that EW-derived hADPN and commercial hADPN induced greater phosphorylation of ERK1/2, Akt, and p38 MAPK than ADPN agonist peptides and globular ADPN, with EW-derived hADPN showing the highest activation. In summary, the finding that EW-derived hADPN strongly activates the ERK1/2, Akt, p38 MAPK signaling pathways highlights that an ADPN production system based on genome-edited chickens is an advantageous alternative to existing methods., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dysfunctional intraneuronal organelles in Alzheimer's Disease (AD) propel aberrant calcium handling, triggering molecular miscommunication within organelles such as mitochondria, endoplasmic reticulum, and lysosomes. This disruption in organelle function not only impairs cellular homeostasis but also exacerbates neurodegenerative processes involving the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, amplifying the disease's vicious cycle. In this review, the concept of Mutual Orchestrated Inter-organelle Communication (MOIC) proposes potential therapeutic avenues for restoring Ca 2+ homeostasis in AD, offering a theoretical framework for developing disease-modifying treatments. The intricate nature of AD necessitates a shift towards combination therapies targeting MOIC-associated pathways, presenting a more effective approach than monotherapy., 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. Published by Elsevier Ltd.)

Background: DNA methylation is a critical regulatory mechanism of gene expression, influencing various human diseases and traits. While traditional expression quantitative trait loci (eQTL) studies have helped elucidate the genetic regulation of gene expression, there is a growing need to explore environmental influences on gene expression. Existing methods such as PrediXcan and FUSION focus on genotype-based associations but overlook the impact of environmental factors. To address this gap, we present MOSES (methylation-based gene association), a novel approach that utilizes DNA methylation to identify environmentally regulated genes associated with traits or diseases without relying on measured gene expression., Results: MOSES involves training, imputation, and association testing. It employs elastic-net penalized regression models to estimate the influence of CpGs and SNPs (if available) on gene expression. We developed and compared four MOSES versions incorporating different methylation and genetic data: (1) cis-DNA methylation within 1 Mb of promoter regions, (2) both cis-SNPs and cis-CpGs, 3) both cis- and a part of trans- CpGs (±5Mb away) from promoter regions), and 4) long-range DNA methylation (±10 Mb away) from promoter regions. Our analysis using nasal epithelium and white blood cell data from the Epigenetic Variation and Childhood Asthma in Puerto Ricans (EVA-PR) study demonstrated that MOSES, particularly the version incorporating long-range CpGs (MOSES-DNAm 10 M), significantly outperformed existing methods like PrediXcan, MethylXcan, and Biomethyl in predicting gene expression. MOSES-DNAm 10 M identified more differentially expressed genes (DEGs) associated with atopic asthma, particularly those involved in immune pathways, highlighting its superior performance in uncovering environmentally regulated genes. Further application of MOSES to lung tissue data from idiopathic pulmonary fibrosis (IPF) patients confirmed its robustness and versatility across different diseases and tissues., Conclusion: MOSES represents an innovative advancement in gene association studies, leveraging DNA methylation to capture the influence of environmental factors on gene expression. By incorporating long-range CpGs, MOSES-DNAm 10 M provides superior predictive accuracy and gene association capabilities compared to traditional genotype-based methods. This novel approach offers valuable insights into the complex interplay between genetics and the environment, enhancing our understanding of disease mechanisms and potentially guiding therapeutic strategies. The user-friendly MOSES R package is publicly available to advance studies in various diseases, including immune-related conditions like asthma., Competing Interests: Declarations Ethical approval and consent to participate The Epigenetic Variation and Childhood Asthma in Puerto Ricans (EVA-PR) study was approved by the institutional review boards of the University of Puerto Rico (San Juan, PR) and the University of Pittsburgh (Pittsburgh, PA). Written parental consent and participant assent were obtained for individuals younger than 18, while consent was obtained from participants 18 years and older. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The present study was designed to identify the preoperative clinical and imaging findings influencing adverse clinical outcomes in patients with chronic constrictive pericarditis after pericardiectomy. Patients with constrictive pericarditis who underwent pericardiectomy between January 2009 and September 2023 were retrospectively analyzed. Preoperative evaluations included assessments of clinical symptoms, comorbidities, laboratory tests, cardiac computed tomography (CT), and transthoracic echocardiography. The volume of pericardial calcifications was quantified on calcium scoring CT. Adverse clinical events were defined as cardiovascular death or hospitalization due to cardiac causes, and all-cause mortality was assessed. Univariable and multivariable Cox proportional hazard model analysis were performed to find factors associated with adverse clinical events. Among the 91 patients with available preoperative CT scans, 26 (28.6%) experienced adverse clinical events after pericardiectomy, with 19 (20.9%) experiencing cardiovascular deaths. On multivariable Cox analysis, larger pericardial calcium volume hazard ratio [HR], 1.004 (95% confidence interval [CI], 1.001-1.006) per 1cm 3 increase; p = 0.005), higher E/E' ratio (HR, 1.059, 95% CI, 1.015-1.105, p = 0.008), and lower albumin level (HR, 0.476, 95% CI, 0.229-0.986, p = 0.046) were significant factors associated with the adverse clinical events after pericardiectomy. The amount of pericardial calcification could be associated with the efficacy of pericardiectomy and potentially have implications for postoperative outcomes. Additionally, a high E/E ratio on echocardiography is indicative of unfavorable postoperative prognosis., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate This retrospective study was approved by the institutional review board of Asan Medical Center. Patients’ informed consent was waived due to retrospective nature of the study., (© 2024. The Author(s).)

