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The long-tailed goral, Naemorhedus caudatus (Mammalia: Bovidae), is one of the endangered animals in the Republic of Korea (Korea). Sarcoptic mange mites infested in diverse species of mammals, including humans, but no case has been reported in long-tailed gorals. We report 2 cases of mange mite, Sarcoptes scabiei, infestation in long-tailed gorals. Mange mites were sampled in the skin legions of the 2 long-tailed gorals, which were rescued in 2 different regions, Uljin-gun, Gyeongsangbuk-do and Cheorwon-gun, Gangwon-do, Korea. Our results showed that the ectoparasite was the itch mite that burrowed into skin and caused scabies on the morphological inspection and placed within the phylogenetic relations of the species. The present study confirmed for the first time in Korea that mange mites are pathogenic scabies of long-tailed goral. Closer surveillance of this pathogenic ectoparasite in zoonotic and infectious ecosystems is warranted.

BackgroundImmune-evading severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are emerging continuously. The clinical effectiveness of monoclonal antibody agents that exhibit decreased in vitro activity against SARS-CoV-2 variants needs to be elucidated.MethodsA nationwide, multicenter, retrospective cohort study was designed to evaluate the effectiveness of regdanvimab, an anti-SARS-CoV-2 monoclonal antibody agent. Regdanvimab was prescribed in South Korea before and after the emergence of the delta variant, against which the in vitro activity of regdanvimab was decreased but present. Mild to moderate coronavirus 2019 (COVID-19) patients with risk factors for disease progression who were admitted within seven days of symptom onset were screened in four designated hospitals between December 2020 and September 2021. The primary outcomes, O2 requirements and progression to severe disease within 21 days of admission, were compared between the regdanvimab and supportive care groups, with a subgroup analysis of delta variant–confirmed patients.ResultsA total of 2,214 mild to moderate COVID-19 patients were included, of whom 1,095 (49.5%) received regdanvimab treatment. In the analysis of the total cohort, significantly fewer patients in the regdanvimab group than the supportive care group required O2 support (18.4% vs. 27.1%, P < 0.001) and progressed to severe disease (4.0% vs. 8.0%, P < 0.001). In the multivariable analysis, regdanvimab was significantly associated with a decreased risk for O2 support (HR 0.677, 95% CI 0.561–0.816) and progression to severe disease (HR 0.489, 95% CI 0.337–0.709). Among the 939 delta-confirmed patients, O2 support (21.5% vs. 23.5%, P = 0.526) and progression to severe disease (4.2% vs. 7.3%, P = 0.055) did not differ significantly between the regdanvimab and supportive care groups. In the multivariable analyses, regdanvimab treatment was not significantly associated with a decreased risk for O2 support (HR 0.963, 95% CI 0.697–1.329) or progression to severe disease (HR 0.665, 95% CI 0.349–1.268) in delta-confirmed group.ConclusionsRegdanvimab treatment effectively reduced progression to severe disease in the overall study population, but did not show significant effectiveness in the delta-confirmed patients. The effectiveness of dose increment of monoclonal antibody agents should be evaluated for variant strains exhibiting reduced susceptibility.

Stress management is necessary for vertebrate survival. Chronic stress drives depression by excitation of the lateral habenula (LHb), which silences dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neuronal projection from the rostromedial tegmental nucleus (RMTg). However, the effect of acute stress on this LHb-RMTg-VTA pathway is not clearly understood. Here, we used fluorescent in situ hybridisation and in vivo electrophysiology in mice to show that LHb aromatic l-amino acid decarboxylase-expressing neurons (D-neurons) are activated by acute stressors and suppress RMTg GABAergic neurons via trace aminergic signalling, thus activating VTA dopaminergic neurons. We show that the LHb regulates RMTg GABAergic neurons biphasically under acute stress. This study, carried out on male mice, has elucidated a molecular mechanism in the efferent LHb-RMTg-VTA pathway whereby trace aminergic signalling enables the brain to manage acute stress by preventing the hypoactivity of VTA dopaminergic neurons.

Although several antiviral agents have become available for coronavirus disease 2019 (COVID-19) treatment, oral drugs are still limited. Camostat mesylate, an orally bioavailable serine protease inhibitor, has been used to treat chronic pancreatitis in South Korea, and it has an in vitro inhibitory potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Background Children's motor development is a crucial tool for assessing developmental levels, identifying developmental disorders early, and taking appropriate action. Although the Korean Developmental Screening Test for Infants and Children (K-DST) can accurately assess childhood development, its dependence on parental surveys rather than reliable, professional observation limits it. This study constructed a dataset based on a skeleton of recordings of K-DST behaviors in children aged between 20 and 71 months, with and without developmental disorders. The dataset was validated using a child behavior artificial intelligence (AI) learning model to highlight its possibilities. Results The 339 participating children were divided into 3 groups by age. We collected videos of 4 behaviors by age group from 3 different angles and extracted skeletons from them. The raw data were used to annotate labels for each image, denoting whether each child performed the behavior properly. Behaviors were selected from the K-DST's gross motor section. The number of images collected differed by age group. The original dataset underwent additional processing to improve its quality. Finally, we confirmed that our dataset can be used in the AI model with 93.94%, 87.50%, and 96.31% test accuracy for the 3 age groups in an action recognition model. Additionally, the models trained with data including multiple views showed the best performance. Conclusion Ours is the first publicly available dataset that constitutes skeleton-based action recognition in young children according to the standardized criteria (K-DST). This dataset will enable the development of various models for developmental tests and screenings.

