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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.

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.

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.

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

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.

Background and aims The phenotypic concordance among familial cases of inflammatory bowel disease (IBD) has been rarely reported. Thus, the present study aimed to evaluate the concordance regarding disease type and phenotypic features in a large cohort of Korean patients with IBD. Methods A total of 6647 patients with IBD who visited the Asan Medical Center between June 1989 and September 2016 were enrolled in the study. When at least two familial cases existed in our cohort, they were included in the concordance analysis (κ index). The concordance between younger and older members for IBD type [Crohn's disease (CD) and ulcerative colitis (UC)] and phenotypic characteristics such as disease extent and location, disease behavior, the use of medication, and need for surgery were evaluated. Results A positive family history of IBD was noted in 216 patients with CD (7.0%) and in 238 patients with UC (6.7%). Of all patients, 167 consanguineous pairs in 146 families were identified. The crude concordance rate for IBD type was 82.6% with a κ index of 0.656 [95% confidence interval (CI): 0.545-0.768, good concordance]. There was mild concordance for disease location in CD (κ = 0.256; 95% CI: 0.007-0.505) and for the use of antitumor necrosis factor agents in UC (κ = 0.354; 95% CI: -0.049-0.757). The concordance for IBD type and several phenotypes in first-degree relative pairs was better than that in the entire pairs. Conclusions Disease type and phenotypic characteristics of patients with familial IBD may be anticipated.

We investigated the effect of oxidative stress (OS) on lipidomic perturbations in the subcellular fractions and exosomes of human embryonic kidney (HEK) 293 cells using asymmetrical flow field–flow fractionation (AF4) and nanoflow ultrahigh performance liquid chromatography–electrospray ionization–tandem mass spectrometry (nUHPLC-ESI-MS/MS). We treated HEK 293 cells with hydrogen peroxide (H2O2) and fractionated the cell lysates using AF4 to determine the change in size and population of the subcellular fractions and exosomes, and to obtain narrow size fractions for lipid analysis. A total of 438 lipids from 642 identified species—including oxidized lipids—were quantified. The relative amount of secreted exosomes increased by 28% during OS, whereas the amount of subcellular species decreased by 35%. There was a significant increase in the level of oxidized phospholipids in the mitochondrion-enriched subcellular fractions, but not in the exosomes. Most high-abundance triacylglycerol (TG) species increased in the stressed cells, whereas they decreased in the exosomes. During OS, ceramides involved in the apoptotic mitochondrial pathway were accumulated in the subcellular fractions, whereas their levels were unaffected in the exosomes. The present study demonstrated that AF4 and nUHPLC-ESI-MS/MS can be used to investigate lipid alterations in subcellular and extracellular species during OS, and the pathological relationships in diseases caused by reactive oxygen species.

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.

This study introduces a high-speed screening method for the quantitative analysis of lipoprotein components in human plasma samples using online miniaturized asymmetrical flow field-flow fractionation and electrospray ionization-tandem mass spectrometry (mAF4-ESI-MS/MS). Using an mAF4 channel, high-density lipoproteins and low-density lipoproteins can be fractionated by size at a high speed (

Calcium-dependent secretion activator 2 (CAPS2) regulates the trafficking and exocytosis of neuropeptide-containing dense-core vesicles (DCVs). CAPS2 is prominently expressed in the medial habenula (MHb), which is related to depressive behavior; however, how MHb neurons cause depressive symptoms and the role of CAPS2 remains unclear. We hypothesized that dysfunction of MHb CAPS neurons might cause defects in neuropeptide secretion and the activity of monoaminergic centers, resulting in depressive-like behaviors. In this study, we examined (1) CAPS2 expression in the habenula of depression animal models and major depressive disorder patients and (2) the effects of down-regulation of MHb CAPS2 on the animal behaviors, synaptic transmission in the interpeduncular nucleus (IPN), and neuronal activity of monoamine centers. Habenular CAPS2 expression was decreased in the rat chronic restraint stress model, mouse learned helplessness model, and showed tendency to decrease in depression patients who died by suicide. Knockdown of CAPS2 in the mouse habenula evoked despair-like behavior and a reduction of the release of DCVs in the IPN. Neuronal activity of IPN and monoaminergic centers was also reduced. These results implicate MHb CAPS2 as playing a pivotal role in depressive behavior through the regulation of neuropeptide secretion of the MHb-IPN pathway and the activity of monoaminergic centers.