Galectin-9 (Gal-9) is a multifaceted regulator of various pathophysiologic processes that exerts positive or negative effects in a context-dependent manner. In this study, we elucidated the distinctive functional properties of Gal-9 on myeloid cells within the brain tumor microenvironment (TME). Gal-9-expressing cells were abundant at the hypoxic tumor edge in the tumor-bearing ipsilateral hemisphere compared with the contralateral hemisphere in an intracranial mouse brain tumor model. Gal-9 was highly expressed in microglia and macrophages in tumor-infiltrating cells. In primary glia, both the expression and secretion of Gal-9 were influenced by tumors. Analysis of a human glioblastoma bulk RNA sequencing dataset and a single-cell RNA sequencing dataset from a murine glioma model revealed a correlation between Gal-9 expression and glial cell activation. Notably, the Gal-9high microglial subset was functionally distinct from the Gal-9neg/low subset in the brain TME. Gal-9high microglia exhibited properties of inflammatory activation and higher rates of cell death, whereas Gal-9neg/low microglia displayed a superior phagocytic ability against brain tumor cells. Blockade of Gal-9 suppressed tumor growth and altered the activity of glial and T cells in a mouse glioma model. Additionally, glial Gal-9 expression was regulated by hypoxia-inducible factor-2α in the hypoxic brain TME. Myeloid-specific hypoxia-inducible factor-2α deficiency led to attenuated tumor progression. Together, these findings reveal that Gal-9 on myeloid cells is an immunoregulator and putative therapeutic target in brain tumors. Significance: Galectin-9 serves as an immune checkpoint molecule that modulates the functional properties of microglia in the brain tumor microenvironment and could potentially be targeted to effectively treat brain tumors., (©2024 American Association for Cancer Research.)

Background/aims: : Accurately diagnosing diffuse gastric wall thickening is challenging. Hypertrophic gastritis (HG), while benign, mimics the morphology of Borrmann type 4 advanced gastric cancer (AGC B-4). We compared the features of endoscopy and endoscopic ultrasonography (EUS) between them., Methods: : We retrospectively reviewed patients who underwent EUS for gastric wall thickening between 2000 and 2021, selecting HG and pathologically confirmed advanced gastric cancer cases. Ulceration and antral wall thickening were determined via endoscopy, while EUS assessed the 5-layered gastric wall structure, measuring the proper muscle (PM) layer and total wall thickness., Results: : Male dominance was observed in AGC B-4, and the hemoglobin and albumin levels were significantly lower. The rate of antral wall thickening and presence of ulceration were significantly higher in AGC B-4 cases. Destruction of the PM layers was observed only in AGC B-4 cases, and the PM was significantly thicker in AGC B-4 cases. Forceps biopsy had an excellent success rate in ulcer-present AGC B-4 cases, but only a 42.6% success rate was observed for cases without ulcers, necessitating additional diagnostic modalities. A PM thickness of 2.39 mm distinguished between AGC B-4 and HG effectively. The multivariable analysis showed that a thickened PM layer and the presence of ulceration were significant risk factors for the diagnosis of AGC B-4., Conclusions: : Endoscopic findings of a thickened gastric wall, including antral involvement, and presence of ulcer were significant risk factors for the diagnosis of AGC B-4. EUS findings of destroyed wall layers and a thickened PM of >2.39 mm were the key points of differentiation between HG and AGC B-4.

Background: The reporting of adverse events in medical devices (MD) is a starting point of post-market surveillance and the most common source of initial safety signals. Because MD adverse events (AE) occur globally and involve high-profile international public health crises, international regulators implanted standard codes for MDAE reporting. This study aimed to assess the application of MDAE terminology and codes by providing examples of virtual events., Methods: An online survey was conducted among participants of the MD Training Program for Regulatory Authorities which provide International Medical Device Regulators Forum (IMDRF) adverse event terminology and codes, and six virtual MDAE cases., Results: All 29 of the 72 participants were regulators. In all cases, most participants selected the broad (level 1) codes rather than the detailed (level 2 or level 3) codes. While responders selected a variety of codes for all annexes in case 1, over 50% of responders selected the intended codes in case 6. The codes for cause investigation were chosen more frequently than other annexes for device problem, components, and health effect. No differences were observed in code selection amongst different stakeholders., Conclusions: We identified the diversification in terminology and code selection for reporting MDAEs., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Institutional Review Board (IRB) of Soonchunhyang University Bucheon Hospital (Approval no. SCHBC 2022–12-011). Informed consent from all subjects and/or their legal guardian(s) for publication of identifying information/images in an online open-access publication was waived by the IRB. All procedures were performed in accordance with the Declaration of Helsinki. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Inhalation toxicity assessment is a crucial tool for the identification and classification of hazardous materials like volatile organic carbons, aerosols, and particulate matter. Unlike traditional acute inhalation toxicity studies that use mortality as an endpoint, the Fixed Concentration Procedure (FCP) emphasizes "evident toxicity" by monitoring behavior, weight, and food intake. This reduces reliance on mortality but doesn't directly address respiratory system impact. The present study introduced a respirometer-based inhalation toxicity and respiratory status assessment method. The toxicity evaluation system integrated a respirometric system with an animal exposure chamber, enabling real-time monitoring of oxygen consumption. The ICR mice were exposed to various concentrations of benzene (10, 20, 40, and 80 mg/L of air), toluene (7.5, 15, 30, and 60 mg/L of air), and xylene (7.5, 15, 30, and 60 mg/L of air). The respiration rate decreased by 70 % and 69 % for benzene (80 mg/L of air) and toluene (60 mg/L of air), respectively, with EC 50 values of 32.5 mg/l and 21.2 mg/L based on oxygen consumption. Xylene did not exhibit EC 50 values at the tested concentrations. However, the oxygen consumption rate significantly decreased (46 %) at high concentrations (60 mg/L of air), indicating sub-lethal toxicological effects. Furthermore, the present study was also validated in the bleomycin-induced idiopathic pulmonary fibrosis (IPF) model, demonstrating its reliability as a respiratory impairment marker. The results exhibited a strong correlation between weight loss and less oxygen consumption in the BLM group (bleomycin-induced) as compared to the SHAM group (control), which was confirmed by histological examination and protein marker analysis. The results suggest the potential use of oxygen consumption as an endpoint measurement in inhalation toxicity assessment tests without animal sacrifice, and the present study could be useful for providing valuable insights into disease progression and pharmacological interventions., 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.)