Background Antibiotic resistance threatens public health worldwide, and inappropriate use of antibiotics is one of the main causes. Antibiotic use for asymptomatic bacteriuria (ABU) has been defined as “antibiotics never events”, and urinary tract infection (UTI) is one of the most common infectious diseases for which antibiotics are prescribed in Korea. To establish an effective antimicrobial stewardship strategy, a qualitative assessment of antibiotic use in actual clinical syndrome is necessary. Methods Cases of positive urine cultures (≥105 CFU/ml), performed in inpatient, outpatient, and emergency departments in April 2021 were screened in 26 hospitals located throughout Korea. Cases were classified into ABU, lower UTI, and upper UTI. The appropriateness of antibiotic use was retrospectively evaluated by infectious disease specialists using quality indicators based on the domestic clinical guideline for ABU and UTI. Figure 1.Study flow diagram Results A total of 2697 cases of ABU or UTI were included. The appropriateness of antibiotic use was assessed in 1157 cases with asymptomatic bacteriuria, 677 and 863 cases with lower and upper UTI (Figure 1). Antibiotics were prescribed in 21.7% (251 of 1157) of ABU without appropriate indication. Of 66 ABU cases with appropriate indication in which prophylactic antibiotics were prescribed, the duration of antibiotics was adequate in only 34.8% (Table 1). For lower UTI, the appropriateness of empirical and definite antibiotics was 77.8% (527 of 677) and 68.0% (353 of 519). In terms of upper UTI, 86.3% (745 of 863) and 78.2% (583 of 746) was appropriate, respectively. The duration of antibiotics was adequate in 65.7% (421 of 641) of lower UTI and 77.9% (592 of 760) in upper UTI (Table 2, 3). Conclusion This nationwide qualitative assessment of antibiotic use in ABU and UTI revealed that a significant proportion of antibiotics were prescribed inappropriately and, furthermore the duration of antibiotics was prolonged unnecessarily. Interventions for appropriate antibiotic use in ABU and UTI at the national level are required. Disclosures All Authors: No reported disclosures.

PURPOSE: Neutralizing antibodies can reduce SARS-CoV-2 cellular entry, viral titers, and pathologic damage. CT-P59 (regdanvimab), a SARS-CoV-2 neutralizing monoclonal antibody, was examined in 2 randomized, double-blind, placebo-controlled, single ascending dose, Phase I studies. METHODS: In study 1.1, healthy adults were sequentially enrolled to receive CT-P59 10, 20, 40, or 80 mg/kg or placebo. In study 1.2, adult patients with mild SARS-CoV-2 infection were enrolled to receive CT-P59 20, 40, or 80 mg/kg or placebo. Primary objectives of both studies were safety and tolerability up to day 14 after infusion. Secondary end points included pharmacokinetic properties. Study 1.2 also measured virology and clinical efficacy. FINDINGS: Thirty-two individuals were randomized to study 1.1 (6 per CT-P59 dose cohort and 8 in the placebo cohort). By day 14 after infusion, adverse events (AEs) were reported in 2 individuals receiving CT-P59 20 mg/kg (headache and elevated C-reactive protein levels) and 1 receiving CT-P59 40 mg/kg (pyrexia) (all Common Terminology Criteria for Adverse Events grade 1). In study 1.2, 18 patients were randomized (5 per dose cohort and 3 in the placebo cohort). Sixteen AEs were reported in 10 patients receiving CT-P59. No AEs in either study led to study discontinuation. Greater reductions in viral titers were reported with CT-P59 than placebo in those with maximum titers >105 copies/mL. Mean time to recovery was 3.39 versus 5.25 days. IMPLICATIONS: CT-P59 exhibited a promising safety profile in healthy individuals and patients with mild SARS-CoV-2 infection, with potential antiviral and clinical efficacy in patients with mild SARS-CoV-2 infection. ClinicalTrials.gov identifier: NCT04525079 (study 1.1) and NCT04593641 (study 1.2).

The vascular complications have been a major cause of morbidity and mortality among all subtypes of BCR-ABL1 negative myeloproliferative neoplasms (MPN), but the ethnicity-specific data was limited. We therefore conducted a multi-center retrospective, longitudinal cohort study to evaluate the incidence, characteristics and risk factors of thromboembolic events of MPN patients. Of 256 patients, 27.3% experienced thromboembolic events, majority of which occurred before or within 12 months of MPN diagnosis. The multivariable Cox proportional analyses identified leukocytosis (HR 2.67, 95% CI 1.36–5.24, q = 0.004) and history of thrombosis (HR 9.68, 95% CI 2.00–46.88, q = 0.005) as the risk factors for thromboembolism. In subgroup analysis of polycythemia vera and hemoglobin concentration (HR 1.97, 95% CI 1.28–3.04, q = 0.002) appeared to be a significant risk factor of thrombosis, along with age and thrombosis history. In essential thrombocythemia, severity of the established IPSET score was closely correlated with the frequency of thromboembolic events. In primary myelofibrosis, history of thrombosis was associated with thrombosis events (HR 13.85, 95% CI 1.2–159.5, q = 0.035). Overall survival was worse in patients who experienced thromboembolic events. Our study highlighted the importance of recognizing high risk patients and implementing personalized intervention.