Background The fatality rate of patients with coronavirus disease 2019 (COVID-19) varies among countries owing to demographics, patient comorbidities, surge capacity of healthcare systems, and the quality of medical care. We assessed the clinical outcomes of patients with COVID-19 during the first wave of the epidemic in Korea. Methods Using a modified World Health Organization clinical record form, we obtained clinical data for 3,060 patients with COVID-19 treated at 55 hospitals in Korea. Disease severity scores were defined as: 1) no limitation of daily activities; 2) limitation of daily activities but no need for supplemental oxygen; 3) supplemental oxygen via nasal cannula; 4) supplemental oxygen via facial mask; 5) non-invasive mechanical ventilation; 6) invasive mechanical ventilation; 7) multi-organ failure or extracorporeal membrane oxygenation therapy; and 8) death. Recovery was defined as a severity score of 1 or 2, or discharge and release from isolation. Results The median age of the patients was 43 years of age; 43.6% were male. The median time from illness onset to admission was 5 days. Of the patients with a disease severity score of 3–4 on admission, 65 (71.5%) of the 91 patients recovered, and 7 (7.7%) died due to illness by day 28. Of the patients with disease severity scores of 5–7, 7 (19.5%) of the 36 patients recovered, and 8 (22.2%) died due to illness by day 28. None of the 1,324 patients who were < 50 years of age died; in contrast, the fatality rate due to illness by day 28 was 0.5% (2/375), 0.9% (2/215), 5.8% (6/104), and 14.0% (7/50) for the patients aged 50–59, 60–69, 70–79, and ≥ 80 years of age, respectively. Conclusion In Korea, almost all patients of < 50 years of age with COVID-19 recovered without supplemental oxygen. In patients of ≥ 50 years of age, the fatality rate increased with age, reaching 14% in patients of ≥ 80 years of age., Graphical Abstract

The labeling of all ingredients contained in consumer products has been requested by consumers concerned regarding their safety. Consequently, regulatory agencies have set guidelines for industries on how to provide safety information regarding the ingredients in their products. However, discordant opinions were raised from stakeholders, resulting in the formation of a risk communication forum among industries, regulatory agencies, consumer groups, and academia. There are several methods that might be utilized to provide ingredient information to consumers: (1) listing all ingredients on the label of products, (2) providing major ingredients on the label of products, (3) presenting all ingredients on the websites of each manufacturer, and (4) listing major ingredients on the label of products and the remainder of ingredients (not on the label) on the websites. Each method might have its own advantages and disadvantages with respect to providing the information regarding the names of the ingredients used in consumer products to the consumers. A continuous risk communication forum might be an effective tool to facilitate an improved understanding of chemical information, toxicological science, regulatory guidelines, labeling methods, and consumers' concern. This study suggests that risk communication efforts may be helpful and a good opportunity for stakeholders to exchange opinions and reach a harmonious conclusion on labeling of consumer products ingredients.

Background This study aimed to investigate the effect of antiviral therapy following influenza outpatient episodes on the incidence of hospitalized pneumonia episodes, one of secondary complications of influenza. Methods In the National Health Insurance Research Database, data from July 2013 to June 2018 were used. All of the claim data with diagnoses of influenza and pneumonia were converted to episodes of care after applying 100 days of window period. With the 100-day episodes of care, the characteristics of influenza outpatient episodes and antiviral therapy for influenza, the incidence of hospitalized pneumonia episodes following influenza, and the effect of antiviral therapy for influenza on hospitalized pneumonia episodes were investigated. Results The crude incidence rate of hospitalized pneumonia after influenza infection was 0.57% in both males and females. Factors affecting hospitalized pneumonia included age, income level except self-employed highest (only in females), municipality, medical institution type, precedent chronic diseases except hepatitis (only in females) and antiviral therapy. In the 2017 flu season, the relative risk was 0.38 (95% confidence interval [CI], 0.29–0.50) in males aged 0–9 and 0.43 (95% CI, 0.32–0.57) in females aged 0–9 without chronic diseases, and it was 0.51 (95% CI, 0.42–0.61) in males aged 0–9 and 0.42 (95% CI, 0.35–0.50) in females aged 0–9 with one or more chronic diseases in the aspect of the effect of antiviral therapy on pneumonia. It suggests that antiviral therapy may decrease the incidence of pneumonia after influenza infection. Conclusion After outpatient episode incidence of influenza, antiviral treatment has been shown to reduce the incidence of hospitalized pneumonia, especially in infants and children, during pandemic season 2017. Antiviral therapy for influenza is recommended to minimize burden caused by influenza virus infection and to reduce pneumonia. In addition, medical costs of hospitalization may decrease by antiviral therapy, especially in infants and children., Graphical Abstract

The Rutgeerts score is used to predict postoperative recurrence in CD patients after ileocolic resection and is primarily based on endoscopic findings at the neoterminal ileum. However, the optimal assessment of anastomotic ulcers (AUs) remains subject to debate. We aimed to investigate the association between anastomotic ulcers (AUs) and endoscopic recurrence in postoperative Crohn’s disease (CD) patients. This single-center retrospective study, conducted between 2000 and 2016, evaluated postoperative CD patients with endoscopic remission at the first ileocolonoscopy within 1 year after ileocolic resection and those who underwent subsequent ileocolonoscopic follow-up. The study outcome was the clinical significance of AUs in predicting endoscopic recurrence. Among 116 patients who were in endoscopic remission defined as the RS of i0 to i1 at the index postoperative ileocolonoscopy, 84.5% (98/116) underwent subsequent ileocolonoscopies. During the median 30.0 months (interquartile range, 21.3–53.3) of follow-up after the first ileocolonoscopy, 56.1% (55/98) of patients showed endoscopic recurrence. Furthermore, 65.8% (48/73) with AUs and 75.5% (40/53) with major AUs, defined as either an ulcer occupying ≥ 1/4 of the circumference, ≥ 3 ulcers confined to anastomotic ring, or any ulcers extending to the ileocolonic mucosa, showed endoscopic recurrence. On multivariable analysis, AUs (adjusted hazard ratio [aHR], 4.33; 95% confidence interval [CI], 1.87–10.0; P