Anaplastic lymphoma kinase (ALK; also known as ALK tyrosine kinase receptor) inhibitors (ALKi) are effective in treating lung cancer patients with chromosomal rearrangement of ALK. However, continuous treatment with ALKis invariably leads to acquired resistance in cancer cells. In this study, we propose an efficient strategy to suppress ALKi resistance through a meta-analysis of transcriptome data from various cell models of acquired resistance to ALKis. We systematically identified gene signatures that consistently showed altered expression during the development of resistance and conducted computational drug screening using these signatures. We identified emetine as a promising candidate compound to inhibit the growth of ALKi-resistant cells. We demonstrated that emetine exhibited effectiveness in inhibiting the growth of ALKi-resistant cells, and further interpreted its impact on the resistant signatures through drug-induced RNA-sequencing data. Our transcriptome-guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Zika virus (ZIKV) infection is primarily transmitted by mosquitoes and often asymptomatic in most individuals. Infection during pregnancy can lead to severe birth defects such as congenital microcephaly, and currently, there is no approved vaccine for ZIKV. Several studies are investigating the development of ZIKV vaccine using DNA and RNA as well as recombinant protein technologies; however, the outcomes thus far have not been consistently noteworthy. In this study, we designed an mRNA vaccine for ZIKV and evaluated its immunogenicity using a mouse model. Our vaccine, termed 3xEIII, encodes a triple repeat of domain III from the ZIKV E protein. We effectively encapsulated the mRNA within lipid nanoparticles (LNPs), administered 3xEIII to mice via two intramuscular injections, and assessed the induced humoral and cellular immune responses. Specifically, the vaccine elicited neutralizing antibodies that effectively eliminated ZIKV from the organs of challenged mice. Notably, 3xEIII conferred both protective effects and long-term immunity. In subsequent challenges conducted 40 weeks after boosting, immunized mice experienced temporary weight loss but showed significantly reduced viral titers in target organs by the 9th day post-infection. Conclusively from these findings, 3xEIII stands out as a promising noteworthy mRNA vaccine candidate for Zika virus., 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. Published by Elsevier Ltd.)

Hypervirulent Klebsiella pneumoniae (hvKp), an emerging Kp subtype, has become a serious global pathogen. However, the information regarding host interactions and innate immune responses during hvKp infection is limited. Here, we found that hvKp clinical strains increased triacylglycerol synthesis, resulting in lipid droplets (LDs) formation via the mammalian target of rapamycin signaling pathway in RAW264.7 cells. Treatment with rapamycin, an inhibitor of this pathway, affected LDs formation and antimicrobial responses against clinical hvKp infections. In accordance with the role of LDs in modulating inflammation, the pharmacological inhibition of lipogenesis reduced proinflammatory cytokine expression during hvKp infections. In addition, inhibition of LDs formation using pharmacological inhibitors and knockdown of lipogenesis regulators decreased the intracellular survival of hvKp in macrophages. Moreover, inhibiting LDs biogenesis reduced mortality, weight loss, and bacterial loads in hvKp-infected mice. Collectively, these data suggest that LDs biogenesis is crucial in linking host immune responses to clinical hvKp infections., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Alzheimer's disease (AD) is a degenerative brain disorder characterized by progressive cognitive decline and neuronal death due to extracellular deposition of amyloid β (Aβ) and intracellular deposition of tau proteins. Recently approved antibody drugs targeting Aβ have been shown to slow the progression of the disease, but they have minimal effects on cognitive improvement. Therefore, there is a need to develop drugs with cognitive-enhancing effects that can be used in conjunction with these antibody treatments. In this study, we investigated whether Polygala tenuifolia (PT), traditionally known for its cognitive-enhancing effects, can improve synaptic plasticity and identified its active components and mechanisms. PT demonstrated a dose-dependent effect in enhancing long-term potentiation (LTP), and among its components, 3,4,5-trimethoxycinnamic acid methyl ester (TMCA) showed a similar LTP-enhancing effect. TMCA increased the phosphorylation of the GluA1 subunit of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and increased the amount of GluA1 on the synapse without affecting the amount of GluA2. Additionally, the increase in GluA1 induced by TMCA was inhibited by a PKA inhibitor. Consistent with these results, the enhancement of LTP by TMCA was inhibited by a GluA1 antagonist and a PKA inhibitor. In silico molecular docking experiments confirmed that TMCA binds to PKA. Finally, we confirmed the LTP-enhancing effect of TMCA in hippocampal slices from 5XFAD mice. These results suggest that PT and its active component, TMCA, can interact with PKA to enhance LTP, indicating the potential for improving cognitive function in AD patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this work, oleic acid (OA)-capped core-heptad-shell (CHS) nanocrystals (NCs) that exhibit multiple emissions achieved through downshifting and orthogonal upconversion are synthesized via layer-by-layer thermal decomposition. This method enables the downshifting process to be accommodated by doping ions in the inert space between two upconversion patterns (the core and fourth shell) and doping Ce/Tb or Ce/Eu ions in the NaGdF 4 layer for the first time. These developed CHS NCs exhibit different emission colors via 980 and 800 nm orthogonal upconversion and downshifting emissions under 256 nm UV excitation in hexane solvent. Furthermore, surface-functionalized OA is removed using mild acid treatment. The resulting bare CHS NCs disperse well in water and exhibit 21.60-fold and 43.59-fold higher Ce/Tb and Ce/Eu luminescence intensities, respectively, than the OA-capped CHS NCs. These NCs are mixed with a carboxymethylcellulose (CMC) polymer in an aqueous medium to form a CMC-CHS NC gel. Invisible patterns and QR codes are printed on nonfluorescent paper using gels and screen-printing techniques. These patterns and QR codes exhibit three different emission colors under three different excitations. This method can be used for high-level anticounterfeiting applications.