This study introduces the thickness-tapered channel design for flow field-flow fractionation (FlFFF) for the first time. In this design, the channel thickness linearly decreases along the channel axis such that the flow velocity increases down the channel. Channel thickness is an important variable for controlling retention time and resolution in field-flow fractionation. Especially, in the steric/hyperlayer mode of FlFFF, in which particles (1 μm) migrate at elevated heights above the channel wall owing to hydrodynamic lift forces, the migration of long-retaining smaller-sized particles can be enhanced in a relatively thin channel or by increasing the migration flow rate; however, an upper size limit that can be resolved is simultaneously sacrificed. A thickness-tapered channel was constructed without a channel spacer by carving the surface of a channel block such that the channel inlet was deeper than the outlet (

Interspecific hybridization occurs among birds, and closely related sister taxa tend to hybridize at a high rate. Genomic hybridization markers are useful for understanding the patterns and processes of hybridization and for conserving endangered species in captivity and the wild. In this study, we developed genomic hybridization markers for the F1 progeny of the sister taxa feral pigeons (Columba livia var. domestica) and endangered hill pigeons (Columba rupestris) (family Columbidae). Using whole-genome re-sequencing data, we performed genome-wide analysis for insertion/deletion (InDel) polymorphisms and validated using primers. We conducted polymerase chain reaction (PCR) and agarose gel electrophoresis to identify species-specific InDels. We produced eight F1 hybrids of hill and feral pigeons, and their samples were tested by re-performing analyses and sequencing using 11 species-specific InDel polymorphisms. Eight InDel markers simultaneously amplified two DNA fragments from all F1 hybrids, and there was no abnormality in the sequencing results. The application of genomic tools to detect hybrids can play a crucial role in the assessment of hybridization frequency in the wild. Moreover, systematic captive propagation efforts with hybrids can help control the population decline of hill pigeons.

Graphene oxide (GO)-a chemical derivative of graphene with numerous oxygen functional groups on its surface-has attracted considerable interest because of its intriguing properties in relation to those of pristine graphene. In addition to the inherent wide lateral size distribution of GO sheets arising from the typical oxidative exfoliation of graphite, control of the lateral size of GO is critical for desired GO-based applications. Herein, flow/hyperlayer field-flow fractionation (flow/hyperlayer FFF) is optimized to separate GO sheets by lateral dimensions. Optimized fractionation is achieved by investigating the influences of carrier solvent, channel thickness, and flow rate conditions on the steric/hyperlayer separation of GO sheets by flow FFF. Due to the strong hydrodynamic lift forces of extremely thin GO sheets, a thick flow FFF channel (w = 350 μm) and a very low field strength are required to retain the GO sheets within the channel. GO sheets with narrow size fractions are successfully collected from two different graphite sources during flow/hyperlayer FFF runs and are examined to verify the size evolution. Considering the average lateral diameter of the GO fraction calculated on the basis of the assumption of a circular disk shape, the retention of the GO sheets is 2.2-5.0 times faster than that of spherical particles of the same diameter. This study demonstrates that through flow/hyperlayer FFF, the size distribution of GO sheets can be determined and narrow size fractions can be collected (which is desirable for GO-based applications), which are commonly influenced by the GO lateral dimension.

Objectives The optimal treatment option for carbapenem-resistant Acinetobacter baumannii (CRAB) is still limited. This study investigated the efficacy of three or more antibiotic types and regimens for treatment of CRAB infection in high CRAB endemic areas. Methods A multicentre retrospective study was conducted to evaluate the efficacy of treatment types and regimens of CRAB infections in 10 tertiary hospitals in the Republic of Korea. The outcomes comprised 7-day and 28-day mortality, and clinical and microbiological responses at 7 days, 28 days, and the end of treatment. Nephrotoxicity and hepatotoxicity were evaluated as drug adverse reactions. Results A total of 282 patients were included in the study. Among the CRAB strains, the two most susceptible antibiotics were colistin (99.6%) and minocycline (80.4%). A combination of colistin and carbapenem significantly reduced 7-day mortality, and a sulbactam-containing regimen significantly reduced 28-day mortality. Colistin monotherapy was significantly associated with increased 7-day and 28-day mortality. A minocycline-containing regimen showed the best microbiological responses at 7 days, 28 days, and the end of treatment. Colistin and tigecycline were associated with increased nephrotoxicity and hepatotoxicity, respectively. Subgroup analysis of patients with pneumonia showed similar results to the overall CRAB infection. Conclusions A combination of colistin and carbapenem and sulbactam-containing regimen may contribute improved mortality in CRAB infections. Colistin monotherapy should be considered cautiously in severe CRAB infections or CRAB pneumonia. A minocycline-containing regimen showed the best microbiological responses, and further studies may be needed to evaluate improved mortality.