Novel coronavirus (SARS-CoV-2) is found to cause a large outbreak started from Wuhan since December 2019 in China and SARS-CoV-2 infections have been reported with epidemiological linkage to China in 25 countries until now. We isolated SARS-CoV-2 from the oropharyngeal sample obtained from the patient with the first laboratory-confirmed SARS-CoV-2 infection in Korea. Cytopathic effects of SARS-CoV-2 in the Vero cell cultures were confluent 3 days after the first blind passage of the sample. Coronavirus was confirmed with spherical particle having a fringe reminiscent of crown on transmission electron microscopy. Phylogenetic analyses of whole genome sequences showed that it clustered with other SARS-CoV-2 reported from Wuhan.

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in psoriatic skin inflammation and acts as a key player in the pathogenesis and progression of this autoimmune disease. Although numerous inhibitors that intervene in STAT3-associated pathways have been tested, an effective, highly specific inhibitor of STAT3 has yet to be identified. Here, we evaluated the in vitro and in vivo biological activity and therapeutic efficacy of a high-affinity peptide specific for STAT3 (APTstat3) after topical treatment via intradermal and transcutaneous delivery. Using a preclinical model of psoriasis, we show that intradermal injection of APTstat3 tagged with a 9-arginine cell-penetrating peptide (APTstat3-9R) reduced disease progression and modulated psoriasis-related cytokine signaling through inhibition of STAT3 phosphorylation. Furthermore, by complexing APTstat3-9R with specific lipid formulations led to formation of discoidal lipid nanoparticles (DLNPs), we were able to achieve efficient skin penetration of the STAT3-inhibiting peptide after transcutaneous administration, thereby effectively inhibiting psoriatic skin inflammation. Collectively, these findings suggest that DLNP-assisted transcutaneous delivery of a STAT3-inhibiting peptide could be a promising strategy for treating psoriatic skin inflammation without causing adverse systemic events. Moreover, the DLNP system could be used for transdermal delivery of other therapeutic peptides.

In this Article, we have reported a fully automated online method to carry out proteolysis and glycopeptide enrichment in sequence for nanoflow liquid chromatography-tandem mass spectrometry (nLC-ESI-MS/MS) analysis. By implementing two serial thermoresponsive porous polymer membrane reactors (TPPMRs), in which the TPPM could be immobilized either with trypsin for proteolysis or with lectins for glycopeptide enrichment, the entire pretreatment procedure can be performed online in about an hour. The TPPM was fabricated by coating polystyrene-maleic anhydride- N-isopropylacrylamide (PS-MAn-PNIPAm), which was synthesized by reversible addition-fragmentation chain transfer polymerization, on a Nylon sheet. Because of the thermoresponsive nature of PNIPAm, it formed micelle cavities and changed its morphology at elevated temperatures, resulting in enhanced interactions between the enzyme or lectins and the proteins/peptides flowing through the membrane. The performances of the TPPMs were evaluated by varying the temperature conditions and the amount of standard proteins, showing that both proteolysis and glycopeptide enrichment with online deglycosylation were highly efficient at 37 °C. The developed online serial TPPMRs-nLC-ESI-MS/MS method was applied to the human plasma sample (1.5 μL) and a total of 262 N-glycopeptides could be identified from 155 glycoproteins. Thus, the present work demonstrates a fully automated high speed analytical protocol for online proteolysis and glycopeptide enrichment, which is extremely useful for analyzing small amounts of the proteome samples.

Background/Aims There is a need for a simple and practical tool adapted for the diagnosis of chronic constipation (CC) in the Asian population. This study compared the Asian Neurogastroenterology and Motility Association (ANMA) CC tool and Rome III criteria for the diagnosis of CC in Asian subjects. Methods This multicenter, cross-sectional study included subjects presenting at outpatient gastrointestinal clinics across Asia. Subjects with CC alert symptoms completed a combination Diagnosis Questionnaire to obtain a diagnosis based on 4 different diagnostic methods: self-defined, investigator`s judgment, ANMA CC tool, and Rome III criteria. The primary endpoint was the level of agreement/ disagreement between the ANMA CC diagnostic tool and Rome III criteria for the diagnosis of CC. Results The primary analysis comprised of 449 subjects, 414 of whom had a positive diagnosis according to the ANMA CC tool. Rome III positive/ANMA positive and Rome III negative/ANMA negative diagnoses were reported in 76.8% and 7.8% of subjects, respectively, resulting in an overall percentage agreement of 84.6% between the 2 diagnostic methods. The overall percentage disagreement between these 2 diagnostic methods was 15.4%. A higher level of agreement was seen between the ANMA CC tool and self-defined (374 subjects [90.3%]) or investigator`s judgment criteria (388 subjects [93.7%]) compared with the Rome III criteria. Conclusion This study demonstrates that the ANMA CC tool can be a useful for Asian patients with CC. (J Neurogastroenterol Motil 2017;23:262-272)

In December 2019, a viral pneumonia outbreak caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV), began in Wuhan, China. We report the epidemiological and clinical features of the first patient with 2019-nCoV pneumonia imported into Korea from Wuhan. This report suggests that in the early phase of 2019-nCoV pneumonia, chest radiography would miss patients with pneumonia and highlights taking travel history is of paramount importance for early detection and isolation of 2019-nCoV cases.