Introduction: Idiopathic pulmonary arterial hypertension (IPAH) is a severe condition characterized by a poor prognosis, rapid deterioration, and high mortality in the absence of lung transplantation. However, non-invasive prognostic markers in assessing IPAH remain uncertain. We aimed to investigate the prognostic significance of chest CT and alterations in heart contours on chest radiography (CXR) in predicting adverse outcomes in IPAH patients., Methods: A retrospective study analyzed medical records of IPAH patients who underwent right heart catheterization and chest CT at a tertiary center between 2001 and 2023. Clinical, hemodynamic, and CT findings, and changes (Δ) in heart contours on CXR were assessed. Adverse events were defined as IPAH-related death or lung transplantation. Cox regression models evaluated the predictive power of these parameters., Results: In 80 patients with IPAH (mean age 42.6 years; 75 % females), the 3- and 5-year survival rates were 65.8 % and 55.1 %, respectively. Adverse events were associated with a history of cardiac arrest (Hazard ratio [HR], 11.67, p = 0.02), mean pulmonary artery pressure (HR, 1.04, p = 0.001), creatinine (HR, 4.12, p < 0.001), 6-min walk distance (HR, 0.997, p = 0.03), CT-derived right atrial (RA) volume index (HR, 1.01, p = 0.02), and ΔRA contour on CXR (HR, 1.27, p < 0.001). Combined clinical, CT, and CXR findings showed a 3-year event-free survival predictive accuracy of 82.2 % (95 % CI, 69.8-94.7), outperforming clinical factors alone., Conclusion: Rapid increases in RA contour on CXR and CT-derived RA volume index were associated with adverse outcomes in IPAH. Assessing these parameters may be helpful in identifying patients who require proactive treatments., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Melanosomes play a pivotal role in skin color and photoprotection. In contrast to the well-elucidated pathway of melanosome biogenesis, the process of melanosome degradation, referred to as melanophagy, is largely unexplored. Previously, we discovered that 3,4,5-trimethoxycinnamate thymol ester (TCTE) effectively inhibits skin pigmentation by activating melanophagy. In this study, we discovered a new regulatory signaling cascade that controls melanophagy in TCTE-treated melanocytes. ITCH (itchy E3 ubiquitin protein ligase) facilitates ubiquitination of the melanosome membrane protein MLANA (melan-A) during TCTE-induced melanophagy. This ubiquitinated MLANA is then recognized by an autophagy receptor protein, OPTN (optineurin). Additionally, a phospho-kinase antibody array revealed that TCTE activates PTK2 (protein tyrosine kinase 2), which phosphorylates ITCH, enhancing the ubiquitination of MLANA. Furthermore, inhibition of either PTK2 or ITCH disrupts the ubiquitination of MLANA and the MLANA-OPTN interaction in TCTE-treated cells. Taken together, our findings highlight the critical role of the PTK2-ITCH-MLANA-OPTN cascade in orchestrating melanophagy progression. Abbreviations : α-MSH: alpha-melanocyte-stimulating hormone; dichlone: 2,3-dichloro-1,4-naphthoquinone; ITCH: itchy E3 ubiquitin protein ligase; MITF: melanocyte inducing transcription factor; MLANA: melan-A; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PINK1: PTEN induced kinase 1; PTK2: protein tyrosine kinase 2; SQSTM1/p62: sequestosome 1; TCTE: 3,4,5-trimethoxycinnamate thymol ester; TPC2: two pore segment channel 2; VDAC1: voltage dependent anion channel 1.

