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Background: Low muscle mass is associated with high insulin resistance and an increased risk of cardiovascular disease. This study aims to determine whether low muscle mass affects the alterations in myocardial substrate metabolism that are associated with the development of cardiovascular disease., Method: The study included 299 individuals (182 men and 117 women) who underwent examination at the Severance Health Check-up Center between January 2018 and February 2019. Myocardial glucose uptake was assessed using [18F]-fluorodeoxyglucose-positron emission tomography ( 18 F-FDG PET/CT) scanning. Direct segmental bioimpedance analysis was used to measure appendicular skeletal muscle mass (ASM)., Results: We analysed men and women separately owing to sex-related body composition differences. ASM/Ht 2 was significantly positively correlated with myocardial glucose uptake measured by 18 F-FDG PET/CT [ln (SUV heart/liver )] only in men (r = 0.154, P = 0.038 in men; r = -0.042, P = 0.652 in women, respectively). In men, myocardial glucose uptake was significantly associated with ASM/Ht 2 even after adjusting for multiple confounders in a multivariable linear regression model (standardized β = 0.397, P = 0.004, in men; β = - 0.051, P = 0.698, in women). In women, age (β = -0.424 P = 0.029) was independent determinants of myocardial glucose uptake., Conclusions: In men, ASM was strongly associated with myocardial glucose uptake as measured by 18 F-FDG PET/CT. In women, age was significantly correlated with myocardial substrate utilization, but not with ASM., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background and Purpose: Lower urinary tract symptoms (LUTS) are frequently observed in patients with Parkinson's disease (PD), but the underlying mechanism remains elusive. The concept of "body-first" and "brain-first" subtypes in PD has been proposed, but the correlation of PD subtype with LUTS remains unclear. We aimed to investigate the disparities in urological dysfunctions between body-first and brain-first subtypes of PD using urodynamic studies (UDS)., Methods: We reviewed patients with PD (disease duration <3 years) who had undergone UDS and completed urological questionnaires (Overactive Bladder Symptom Score [OABSS] and International Prostate Symptom Score [IPSS]) and a voiding diary. Patients were categorized as having body-first or brain-first PD based on cardiac sympathetic denervation (CSD) using cardiac meta-iodobenzylguanidine (MIBG) uptake and the presence of rapid eye movement sleep behavior disorder (RBD), assessed using a questionnaire (PD with CSD and RBD indicating the body-first subtype)., Results: A total of 55 patients with PD were categorized into body-first PD (n = 37) and brain-first PD (n = 18) groups. The body-first PD group exhibited smaller voiding volume and first desire volume (FDV) than the brain-first PD group (p < 0.05 in both). Also, the body-first PD group had higher OABSS and IPSS scores, and higher prevalence of overactive bladder diagnosed by OABSS, compared to the brain-first PD group. In multiple linear regression, cardiac MIBG uptake was positively correlated with FDV and voiding volume and negatively correlated with OABSS and IPSS (p < 0.05 in all)., Conclusions: Patients with the body-first PD subtype exhibited more pronounced overactive bladder symptoms and impaired storage function in the early stage of disease. Additionally, cardiac MIBG was significantly associated with urological dysfunction., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Based on the hypothesis that the 2-mercaptoacetamide moiety chelates the copper ions of tyrosinase, 2-mercapto- N -arylacetamide (2-MAA) analogs were designed and synthesized as potential tyrosinase inhibitors. Four 2-MAA analogs showed low IC 50 values ranging from 0.95 to 2.0 μM against mushroom tyrosinase, which was 12-26 times lower than that of kojic acid (IC 50 value = 24.3 μM). However, according to a copper ion chelation experiment performed, the 2-MAA analogs did not participate in chelation with copper ions. To identify the mode of inhibition of the 2-MAA analogs, kinetic studies were performed, and the results were supported by docking results. In addition, docking simulation results suggested that the 2-MAA analogs strongly inhibited tyrosinase activity because of the hydrogen bonding of the amide NH group and the hydrophobic interaction of the aryl ring instead of chelation with copper ions. In experiments using B16F10 cells, 2-MAA analogs were shown to inhibit melanin production by inhibiting cellular tyrosinase activity. Western blotting showed that in addition to directly inhibiting tyrosinase activity, analog 7 also has an anti-melanogenic effect by inhibiting the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. The 2-MAA analogs showed no appreciable cytotoxicity against HaCaT and B16F10 cells, making them suitable for dermal applications. In a depigmentation experiment using zebrafish embryos, analogs 1 and 2 showed more potent depigmentation effects than kojic acid even at 1000 times lower concentration than that of kojic acid. These results suggest that the 2-MAA analogs are promising anti-melanogenic agents that can inhibit most tyrosinases in various species.

This study investigates the impact of sodium channel protein type 1 subunit alpha (SCN1A) gene knockout (SCN1A KO) on brain development and function using cerebral organoids coupled with a multiomics approach. From comprehensive omics analyses, we found that SCN1A KO organoids exhibit decreased growth, dysregulated neurotransmitter levels, and altered lipidomic, proteomic, and transcriptomic profiles compared to controls under matrix-free differentiation conditions. Neurochemical analysis reveals reduced levels of key neurotransmitters, and lipidomic analysis highlights changes in ether phospholipids and sphingomyelin. Furthermore, quantitative profiling of the SCN1A KO organoid proteome shows perturbations in cholesterol metabolism and sodium ion transportation, potentially affecting synaptic transmission. These findings suggest dysregulation of cholesterol metabolism and sodium ion transport, with implications for synaptic transmission. Overall, these insights shed light on the molecular mechanisms underlying SCN1A-associated disorders, such as Dravet syndrome, and offer potential avenues for therapeutic intervention., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Clinical manifestations and risk factors associated with systemic lupus erythematosus (SLE) flares, including recurrent lupus nephritis (LN), in patients with LN who undergo kidney transplantation have been unclear., Methods: Kidney transplant recipients with LN from January 1995 to December 2021 were included in this study. A disease flare was defined as either an increase in the non-renal SLE disease activity index score or the presence of biopsy-proven recurrent LN., Results: Among a total of 93 patients with LN who underwent kidney transplantation, 11 patients (11.8%) experienced SLE flares during a median follow-up period of 76.9 months (IQR, 43.0-122.4). The most common clinical manifestations of SLE flares were recurrent LN (4/11, 36.4%) and hematologic manifestations (4/11, 36.4%). Patients who had flares had significantly higher anti-double-stranded DNA (anti-dsDNA) antibody titers both before and after transplantation. Furthermore, an increased anti-dsDNA antibody level before transplantation was associated with a high risk of an SLE flare (HR, 1.030; p = .008). Conversely, preemptive transplantation was associated with a lower risk of a flare (HR, 0.617; p = .026). The rate of patient death-censored graft survival was found to be considerably lower in patients with recurrent LN than in those without LN., Conclusions: Approximately 10% of patients with LN experienced an SLE flare after transplantation, with recurrent LN being the most frequent manifestation. Anti-dsDNA antibody titers before transplantation were significantly related to the risk of an SLE flare. Notably, preemptive transplantation was associated with a reduced risk of flares following transplantation., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Introduction: Herbal medicines (HMs) are commonly used during the postpartum period in South Korea. However, the safety concerns associated with these medicines remain unresolved. This study aims to establish a registry of patients receiving HM treatment during the postpartum period and collect clinical data on treatments and adverse reactions to build evidence evaluating the safety of HM use., Methods and Analysis: This study will use a prospective observational registry, including patients admitted to the obstetrics and gynaecology department of the Woosuk University Korean Medicine Hospital's postpartum care centre. A total of 1000 eligible patients visiting the Korean medicine hospital to recover from various postchildbirth symptoms and opting for HM treatment will be enrolled in the registry. For safety assessment, demographic information, medical history, adverse events (AEs) and treatment details, including HM prescription and concomitant medication usage, will be collected throughout the patient's hospitalisation period at the postpartum care centre for analysis. Adverse reactions will be monitored daily during hospitalisation, and collected AEs will be analysed for causality using the WHO Uppsala Monitoring Centre causality assessment and the Naranjo Algorithm Score., Ethics and Dissemination: This study was approved by the Institutional Review Board of Woosuk University Korean Medicine Medical Center (WSOH IRB H2311-03-01). The results will be published in peer-reviewed journals or disseminated through conference presentations., Trial Registration Number: KCT0009060., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Acute lung injury (ALI) following pneumonia involves uncontrolled inflammation and tissue injury, leading to high mortality. We previously confirmed the significantly increased cargo content and extracellular vesicle (EV) production in thrombin-preconditioned human mesenchymal stromal cells (thMSCs) compared to those in naïve and other preconditioning methods. This study aimed to investigate the therapeutic efficacy of EVs derived from thMSCs in protecting against inflammation and tissue injury in an Escherichia coli (E. coli)-induced ALI mouse model., Methods: In vitro, RAW 264.7 cells were stimulated with 0.1 µg/mL liposaccharides (LPS) for 1 h, then were treated with either PBS (LPS Ctrl) or 5 × 10 7 particles of thMSC-EVs (LPS + thMSC-EVs) for 24 h. Cells and media were harvested for flow cytometry and ELISA. In vivo, ICR mice were anesthetized, intubated, administered 2 × 10 7 CFU/100 µl of E. coli. 50 min after, mice were then either administered 50 µL saline (ECS) or 1 × 10 9 particles/50 µL of thMSC-EVs (EME). Three days later, the therapeutic efficacy of thMSC-EVs was assessed using extracted lung tissue, bronchoalveolar lavage fluid (BALF), and in vivo computed tomography scans. One-way analysis of variance with post-hoc TUKEY test was used to compare the experimental groups statistically., Results: In vitro, IL-1β, CCL-2, and MMP-9 levels were significantly lower in the LPS + thMSC-EVs group than in the LPS Ctrl group. The percentages of M1 macrophages in the normal control, LPS Ctrl, and LPS + thMSC-EV groups were 12.5, 98.4, and 65.9%, respectively. In vivo, the EME group exhibited significantly lower histological scores for alveolar congestion, hemorrhage, wall thickening, and leukocyte infiltration than the ECS group. The wet-dry ratio for the lungs was significantly lower in the EME group than in the ECS group. The BALF levels of CCL2, TNF-a, and IL-6 were significantly lower in the EME group than in the ECS group. In vivo CT analysis revealed a significantly lower percentage of damaged lungs in the EME group than in the ECS group., Conclusion: Intratracheal thMSC-EVs administration significantly reduced E. coli-induced inflammation and lung tissue damage. Overall, these results suggest therapeutically enhanced thMSC-EVs as a novel promising therapeutic option for ARDS/ALI., (© 2024. The Author(s).)