In recent years, the demand for medium and large secondary batteries in EV (electric vehicle) and ESS (energy storage systems) applications has been rapidly increasing worldwide, and accordingly, the market size is increasing exponentially. However, the recent fire accidents related to secondary batteries for EVs and ESS are having a negative impact on the battery market. Therefore, this paper implements an accident simulation device to perform an external short-circuit test, one of the typical safety tests for NMC-series prismatic and pouch-type batteries that are widely used among battery cells used in medium and large secondary batteries. The implemented accident simulation device for the external short-circuit test is composed of short-circuit resistance, measuring device, control device, etc., and is configured to analyze external short-circuit characteristics according to various test conditions. Based on this, an external short-circuit test according to the type, short-circuit resistance and SOC (states of charge) of the lithium-ion battery was performed to confirm the current and temperature characteristics according to each condition. As a result of performing an external short-circuit test for each protection device in the battery module and preprocessing temperature, it is certain that the module fuse operates over 120 times faster than the cell fuse based on the same SOC conditions, and the quantity of electric charge in the module fuse is over 110 times smaller than of the cell fuse in the case of a short-circuit fault. It is also found that the highest and lowest preprocessing temperatures are considered to be severe conditions. Based on the proposed mechanism of an external short circuit in a Li-ion battery and the test device for the external short circuit, it is confirmed that this paper can contribute to the safety assessment of Li-ion battery-based ESS.

Many interesting properties of 2D materials and their assembled structures are strongly dependent on the lateral size and size distribution of 2D materials. Accordingly, effective size separation of polydisperse 2D sheets is critical for desirable applications. Here, we introduce flow field-flow fractionation (FlFFF) for a wide-range size fractionation of graphene oxide (GO) up to 100 μm. Two different separation mechanisms are identified for FlFFF, including normal mode and steric/hyperlayer mode, to size fractionate wide size-distributed GOs while employing a crossflow field for either diffusion or size-controlled migration of GO. Obviously, the 2D GO sheet reveals size separation behavior distinctive from typical spherical particles arising from its innate planar geometry. We also investigate 2D sheet size-dependent mechanical and electrical properties of three different graphene fibers produced from size-fractionated GOs. This FlFFF-based size selection methodology can be used as a generic approach for effective wide-range size separation for 2D materials, including rGO, TMDs, and MXene.

Allogeneic stem cell transplantation is a curative immunotherapy where patients receive myeloablative chemotherapy and/or radiotherapy, followed by donor stem cell transplantation. Graft versus host disease (GVHD) is a major complication caused by dysregulated donor immune system, thus a novel strategy to modulate donor immunity is needed to mitigate GVHD. Tissue damage by conditioning regimen is thought to initiate the inflammatory milieu that recruits various donor immune cells for cross-priming of donor T cells against alloantigen and eventually promote strong Th1 cytokine storm escalating further tissue damage. Bilirubin nanoparticles (BRNP) are water-soluble conjugated of bilirubin and polyethylene glycol (PEG) with potent anti-inflammatory properties through its ability to scavenge reactive oxygen species generated at the site of inflammation. Here, we evaluated whether BRNP treatment post-transplantation can reduce initial inflammation and subsequently prevent GVHD in a major histocompatibility (MHC) mismatched murine GVHD model. After myeloablative irradiation, BALB/c mice received bone marrow and splenocytes isolated from C57BL/6 mice, with or without BRNP (10 mg/kg) daily on days 0 through 4 post-transplantation, and clinical GVHD and survival was monitored for 90 days. First, BRNP treatment significantly improved clinical GVHD score compared to untreated mice (3.4 vs 0.3, p=0.0003), and this translated into better overall survival (HR 0.0638, p=0.0003). Further, BRNPs showed a preferential accumulation in GVHD target organs leading to a reduced systemic and local inflammation evidenced by lower pathologic GVHD severity as well as circulating inflammatory cytokines such as IFN-γ. Lastly, BRNP treatment post-transplantation facilitated the reconstitution of CD4+ iNK T cells and reduced expansion of proinflammatory CD8α+ iNK T cells and neutrophils especially in GVHD organs. Lastly, BRNP treatment decreased ICOS+ or CTLA-4+ T cells but not PD-1+ T cells suggesting a decreased level of T cell activation but maintaining T cell tolerance. In conclusion, we demonstrated that BRNP treatment post-transplantation ameliorates murine GVHD via diminishing the initial tissue damage and subsequent inflammatory responses from immune subsets.

Background We evaluated clinical effectiveness of regdanvimab (CT-P59), a severe acute respiratory syndrome coronavirus 2 neutralizing monoclonal antibody, in reducing disease progression and clinical recovery time in patients with mild-to-moderate coronavirus disease 2019 (COVID-19), primarily Alpha variant. Methods This was phase 3 of a phase 2/3 parallel-group, double-blind, randomized clinical trial. Outpatients with mild-to-moderate COVID-19 were randomized to single-dose regdanvimab 40 mg/kg (n = 656) or placebo (n = 659), alongside standard of care. The primary endpoint was COVID-19 disease progression up to day 28 among “high-risk” patients. Key secondary endpoints were disease progression (all randomized patients) and time to recovery (high-risk and all randomized patients). Results Of 1315 randomized patients, 880 were high risk; the majority were infected with Alpha variant. The proportion with disease progression was lower (14/446, 3.1% [95% confidence interval {CI}, 1.9%–5.2%] vs 48/434, 11.1% [95% CI, 8.4%–14.4%]; P Conclusions Regdanvimab was an effective treatment for patients with mild-to-moderate COVID-19, significantly reducing disease progression and clinical recovery time without notable safety concerns prior to the emergence of the Omicron variant. Clinical Trials Registration NCT04602000; 2020-003369-20 (EudraCT).