Background: Renal replacement therapy (RRT) is an important treatment option for sepsis-associated acute kidney injury (AKI); however, the optimal timing for its initiation remains controversial. Herein, we investigated the clinical outcomes of early continuous kidney replacement therapy (CKRT), defined as CKRT initiation within 6 hours of sepsis-associated AKI onset, which was earlier than the initiation time defined in previous studies., Methods: We used clinical data sourced from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. This study included patients aged ≥ 18 years who met the sepsis diagnostic criteria and received CKRT because of stage 2 or 3 AKI. Early and late CKRTs were defined as CKRT initiation within 6 hours and after 6 hours of the development of sepsis-associated AKI, respectively., Results: Of the 33,236 patients diagnosed with sepsis, 553 underwent CKRT for sepsis-associated AKI. After excluding cases of early mortality and patients with a dialysis history, 45 and 334 patients were included in the early and late CKRT groups, respectively. After propensity score matching, the 28-day mortality rate was significantly lower in the early CKRT group than in the late CKRT group (26.7% vs. 43.9%, P = 0.035). The early CKRT group also had a significantly greater number of days free of mechanical ventilation (median, 19; interquartile range [IQR], 3-25) and vasopressor administration (median, 21; IQR, 5-26) than the late CKRT group did (median, 10.5; IQR, 0-23; P = 0.037 and median, 13.5; IQR, 0-25; P = 0.028, respectively). The Kaplan-Meier curve also showed that early CKRT initiation was associated with an improved 28-day mortality rate (log-rank test, P = 0.040). In contrast, there was no significant difference in the 28-day mortality between patients who started CKRT within 12 hours and those who did not (log-rank test, P = 0.237)., Conclusion: Early CKRT initiation improved the survival of patients with sepsis-associated AKI. Initiation of CKRT should be considered as early as possible after sepsis-associated AKI onset, preferably within 6 hours., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Objectives: This study investigates the association between toothbrushing frequency and self-rated oral health to evaluate the effectiveness of the 3-3-3 toothbrushing campaign., Methods: Employing a cross-sectional study design, we analysed responses from 13,199 adults using structured questionnaires. The dependent variable was self-rated oral health. The independent variables were toothbrushing habits. We compared both groups; control group: twice a day and case group: three times a day. Predisposing, enabling and need factors were adjusted as confounders based on the Anderson behaviour model., Results: Our findings reveal no significant correlation between toothbrushing frequency (twice vs. three times daily) and self-perceived oral health status. These results suggest re-evaluating the 3-3-3 campaign's recommendations. Further research is necessary to identify factors that more directly influence self-rated oral health., Conclusion: Our research found that increasing toothbrushing from twice to three times daily does not significantly enhance oral health, as evidenced by an odds ratio of 0.97 and a negligible Cohen's d value. We recommend public health campaigns emphasise toothbrushing quality over frequency to improve oral health outcomes., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Intratumoral TLR9 agonists and anti-PD-1 produce clinical responses and broad immune activation. We conducted a single-arm study of neoadjuvant TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in high-risk resectable melanoma. In 31 evaluable patients, 55% major pathologic response (MPR) was observed, meeting primary endpoint. MPR was associated with necrosis, and melanophagocytosis with increased CD8 + tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67 + CD8 + T cells peripherally. MPRs had an enriched pre-treatment gene signature of myeloid cells, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. MPRs gut microbiota were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidutolimod and nivolumab stimulates a broad anti-tumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiota. ClinicalTrials.gov identifier: NCT03618641., Competing Interests: Declaration of interests D.D. reports grants/research support (NIH/NCI and Checkmate Pharmaceuticals) and consulting (Checkmate Pharmaceuticals) during the conduct of the study. D.D. also reports grants/research support (Arcus, Immunocore, Merck, Regeneron Pharmaceuticals Inc., Tesaro/GSK.), consulting (ACM Bio, Ascendis, Castle, Clinical Care Options [CCO], Gerson Lehrman Group [GLG], Immunitas, Medical Learning Group [MLG], Replimmune, Trisalus, Xilio Therapeutics), speakers’ bureau (Castle Biosciences), steering committee membership (Immunocore, Replimmune) and patents related to gut microbial signatures of response and toxicity to immune checkpoint blockade (US Patent 63/124,231 and US Patent 63/208,719) outside the submitted work. P.D. is currently employed by Nanostring Technologies and reports stock options. Y.G.N. reports grants/research support (Bristol-Myers Squibb, Merck Sharp & Dohme and Pfizer) and consulting (Checkmate Pharmaceuticals) outside the submitted work. J.J.L. reports grants/research support (multiple), membership on data safety monitoring boards (multiple), membership on scientific advisory boards with no stock ownership or stock options (multiple), membership on scientific advisory boards with stock for (multiple), consulting (multiple) and a provisional patent for cancer immunotherapy (PCT/US18/36052: Microbiome Biomarkers for anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic and therapeutic uses thereof) all outside the submitted work. D.M. is currently employed by Codiak Biosciences and reports stock options. D.B., J.W. and A.K. were formerly employed by CheckMate and report stock options. M.G.F. is currently employed by Regeneron Pharmaceuticals Inc. and reports stock options. J.M.K. reports grants/research support (Bristol-Myers Squibb, Amgen Inc.) and consulting (Bristol-Myers Squibb, Checkmate Pharmaceuticals, Novartis, Amgen Inc., Checkmate, Castle Biosciences, Inc., Immunocore LLC, Iovance, Novartis.) outside the submitted work. J.M.T. reports grants and consulting from Bristol-Myers Squibb, Merck Sharp & Dohme, Astra Zeneca, and Compugen outside the submitted work. H.M.Z. reports grants/research support (NIH/NCI and Checkmate Pharmaceuticals) and consulting (Checkmate Pharmaceuticals) during the conduct of the study. H.M.Z. also reports grants/research support (NIH/NCI, Bristol-Myers Squibb and GlaxoSmithKline), personal fees (GlaxoSmithKline, Bayer, and Vedanta) and pending provisional patents related to gut microbial signatures of response and toxicity to immune checkpoint blockade (US Patent 63/124,231 and US Patent 63/208,719) outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Antibiotic usage in early life has been proposed as a risk factor for inflammatory bowel disease, especially Crohn's disease. However, most studies were conducted in Western countries., Aims: We evaluated the association between antibiotic usage and the incidence of inflammatory bowel disease in the Asian population., Methods: This nationwide population-based retrospective cohort study included 2,941,889 South Korean infants born between 2007 and 2015, using the National Health Insurance Service database. We assessed whether antibiotic use was associated with the incidence of inflammatory bowel disease. Additionally, we conducted sensitivity analyses, considering protopathic bias and dietary variables. The Cox proportional hazards model was used., Results: Among 2,941,889 infants, 2,566,390 (87 %) used antibiotics within a year after birth. Antibiotic usage within a year, number of antibiotic classes, and cumulative days of usage were shown to decrease the risk of ulcerative colitis. This association was particularly prominent with earlier antibiotic exposure. Penicillin was the only antibiotic class related to the reduced risk. The results were robust after adjusting for dietary variables and considering protopathic effect., Conclusions: Antibiotic exposure during the first year of life, particularly at a younger age, is linked to a reduced risk of early-onset ulcerative colitis in South Korea., Competing Interests: Conflicts of interest There are no conflicts of interest to declare for all authors., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