This study investigated the technical feasibility of using electrogermination to activate dormant cysts as an inoculum for subsequent 14-d photosynthetic astaxanthin production in Haematococcus lacustris. Electrotreatment affected the cell viability, surface charge, and morphology of H. lacustris cysts. At an optimal voltage of 2 V for 60 min, the cyst germination rate peaked at 44.6 % after 1 d, representing a 2.2-fold increase compared with that of the untreated control. Notably, electrogermination significantly enhanced both the astaxanthin content (44.9 mg/g cell) and productivity (13.2 mg/L/d) after 14 d of photobioreactor cultivation, corresponding to 1.7- and 1.5-fold increases compared with those in control, respectively. However, excessive electrotreatment, particularly at voltages exceeding 2 V or for durations beyond 60 min, did not enhance the astaxanthin production capability of H. lacustris. Proper optimization of renewable electrogermination can enable sustainable algal biorefinery to produce multiple bioactive products without compromising cell viability and astaxanthin productivity., 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 Ltd. All rights reserved.)

Paralytic shellfish toxins (PSTs) are potent neurotoxins produced by certain microalgae, particularly dinoflagellates, and they can accumulate in shellfish in coastal seawater and thus pose significant health risks to humans. To explore the relationship between toxicity and PST profiles in seawater and mussels, the spatiotemporal variations in PST concentrations and profiles were investigated along the southern coast of Korea under peak PST levels during spring. Seawater and mussel samples were collected biweekly from multiple stations, and the toxin concentrations in the samples were measured. Moreover, the dinoflagellate community composition was analyzed using next-generation sequencing to identify potential PST-producing species. The PST concentrations and toxin profiles showed substantial spatiotemporal variability, with GTX1 and GTX4 representing the dominant toxins in both samples, and C1/2 tending to be higher in seawater. Alexandrium species were identified as the primary sources of PSTs. Environmental factors such as water temperature and salinity influenced PST production. This study demonstrates that variability in the amount and composition of PSTs is due to intricate ecological interactions. To mitigate shellfish poisoning, continuous monitoring must be conducted to gain a deeper understanding of these interactions.

Diagnosing the current health status and disease burden in a population is crucial for public health interventions. The ability to compare the burden of different diseases through a single measure, such as disability-adjusted life years has become feasible and continues to be produced and updated through the Global Burden of Diseases (GBD) study. However, the disease burden values of the GBD study do not accurately reflect the unique situation in a specific country with various circumstances. In response, the Korean National Burden of Disease (KNBD) study was conducted to estimate the disease burden in Koreans by considering Korea's cultural context and utilizing the available data sources at the national level. Both studies identified non-communicable diseases, such as diabetes mellitus (DM), as the primary cause of disease burden among Koreans. However, the extent of public health interventions currently being conducted by the central and local governments does not align with the severity of the disease burden. This review suggests that despite the high burden of DM in South Korea, the current policies may not fully address its impact, underscoring the need for expanded chronic disease management programs and a shift towards prevention-focused healthcare paradigms.

Importance: The persistent stigma associated with mental health conditions is a major challenge worldwide. Celebrities may improve this by openly discussing their own mental health issues, potentially influencing public attitudes and encouraging individuals to seek treatment for these conditions., Objective: To evaluate the impact of celebrity mental health disclosures on the incidence and prevalence of panic disorder diagnosis in South Korea., Design, Setting, and Participants: This cohort study included the entire South Korean population from January 2004 to December 2021, as reflected in the National Health Insurance Service data. Analysis was conducted from May 2022 through January 2024., Exposure: Time periods analyzed included the timeframe before (from January 2004 to December 2010) and after the public disclosures of panic disorder by 3 high-profile Korean celebrities between December 2010 and January 2012 (from January 2011 to December 2021)., Main Outcomes and Measures: Monthly incidence and prevalence of panic disorder, defined by the presence of a clinical diagnosis of the condition. Trends were assessed using interrupted time series analysis with autoregressive integrated moving average models. To assess public interest in panic disorder, trends in search data were analyzed, examining the association between the timing of increased searches and changes in the incidence and prevalence of panic disorder. Data on obsessive-compulsive disorder (OCD) were included as a control., Results: The study covered the entire population of South Korea, including 48 559 946 individuals in January 2004 and 52 593 886 individuals in December 2021. Before 2011, the mean (SD) annual prevalence of panic disorder was stable at 560 (140) persons per 100 000 persons per year. The celebrity disclosure in December 2010 was associated with higher monthly incidence rates of panic disorder, as measured by insurance claims data, changes that were observed in both the level (5.8 persons; 95% CI, 2.2-9.5 persons) and slope (0.78 persons per month; 95% CI, 0.19-1.40 persons per month) per 100 000 persons. By 2021, the observed annual prevalence per 100 000 persons reached 7530 persons, an increase of 775.6% compared with the 860 persons (95% CI, 330-1400 persons) estimated if the disclosures had not occurred. Internet searches anticipated changes in monthly prevalence with a lag of 2 or 3 months (F = 4.26, P = .02 and F = 3.11, P = .03, respectively). The celebrity disclosures had no significant association with the incidence or prevalence of OCD., Conclusions and Relevance: In this observational cohort study, celebrity disclosure of mental health conditions was associated with a sustained reduction in stigma, as reflected in increased help-seeking behavior for the condition over more than a decade. This underscores the influential role celebrities can play in shaping public health perceptions and behaviors, offering valuable insights for the development of future mental health policies and public awareness campaigns.

Based on the fact that substances with a β-phenyl-α,β-unsaturated carbonyl (PUSC) motif confer strong tyrosinase inhibitory activity, benzylidene-3-methyl-2-thioxothiazolidin-4-one (BMTTZD) analogs 1 - 8 were prepared as potential tyrosinase inhibitors. Four analogs ( 1 - 3 and 5 ) inhibited mushroom tyrosinase strongly. Especially, analog 3 showed an inhibitory effect that was 220 and 22 times more powerful than kojic acid in the presence of l-tyrosine and l-dopa, respectively. A kinetic study utilizing mushroom tyrosinase showed that analogs 1 and 3 competitively inhibited tyrosinase, whereas analogs 2 and 5 inhibited tyrosinase in a mixed manner. A docking simulation study indicated that analogs 2 and 5 could bind to both the tyrosinase active and allosteric sites with high binding affinities. In cell-based experiments using B16F10 cells, analogs 1 , 3 , and 5 effectively inhibited melanin production; their anti-melanogenic effects were attributed to their ability to inhibit intracellular tyrosinase activity. Moreover, analogs 1 , 3 , and 5 inhibited in situ B16F10 cellular tyrosinase activity. In three antioxidant experiments, analogs 2 and 3 exhibited strong antioxidant efficacy, similar to that of the positive controls. These results suggest that the BMTTZD analogs are promising tyrosinase inhibitors for the treatment of hyperpigmentation-related disorders.

