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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.

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.

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.

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.

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.

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.

Background Hill pigeons (Columba rupestris) are close to local extinction (ca. less than 100 individuals) in South Korea where a variety of conservation management procedures are urgently required. Objective This study was aimed at determining the conservation direction of captive propagation and reintroduction of hill pigeons using genetic information based on mitochondrial DNA. We also evaluated the extent of hybridization between hill pigeons and cohabiting domestic pigeons. Methods We used 51 blood samples of hill pigeons from Goheung (GH), Gurye (GR), and Uiryeong (UR), and domestic pigeons cohabiting with hill pigeon populations. Genetic diversity, pairwise Fst, analysis of molecular variance, and haplotype network analysis were used to examine the genetic structure of hill pigeons. Results Hill pigeons that inhabited South Korea were not genetically distinct from Mongolian and Russian populations and showed relatively low genetic diversity compared with other endangered species in Columbidae. The GR population that exhibited the largest population size showed lower genetic diversity, compared to the other populations, although the pairwise Fst values of the three populations indicated low genetic differentiation. The GH and GR populations were confirmed to lack hybridization, relatively, whereas the UR population was found to exhibit some degrees of hybridization. Conclusion To conserve hill pigeons with low genetic diversity and differentiation in South Korea, the conservation process of captive propagation and reintroduction may require artificial gene flows among genetically verified populations in captivity and wildness. The introduction of foreign individuals from surrounding countries is also considered an alternative strategy for maintaining genetic diversity.

Rationale: Magnetic relaxation switching (MRSw) induced by target-triggered aggregation or dissociation of superparamagnetic iron oxide nanoparticles (SPIONs) have been utilized for detection of diverse biomarkers. However, an MRSw-based biosensor for reactive oxygen species (ROS) has never been documented. Methods: To this end, we constructed a biosensor for ROS detection based on PEGylated bilirubin (PEG-BR)-coated SPIONs (PEG-BR@SPIONs) that were prepared by simple sonication via ligand exchange. In addition, near infra-red (NIR) fluorescent dye was loaded onto PEG-BR@SPIONs as a secondary option for fluorescence-based ROS detection. Results: PEG-BR@SPIONs showed high colloidal stability under physiological conditions, but upon exposure to the model ROS, NaOCl, in vitro, they aggregated, causing a decrease in signal intensity in T2-weighted MR images. Furthermore, ROS-responsive PEG-BR@SPIONs were taken up by lipopolysaccharide (LPS)-activated macrophages to a much greater extent than ROS-unresponsive control nanoparticles (PEG-DSPE@SPIONs). In a sepsis-mimetic clinical setting, PEG-BR@SPIONs were able to directly detect the concentrations of ROS in whole blood samples through a clear change in T2 MR signals and a 'turn-on' signal of fluorescence. Conclusions: These findings suggest that PEG-BR@SPIONs have the potential as a new type of dual mode (MRSw-based and fluorescence-based) biosensors for ROS detection and could be used to diagnose many diseases associated with ROS overproduction.

The habenula (Hb) is small but important brain structure, anatomically and functionally links the forebrain with the midbrain to modulate various neuropsychiatric functions associated with drug addiction and emotion-associated dysfunctions. Several reports suggested that the dysfunction of Hb-related functions affected the Hb structurally and functionally. However, the technical limitation has awaited the solid conclusion of whether Hb change due to depression is likely to occur in certain subnuclei of the Hb. To probe this possibility, we developed 3-dimensional reconstruction methods for the high-resolution volumetric analysis of Hb and the mRNA levels at the given volume in normal or lipopolysaccharide (LPS)-mediated mouse model of depression. Notably, we discovered that the volume reduction was prominent in medial Hb but not in lateral Hb after LPS treatments. On the other hand, the RNA expression levels of known Hb regional markers such as Tac1 (dorsal part of medial Hb), ChAT (ventral part of medial Hb), and Tacr1 (medial and lateral Hb) were all decreased in all Hb subnuclei in LPS-injected mice. Accordingly, accurate volumetry with marker labeling was not feasible. Collectively, these established 3D analyses of mouse Hb successfully and precisely determine the volume-based changes of small brain structure, which should be applicable in a wider range of mouse models or pathological specimens.