As the coronavirus disease 2019 (COVID-19) outbreak is ongoing, the number of individuals to be tested for COVID-19 is rapidly increasing. For safe and efficient screening for COVID-19, drive-through (DT) screening centers have been designed and implemented in Korea. Herein, we present the overall concept, advantages, and limitations of the COVID-19 DT screening centers. The steps of the DT centers include registration, examination, specimen collection, and instructions. The entire service takes about 10 minutes for one testee without leaving his or her cars. Increased testing capacity over 100 tests per day and prevention of cross-infection between testees in the waiting space are the major advantages, while protection of staff from the outdoor atmosphere is challenging. It could be implemented in other countries to cope with the global COVID-19 outbreak and transformed according to their own situations., Graphical Abstract

As of February 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak started in China in December 2019 has been spreading in many countries in the world. With the numbers of confirmed cases are increasing, information on the epidemiologic investigation and clinical manifestation have been accumulated. However, data on viral load kinetics in confirmed cases are lacking. Here, we present the viral load kinetics of the first two confirmed patients with mild to moderate illnesses in Korea in whom distinct viral load kinetics are shown. This report suggests that viral load kinetics of SARS-CoV-2 may be different from that of previously reported other coronavirus infections such as SARS-CoV.

Since mid-December of 2019, coronavirus disease 2019 (COVID-19) has been spreading from Wuhan, China. The confirmed COVID-19 patients in South Korea are those who came from or visited China. As secondary transmissions have occurred and the speed of transmission is accelerating, there are rising concerns about community infections. The 54-year old male is the third patient diagnosed with COVID-19 in Korea. He is a worker for a clothing business and had mild respiratory symptoms and intermittent fever in the beginning of hospitalization, and pneumonia symptoms on chest computerized tomography scan on day 6 of admission. This patient caused one case of secondary transmission and three cases of tertiary transmission. Hereby, we report the clinical findings of the index patient who was the first to cause tertiary transmission outside China. Interestingly, after lopinavir/ritonavir (Kaletra, AbbVie) was administered, β-coronavirus viral loads significantly decreased and no or little coronavirus titers were observed., Graphical Abstract

GOALS The study aimed to compare the level and characteristics of disease-related knowledge of patients with inflammatory bowel disease (IBD) between the West and the East using an international version of a questionnaire regarding knowledge of inflammatory bowel disease (IBD-KNOW). BACKGROUND The authors recently developed a new questionnaire regarding IBD-KNOW, which showed excellent test characteristics in Korea. STUDY The IBD-KNOW questionnaire was administered to 100 patients with IBD from tertiary referral hospitals in the United States and Korea. Scores were calculated and compared between US and Korean patients, and factors associated with high scores were analyzed. RESULTS A total of 196 (100 US and 96 Korean) patients with IBD completed the questionnaires. Analysis of the baseline characteristics revealed that male sex, smoking status, disease duration, history of IBD-related operations, family history of IBD, and use of corticosteroids or biologics were significantly different between US and Korean patients. The mean IBD-KNOW score was higher in US patients than in Korean patients (14.8 vs. 11.3; P

Background This study aimed to identify the incidence rate of episodes diagnosed with influenza and the effects of age-period-cohort (APC) in Koreans. Methods The 2009–2018 National Health Insurance Research Database was used for analysis. All time-related claims connected relatively short window period in 100 days. The case definition was defined by all codes diagnosed with J09, J10, and J11. Calculation of the incidence rate and APC analysis adjusted income levels by insurance type, metropolitan city was performed to identify the characteristics of episodes diagnosed with influenza. Results Incidence rate by age and cohort gradually increased since 2014. The incidence rate of males aged 0–4 years was 171.02 and that of females was 173.31 in 2015–2016 season. In males, 29.19 in 1963 cohort and 243.79 in 2013 cohort were confirmed as high incidence rates in 2017–2018 season. In the females, a high incidence was confirmed in 1953–1967 cohort and 1978–1987 cohort, and the incidence was 251.38 in 2013–2017 cohort. APC effects showed a high relative risk in the infants, the pandemic influenza season in 2010 (1/7/2009 to 30/6/2010) and the adults of 1978–1987 cohort. Conclusion Since 2014, influenza outbreaks have been increasing every year. The start year of free vaccination decreased the incidence in infants and adults over 65 years of age but the incidence increased from the following year. Because influenza can be primarily prevented by vaccination, reinforcement of vaccination in infants may reduce the disease burden in their parents, and also the risk of infection caused by family transmission. A new vaccination strategy is needed to reduce the incidence and burden of diseases caused by influenza infection., Graphical Abstract