Background Many patients with ulcerative colitis (UC) in clinical remission frequently complain of bowel symptoms such as increased stool frequency (SF) and rectal bleeding (RB). However, studies on these patient-reported outcomes in patients with inactive UC are limited, especially in Korea. Therefore, we investigated the prevalence and risk factors of bowel symptoms in Korean patients with inactive UC. Methods We investigated the prevalence of bowel symptoms in patients with endoscopically quiescent UC between June 1989 and December 2016 using a well-characterized referral center-based cohort. The Mayo clinic score (MCS) was used to evaluate bowel symptoms at the most recent visit near the date of endoscopy. Clinical characteristics of the patients were compared based on the presence or absence of bowel symptoms. Results Overall, 741 patients with endoscopically quiescent UC were identified, of whom 222 (30%) and 48 (6.5%) had an SF and RB subscore of ≥ 1, respectively. Patients with bowel symptoms (SF + RB ≥ 1; n = 244 [32.9%]) had higher rates of left-sided colitis (E2) or extensive colitis (E3) than patients without bowel symptoms (SF + RB = 0; n = 497 [67.1%]; P = 0.002). Multivariate analysis revealed that female sex (odds ratio [OR]: 1.568; 95% confidence interval [CI]: 1.023–2.402; P = 0.039) and E2 or E3 (OR 1.411; 95% CI 1.020–1.951; P = 0.038) were the significant risk factors for increased SF. Conclusions This study revealed that one-third of patients with endoscopically quiescent UC reported increased SF. Female sex and disease extent may be associated with bowel symptoms.

Objectives:We calculated the human resources required for an antimicrobial stewardship program (ASP) in Korean hospitals.Design:Multicenter retrospective study.Setting:Eight Korean hospitals ranging in size from 295 to 1,337 beds.Methods:The time required for performing ASP activities for all hospitalized patients under antibiotic therapy was estimated and converted into hours per week. The actual time spent on patient reviews of each ASP activity was measured with a small number of cases, then the total time was estimated by applying the determined times to a larger number of cases. Full-time equivalents (FTEs) were measured according to labor laws in Korea (52 hours per week).Results:In total, 225 cases were reviewed to measure time spent on patient reviews. The median time spent per patient review for ASP activities ranged from 10 to 16 minutes. The total time spent on the review for all hospitalized patients was estimated using the observed number of ASP activities for 1,534 patients who underwent antibiotic therapy on surveillance days. The most commonly observed ASP activity was ‘review of surgical prophylactic antibiotics’ (32.7%), followed by ‘appropriate antibiotics recommendations for patients with suspected infection without a proven site of infection but without causative pathogens’ (28.6%). The personnel requirement was calculated as 1.20 FTEs (interquartile range [IQR], 1.02–1.38) per 100 beds and 2.28 FTEs (IQR, 1.93–2.62) per 100 patients who underwent antibiotic therapy, respectively.Conclusion:The estimated time required for human resources performing extensive ASP activities on all hospitalized patients undergoing antibiotic therapy in Korean hospitals was ~1.20 FTEs (IQR, 1.02–1.38) per 100 beds.

Recent observations showed that boreal winter exhibits significant cooling events in the Eurasian and North American continents despite the global warming trend. To better understand the boreal winter surface air temperature (SAT) variability and its physical characteristics, we investigated the three distinct Empirical Orthogonal Function (EOF) modes of the extratropical 2-m air temperature (T2m) variation and found that each mode can be related to the well-known physical processes: The first mode is characterized by the coherent change of wintertime SAT anomalies over northern Eurasia and central-eastern North America and it is found that snow cover variation in the Eurasian region can modulate Arctic Oscillation (AO) circulation through the troposphere–stratosphere interaction, which can affect wintertime SAT in the two continents. The second leading mode shows warm anomalies over the North Pacific especially around the Bering Strait and cold anomalies over most of Canada and the central part of North America. Associated with this mode, La Nina-like sea surface temperature (SST) anomaly can modulate the North American SAT variability through the generation of the tropospheric Pacific–North American (PNA) teleconnection pattern. The third mode represents warm anomalies over the Barents and Kara (B–K) seas and cold anomalies over East Asia. Sea ice loss over the B–K sea is analyzed to be closely related to the SAT variability over the East Asian region.

Carbon dioxide is widely used for a variety of purposes. As it is a normal constituent of air, the public generally regards it as safe. Although low concentrations of carbon dioxide are not harmful to human beings, high concentrations are toxic, and can cause serious harm, including cardiac arrest. Only a limited number of cases of carbon dioxide intoxication have been reported in Korea, and they have all been mild, with no cases of cardiac arrest following acute exposure to high concentrations of carbon dioxide, reported previously. We describe a case of carbon dioxide poisoning following an explosion of a carbon dioxide tank, which led to cardiac arrest in a 66-year-old patient. This cardiac arrest could have been avoided if the patient was fully aware of the hazardous effects and serious consequences of exposure to high concentrations of carbon dioxide.

OBJECTIVE Genetic variants of the cytoplasmic FMR1-interacting protein 2 (CYFIP2) encoding an actin-regulatory protein are associated with brain disorders, including intellectual disability and epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2-associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2+/- ) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2+/- mice and specified a neuronal function mediating its efficacy. METHODS We performed behavioral analyses of Cyfip2+/- mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses of Cyfip2+/- prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections. RESULTS Adult Cyfip2+/- mice exhibited lithium-responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2+/- PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2+/- mice showed increased seizure susceptibility and auditory steady-state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2+/- L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2+/- PFC. Virus-mediated reduction of CYFIP2 in the PFC was sufficient to induce L5 hyperexcitability and lithium-responsive abnormal behavior. INTERPRETATION These results suggest that L5-specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and the lithium-mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/- mice, which can be implicated in CYFIP2-associated brain disorders. ANN NEUROL 2020;88:526-543.