Background: Health-adjusted life expectancy (HALE) is an indicator of the average lifespan in good health. Through this study, we aimed to identify regional disparities in the gap between HALE and life expectancy, considering the trends that have changed over time in Korea., Methods: We employed a group-based multi-trajectory modeling approach to capture trends in the gap between HALE and life expectancy at the regional level from 2008 to 2019. HALE was calculated using incidence-based "years lived with disability." This methodology was also employed in the Korean National Burden of Disease Study., Results: Based on five different information criteria, the most fitted number of trajectory groups was seven, with at least 11 regions in each group. Among the seven groups, one had an exceptionally large gap between HALE and life expectancy compared to that of the others. This group was assigned to 17 regions, of which six were metropolitan cities., Conclusion: Based on the results of this study, we identified regions in which health levels have deteriorated over time, particularly within specific areas of metropolitan cities. These findings can be used to design comprehensive policy interventions for community health promotion and urban regeneration projects in the future., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Objective: We investigated the incidence of and risk factors for myelodysplastic syndrome (MDS) in patients with rheumatologic disease., Methods: We conducted a retrospective cohort study of patients who were diagnosed with rheumatologic diseases at a tertiary care hospital between May 2009 and July 2022 and identified the patients who were subsequently diagnosed with MDS. Each patient with MDS was matched with five age- and sex-matched controls chosen from the cohort of patients with each specific rheumatologic disease., Results: During a total follow-up of 55 841 person-years (PY), MDS occurred in 64 patients, yielding an incidence rate of 1.15/1000 PY {median age 57.0 years [interquartile range (IQR) 41.0-69.0], median duration to MDS diagnosis 6.5 years (IQR 3.0-9.0)]. In an age-matched analysis, SLE was a significant risk factor for MDS [adjusted hazard ratio 2.61 (CI 1.19, 36.06), P = 0.01]. Refractory cytopenia with multilineage dysplasia was the most common phenotype of MDS (35.9%), and more than half of the patients had karyotypes with a favourable prognosis (54.7%). Compared with matched controls, RA, SLE and AS patients with MDS had lower levels of haemoglobin at the time of diagnosis of rheumatologic disease. Furthermore, the MDS patients with SLE and Behçet's disease had higher levels of glucocorticoid use in terms of frequency of use and mean dose than control patients., Conclusion: SLE is a significant risk factor for MDS among patients with rheumatologic diseases. A lower haemoglobin level at the time of diagnosis of rheumatologic disease was associated with the future development of MDS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: This nationwide cohort study compared the incidence of adverse events of special interest (AESIs) between adenoviral vector-based (ChAdOx1) and mRNA-based (BNT162b2 or mRNA-1273) coronavirus disease 2019 (COVID-19) vaccines., Methods: A targeted trial emulation study was conducted using data from the National Health Insurance Service database. Vaccinees aged 18-85 years who had received at least one dose of ChAdOx1 or an mRNA-based vaccine were identified. The 42-day risks of AESIs were calculated., Results: A total of 1 767 539 ChAdOx1 vaccinees were matched exactly with mRNA vaccinees according to their risk factors. The 42-day risks of adverse events were low (∼0 to 176 events per 100 000 persons in both vaccine groups), and the incidence rates of AESIs were comparable between the two platforms, except for a higher occurrence of acute cardiac injury (incidence rate ratio [IRR], 1.22; 95% CI, 1.10-1.35), myocarditis or pericarditis (IRR, 2.14; 95% CI, 1.14-4.04), and arrhythmia (IRR, 1.46; 95% CI, 1.24-1.71) in mRNA vaccinees. The incidence of Guillain-Barré syndrome (IRR, 0.20; 95% CI, 0.06-0.69), vasovagal syncope (IRR, 0.77; 95% CI, 0.62-0.97), radiculopathy (IRR = 0.59, 95% CI, 0.41-0.84), and aseptic arthritis (IRR, 0.81; 95% CI, 0.70-0.93) was significantly lower in mRNA-based vaccinees compared with ChAdOx1 vaccinees., Discussion: A remarkable platform-dependent difference was observed in the safety profiles of COVID-19 vaccines, particularly for myocarditis or pericarditis and Guillain-Barré syndrome. However, the overall risk of AESIs was low for both vaccine platforms., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To assess the association of primary and third doses of vaccination with the risk of post-acute sequelae of COVID-19., Methods: This retrospective cohort study utilized a combined database of nationwide health care claims data, COVID-19 patient registry, and vaccination records from South Korea. Individuals diagnosed with COVID-19 in the Omicron variant-dominant period of January-March 2022 were tracked for 30-120 days post-infection. The exposure of interest was the receipt of primary and third doses of the SARS-CoV-2 vaccine. The occurrence of 26 specific conditions in eight domains was compared using Cox regression with inverse probability of treatment weighting., Results: This study included 394 773 unvaccinated individuals and 7 604 081 individuals receiving ≥2 doses of vaccine. Compared with unvaccinated individuals, vaccination with at least two doses was associated with a reduced risk (adjusted hazard ratio; 95% CI) of several conditions, including ischaemic heart disease (0.73; 0.57-0.94), heart failure (0.55; 0.48-0.63), cardiac dysrhythmia (0.72; 0.61-0.85), cardiac arrest (0.41; 0.33-0.51), pulmonary embolism (0.66; 0.52-0.84), venous thromboembolism (0.54; 0.44-0.66), acute renal failure (0.56; 0.46-0.67), new dialysis (0.45; 0.34-0.59), chronic obstructive pulmonary disease (0.74; 0.65-0.84), acute pancreatitis (0.64; 0.51-0.80), and diabetes (0.82; 0.71-0.95). The risks of heart failure, cardiac dysrhythmias, cardiac arrest, pulmonary embolism, and new dialysis were lower in those who were vaccinated with three doses compared with those who were vaccinated with two doses., Discussion: Vaccination was associated with a decreased risk of post-acute sequelae of COVID-19, suggesting its potential role in mitigating the indirect impacts of COVID-19., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

We established a protocol for the traditional Korean medicine examination (KME) and methodically gathered data following this protocol. Potential indicators for KME were extracted through a literature review; the first KME protocol was developed based on three rounds of expert opinions. The first KME protocol's feasibility was confirmed, and data were collected over four years from traditional Korean medicine (KM) hospitals, focusing on healthy adults, using the final KME protocol. A literature review identified 175 potential core indicators, condensed into 73 indicators after three rounds of expert consultation. The first KME protocol, which was categorized under questionnaires and medical examinations, was developed after the third round of expert opinions. A pilot study using the first KME protocol was conducted to ensure its validity, leading to modifications resulting in the development of the final KME protocol. Over four years, data were collected from six KM hospitals, focusing on healthy adults; we obtained a dataset comprising 11,036 healthy adults. This is the first protocol incorporating core indicators of KME in a quantitative form and systematically collecting data. Our protocol holds potential merit in evaluating predisposition to diseases or predicting diseases.