The maintenance of genetic integrity is critical for stem cells to ensure homeostasis and regeneration. Little is known about how adult stem cells respond to irreversible DNA damage, resulting in loss of regeneration in humans. Here, we establish a permanent regeneration loss model using cycling human hair follicles treated with alkylating agents: busulfan followed by cyclophosphamide. We uncover the underlying mechanisms by which hair follicle stem cells (HFSCs) lose their pool. In contrast to immediate destructive changes in rapidly proliferating hair matrix cells, quiescent HFSCs show unexpected massive proliferation after busulfan and then undergo large-scale apoptosis following cyclophosphamide. HFSC proliferation is activated through PI3K/Akt pathway, and depletion is driven by p53/p38-induced cell death. RNA-seq analysis shows that HFSCs experience mitotic catastrophe with G2/M checkpoint activation. Our findings indicate that priming mobilization causes stem cells to lose their resistance to DNA damage, resulting in permanent loss of regeneration after alkylating chemotherapy., Hair follicles (HFs) are sensitive to chemotherapy but recover from quiescent HF stem cells, although sometimes chemotherapy results in permanent loss. Here, Kim et al. establish a model of permanent chemotherapy-induced alopecia to uncover the underlying mechanisms depleting human HF stem cells.

Summary Background Antimicrobial stewardship programmes (ASPs) are suggested as a vital strategy to address antimicrobial resistance. Aim To examine the current status of ASPs in Korean hospitals, to identify problems and challenges for the implementation of proper ASPs, and to provide a reference for developing more effective ASP policies. Methods A questionnaire based on the ‘Seven Core Elements of Hospital Antibiotic Stewardship Programs’ from the US Centers for Disease Control and Prevention was developed, modified from the previous questionnaire on ASPs in Korea, 2015. ASP-participating physicians such as infectious disease specialists (IDSs), paediatric IDSs, and directors of infection control departments were targeted. Only one ASP-associated physician per hospital participated in the survey. Findings The survey response rate was 88.4% (84/95). The median number of medical personnel participating in ASPs was 3 (interquartile range (IQR): 1–5), most of whom were IDS (median: 2; IQR: 1–2). Only 6.0% (5/84) of hospitals had full-time workers for ASPs. Whereas restrictive measures for designated antimicrobials were widely implemented among Korean hospitals (88.1%, 74/84), the proportion of hospitals with interventions for inappropriate long-term antimicrobial use and a conversion strategy from parenteral to oral antimicrobial administration was only 9.5% (8/84) and 1.2% (1/84), respectively. Lack of time, personnel, and appropriate compensation was perceived as the major barrier to establishing an ASP in Korean hospitals. Conclusion ASPs in Korean hospitals were primarily carried out by one or two IDSs, and programmes mostly comprised restrictive measures for designated antimicrobials. National-level support to implement appropriate ASPs in Korean hospitals is necessary.

Background and aim Little is known whether routine prophylaxis against Pneumocystis jirovecii pneumonia (PJP) is needed in patients with inflammatory bowel disease (IBD) on immunosuppression, especially in Asian populations. We, therefore, sought to investigate the incidence and risk factors of PJP in patients with IBD in Korea. Methods We investigated the incidence of PJP in patients with IBD and compared the characteristics of IBD patients with PJP episodes (IBD-PJP group) with those of matched controls (IBD-only group) using a large, well-characterized referral center-based cohort. Results Among the 6803 IBD patients (3171 with Crohn's disease and 3632 with ulcerative colitis) enrolled in the Asan IBD Registry between June 1989 and December 2016, six patients (0.09%) were diagnosed with PJP. During the 57 776.0 patient-years of follow-up (median 7.2 years per patient), the incidence of PJP was 10.4 cases per 100 000 person-years, and none of these patients had received PJP prophylaxis. In case-control analysis, the IBD-PJP group (n = 6) showed significantly higher C-reactive protein level at diagnosis of IBD (P = 0.006), as well as higher exposure to corticosteroids (P = 0.017), than did controls (n = 24). In addition, the IBD-PJP group showed higher rates of double (50% vs 12.5%) or triple (33.3% vs 4.2%) immunosuppression than did controls, although these are not statistically significant. Conclusions Although the incidence of PJP in Korean patients with IBD is low, careful monitoring is necessary for the early detection of PJP. In addition to the patients receiving double or triple immunosuppression, PJP prophylaxis should be considered especially in patients with severe disease activities requiring corticosteroids.

A deficiency of α-galactosidase A causes Fabry disease (FD) by disrupting lipid metabolism, especially trihexosylceramide (THC). Enzyme replacement therapy (ERT) is clinically offered to FD patients in an attempt to lower the accumulated lipids. Studies on specific types of lipids that are directly or indirectly altered by FD are very scarce, even though they are crucial in understanding the biological process linked to the pathogenesis of FD. We performed a comprehensive lipid profiling of plasma and urinary lipids from FD patients with nanoflow liquid chromatography electrospray-ionization tandem mass spectrometry (nLC-ESI-MS/MS) and identified 129 plasma and 111 urinary lipids. Among these, lipids that exhibited alternations (>twofold) in patients were selected as targets for selected reaction monitoring (SRM)-based high-speed quantitation using nanoflow ultra-performance LC-ESI-MS/MS (nUPLC-ESI-MS/MS) and 31 plasma and 26 urinary lipids showed significant elevation among FD patients. Higher percentages of sphingolipids (SLs; 48% for plasma and 42% for urine) were highly elevated in patients; whereas, a smaller percentage of phospholipids (PLs; 15% for plasma and 13% for urine) were significantly affected. Even though α-galactosidase A is reported to affect THC only, the results show that other classes of lipids (especially SLs) are changed as well, indicating that FD not only alters metabolism of THC but various classes of lipids too. Most lipids showing significant increases in relative amounts before ERT decreased after ERT, but overall, ERT influenced plasma lipids more than urinary lipids.