We have previously shown that nano-sized graphene oxide (NGO) displays anti-inflammatory activities against natural killer T (NKT) cell-mediated sepsis. To address whether NGO could be applied to treat acute skin inflammation we developed a conventional skin Cetaphil® cream containing NGO (NGO cream) for topical application to skin lesions and investigated its therapeutic efficacy by employing the tape-stripping-induced acute skin inflammation model. Topical application of NGO cream to the wounded area significantly reduced skin lesions compared with the control cream. Moreover, NGO cream treatment prevented the tape-stripping-elicited infiltration of and IL1β production by skin neutrophils and dendritic cells (DCs). Furthermore, such anti-inflammatory effects of NGO cream were attributed to decreased infiltration of IL12-producing DCs and IFNγ-producing cells (e.g., CD4 + T, CD8 + T, γδ T, NK, and NKT cells) into the skin. In addition, topical NGO cream administration enhanced the expression of suppressive molecules such as FR4 on skin regulatory T cells. Through RNA sequencing analysis, we found that the preventive effect of NGO cream on acute skin inflammation may be correlated with the activation of keratinocytes located in the epidermis. Our results support NGO cream as a therapeutic option to control acute skin inflammation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: We declare no competing interests.

Purpose: Lateral pharyngeal wall collapse, linked to weak pharyngeal wall stability, is characteristic of severe obstructive sleep apnea (OSA) patients. Soft palate webbing flap palatopharyngoplasty (SPWFPP) has been introduced to enhance the stability of the lateral pharyngeal wall with minimal postoperative complications by eliminating the need for tonsillectomy. This study analyzed the anatomic findings of oropharynx for determination of outcome in OSA patients requiring SPWFPP., Methods: Twenty-eight OSA patients who underwent SPWFPP combined with septoturbinoplasty were included in this study. Patient medical records, including endoscopic findings, polysomnography (PSG) data, and drug-induced sleep endoscopy (DISE), were analyzed., Results: PSG data revealed that SPWFPP provided significant improvements of AHI scores in severe OSA patients with lateral pharyngeal wall collapse, whereas AHI scores of mild and moderate OSA cases minimally declined after SPWFPP. Notably, among the patients who underwent SPWFPP, some experienced abrupt increases in AHI levels after surgery, particularly in mild OSA cases, and those patients showed collapse of the epiglottis before surgery according to DISE findings. The outcome of SPWFPP was successful in severe OSA patients whose epiglottis was not collapsible on preoperative DISE findings and in patients with palatal collapse of grade III or higher., Conclusion: SPWFPP provides good surgical outcomes even in severe OSA patients with lateral pharyngeal wall collapse. However, the surgical results may be worse in certain patients depending on epiglottis collapsibility. A close analysis of DISE findings before SPWFPP reveals important indicators for predicting better surgical results and selecting OSA patients suitable for SPWFPP., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Purpose: To compare mammography, breast ultrasound (US), high-resolution diffusion-weighted magnetic resonance imaging (DW-MRI), dynamic contrast-enhanced breast MRI (DCE-MRI), and their combinations for detecting clinically occult early breast cancers (EBCs), including ductal carcinoma in situ (DCIS)., Methods: Three hundred and three consecutive women with screening imaging-detected early breast cancers (60 pure DCIS, 36 DCIS with microinvasion, and 207 invasive carcinoma less than 20 mm) who underwent breast MRI at 3 T including DW-MRI (b-values of 0, 800 and 1200 s/mm 2 ; in-plane resolution, 1.1 × 1.1 mm 2 or 1.3 × 1.3 mm 2 ; section thickness, 3 mm) were retrospectively reviewed. Three radiologists independently reviewed each examination. Statistical analysis included Chi-square test, McNemar test for comparison of cancer detection rates, and Fleiss' Kappa for interreader agreement. Mixed-effect logistic regression analysis was employed to evaluate factors associated with cancer detection on DW-MRI., Results: The overall cancer detection rates were 54.8% on mammography, 71.0% on breast US, 81.5% on DW-MRI, and 87.1% on DCE-MRI. On McNemar test, DW-MRI detected more cancers than mammography (adjusted p < 0.001), and its combination with mammography showed a similar cancer detection rate to DCE-MRI combined with mammography (adjusted p = 0.808). On multivariable analysis, histologic type, lesion size, ADC and CNR on DW-MRI were independent factors for cancer detection on DW-MRI. The interreader agreement for cancer detection was moderate to substantial (Fleiss' kappa: 0.52-0.65) across each modality., Conclusion: High-resolution DW-MRI plus mammography showed comparable cancer detection rate to DCE-MRI plus mammography for detecting clinically occult EBCs including DCIS., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

As the non-steroidal anti-inflammatory drugs (NSAIDs) are typically used in the treatment of chronic conditions, the incidence of NSAID-induced enteropathy is increasing. Given the challenges associated with discontinuing NSAIDs, effective preventive and treatment strategies are crucial. We assessed the effect of tegoprazan on NSAID-induced enteropathy. Human epithelial cells (HIEC-6, HT-29, and Caco-2) were treated with indomethacin and tegoprazan. Cell viability, expression levels of tight-junction proteins, levels of proinflammatory cytokines, and apoptosis were assessed by conducting MTT assays, RT-PCR, western blotting, and immunofluorescence staining, respectively. Tegoprazan significantly ameliorated the inhibition of cell proliferation induced by indomethacin. Tegoprazan also mitigated the suppression of occludin and ZO-1 expression by indomethacin, thereby restoring intestinal permeability. Additionally, tegoprazan reversed the indomethacin-induced elevation of the levels of proinflammatory cytokines and the rate of apoptosis of small intestinal epithelial cells. Our findings indicate that tegoprazan exerts a protective effect against NSAID-induced injury to small intestinal epithelial cells. The effect involves enhancement of the expression levels of tight junction proteins and the suppression of inflammation and apoptosis., (© 2024. The Author(s).)