Background: Solid organ transplant recipients (SOTRs) are at higher risk for severe infection. However, the risk for severe COVID-19 and vaccine effectiveness among SOTRs remain unclear., Methods: This retrospective study used a nationwide health care claims database and COVID-19 registry from the Republic of Korea (2020 to 2022). Adult SOTRs diagnosed with COVID-19 were matched with up to 4 non-SOTR COVID-19 patients by propensity score. Severe COVID-19 was defined as treatment with high-flow nasal cannulae, mechanical ventilation, or extracorporeal membrane oxygenation., Results: Among 6783 SOTRs with COVID-19, severe COVID-19 was reported with the highest rate in lung transplant recipients (13.16%), followed by the heart (6.30%), kidney (3.90%), and liver (2.40%). SOTRs had a higher risk of severe COVID-19 compared to non-SOTRs, and lung transplant recipients showed the highest risk (adjusted odds ratio, 18.14; 95% confidence interval [CI], 8.53-38.58). Vaccine effectiveness against severe disease among SOTRs was 47% (95% CI, 18%-65%), 64% (95% CI, 49%-75%), and 64% (95% CI, 29%-81%) for 2, 3, and 4 doses, respectively., Conclusions: SOTRs are at significantly higher risk for severe COVID-19 compared to non-SOTRs. Vaccination is effective in preventing the progression to severe COVID-19. Efforts should be made to improve vaccine uptake among SOTRs, while additional protective measures should be developed., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Akkermansia muciniphila has received great attention because of its beneficial roles in gut health by regulating gut immunity, promoting intestinal epithelial development, and improving barrier integrity. However, A. muciniphila-derived functional molecules regulating gut health are not well understood. Microbiome-secreted proteins act as key arbitrators of host-microbiome crosstalk through interactions with host cells in the gut and are important for understanding host-microbiome relationships. Herein, we report the biological function of Amuc&#95;1409, a previously uncharacterised A. muciniphila-secreted protein. Amuc&#95;1409 increased intestinal stem cell (ISC) proliferation and regeneration in ex vivo intestinal organoids and in vivo models of radiation- or chemotherapeutic drug-induced intestinal injury and natural aging with male mice. Mechanistically, Amuc&#95;1409 promoted E-cadherin/β-catenin complex dissociation via interaction with E-cadherin, resulting in the activation of Wnt/β-catenin signaling. Our results demonstrate that Amuc&#95;1409 plays a crucial role in intestinal homeostasis by regulating ISC activity in an E-cadherin-dependent manner and is a promising biomolecule for improving and maintaining gut health., (© 2024. The Author(s).)

Background: To investigate the risk of recurrent herpes zoster (HZ) reactivation under continued Janus kinase inhibitor (JAKi) therapy in patients with immune-mediated inflammatory diseases (IMID) who developed HZ reactivation., Methods: Data from the Korean Health Insurance Review and Assessment Service (HIRA) of patients with rheumatoid arthritis (RA) or ulcerative colitis (UC) gathered from 2007 to 2021 were analyzed., Results: A total of 3947 (RA 3540, UC 407) receiving JAKi were included. After median 0.95 years (IQR, 0.93-2.58) of therapy, 611 (15.5%) patients developed HZ reactivation (incidence rate: 8.38/100 person-years [PY]). After excluding 151 patients with lack of data after HZ reactivation, 460 patients (JAKi continuation group, n = 386 [83.9%]; JAKi discontinuation group, n = 74 [16.1%]) were analyzed for the risk of subsequent recurrent HZ reactivation. During further follow-up of median 1.11 years (IQR, 0.53-1.91), 36 (9.3%) and 6 (8.1%) patients in the JAKi continuation group and JAKi discontinuation group experienced a recurrence of HZ, respectively. The incidence rate of subsequent recurrent HZ reactivation was not significantly different between the two groups (5.3/100 vs. 5.9/100 PY; P = 0.52). After adjusting for age, sex, usage of corticosteroids, and antiviral agents, continued use of JAKi was not a significant risk factor for subsequent HZ reactivation (adjusted hazard ratio, 0.71 [CI, 0.29-1.72], P = 0.45)., Conclusion: In this nationwide population-based study on patients with RA or UC, continued use of JAKi was not associated with a significant risk of subsequent recurrent HZ reactivation. JAKi therapy may be maintained in patients with IMID even after HZ reactivation., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest (in relation to this article)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Mitochondrial DNA (mtDNA) released from dead or injured cells can activate inflammation, and mesenchymal stem cell (MSC) transplantation can reduce inflammation and injury. However, it has not been tested whether the release of mtDNA can be reduced by MSC transplantation. We hypothesized that the level of extracellular mtDNA would be increased after hyperoxia-induced lung injury but reduced after lung injury attenuation by MSC therapy in our newborn rat model. In an in vitro study using a rat lung epithelial L2 cell line, we found that the level of extracellular mtDNA was significantly increased with H 2 O 2 -induced cell death but reduced after MSC co-incubation. In an in vivo study, we confirmed that the levels of cell death, extracellular mtDNA, and inflammatory cytokines were significantly increased in hyperoxic newborn rat lungs but reduced after MSC transplantation. The levels of extracellular mtDNA were significantly and positively correlated with the levels of the inflammatory cytokines. The TLR9/MyD88/NF-κB pathway, which is activated by binding to mtDNA, was also significantly upregulated but downregulated after MSC transplantation. We found a significant positive correlation between inflammatory cytokines and extracellular mtDNA in intubated neonates. The levels of inflammatory cytokines and extracellular mtDNA changed over time in a similar pattern in transtracheal aspirate samples from intubated neonates. In conclusion, increased levels of extracellular mtDNA are associated with increased inflammation in hyperoxia-induced lung injury, and attenuation of lung inflammation by MSC therapy is associated with reduced levels of extracellular mtDNA.

Objectives: To determine the febuxostat dose requirement according to renal function in patients who achieve target serum urate (SU) levels., Methods: Of 3153 gout patients who underwent febuxostat treatment, 873 patients with an initial SU level>6mg/dL were included and categorized by the estimated glomerular filtration rate: normal, chronic kidney disease (CKD) stage 3, and stages 4-5. Ninety-five patients with insufficient follow-up were further excluded. The dose of febuxostat in patients who achieved the SU target (< 6mg/dL) was defined as the average daily dosage at the time of SU target achievement., Results: The cohort of 778 gout patients had a median age of 52.0 years (IQR, 41.0-63.0) and comprised 711 (91.4%) men. The mean SU at febuxostat initiation was higher in the CKD 4-5 (9.6 [± 3.1] mg/dL) than in the other groups (CKD 3, 8.7 [± 1.7]; normal, 8.4 [± 1.7]; P<0.001). Patients achieved target SU at a median of 4.0 (1.9-9.6) months and in those who achieved target SU, the dose of febuxostat at the time of SU target achievement was significantly lower in the CKD 4-5 group (50.0 [± 16.5] mg) than in the other groups (vs. CKD stage 3, 60.0 [± 19.5] mg; P<0.01, vs. normal, 60.0 [± 19.8] mg; P<0.01). Furthermore, CKD stage 4-5 had a negative correlation with the febuxostat dose requirement (Beta: -2.334, P<0.05)., Conclusion: Among patients who achieved SU target, those with severely decreased renal function (CKD 4-5) required a lower febuxostat dose to achieve the target SU level compared to patients with normal or mild renal impairment., (Copyright © 2023 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Background: The measurement of health levels and monitoring of characteristics and trends among populations and subgroups are essential for informing evidence-based policy decisions. This study aimed to examine the burden of disease in Korea for both the total population and subgroups in 2020, as well as analyze changes in disease burden from 2008 to 2020., Methods: We employed the methodology developed in the Korean National Burden of Disease and Injuries Study to calculate disability-adjusted life years (DALYs) by sex, causes, region, and income level from 2008 to 2020. DALYs were derived by combining years of life lost and years lived with disability., Results: In 2020, the burden of disease for the Korean population was estimated to be 25,439 DALYs per 100,000 population, reflecting a 13.8% increase since 2008. The leading causes of DALYs were diabetes mellitus, followed by low back pain and ischemic stroke. A sex-specific gap reversal was observed, with the disease burden for men surpassing that of women starting in 2017. Furthermore, variations in disease burden were identified across 250 regions and income quintiles., Conclusion: It is imperative to establish appropriate health policies that prioritize the diseases with significantly increasing burdens and subgroups experiencing high disease burdens. The findings of this study are expected to serve as a foundation for developing healthcare policies aimed at improving the health levels of Koreans and achieving health equity., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Background: Healthy life expectancy is a well-recognized indicator for establishing health policy goals used in Korea's Health Plan. This study aimed to explore Koreans' healthy life expectancy and its gender, income, and regional disparities from 2008 to 2020., Methods: This study was conducted on the entire population covered by health insurance and medical aid program in Korea. The incidence-based "years lived with disability" for 260 disease groups by gender, income level, and region was calculated employing the methodology developed in the Korean National Burden of Disease Study, and it was used as the number of healthy years lost to calculate health-adjusted life expectancy (HALE)., Results: Koreans' HALE increased from 68.89 years in 2008 to 71.82 years in 2020. Although the gender disparity in HALE had been decreasing, it increased to 4.55 years in 2020. As of 2020, 5.90 years out of 8.67 years of the income disparity (Q5-Q1) in HALE were due to the disparity between Q1 and Q2, the low-income groups. Income and regional disparities in HALE exhibited an increasing trend, and these disparities were higher in men than in women., Conclusion: A subgroup with a low health level was identified through the HALE results, and it was confirmed that improving the health level of this population can reduce health inequalities and improve health at the national level. Further exploration of the HALE calculation methodology may help in the development of effective policies such as prioritizing interventions for health risk factors., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Background: Progranulin (PGRN) haploinsufficiency due to progranulin gene (GRN) variants can cause frontotemporal dementia (FTD) with aberrant TAR DNA-binding protein 43 (TDP-43) accumulation. Despite microglial burden with TDP-43-related pathophysiology, direct microglial TDP-43 pathology has not been clarified yet, only emphasized in neuronal pathology. Thus, the objective of this study was to investigate TDP-43 pathology in microglia of patients with PGRN haploinsufficiency., Methods: To design a human microglial cell model with PGRN haploinsufficiency, monocyte-derived microglia (iMGs) were generated from FTD-GRN patients carrying pathogenic or likely pathogenic variants (p.M1? and p.W147*) and three healthy controls., Results: iMGs from FTD-GRN patients with PGRN deficiency exhibited severe neuroinflammation phenotype and failure to maintain their homeostatic molecular signatures, along with impaired phagocytosis. In FTD-GRN patients-derived iMGs, significant cytoplasmic TDP-43 aggregation and accumulation of lipid droplets with profound lysosomal abnormalities were observed. These pathomechanisms were mediated by complement C1q activation and upregulation of pro-inflammatory cytokines., Conclusions: Our study provides considerable cellular and molecular evidence that loss-of-function variants of GRN in human microglia can cause microglial dysfunction with abnormal TDP-43 aggregation induced by inflammatory milieu as well as the impaired lysosome. Elucidating the role of microglial TDP-43 pathology in intensifying neuroinflammation in individuals with FTD due to PGRN deficiency and examining consequential effects on microglial dysfunction might yield novel insights into the mechanisms underlying FTD and neurodegenerative disorders., (© 2024. The Author(s).)