Objective: In 2020, the coronavirus disease 2019 (COVID-19) respiratory infection is spreading in Korea. In order to prevent the spread of an infectious disease, infected people must be quickly identified and isolated, and contact with the infected must be blocked early. This study attempted to verify the intervention effects on the spread of an infectious disease by using these measures in a mathematical model. Methods: We used the susceptible-infectious-recovery (SIR) model for a virtual population group connected by a special structured network. In the model, the infected state (I) was divided into I in which the infection is undetected and Ix in which the infection is detected. The probability of transitioning from an I state to Ix can be viewed as the rate at which an infected person is found. We assumed that only those connected to each other in the network can cause infection. In addition, this study attempted to evaluate the effects of isolation by temporarily removing the connection among these people. Results: In Scenario 1, only the infected are isolated; in Scenario 2, those who are connected to an infected person and are also found to be infected are isolated as well. In Scenario 3, everyone connected to an infected person are isolated. In Scenario 3, it was possible to effectively suppress the infectious disease even with a relatively slow rate of diagnosis and relatively high infection rate. Conclusion: During the epidemic, quick identification of the infected is helpful. In addition, it was possible to quantitatively show through a simulation evaluation that the management of infected individuals as well as those who are connected greatly helped to suppress the spread of infectious diseases.

Objectives This study was performed to evaluate the association between red blood cell distribution width (RDW) and 3-month mortality in patients with aneurysmal subarachnoid hemorrhage. Patients and methods This observational study was performed from March 2007 to May 2017 in an emergency department. The baseline characteristics and clinical and laboratory data were collected prospectively and analyzed. Clinical outcomes included 3-month mortality and poor functional outcome referred to as modified Rankin scale 3–6. Results A total 364 patients were included, and the overall 3-month mortality was 8.5%. The median RDW increased with disease severity classified according to the Hunt and Hess scale. RDW was significantly higher in patients with poor functional outcome than in patients with good functional outcome. The optimal RDW cutoff for predicting 3-month mortality was 13.9%. Cox regression analysis showed that higher RDW was independently associated with 3-month mortality (hazard ration 17.187, 95% CI 4.474–66.022). The area under the receiver-operating curve for RDW was 0.917 (95% CI 0.883–0.943). Conclusion An elevated RDW is associated with poor functional outcome and 3-month mortality in patients with aneurysmal subarachnoid hemorrhage.

Although cancer stem cells (CSC) are thought to be responsible for tumor recurrence and resistance to chemotherapy, CSC-related research and drug development have been hampered by the limited supply of diverse, patient-derived CSC. Here, we present a functional polymer thin film (PTF) platform that promotes conversion of cancer cells to highly tumorigenic three-dimensional (3D) spheroids without the use of biochemical or genetic manipulations. Culturing various human cancer cells on the specific PTF, poly(2,4,6,8-tetravinyl-2,4,6,8-tetramethyl cyclotetrasiloxane) (pV4D4), gave rise to numerous multicellular tumor spheroids within 24 hours with high efficiency and reproducibility. Cancer cells in the resulting spheroids showed a significant increase in the expression of CSC-associated genes and acquired increased drug resistance compared with two-dimensional monolayer-cultured controls. These spheroids also exhibited enhanced xenograft tumor-forming ability and metastatic capacity in nude mice. By enabling the generation of tumorigenic spheroids from diverse cancer cells, the surface platform described here harbors the potential to contribute to CSC-related basic research and drug development. Significance: A new cell culture technology enables highly tumorigenic 3D spheroids to be easily generated from various cancer cell sources in the common laboratory.

Background/Aims: This integrated analysis aimed to identify the factors associated with the most frequently re- ported treatment-emergent adverse events (TEAEs) in Asian and non-Asian patients with chronic constipation (CC) who receive prucalopride or placebo over 12 weeks. Methods: Pooled data from four randomized, double-blind, placebo- controlled, multicenter, phase III studies (NCT00488137, NCT00483886, NCT00485940, and NCT01116206) on pa- tients treated with prucalopride 2 mg or placebo were ana- lyzed. The associations between predictors and TEAEs were evaluated based on a logistic regression model. Results: Overall, 1,821 patients (Asian, 26.1%; non-Asian, 73.9%) were analyzed. Prucalopride treatment was significantly as- sociated with diarrhea, headache, and nausea (p