The dynamic nature of coronavirus disease 2019 (COVID-19) pandemic requires us to be efficient and flexible in resource utilization. The strategical preparedness and response actions of the healthcare system are the key component to contain COVID-19 and to decrease its case fatality ratio. Depending on the epidemiological situation, each medical institution should systematically share the responsibility for patient screening, disposition and treatment according to clinical severity. To overcome fast-paced COVID-19 pandemic, the government should be rapidly ready and primed for action according to the specific transmission scenario.

A modified endoscopic mucosal resection (EMR) technique, Tip-in EMR, was recently introduced to enhance the complete resection of colorectal neoplasia (CRN). We aimed to evaluate the feasibility of Tip-in EMR for flat CRNs. From January to September 2018, conventional or Tip-in EMR was consecutively performed for 112 flat CRNs ≥ 10 mm in diameter. Tip-in EMR was performed when en bloc snaring was impossible with conventional EMR or when a lesion was inadequately lifted owing to a previous forceps biopsy. We retrospectively collected the clinical, procedural, and histologic data of the conventional and Tip-in EMR groups and compared the en bloc resection rate, complete resection rate, and complications between the two groups. Among 112 flat CRNs of 80 patients, conventional EMR and Tip-in EMR were performed for 74 and 38 lesions, respectively. The median lesion size was 12 (10–27) mm. Tip-in EMR was superior to conventional EMR in terms of en bloc resection (94.7% vs. 77.0%, p = 0.018) and histologic complete resection (76.3% vs. 54.1%, p = 0.022). There was no difference in postprocedural bleeding between the two groups; however, overall adverse events, including bleeding and postpolypectomy electrocoagulation syndrome, were more frequent in the Tip-in EMR group. Tip-in EMR is a feasible technique for flat colorectal lesions ≥ 10 mm and is superior to conventional EMR with respect to en bloc and complete resection rates. The safety profiles of Tip-in EMR and conventional EMR should be compared via large-scale prospective studies.

Background and AimsCombined endoscopic and radiological healing, or deep healing, is associated with favourable outcomes in patients with Crohn’s disease; thus, a non-invasive biomarker for predicting deep healing would be invaluable. We evaluated the usefulness of faecal calprotectin for predicting deep healing in patients with Crohn’s disease receiving anti-tumour necrosis factor [TNF] therapy.MethodsWe analysed the records of patients with Crohn’s disease who received anti-tumour necrosis factor therapy and underwent endoscopic evaluation, radiological evaluation, and faecal calprotectin measurement within a period of 3 months between August 2017 and November 2018. Results of endoscopic and radiological studies were independently reviewed by two gastrointestinal endoscopists and a gastrointestinal radiologist, respectively. Serum C-reactive protein and albumin were also measured.ResultsOut of 268 patients analysed, 77 [28.7%] had deep healing, 36 [13.4%] had endoscopic healing only, 36 [13.4%] had radiological healing only, and 119 [44.4%] had neither. The median duration of anti-TNF treatment was 40.0 months. The deep healing group had the lowest median faecal calprotectin level [56.5 mg/kg] among the four groups [p ConclusionsFaecal calprotectin, when combined with serum C-reactive protein and albumin, showed acceptable performance in predicting deep healing in patients with Crohn’s disease.

We aimed to develop and validate the automatic quantification of coronavirus disease 2019 (COVID-19) pneumonia on computed tomography (CT) images.This retrospective study included 176 chest CT scans of 131 COVID-19 patients from 14 Korean and Chinese institutions from January 23 to March 15, 2020. Two experienced radiologists semiautomatically drew pneumonia masks on CT images to develop the 2D U-Net for segmenting pneumonia. External validation was performed using Japanese (n = 101), Italian (n = 99), Radiopaedia (n = 9), and Chinese data sets (n = 10). The primary measures for the system's performance were correlation coefficients for extent (%) and weight (g) of pneumonia in comparison with visual CT scores or human-derived segmentation. Multivariable logistic regression analyses were performed to evaluate the association of the extent and weight with symptoms in the Japanese data set and composite outcome (respiratory failure and death) in the Spanish data set (n = 115).In the internal test data set, the intraclass correlation coefficients between U-Net outputs and references for the extent and weight were 0.990 and 0.993. In the Japanese data set, the Pearson correlation coefficients between U-Net outputs and visual CT scores were 0.908 and 0.899. In the other external data sets, intraclass correlation coefficients were between 0.949-0.965 (extent) and between 0.978-0.993 (weight). Extent and weight in the top quartile were independently associated with symptoms (odds ratio, 5.523 and 10.561; P = 0.041 and 0.016) and the composite outcome (odds ratio, 9.365 and 7.085; P = 0.021 and P = 0.035).Automatically quantified CT extent and weight of COVID-19 pneumonia were well correlated with human-derived references and independently associated with symptoms and prognosis in multinational external data sets.