The accumulation of alpha-synuclein (αSyn) is widely recognized as the main pathological process in Parkinson's disease (PD). Additionally, neuroinflammation is considered to be one of the contributing mechanisms in the development of PD. In light of this, it is hypothesized that the reactive microglia exacerbate the propagation of αSyn and neurodegeneration, while the inhibition of microglial activity may mitigate these effects. To test this hypothesis, αSyn preformed fibrils (PFF)-injected PD mouse model was employed. Co-injection of lipopolysaccharide (LPS) and PFF was performed to investigate if microglial reactivity intensified αSyn propagation and neurodegeneration. Additionally, oral administration of PLX5622, a microglial inhibitor that targets the colony-stimulating factor 1 receptor, was given for two weeks before and after PFF injection each to explore if microglial inhibition could prevent or reduce αSyn pathology. Intrastriatal co-injection of LPS and PFF resulted in increased microglial reactivity, αSyn accumulation, and neurodegeneration compared to PFF injection alone. However, treatment with PLX5622 significantly suppressed microglial reactivity, reduced αSyn pathology, and alleviated dopaminergic neuron degeneration in the PD mouse model injected with PFF. Based on these findings, it is evident that microglial reactivity plays a crucial role in the progression of αSyn pathology and neurodegeneration in PD. Furthermore, the results suggest that microglial inhibition may hold promise as a therapeutic strategy to delay the progression of αSyn pathology in PD., (© 2024. The Author(s).)

Objective: This is the first prospective cohort study of Huntington's disease (HD) in Korea. This study aimed to investigate the caregiver burden in relation to the characteristics of patients and caregivers., Methods: From August 2020 to February 2022, we enrolled patients with HD from 13 university hospitals in Korea. We used the 12-item Zarit Burden Interview (ZBI-12) to evaluate the caregiver burden. We evaluated the clinical associations of the ZBI-12 scores by linear regression analysis and investigated the differences between the low- and high-burden groups., Results: Sixty-five patients with HD and 45 caregivers were enrolled in this cohort study. The average age at onset of motor symptoms was 49.3 ± 12.3 years, with an average cytosine-adenine-guanine (CAG)n of 42.9 ± 4.0 (38-65). The median ZBI-12 score among our caregivers was 17.6 ± 14.2. A higher caregiver burden was associated with a more severe Shoulson-Fahn stage (p = 0.038) of the patients. A higher ZBI-12 score was also associated with lower independence scale (B = -0.154, p = 0.006) and functional capacity (B = -1.082, p = 0.002) scores of patients. The caregiving duration was longer in the high- than in the low-burden group. Caregivers' demographics, blood relation, and marital and social status did not affect the burden significantly., Conclusion: HD patients' neurological status exerts an enormous impact on the caregiver burden regardless of the demographic or social status of the caregiver. This study emphasizes the need to establish an optimal support system for families dealing with HD in Korea. A future longitudinal analysis could help us understand how disease progression aggravates the caregiver burden throughout the entire disease course.

Objective: Parkinson's disease (PD) patients often find it difficult to visit hospitals because of motor symptoms, distance to the hospital, or the absence of caregivers. Telemedicine is one way to solve this problem., Methods: We surveyed 554 PD patients from eight university hospitals in Korea. The questionnaire consisted of the clinical characteristics of the participants, possible teleconferencing., Methods: , and preferences for telemedicine., Results: A total of 385 patients (70%) expressed interest in receiving telemedicine. Among them, 174 preferred telemedicine whereas 211 preferred in-person visits. The longer the duration of disease, and the longer the time required to visit the hospital, the more patients were interested in receiving telemedicine., Conclusion: This is the first study on PD patients' preferences regarding telemedicine in Korea. Although the majority of patients with PD have a positive view of telemedicine, their interest in receiving telemedicine depends on their different circumstances.

Objective: Drug-induced parkinsonism (DIP) is a frequently encountered diagnostic possibility when considering Parkinson's disease (PD). While olfactory dysfunction is a common clinical feature in PD, the comparison of olfactory function between the two conditions remains insufficient. This study aimed to compare olfactory function, including threshold, discrimination, and identification (TDI) profiles, between PD and DIP., Methods: Consecutive patients with drug-naïve PD (n = 78) or DIP (n = 31) confirmed through dopamine transporter imaging were enrolled in this study. The YSK olfactory function (YOF) test, composed of TDI domains culturally familiar odorants to Koreans, was administered to all patients., Results: In the study population, patients with DIP were significantly older than patients with PD. Over 70% of patients in each group had hyposmia or anosmia, and there was no significant difference in the occurrence of olfactory dysfunction between the two groups. In addition, there were no differences in the total YOF score and threshold score between the two groups. Meanwhile, the PD group had a significantly lower discrimination and identification score than the DIP group after adjusting for age, sex, the existence of diabetes, disease duration, and cognitive function., Conclusion: This study demonstrated that detailed olfactory profiles are different in PD and DIP, even though olfactory dysfunction can be observed in both conditions.

Backgruound: Post-transplant diabetes mellitus (PTDM) is one of the most significant complications after transplantation. Patients with end-stage liver diseases requiring transplantation are prone to sarcopenia, but the association between sarcopenia and PTDM remains to be elucidated. We aimed to investigate the effect of postoperative muscle mass loss on PTDM development., Methods: A total of 500 patients who underwent liver transplantation at a tertiary care hospital between 2005 and 2020 were included. Skeletal muscle area at the level of the L3-L5 vertebrae was measured using computed tomography scans performed before and 1 year after the transplantation. The associations between the change in the muscle area after the transplantation and the incidence of PTDM was investigated using a Cox proportional hazard model., Results: During the follow-up period (median, 4.9 years), PTDM occurred in 165 patients (33%). The muscle mass loss was greater in patients who developed PTDM than in those without PTDM. Muscle depletion significantly increased risk of developing PTDM after adjustment for other confounding factors (hazard ratio, 1.50; 95% confidence interval, 1.23 to 1.84; P=0.001). Of the 357 subjects who had muscle mass loss, 124 (34.7%) developed PTDM, whereas of the 143 patients in the muscle mass maintenance group, 41 (28.7%) developed PTDM. The cumulative incidence of PTDM was significantly higher in patients with muscle loss than in patients without muscle loss (P=0.034)., Conclusion: Muscle depletion after liver transplantation is associated with increased risk of PTDM development.