Background: Differential counting (DC) of different cell types in bone marrow (BM) aspiration smears is crucial for diagnosing hematological diseases. However, a clinically applicable method for automatic DC has yet to be developed., Objective: This study developed and validated an artificial intelligence (AI)-based algorithm for identifying and classifying nucleated cells in BM smears., Methods: In the development phase, a mask region-based convolutional neural network (Mask R-CNN)-based AI model was trained to detect and classify individual BM cells. We used a large data set of expert-annotated images representing a variety of disease categories. The BM slides were stained with Liu's stain or Wright-Giemsa stain. Consensus meetings were held to ensure experts from different institutes applied consistent criteria in classifying cells. Subsequently, the performance of the AI algorithm in identifying cell images and determining cell ratios was evaluated using a multinational clinical dataset., Results: The AI model was trained on 542 slides (85.1 % stained with Liu's stain and 14.9 % with Wright-Giemsa stain) containing 597,222 annotated cells. It achieved an accuracy of 0.94 for the testing dataset containing 26,170 cells. The performance of the AI model was further validated using another multinational real-world dataset (data obtained from three centers in Taiwan and one in the United States) comprising 200,639 cells. The AI model achieved an accuracy of 0.881 in classifying individual cells and demonstrated high precision in classifying blasts (0.927), bands and polymorphonuclear neutrophils (0.955), plasma cells (0.930), and lymphocytes (0.789). When the differential counting percentage of each cell type was assessed, a strong correlation (ρ > 0.8) between the AI and manual methods was observed for most cell categories., Conclusions: In this study, an AI algorithm was developed and clinically validated using large, multinational datasets. Our algorithm can locate and classify BM cells simultaneously and has potential clinical applicability for automating BM differential counting., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: NTUH and aetherAI Co., Ltd. own the intellectual property and possible commercial profit of the AI-based product derived from this study. Authors who are employees of the manufacturer of the AI-based product (aetherAI Co., Ltd.) contributed to study design, data annotation, software development, and website development for annotation, AI model development, clinical research, manuscript writing, manuscript review, and manuscript editing., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Neuropathic pain (NP) affects countless people worldwide; however, few effective treatments are currently available. Histone deacetylases (HDACs) participate in epigenetic modifications in neuropathy-induced nociceptive sensitization. Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter that can inhibit NP. The present study aimed to examine the role of spinal HDAC and its isoforms in neuropathy., Methods: Male Wistar Rat with chronic constriction injury (CCI)-induced peripheral neuropathy and HDAC inhibitor, panobinostat, was administrated intrathecally. We performed quantitative real-time polymerase chain reaction (RT-qPCR), western blot, and immunohistochemical analysis of lumbar spinal cord dorsal horn and nociceptive behaviors (thermal hyperalgesia and mechanical allodynia) measurements., Results: Herein, RT-qPCR analysis revealed that spinal hdac3 , hdac4 , and hdac6 were upregulated in CCI rats. Western blotting and immunofluorescence staining further confirmed that HDAC3, HDAC4, and HDAC6 were significantly upregulated, whereas GABA and its synthesis key enzyme glutamic acid decarboxylase (GAD) 65 were dramatically downregulated. Intrathecal panobinostat attenuated nociceptive behavior and restored the downregulated spinal GAD65 and GABA expression in CCI rats., Conclusions: HDAC upregulation might induce nociception through GAD65 and GABA inhibition in CCI-induced neuropathy. These findings strongly suggest that HDACs negatively regulate inhibitory neurotransmitters, constituting a potential therapeutic strategy for an epigenetic approach to manage NP., Competing Interests: The authors have no conflict of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Following their approval by the Food and Drug Administration, lipid nanoparticles (LNPs) have emerged as promising tools for delivering mRNA vaccines and therapeutics. Ionizable lipids are among the essential components of LNPs, as they play crucial roles in encapsulating mRNA and facilitating its release into the cytosol. In this study, 17 innovative ionizable lipids using vitamin B5 are designed as the core structure, aiming to reduce toxicity, to maintain vaccine efficiency, and to ensure synthetic feasibility. The top-performing LNP in terms of mRNA vaccine delivery in the mouse model is LNP 5097, which is generated by incorporating ionizable lipid I97. mRNA⊂LNP 5097 demonstrates favorable structural and physicochemical properties, high mRNA transfection efficiency, and long-term stability. Moreover, mRNA⊂LNP 5097 specifically delivers the mRNA to the spleen and lymph nodes in model mice, induces balanced Th1/Th2 immune responses, and elicits the production of high levels of neutralizing antibodies with low toxicity. The findings here suggest the high utility of LNP 5097, which includes novel vitamin B5-derived ionizable lipids with reduced toxicity, in mRNA vaccine research for both infectious diseases and cancer., (© 2024 Wiley‐VCH GmbH.)