Cysteine plays a crucial role in cellular functions and in human pathologies. However, the development of cysteine probes with extremely accurate detection is still a key challenge for the field. Herein, we have fully characterized and developed a novel selective fluorescent probe: red emission, aqueous detection and large Stokes' shift for cysteine (Reals-C). Key in the probe synthesis is a Michael addition onto an acroylate group and subsequent intramolecular cyclization. The probe exhibits analyte detection via an intricate role set up by the leaving groups so to discriminate and form the red-emissive analyte sensing platform (λex =471 nm, λem =637 nm) through a chemical cascade pathway. Furthermore, the sensing ability of the probe was demonstrated by both in vitro and in vivo assays. This probe enables for successfully endogenous cysteine sensing in HaCaT human keratinocytes through comparison with a commercial thiol-sensitive probe; Reals-C shows excellent in vivo cysteine detection in a drug-induced animal liver injury model.

Bilirubin (BR), a bile pigment that exerts potent antioxidant and anti-inflammatory effects, is also a major constituent of black pigment gallstones found in bile ducts under certain pathological conditions. Inspired by the intrinsic metal-chelating power of BR found in gallstones, herein we report a cisplatin-chelated BR-based nanoparticle (cisPt@BRNP) for use as a new photonic nanomedicine for combined photoacoustic imaging and photothermal therapy of cancers. The cisPt@BRNPs were prepared by simply mixing cisplatin with BRNPs, yielding ca. 150-nm-size NPs. Upon near-IR laser irradiation at 808 nm, cisPt@BRNPs generated considerable heat and induced clear death of cancer cells in vitro. Following intravenous injection into human colon cancer-bearing mice, cisPt@BRNPs allowed effective tumor visualization by photoacoustic imaging and remarkable antitumor efficacy by photothermal therapy, suggesting their potential for use as a new photonic nanomedicine for cancer therapy.

Background: Eyelashes of Asians differ from those of Caucasians in morphology and growth characteristics. Ethnic differences also exist for the tolerability profile of prostaglandin analogues. Objective: To evaluate the long-term utility and durability of bimatoprost 0.03% in eyelash augmentation in Asian females. Methods: One cohort received bimatoprost 0.03% for 36 weeks and another for 20 weeks, with the latter cohort followed for 16 weeks after treatment cessation. The primary endpoint was the percent change in eyelash length at week 20. Secondary measures included percent change in eyelash thickness and darkness, physician's Global Eyelash Assessment and patient satisfaction. Results: At week 20, eyelash length was enhanced in a time-dependent manner, with maximum improvement achieved (19.3%; p < 0.0001). Significant improvements in thickness and darkness were also achieved (22.9%, 6.0%; p < 0.0001). 77.8% of subjects improved by ≥1 grade on Global Eyelash Assessment, with 83.1% satisfied/very satisfied. Improvements were maintained with ongoing treatment to 36 weeks, while these effects were progressively lost with discontinuation. Conclusion: Bimatoprost 0.03% safely enhanced eyelashes in Asian females, maintained with ongoing treatment. Cessation of treatment was associated with progressive loss of effects.

Summary Background Despite a growing understanding of the clinical effectiveness of endoscopic treatment for small rectal carcinoid tumors, there is still controversy concerning the best endoscopic treatment for resecting rectal carcinoid tumors easily and effectively. Objectives The objective of the present study was to compare the therapeutic efficacy and safety of endoscopic submucosal resection with a ligation device (ESMR-L) with endoscopic submucosal dissection (ESD) for rectal carcinoid tumors. In addition, a conventional snare-based endoscopic mucosal resection (EMR) was included in the study and compared with both ESMR-L and ESD. Methods A retrospective analysis was performed in 115 patients who underwent endoscopic resection of a rectal carcinoid tumor between January 2005 and June 2011. These patients were classified into three groups according to the type of endoscopic procedure: EMR group ( n = 33), ESMR-L group ( n = 40) and ESD group ( n = 44). Results The complete resection rate of the EMR group was significantly lower than those of the ESMR-L and ESD groups (77.4 vs. 100 and 97.7%, P = 0.002 and P = 0.007). Tumor-free vertical margins were significantly greater in the ESMR-L and ESD groups than in the EMR group (ESMR-L and ESD vs. EMR group, P = 0.013 and P = 0.041). The curative resection rate of rectal carcinoid tumors in the EMR group was 77.4%, which was significantly lower than that of the ESMR-L (95%, 38/40) and EDS groups (97.7%, 43/44) (77.4% vs. 95%, P = 0.036 and 77.4% vs. 97.7%, P = 0.007). Conclusions Our results show that ESMR-L and ESD might be superior to conventional EMR for the treatment of small rectal carcinoid tumors.

Metalloproteins (metal-binding proteins) refer to proteins containing metal ion cofactors. The importance of these proteins has increased owing to their involvement in many biological processes. Here, we introduce an analytical platform based on online coupling of miniaturized asymmetrical flow field-flow fractionation (mAF4) and inductively coupled plasma mass spectrometry (ICPMS) for size separation of proteins followed by the detection of metals associated with plasma metalloproteins. Not only did the mild separation of mAF4 get carried out in a biological buffer solution to minimize disruption of the metal-complex structure but free metal ions and salts from complicated biological samples were also removed during separation by crossflow. The relative quantities of metalloproteins detected by mAF4-ICPMS between plasma samples from patients with lung cancer and healthy controls were compared by determining the peak areas of detected elements and retention times; among these, 7 (55Mn, 60Ni, 63Cu, 66Zn, 9...