The coronavirus disease 2019 pandemic has brought significant changes to infectious disease management globally. This study explored changes in clinical microbiological testing trends and their implications for infectious disease incidence and medical utilization during the pandemic. We collected nationwide claims for monthly clinical microbiology tests from January 2018 to March 2022 using the National Health Insurance Service database. Seasonal autoregressive integrated moving average models were employed to make predictions for each disease based on the baseline period (January 2018 to January 2020). The results showed a significant decrease in general bacterial and fungal cultures, respiratory infectious disease-related, and inflammatory markers, while the representatives of tests for vector-borne diseases, healthcare-associated infections, and chronic viral infections remained stable. The study highlights the potential of clinical microbiological testing trends as an additional surveillance tool and offers implications for future infectious disease management and surveillance strategies in pandemic settings., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Forsythiaside A (FA) is an active constituent isolated from Forsythia suspensa , a beneficial herb used in traditional medicine known for its antioxidant and anti-inflammatory properties. Although various studies have suggested that FA has the protective effects, its impacts on arachidonic acid (AA) plus iron in vitro models and carbon tetrachloride (CCl₄)-induced mouse liver damage in vivo have not been explored. In this study, HepG2 cells were subjected to AA + iron treatment to induce apoptosis and mitochondrial impairment and determine the molecular mechanisms. FA exhibited protective effects by inhibiting cell damage and reactive oxygen species (ROS) production induced by AA + iron, as assessed via immunoblot and flow cytometry analyses. Further molecular investigations revealed that FA resulted in the activation of extracellular-signal-related protein kinase (ERK), which subsequently triggered the activation of AMP-activated protein kinase (AMPK), a critical regulator of cellular oxidative stress. Additionally, FA modulated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which is a significant antioxidant transcription factor regulated by the AMPK pathway. For in vivo studies, mice were orally administered FA and then subjected to induction of CCl₄-based hepatotoxicity. The protective effect of FA was confirmed via blood biochemistry and immunohistochemical analyses. In conclusion, our findings demonstrated the protective effects of FA against oxidative stress both in vitro and in vivo, thus indicating that FA is a potential candidate for liver protection. Our study sheds light on the mechanistic pathways involved in the antioxidant effects of FA, highlighting the hepatoprotective potential of naturally occurring compounds in traditional herbs, such as FA.

Chromosome 9 open reading frame 72 ( C9orf72 ) gene pathogenic variants have been typically associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), but recent studies suggest their involvement in other disorders. This report describes a family with an autosomal dominant pattern of inheritance of progressive verbal auditory agnosia due to GGGGCC repeat expansion in C9orf72. A 60-year-old right-handed male truck driver presented with slowly progressive poor speech perception for 8 years, which became most troublesome when receiving verbal orders over the phone. He had difficulty recognizing single-syllable spoken words beyond his hearing loss but had no problem understanding complex written language. He had a heterozygous pathogenic variant carrying 160 hexanucleotide repeats in the C9orf72 gene. His family history included his deceased mother with similar symptoms that had progressed over 30 years, as well as his older brother and youngest sister who experienced speech perception difficulty beginning in their early fifties. His asymptomatic younger brother had a heterozygous 2 repeat in the C9orf72 gene, while his symptomatic youngest sister had a heterozygous 159 repeat. The patient and his sister exhibited more pronounced cortical thinning in the frontotemporoparietal areas. The discrepancy observed between the distribution of atrophy and the presentation of symptoms in patients with C9orf72 pathogenic repeat expansion may be attributable to the slow progression of their clinical course over time. The variable symptom presentation of C9orf72 pathogenic repeat expansion highlights the importance of considering this pathogenic variant as a potential cause of autosomal dominant degenerative brain diseases beyond FTD and ALS., (© 2023 American Academy of Neurology.)

Although it has been suggested that toll-like receptor (TLR) 3 and TLR4 activation alters mesenchymal stromal cells (MSCs)' immunoregulatory function as anti- or pro-inflammatory phenotypes, we have previously confirmed that TLR4-primed hUCB-MSCs alleviate lung inflammation and tissue injury in an E. coli -induced acute lung injury (ALI) mouse model. Therefore, we hypothesized that strong stimulation of TLR3 or TLR4 prompts hUCB-MSCs to exhibit an anti-inflammatory phenotype mediated by extracellular vesicles (EVs). In this study, we compared the anti-inflammatory effect of TLR3-primed and TLR4-primed hUCB-MSCs against an LPS-induced ALI in vitro model by treating MSCs, MSC-derived conditioned medium (CM), and MSC-derived extracellular vesicles (EVs). LPS-induced rat primary alveolar macrophage and RAW 264.7 cells were treated with naïve, TLR3-, and TLR4-primed MSCs and their derived CM and EVs. Flow cytometry and ELISA were used to evaluate M1-M2 polarization of macrophages and pro-inflammatory cytokine levels, respectively. LPS-stimulated macrophages showed significantly increased pro-inflammatory cytokines compared to those of the normal control, and the percentage of M2 macrophage phenotype was predominantly low. In reducing the inflammatory cytokines and enhancing M2 polarization, TLR3- and TLR4-primed MSCs were significantly more effective than the naïve MSCs, and this finding was also observed with the treatment of MSC-derived CMs and EVs. No significant difference between the efficacy of TLR3- and TLR-primed MSCs was observed. Strong stimulation of TLR3- and TLR4-stimulated hUCB-MSCs significantly reduced pro-inflammatory cytokine secretion from LPS-induced macrophages and significantly enhanced the M2 polarization of macrophages. We further confirmed that TLR-primed MSC-derived EVs can exert anti-inflammatory and immunosuppressive effects alone comparable to MSC treatment. We hereby suggest that in the LPS-induced macrophage in vitro model, EVs derived from both TLR3 and TLR4-primed MSCs can be a therapeutic candidate by promoting the M2 phenotype.

Background: Our study aimed to determine the risk of herpes zoster reactivation and coronavirus disease 2019 (COVID-19) vaccination (mRNA vaccine [BNT162b2] and adenovirus-vectored vaccine [ChAdOx1 nCoV-19])., Methods: This retrospective study analyzed herpes zoster cases diagnosed between 26 February 2021 and 30 June 2021 and registered in the National Health Insurance Service database. A matched case-control study with a 1:3 matching ratio and a propensity score matching (PSM) study with a 1:1 ratio of vaccinated and unvaccinated individuals were performed., Results: In the matched case control analysis, BNT162b2 was associated with an increased risk of herpes zoster reactivation (first dose adjusted odds ratio [aOR], 1.11; 95% confidence interval [CI], 1.06-1.15; second dose aOR, 1.17; 95% CI, 1.12-1.23). PSM analysis revealed a statistically significant increase in risk within 18 days following any vaccination (adjusted hazard ratio [aHR], 1.09; 95% CI, 1.02-1.16). BNT162b2 was associated with an increased risk at 18 days postvaccination (aHR, 1.65; 95% CI, 1.35-2.02) and second dose (aHR, 1.10; 95% CI, 1.02-1.19). However, the risk did not increase in both analyses of ChAdOx1 vaccination., Conclusions: mRNA COVID-19 vaccination possibly increases the risk of herpes zoster reactivation, and thus close follow-up for herpes zoster reactivation is required., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Recent studies have highlighted the positive effects of Kaempferol (KP), including its anti-inflammatory and antioxidant properties. However, its impact on oxidative damage induced by heavy metals and pro-inflammatory mediators, such as arachidonic acid (AA), has not yet been identified. Our objective was to specifically evaluate liver damage due to AA + iron-induced oxidative stress, both in vitro and in vivo. In HepG2 cells, KP activated the AMP-activated protein kinase (AMPK), suggesting a hepatoprotective effect through AMPK inhibition, as assessed by immunoblot and FACS analysis (EC 50  = 10 μM). KP also stimulated autophagy, a degradation process that eliminates aged, damaged, and unnecessary components, via mTOR inhibition and ULK1 phosphorylation. This activation was further validated by the upregulation of autophagy-related genes (ATG5) and Beclin-1, along with the conversion of LC3BI to LC3BII. Ferroptosis, a non-apoptotic type of cell death characterized by oxidative stress from the production of reactive oxygen species (ROS) and excessive iron accumulation, was linked to the activation of autophagy, as confirmed through the protein expression of deferoxamine (DFO) and ferrostatin-1 (Fer-1), the representative ferroptosis inhibitors (positive controls). In mice, oral administration of KP demonstrated protective effects against CCl 4 -induced hepatotoxicity. In conclusion, KP provides hepatoprotective effects against oxidative stress induced by AA + iron treatment in vitro and CCl 4 treatment in vivo., 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. Published by Elsevier Inc.)