Allogeneic stem cell transplantation is a curative immunotherapy where patients receive myeloablative chemotherapy and/or radiotherapy, followed by donor stem cell transplantation. Graft versus host disease (GVHD) is a major complication caused by dysregulated donor immune system, thus a novel strategy to modulate donor immunity is needed to mitigate GVHD. Tissue damage by conditioning regimen is thought to initiate the inflammatory milieu that recruits various donor immune cells for cross-priming of donor T cells against alloantigen and eventually promote strong Th1 cytokine storm escalating further tissue damage. Bilirubin nanoparticles (BRNP) are water-soluble conjugated of bilirubin and polyethylene glycol (PEG) with potent anti-inflammatory properties through its ability to scavenge reactive oxygen species generated at the site of inflammation. Here, we evaluated whether BRNP treatment post-transplantation can reduce initial inflammation and subsequently prevent GVHD in a major histocompatibility (MHC) mismatched murine GVHD model. After myeloablative irradiation, BALB/c mice received bone marrow and splenocytes isolated from C57BL/6 mice, with or without BRNP (10 mg/kg) daily on days 0 through 4 post-transplantation, and clinical GVHD and survival was monitored for 90 days. First, BRNP treatment significantly improved clinical GVHD score compared to untreated mice (3.4 vs 0.3, p=0.0003), and this translated into better overall survival (HR 0.0638, p=0.0003). Further, BRNPs showed a preferential accumulation in GVHD target organs leading to a reduced systemic and local inflammation evidenced by lower pathologic GVHD severity as well as circulating inflammatory cytokines such as IFN-γ. Lastly, BRNP treatment post-transplantation facilitated the reconstitution of CD4

The Omicron variant, with numerous mutations in the spike protein, reduces vaccine-induced immunity, leading to breakthrough infections. However, vaccine protection after infection with the Omicron variant is unclear.To compare the neutralizing antibody responses between unvaccinated and vaccinated individuals infected with the Omicron variant, we have collected serial plasma samples from five unvaccinated and four vaccinated individuals with Omicron variant infection, including the first Omicron breakthrough infection case in the Republic of Korea. We evaluated neutralization antibody titers against D614G, Delta, and Omicron using live virus neutralizing assay, and calculated the plaque reduction neutralizing test value.In patients with two-dose vaccinations, neutralizing antibodies against Omicron variant were detected in plasma collected 4-9 days post symptom onset. However, in the plasma from unvaccinated patients and those vaccinated with one dose, neutralizing antibodies against the Omicron variant at the same time point were undetectable. Next, the 1- or 2-dose vaccinated infected groups showed potent cross-neutralizing activity against D614G and Delta variants after 11-14 days. In contrast, the neutralizing antibody titers in the unvaccinated group were low or undetectable.The major limitation of this study is the small sample size due to the limited samples targeting the first reported cases of Omicron BA.1 variant infection in the Republic of Korea (n = 9). Nevertheless, we found that vaccinated individuals rapidly produced neutralizing antibodies against Omicron, and potent cross-neutralizing antibodies against D614G and Delta upon infection with Omicron.

Stress management is a prerequisite for the survival of vertebrates because chronic stress may cause depression and is known to negatively modulate the dopaminergic reward system1. Enhanced excitability of neurons in the lateral habenula (LHb) induced by chronic stress is essential for silencing dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neurons in the rostromedial tegmental nucleus (RMTg)2–10. However, the effect of acute stress on the LHb-RMTg-VTA pathway is unknown11–14. Here, we show that both aromatic L-amino acid decarboxylase (AADC)-expressing neurons (D-neurons)15 in the LHb and dopaminergic neurons in the VTA are activated by acute stress, whereas GABAergic neurons in the RMTg are not. Selective stimulation of LHb D-neurons and AADC knockdown of these neurons reverse-regulate the RMTg-VTA pathway. Circuit tracing and electrophysiology data demonstrate that trace aminergic signalling by LHb D-neurons directly suppresses RMTg GABAergic neurons. Furthermore, local activation of trace amine-associated receptor 1 (TAAR1; a trace amine receptor) in the RMTg is sufficient to rescue the despair-like behaviour produced by the loss of AADC expression. Our results identify a novel efferent pathway from the LHb to the RMTg whereby trace aminergic signalling allows the brain to manage acute stress by preventing VTA dopaminergic neuron hypoactivity. The TAAR1-mediated trace aminergic signalling in the LHb-RMTg pathway may hold promise as a therapeutic target for stress-mediated psychological diseases.

Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition of Mycobacterium tuberculosis viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against M. tuberculosis in vitro , including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis . The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition of M. tuberculosis growth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistant M. tuberculosis strains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target against M. tuberculosis , and ecumicin may serve as a lead compound for anti-TB drug development.