Lynch syndrome is a hereditary cancer syndrome caused by germline mutations in one of several DNA mismatch repair genes. Lynch syndrome leads to an increased lifetime risk of various cancers, particularly colorectal, and endometrial cancers. After identifying patients suspected of having Lynch syndrome by clinical criteria, computational prediction models, and/or universal tumor testing, genetic testing is performed to confirm the diagnosis. Before and after genetic testing, genetic counseling should be provided. Genetic counseling should involve a detailed personal and family history, information on the disorder and genetic tests, discussion of the management and surveillance of the disease, career plan, family plan, and psychosocial support. Surveillance of colorectal cancer and other malignancies is of paramount importance for properly managing Lynch syndrome. This review focuses on important considerations in genetic counseling and the latest insights into the surveillance of individuals and families with Lynch syndrome.

The latitudinal and elevational patterns of species richness of resident and migrant birds have been of interest to researchers over the past few decades, and various hypotheses have been proposed to explain the factors that may affect these patterns. This study aimed to shed light on the elevational distribution patterns of resident and migrant bird species richness by examining biotic and abiotic factors such as climate, and habitat heterogeneity using a piecewise structural equation model (pSEM). The overall pattern of resident species richness showed a decreasing trend with increasing elevation, whereas that of migrant species richness showed an increasing trend. The mid-peak pattern of species richness was affected by a combination of resident and migrant species and not by either resident or migrant species. Our results showed that resident species were distributed in lower elevation regions with higher mean spring temperatures, whereas migrant species were found in higher elevation regions with lower mean spring temperatures and higher overstory vegetation coverage. Although high elevation conditions might adversely affect the reproduction of migrant birds, higher overstory vegetation coverage at high elevations seemed to compensate for this by providing a better nesting and roosting environment. Despite the significance of habitat diversity and understory vegetation coverage in univariate linear regression models, multiple regression models of the interconnection of ecological processes demonstrated that mean spring temperature and overstory vegetation coverage were more explanatory than other variables.

OBJECTIVE: To investigate the duration and peak of severe acute respiratory syndrome coronavirus 2 shedding as infectivity markers for determining the isolation period. METHODS: A total of 2,558 upper respiratory tract (URT) and lower respiratory tract (LRT) specimens from 138 patients with laboratory-confirmed coronavirus disease were analyzed. Measurements of sequential viral loads were aggregated using the cubic spline smoothing function of a generalized additive model. The time to negative conversion was compared between symptom groups using survival analysis. RESULTS: In URT samples, viral RNA levels peaked on day 4 after symptom onset and rapidly decreased until day 10 for both E and RdRp genes, whereas those in LRT samples immediately peaked from symptom onset and decreased until days 15.6 and 15.0 for E and RdRp genes, respectively. Median (interquartile range) time to negative conversion was significantly longer in symptomatic (18.0 [13.0-25.0] days) patients than in asymptomatic (13.0 [9.5-17.5] days) patients. The more types of symptoms a patient had, the longer the time to negative conversion. CONCLUSIONS: The viral load rapidly changes depending on the time after symptom onset; the viral shedding period may be longer with more clinical symptoms. Different isolation policies should be applied depending on disease severity.