The TARDBP gene variant is a known major cause of amyotrophic lateral sclerosis (ALS), with limited reports of Korean patients with ALS harboring the variants in TARDBP. This large cohort study introduces four ALS patients who share the p.M337V variant of the TARDBP, allowing for an investigation of clinical characteristics and prognosis by analyzing previously reported cases with the same variant. From November 2014 to August 2022, participants were recruited from two tertiary hospitals in Seoul, Korea. Clinical characteristics of patients diagnosed with ALS carrying the variant in TARDBP were evaluated. Previous articles demonstrating subjects' characteristics were reviewed. Four patients were identified with the pathogenic missense variant (c.1009A>G; p.M337V) in the TARDBP. The mean age of onset was 55 years old, and none of the patients showed severe cognitive impairment. Sixty-three patients carrying the p.M337V variant in TARDBP from this study and previous reports delineated young age of onset (51.6 years), high frequency of bulbar onset patients (61.9%), and low comorbidity of frontotemporal dementia. This study reveals the presence of pathogenic variant of TARDBP in Korea and emphasizes the importance of genetic screening of the TARDBP gene, in diagnosing ALS and evaluating prognosis among familial and simplex ALS patients in Korea., (© 2023. The Author(s).)

In the human brain, neurophysiological activity is modulated by the movement of neurotransmitters and neurosteroids. To date, the similarity between cerebral organoids and actual human brains has been evaluated using comprehensive multiomics approaches. However, a systematic analysis of both neurotransmitters and neurosteroids from cerebral organoids has not yet been reported. Here, we performed quantitative and qualitative assessments of neurotransmitters and neurosteroids over the course of cerebral organoid differentiation. Our multiomics approaches revealed that the expression levels of neurotransmitter-related proteins and RNA, including neurosteroids, increase as cerebral organoids mature. We also found that the electrophysiological activity of human cerebral organoids increases in tandem with the expression levels of both neurotransmitters and neurosteroids. Our study demonstrates that the expression levels of neurotransmitters and neurosteroids can serve as key factors in evaluating the maturity and functionality of human cerebral organoids.

Nicotine, an abundant molecule in tobacco, has immunomodulatory effects on inflammatory diseases, primarily due to the activation of alpha7 nicotinic acetylcholine receptor (α7 nAChR). We aim to evaluate the expression of the α7 nAChR + cells in joint tissue and the effect of smoking on immune cells and peripheral arthritis in curdlan-administered SKG mice, a murine model of spondyloarthropathy (SpA). The SKG mice were injected with curdlan two times at 2-week intervals and were divided into two groups; one exposed to cigarette smoke and the other not exposed. We found that the α7 nAChR + cells increased in the joint tissue of curdlan-administered SKG mice compared to in the wild type. Furthermore, the peripheral arthritis scores and histological scores for synovial inflammation were lower in smoke-exposed curdlan-administered SKG mice than in mice not exposed to smoke. Immunofluorescence staining of the α7 nAChR + and IL-17A + cells was lower in the synovia of smoke-exposed mice than the control mice. The proportions of α7 nAChR + IL-17A + and α7 nAChR + IL-17A + FOXP3 + cells also decreased in the synovia of smoke-exposed mice compared with the controls. We observed an increase in the α7 nAChR + cells within the joint tissue of curdlan-administered SKG mice and that cigarette smoke had an influence on both peripheral arthritis and immune cell population, especially α7 nAChR + cells. Thus, exposure to cigarette smoke after arthritogenic stimuli may have an anti-arthritogenic effect in curdlan-administered SKG mice.

Objective: To investigate neurofilament light chain (NfL), phosphorylated tau (p-Tau) and total tau (t-Tau) as plasma markers for clinical severity in Korean Huntington's disease (HD) cohort., Methods: Genetically-confirmed 67 HD patients participated from 13 referral hospitals in South Korea. The subjects were evaluated with the Unified Huntington's Disease Rating Scale (UHDRS), total motor score (TMS) and total functional capacity (TFC), Mini-Mental Status Examination (K-MMSE), Montreal Cognitive Assessment (MoCA-K), and Beck's depression inventory (K-BDI). We measured plasma NfL, p-Tau and t-Tau concentrations using single-molecule array (SIMOA) assays. Stages of HD were classified based on UHDRS-TFC score and plasma markers were analyzed for correlation with clinical severity scales., Results: Plasma NfL was elevated in both 6 premanifest and 61 full manifest HD patients compared to the reference value, which increased further from premanifest to manifest HD groups. The NfL level was not significantly correlated with UHDRS TMS or TFC scores in manifest HD patients. Plasma p-Tau was also elevated in HD patients (p = 0.038). The level was the highest in stage III-V HD (n = 30) group (post-hoc p < 0.05). The p-Tau was correlated with UHDRS TFC scores (adjusted p = 0.002). Plasma t-Tau neither differed among the groups nor associated with any clinical variables., Conclusions: This study supports plasma NfL being a biomarker for initial HD manifestation in Korean cohort, and a novel suggestion of plasma p-Tau as a potential biomarker reflecting the clinical severity in full-manifest HD., Competing Interests: Declaration of Competing Interest Authors declare that there is no conflict of interest in this work., (Copyright © 2023. Published by Elsevier B.V.)

Background: To evaluate the usefulness of urine SERPINC1 and ORM1 as biomarkers for early detection of lupus nephritis (LN)., Methods: Using proteomics, we screened for potential urine biomarkers that differentiate LN from systemic lupus erythematosus (SLE) patients without nephritis. In addition, urine levels of target biomarkers were measured by ELISA in 13- and 23-week-old MRL-lpr (murine model for LN) and MRL/MpJ mice. Histological analysis was also performed on the kidneys of 23-week-old mice., Results: Urine SERPINC1 and ORM1 were elevated in SLE patients with newly diagnosed LN compared with SLE patients without LN (SERPINC1, AUC=.892, P<.001; ORM1, AUC=.886, P<.001). Levels of urine SERPINC1 and ORM1 were also significantly higher in MRL-lpr mice than in MRL/MpJ mice at 13 and 23 weeks (SERPINC1: p<.01 and p<.001 at 13 and 23 weeks, respectively; ORM1: p<.01 at 13 and 23 weeks). In contrast, a significant difference in urine albumin between the two groups was only observed at 23 weeks (p<.001) not at 13 weeks (p=.83). Regarding the kidney pathology of MPL-lpr mice, urine ORM1 and urine albumin, but not urine SERPINC1, were positively correlated with the activity index (ORM1, rho =.879, p<.001; albumin, rho =.807, p=.003) and chronicity index (ORM1, rho =.947, p<.001; albumin, rho =.869, p<.001)., Conclusion: We propose that urine SERPINC1 and ORM1 are novel biomarkers for early LN., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kim, Lee, Kim, Kim, Jeong, Yu, Hong, Lee, Yoo and Kim.)

Objectives: The risk of severe COVID-19 in children with a solid organ transplant (SOT) is not well established. We compare the relative risk of severe COVID-19 infection between pediatric SOT and non-SOT children., Methods: The newly constructed K-COV-N cohort (Korea Disease Control and Prevention Agency-COVID-19-National Health Insurance Service) was used. Children with COVID-19 (<18 years old) who underwent SOT between January 2008 to January 2022 were included. Non-SOT children with COVID-19 were selected in a ratio of 1:4 using propensity score matching. Three definitions of severe COVID-19 were established based on their requirement for respiratory support: severe I (requiring respiratory support above a high-flow nasal cannula or prolonged hospitalization ≥6 days), severe II (requiring any oxygen supplement), and severe III (requiring any oxygen supplement or prolonged hospitalization ≥6 days)., Results: Among 2,957,323 children with COVID-19, 206 pediatric SOT recipients (SOTRs) were identified and included in the analysis along with 803 matched non-SOT children. Most infections (96.6%) occurred during the Omicron period; no cases of mortality were reported. Pediatric SOTR had a 3.6-fold (95% confidence interval = 1.1-11.7, P = 0.03) higher risk of severe I, and a 4.9-fold (95% confidence interval = 1.6-15.0, P = 0.006) higher risk of severe III than non-SOT children. No cases of severe II occurred in the non-SOT children. Although not statistically significant, no severe COVID-19 cases were reported in the vaccinated SOT group (0.0% vs 5.7%, P = 0.09 in severe III)., Conclusion: Pediatric SOTRs have a significantly higher risk of severe COVID-19 than non-SOT children. Our findings support the need for tailored strategies for these high-risk children., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Magnesium aminoclay nanoparticles (MgANs) exert opposing effects on photosynthetic microalgae by promoting carbon dioxide (CO 2 ) uptake and inducing oxidative stress. This study explored the potential application of MgAN in the production of algal lipids under high CO 2 concentrations. The impact of MgAN (0.05-1.0 g/L) on cell growth, lipid accumulation, and solvent extractability varied among three tested oleaginous Chlorella strains (N113, KR-1, and M082). Among them, only KR-1 exhibited significant improvement in both total lipid content (379.4 mg/g cell) and hexane lipid extraction efficiency (54.5%) in the presence of MgAN compared to those of controls (320.3 mg/g cell and 46.1%, respectively). This improvement was attributed to the increased biosynthesis of triacylglycerols and a thinner cell wall based on thin-layer chromatography and electronic microscopy, respectively. These findings suggest that using MgAN with robust algal strains can enhance the efficiency of cost-intensive extraction processes while simultaneously increasing the algal lipid content., 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 Ltd. All rights reserved.)