Aims: Patients with moderate aortic stenosis (AS) show a poor prognosis if they have high-risk features. We investigated the incremental prognostic value of left ventricular (LV) and left atrial (LA) strain in patients with moderate AS., Methods and Results: In a cohort of 923 patients with moderate AS (median age 74 years, men 55%, aortic valve area 1.18 [IQR 1.08-1.30] cm2, mean pressure gradient 25 [IQR 23-30] mmHg), LV global longitudinal strain (LV-GLS) and LA reservoir strain (LARS), were measured using speckle-tracking echocardiography. Absolute values of myocardial strain were used. The primary endpoint was a composite of all-cause mortality and heart failure hospitalization.During a median of 5.9 years, the primary endpoint occurred in 186 patients (20.2%). The median LV-GLS and LARS were 17.7% (IQR 14.8-19.7) and 24.5% (IQR 18.7-29.3). LV-GLS (adjusted HR 0.92, 95% CI 0.87-0.97) and LARS (adjusted HR 0.97, 95% CI 0.95-0.99) were significant predictors of the primary outcome, independent of clinical and echocardiographic variables including LV ejection fraction. Notably, the prognostic value of LV-GLS was stronger than that of LARS, remaining significant after further adjustment for LARS. LV-GLS<17% and LARS<22% were identified as optimal cutoffs for the primary outcome. Patients with both reduced LV-GLS and LARS had the worst outcome (log-rank p<0.001). LV-GLS<17% and LARS<22% had incremental prognostic value on top of other clinical and echocardiographic variables., Conclusion: In moderate AS, reduced LV-GLS and LARS have incremental prognostic value, and can refine risk stratification to identify high-risk patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

High-dose melphalan at 200 mg/m 2 (MEL-200) is the standard conditioning regimen before autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). Busulfan (BU) and cyclophosphamide (CY) can be used as alternatives when MEL is unavailable. However, most studies on BU/CY conditioning regimens were conducted before proteasome inhibitors (PIs) and immunomodulatory drugs (IMIDs) were available. This non-interventional comparative cohort study compared progression-free survival (PFS) between the MEL-200 and BU/CY in patients with MM treated with PIs and/or IMIDs. A total of 137 patients were analyzed (MEL-200,113 patients; BU/CY, 24 patients). The BU/CY group had a higher rate of PI and/or IMID use and very good partial response (VGPR) or complete remission (CR) at ASCT and post-ASCT maintenance. Median PFS was 29.7 and 46.8 months in the MEL-200 and BU/CY groups, respectively. In the multivariate analysis, PFS was significantly better in the BU/CY group. International Staging System Stage I and VGPR or CR at ASCT were significantly associated with longer PFS. No treatment-related mortality was observed in either group by day 100. The BU/CY conditioning regimen may be a viable alternative to the MEL-200 regimen in patients with MM who undergo ASCT after treatment with PIs and/or IMIDs., (© 2024. The Author(s).)

Background: The rate of survival after out-of-hospital cardiac arrest varies depending on the timeliness and effectiveness of prehospital interventions. This study was conducted to compare out-of-hospital cardiac arrest outcomes between intravenous and intraosseous routes and between upper and lower extremity routes for drug administration., Methods and Results: We retrospectively analyzed data (collected using the Utstein template) from 1220 patients who had experienced out-of-hospital cardiac arrest in Taiwan's Taoyuan City between January 2021 and August 2023. The patients were stratified into intravenous and intraosseous groups by treatment approach and upper and lower extremity access groups by access site. The study outcomes were survival to discharge, favorable neurologic outcomes (Cerebral Performance Category score 1 or 2), and survival for >2 hours. The study groups were statistically compared before and after propensity score matching. Significant pre-propensity score matching differences were observed between intravenous and intraosseous groups, and the aforementioned study outcomes were better in the intravenous group than in the intraosseous group. However, the between-group differences became nonsignificant after propensity score matching. Furthermore, lower extremity access and delayed epinephrine administration were associated with worse outcomes. Survival rates fell below 12.6% when time to treatment exceeded 15 minutes, particularly in the cases of intraosseous access and lower extremity access., Conclusions: This study highlights the benefits of early intervention and upper extremity access for drug administration in patients with out-of-hospital cardiac arrest. Intraosseous access may serve as a viable alternative to intravenous access. Timely administration of essential drugs during resuscitation can improve clinical outcomes and thus has implications for emergency medical service training.

Background: This study aimed to investigate the hemodynamic and anatomic factors associated with sinus thrombosis following transcatheter aortic valve replacement (TAVR), integrating in vivo patient data analysis and in vitro experiments., Methods and Results: Postprocedural, 4-dimensional, multiphase computed tomography data from 211 patients enrolled in the ADAPT-TAVR (Anticoagulation Versus Dual Antiplatelet Therapy for Prevention of Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement) study were analyzed. The prevalence of native sinus thrombosis was examined in relation to valve type, implant depth, and anatomic features. In vitro experiments used particle image velocimetry to observe changes in sinus flow based on the transcatheter heart valves (23-mm SAPIEN3, Edwards Lifesciences; and 29-mm CoreValve, Medtronic) height and coronary artery flow. Native sinus thrombosis was more common in self-expanding valves (39.1% versus 14.9%, P =0.004). In per-cusp analysis of in vivo patient data, adjusted transcatheter heart valve implant depth (odds ratio, 1.2 [95% CI, 1.1-1.3]; P <0.001), noncoronary sinus of Valsalva (odds ratio, 4.0 [95% CI, 2.0-7.8]; P <0.001), sinus inflow diameter (odds ratio, 0.8 [95% CI, 0.6-0.9]; P =0.008), and implanted valve size (odds ratio, 0.8 [95% CI, 0.7-1.0]; P =0.025) were significant factors associated with native sinus thrombosis. In the in vitro experiments, CoreValve showed noticeable flow stasis compared with SAPIEN3. High-positioned SAPIEN3 was linked to reduced velocity within the native sinus of Valsalva. Coronary artery flow led to higher sinus velocity and improved particle washout, reducing sinus thrombosis risk., Conclusions: This study provides insights into the relationship between transcatheter heart valve deployment and native sinus thrombosis, emphasizing the role of anatomic factors in relation to the risk of sinus thrombosis.