CT-P59, a monoclonal antibody with potent neutralizing activity against severe acute respiratory syndrome coronavirus 2, may ameliorate symptoms and prevent hospitalization in outpatients with mild-to-moderate disease. We report findings from part one of a two-part randomized, placebo-controlled, double-blind study (NCT04602000; EudraCT: 2020-003369-20). Outpatients with mild-to-moderate COVID-19 received a single dose of CT-P59 40 mg/kg (n=101), CT-P59 80 mg/kg (n=103), or placebo (n=103). Median (95% confidence interval [CI]) time to conversion to negative RT-qPCR result (coprimary endpoint) was 12.8 days (9.00–12.84) with CT-P59 40 mg/kg, 11.9 days (8.94–12.91) with CT-P59 80 mg/kg, and 12.9 days (12.75–13.99) with placebo. Median (95% CI) time to clinical recovery (coprimary endpoint) was 5.4 days (3.97–6.78) with CT-P59 40 mg/kg, 6.2 days (5.53–7.85) with CT-P59 80 mg/kg, and 8.8 days (6.72–11.73) with placebo. The proportion (95% CI) of patients requiring hospitalization or oxygen therapy was lower with CT-P59 40 mg/kg (4.0% [1.6–9.7%]) and CT-P59 80 mg/kg (4.9% [2.1–10.9%]) versus placebo (8.7% [4.7–15.8%). CT-P59 was well tolerated and no serious treatment-emergent adverse events or deaths occurred. In summary, CT-P59 accelerated viral and clinical recovery from COVID-19 and was well tolerated in patients with mild-to-moderate infection.

Dermal fibroblasts lose stem cell potency after birth, which prevents regenerative healing. However, the underlying intracellular mechanisms are largely unknown. We uncover the postnatal maturation of papillary fibroblasts (PFs) driven by the extensive Twist2-mediated remodeling of chromatin accessibility. A loss of the regenerative ability of postnatal PFs occurs with decreased H3K27ac levels. Single-cell transcriptomics, assay for transposase-accessible chromatin sequencing (ATAC-seq), and chromatin immunoprecipitation sequencing (ChIP-seq) reveal the postnatal maturation trajectory associated with the loss of the regenerative trajectory in PFs, which is characterized by a marked decrease in chromatin accessibility and H3K27ac modifications. Histone deacetylase inhibition delays spontaneous chromatin remodeling, thus maintaining the regenerative ability of postnatal PFs. Genomic analysis identifies Twist2 as a major regulator within chromatin regions with decreased accessibility during the postnatal period. When Twist2 is genetically deleted in dermal fibroblasts, the intracellular cascade of postnatal maturation is significantly delayed. Our findings reveal the comprehensive intracellular mechanisms underlying intrinsic postnatal changes in dermal fibroblasts.

To study the extent of pulmonary involvement in coronavirus 19 (COVID-19) with quantitative CT and to assess the impact of disease burden on opacity visibility on chest radiographs.This retrospective study included 20 pairs of CT scans and same-day chest radiographs from 17 patients with COVID-19, along with 20 chest radiographs of controls. All pulmonary opacities were semiautomatically segmented on CT images, producing an anteroposterior projection image to match the corresponding frontal chest radiograph. The quantitative CT lung opacification mass (QCTThe mean QCTQCT

Recently, as a new precast concrete (PC) construction method for increasing economy and constructability, the PC double-beam system has been developed for factories or logistic centers, where construction duration is particularly important. In this study, half-scaled PC double beam–column connection was tested under gravity loading and cyclic lateral loading. The major test parameters included the use of the spliced PC column and the addition of reinforcement at the beam–column joint. In the gravity loading test, the flexural behavior of the PC double beam was investigated. The test results showed satisfactory flexural capacity at the PC double-beam section, validating the composite action between the PC and RC members. In the cyclic lateral loading test, the seismic performance of the PC double beam–column connection was investigated. Based on the test results, the failure mode, load-carrying capacity, deformation capacity, energy dissipation capacity, secant stiffness, and shear strength of the PC double-beam system were evaluated and compared with those of a conventional RC double beam–column connection. According to the test results, the structural performance of the PC double beam–column connection was comparable to that of the RC double beam–column connection and satisfied the acceptance criteria of moment frame in the ACI 374.1-05 provision.