Background: The decoction form of herbal medicine (D-HM) is mainly prescribed to patients with allergic rhinitis (AR) in Korean Medicine (KM) clinics in the Republic of Korea; however, it is difficult to conduct clinical trials of D-HM due to regulatory issues. This study investigated the clinical safety and effectiveness of D-HM combination therapy for the treatment of AR by analyzing the AR outpatient data from 17 KM clinics., Methods: This retrospective cohort study included patients who visited KM clinics for AR treatment from January 1, 2021, to March 31, 2022. Cases were collated using structured case report forms and divided into the D-HM with KM usual care group (D-HM group) and the KM usual care group (UC group). Since D-HM therapy could not be randomly assigned to the study population, we used optimal propensity score (PS) matching to investigate the effectiveness and safety of D-HM combination therapy in the treatment of AR., Results: Data from 228 patients were collected. After PS matching, 144 patients were finally analyzed. The total nasal symptom score (TNSS) and mini-rhinoconjunctivitis quality of life questionnaire (mini-RQLQ) were significantly improved in the D-HM group compared with those in the UC group (TNSS: p=0.02; mini-RQLQ: p=0.04). Four patients in the D-HM group experienced minor adverse events that were mild and resolved within 15 days., Conclusions: D-HM combination therapy may be beneficial in the management of symptoms and rhinitis-associated quality of life and potentially useful in clinical practice. However, randomized placebo-controlled clinical trials are required to confirm their effectiveness., Study Registration: This study has been registered at Clinical Research Information Service (KCT0007242)., (© 2023 Korea Institute of Oriental Medicine. Published by Elsevier B.V.)

Background: Immunoproteasome, a part of ubiquitin-proteasome system, is involved in immune response as well as protein degradation. However, the relationship between immunoproteasome and Parkinson's disease (PD) was not evaluated clearly. We hypothesized that the shift of immunoproteasome attributes to PD pathogenesis due to its role in inflammation and protein homeostasis., Objective: To determine whether immunoproteasome in peripheral blood mononuclear cells (PBMC) and brain is expressed differently between patients with PD and healthy controls (HC)., Methods: Blood samples were collected from 19 HC to 40 patients with PD of comparable ages. Peripheral blood mononuclear cells were isolated and followed by RT-qPCR to measure the mRNA levels of three catalytic subunits of immunoproteasome, namely, PSMB8, PSMB9, and PSMB10. Then, the protein levels of each subunit were measured by western blot. Finally, we confirmed the altered immunoproteasome subunit in the post-mortem human brain of PD., Results: In PBMCs, PSMB8 mRNA expression of PD group significantly increased compared to HC (p = 0.004), whereas PSMB9 and PSMB10 mRNA were not different between the PD and HC. The ratio of PSMB10 and PSMB8 mRNA (PSMB10/8 ratio) also reflected the significant difference between the PD and HC (p = 0.002). The PSMB10/8 ratio was well correlated with the UPDRS total and Part III score in the early stage of PD (Hoehn and Yahr ≤2.5) or drug-naïve PD subgroups. In terms of the protein level of immunoproteasome subunits in PBMCs, the increase of PSMB8 protein was observed in PD compared to HC (p = 0.0009), while PSMB9 and PSMB10 were not different between groups. Finally, we confirmed that immunoproteasome PSMB8 was expressed abundantly in the postmortem PD brain compared with normal control., Conclusion: Our novel findings implicate that immunoproteasome PSMB8 is engaged in PD pathomechanism., Competing Interests: Declaration of competing interest All authors declare no competing non-financial or financial interests., (Copyright © 2023. Published by Elsevier Ltd.)

The pediatric population with comorbidities is a high-risk group for severe coronavirus disease 2019 (COVID-19). As of January 2023, the COVID-19 vaccination rate for at least two doses among Korean children 5-11 years is low at 1.1%. We summarized the COVID-19 vaccination status for the pediatric population (5-17 years) with comorbidities through July 2022 using the National Health Insurance Service database. Pediatric patients with comorbidities had higher vaccination rates than the general pediatric population (2.4% vs. 1.1% in 5-11-year-olds [ P < 0.001], 76.5% vs. 66.1% in 12-17-year-olds [ P < 0.001]). However, there were substantial differences according to comorbidity category, and the 2-dose vaccination rate was lowest among children with immunodeficiency in all age groups (1.1% in 5-11-year-olds, 51.2% in 12-17-year-olds). The COVID-19 vaccination rate among Korean children has remained stagnant at a low proportion despite ongoing outreach. Thus, more proactive strategies are needed alongside continuous surveillance., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Microglia plays a key role in determining the progression of amyotrophic lateral sclerosis (ALS), yet their precise role in ALS has not been identified in humans. This study aimed to identify a key factor related to the functional characteristics of microglia in rapidly progressing sporadic ALS patients using the induced microglia model, although it is not identical to brain resident microglia. After confirming that microglia-like cells (iMGs) induced by human monocytes could recapitulate the main signatures of brain microglia, step-by-step comparative studies were conducted to delineate functional differences using iMGs from patients with slowly progressive ALS [ALS(S), n = 14] versus rapidly progressive ALS [ALS(R), n = 15]. Despite an absence of significant differences in the expression of microglial homeostatic genes, ALS(R)-iMGs preferentially showed defective phagocytosis and an exaggerated pro-inflammatory response to LPS stimuli compared to ALS(S)-iMGs. Transcriptome analysis revealed that the perturbed phagocytosis seen in ALS(R)-iMGs was closely associated with decreased NCKAP1 (NCK-associated protein 1)-mediated abnormal actin polymerization. NCKAP1 overexpression was sufficient to rescue impaired phagocytosis in ALS(R)-iMGs. Post-hoc analysis indicated that decreased NCKAP1 expression in iMGs was correlated with the progression of ALS. Our data suggest that microglial NCKAP1 may be an alternative therapeutic target in rapidly progressive sporadic ALS., (© 2023. The Author(s).)

Objectives: Disability weights require regular updates, as they are influenced by both diseases and societal perceptions. Consequently, it is necessary to develop an up-to-date list of the causes of diseases and establish a survey panel for estimating disability weights. Accordingly, this study was conducted to calculate, assess, modify, and validate disability weights suitable for Korea, accounting for its cultural and social characteristics., Methods: The 380 causes of disease used in the survey were derived from the 2019 Global Burden of Disease Collaborative Network and from 2019 and 2020 Korean studies on disability weights for causes of disease. Disability weights were reanalyzed by integrating the findings of an earlier survey on disability weights in Korea with those of the additional survey conducted in this study. The responses were transformed into paired comparisons and analyzed using probit regression analysis. Coefficients for the causes of disease were converted into predicted probabilities, and disability weights in 2 models (model 1 and 2) were rescaled using a normal distribution and the natural logarithm, respectively., Results: The mean values for the 380 causes of disease in models 1 and 2 were 0.488 and 0.369, respectively. Both models exhibited the same order of disability weights. The disability weights for the 300 causes of disease present in both the current and 2019 studies demonstrated a Pearson correlation coefficient of 0.994 (p=0.001 for both models). This study presents a detailed add-on approach for calculating disability weights., Conclusions: This method can be employed in other countries to obtain timely disability weight estimations.