Background Coronavirus disease 2019 (COVID-19) is generally asymptomatic or mild in otherwise healthy children, however, severe cases may occur. In this study, we report the clinical characteristics of children classified as critical COVID-19 in Korea to provide further insights into risk factors and management in children. Methods This study was a retrospective case series of children < 18 years of age classified as critical COVID-19. Cases were identified by the Korea Disease Control and Prevention Agency surveillance system and medical records were reviewed. Critical COVID-19 was defined as cases with severe illness requiring noninvasive (high flow nasal cannula, continuous positive airway pressure, or bilevel positive airway pressure) or invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO) or continuous renal replacement therapy (CRRT), between January 20, 2020 and October 7, 2021. Results Among 39,146 cases diagnosed with COVID-19 in subjects < 18 years of age, eight cases (0.02%) were identified as critical COVID-19. The median age was 13 years (range 10 month–17 years) and male-to-female ratio was 1:1. Three children had underlying diseases; one child has asthma and major depressive disorder, one child had Lennox-Gastaut syndrome and one child had mental retardation and was newly diagnosed with type 2 diabetes mellitus with the diagnosis of COVID-19. Among the eight children, seven were obese (body mass index range [BMI] median 29.3, range 25.9–38.2, weight-for-length > 97% for infant) and one was overweight (BMI 21.3). All patients had fever, six patients had dyspnea or cough and other accompanied symptoms included sore throat, headache, lethargy and myalgia. Radiologic findings showed pneumonia within 1–8 days after symptom onset. Pneumonia progressed in these children for 2–6 days and was improved within 5–32 days after diagnosis. Among the eight critical cases, remdesivir was administered in six cases. Steroids were provided for all cases. Inotropics were administered in one case. Six cases were treated with noninvasive mechanical ventilator and three required mechanical ventilator. One case required ECMO due to acute respiratory distress syndrome. All cases were admitted to the intensive care unit and admission period ranged from 9–39 days. Among all critical COVID-19 cases < 18 years of age, there were no fatal cases. Conclusion To develop appropriate policies for children in the COVID-19 pandemic, it is important to monitor and assess the clinical burden in this population., Graphical Abstract

BackgroundClevudine, an antiviral drug for chronic hepatitis B virus infection, is expected to inhibit the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Therefore, we conducted a prospective, single-blind, proof of concept clinical study to examine the antiviral efficacy and safety of clevudine compared to placebo in Korean corona virus disease 19 (COVID-19) patients with moderate severity.MethodsAdults with confirmed SARS-CoV-2 infection and symptom onset within 7 days were randomized 2:1 to 120 mg clevudine or placebo to receive one of treatments orally once-daily for 14 days. Antiviral efficacy outcomes were the proportion of patients with real-time reverse transcription polymerase chain reaction (RT-PCR) negative result for SARS-CoV-2 infection and cycle threshold (Ct) value changes from baseline. Clinical efficacy outcomes included proportion of patients who showed improvement in lung involvement by imaging tests, proportion of patients with normal body temperature, proportion of patients with normal oxygen saturation, and the changes in C-reactive protein (CRP) from baseline. Safety outcomes included changes in clinical laboratory tests, vital signs measurement, and physical examination from baseline, and incidence of adverse events.ResultsThe proportion of patients with real-time RT-PCR negative test and Ct value changes showed no significant difference between clevudine group and placebo group. The changes in Ct value from baseline were significantly greater in clevudine group compared to placebo group in patients with hypertension, and patients who underwent randomization during the first 5 and 7 days after the onset of symptoms. All clinical efficacy outcomes had no significant difference between clevudine group and placebo group. Clevudine was well tolerated and there was no significant difference in safety profile between two treatment groups.ConclusionsThis is the first clinical study to compare the antiviral efficacy and safety of clevudine to placebo in Korean COVID-19 patients with moderate severity. The study has demonstrated a possible favorable outcome for the reduction of SARS-CoV-2 replication, with acceptable safety profile, when COVID-19 patients were treated with clevudine. Further large-scale clinical studies, preferably with various clinical endpoints and virus titer evaluation, are required to better understand the effectiveness of using clevudine in COVID-19 treatment. Considering recent trend in clinical development for antiviral drugs, we need to design a clinical study aiming for reducing clinical risk of COVID-19 in mild to moderate patients with at least one risk factor for serious illness.

Background Regdanvimab (CT-P59) is a monoclonal antibody with neutralizing activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report on part 1 of a 2-part randomized, placebo-controlled, double-blind study for patients with mild-to-moderate coronavirus disease 2019 (COVID-19). Methods Outpatients with mild-to-moderate COVID-19 received a single dose of regdanvimab 40 mg/kg (n = 100), regdanvimab 80 mg/kg (n = 103), or placebo (n = 104). The primary end points were time to negative conversion of SARS-CoV-2 from nasopharyngeal swab based on quantitative reverse transcription polymerase chain reaction (RT-qPCR) up to day 28 and time to clinical recovery up to day 14. Secondary end points included the proportion of patients requiring hospitalization, oxygen therapy, or mortality due to COVID-19. Results Median (95% CI) time to negative conversion of RT-qPCR was 12.8 (9.0–12.9) days with regdanvimab 40 mg/kg, 11.9 (8.9–12.9) days with regdanvimab 80 mg/kg, and 12.9 (12.7–13.9) days with placebo. Median (95% CI) time to clinical recovery was 5.3 (4.0–6.8) days with regdanvimab 40 mg/kg, 6.2 (5.5–7.9) days with regdanvimab 80 mg/kg, and 8.8 (6.8–11.6) days with placebo. The proportion (95% CI) of patients requiring hospitalization or oxygen therapy was lower with regdanvimab 40 mg/kg (4.0% [1.6%–9.8%]) and regdanvimab 80 mg/kg (4.9% [2.1%–10.9%]) vs placebo (8.7% [4.6%–15.6%]). No serious treatment-emergent adverse events or deaths occurred. Conclusions Regdanvimab showed a trend toward a minor decrease in time to negative conversion of RT-qPCR results compared with placebo and reduced the need for hospitalization and oxygen therapy in patients with mild-to-moderate COVID-19. Clinical trial registration. NCT04602000 and EudraCT 2020-003369-20.