Introduction.The goal of this study was to determine the preventive effect on head injury by helmet type: full face helmet (FFH), open face helmet (OFH), and half-coverage helmet (HCH).Methods.This is a retrospective observational study of motorcycle crash victims between June 2012 and May 2015 in a rural town in Korea. We performed multiple linear regression to predict the effect of each type of helmet compared to unhelmeted status in preventing head injury using dependent variables based on the Abbreviated Injury Scale (AIS) and applied logistic regression modeling to compare the incidence of head injury.Results.Of the 738 patients, the number of FFH patients was 33.5%, followed by unhelmeted (27.8%), OFH (17.6%), and HCH (13.0%) patients. The FFH and OFH group had a lower head maximum AIS than unhelmeted group (coefficient: −0.368, 95% CI: −0.559 to −0.177 and coefficient: −0.235, 95% CI: −0.459 to −0.010, resp.) and only FFHs experienced a reduction effect of severe and minor head injury (OR: 0.206, 95% CI: 0.080 to 0.533 and OR: 0.589, 95% CI: 0.377 to 0.920, resp.).Conclusions.FFHs and OFHs reduce the risk of head injury, and FFHs have a more preventive effect on head injury in motorcycle crashes.

Combination of photodynamic therapy (PDT) with photothermal therapy (PTT) has achieved significantly improved therapeutic efficacy compared to a single phototherapy modality. However, most nanomaterials used for combined PDT/PTT are made of non-biodegradable materials (e.g., gold nanorods, carbon nanotubes, and graphenes) and may remain intact in the body for long time, raising concerns over their potential long-term toxicity. Here we report a new combined PDT/PTT nanomedicine, designated SP(3)NPs, that exhibit photo-decomposable, photodynamic and photothermal properties. SP(3)NPs were prepared by self-assembly of PEGylated cypate, comprising FDA-approved PEG and an ICG derivative. We confirmed the ability of SP(3)NPs to generate both singlet oxygen for a photodynamic effect and heat for photothermal therapy in response to NIR laser irradiation in vitro. Also, the unique ability of SP3NPs to undergo irreversible decomposition upon NIR laser irradiation was demonstrated. Further our experimental results demonstrated that SP(3)NPs strongly accumulated in tumor tissue owing to their highly PEGylated surface and relatively small size (similar to 60 nm), offering subsequent imaging-guided combined PDT/PTT treatment that resulted in tumor eradication and prolonged survival of mice. Taken together, our SP3NPs described here may represent a novel and facile approach for next-generation theranostics with great promise for translation into clinical practice in the future.

Summary The aim of this study was to determine the correlation between microsatellite instability (MSI) and young age in patients with advanced colorectal adenomas. We retrospectively analyzed young patients (≤ 40 years of age) with advanced adenomas (n = 84) between January 1996 and December 2006. We randomly selected the control group as patients ≥ 50 years of age with advanced adenomas (n = 84) during the same time period. Of these patients, the MSI test and MLH1 immunohistochemistry were performed in the available tissue samples from patients with advanced adenomas. The number of patients who had the two tests was 52 in the young group and 49 in the old group. The monomorphic nature of the BAT26 panel for MSI analysis was used without comparison of normal tissue. MSI was detected in three young patients (n = 52) and none of the old patients (n = 49). There was no statistical difference between the two groups (P = 0.243). All three young patients with MSI had a strong family history of colorectal cancer. MSI analysis was not a useful method of screening for HNPCC in young patients with advanced colorectal adenoma, at least in cases without a family history of colorectal cancer.

Newly developed uncovered stents are designed to have varied radial force and high conformability to improve clinical outcome and safety. This study aimed to determine and compare the clinical outcome and safety of the Taewoong D-type uncovered stent and the Boston Scientific Wallfex stent.Patients with acute malignant colonic obstruction were treated with a colonic stent. For the purpose of palliation, patients were randomly allocated. For the purpose of bridging, the type of stent was determined by the discretion of the individual doctors. Technical and clinical success and complication occurrence were measured as primary outcomes.From 12 university hospitals, 123 patients with malignant colonic obstruction were enrolled. Of these 123 patients, 58 were treated with colonic stents for palliative purposes. The technical and clinical success rate was 100 % for both stents in the palliative group. Perforation occurred for one patient (3.6 %) in the Wallflex stent group (n = 28) on day 5 and for no patients in the D-type stent group (n = 30). Two cases of migration occurred: one with the Wallflex stent and one with the D-type stent. Stent restenosis occurred for one patient with the Wallflex stent. Preoperative bridging stents were placed in 65 patients. The median time to surgery was 10 days. The technical success rate was 93.4 %, and clinical success was achieved for 86.2 % of the patients. Perforation occurred for five patients: four with the Wallflex stent and one with the D-type stent. The efficacy and safety of the two stents did not differ statistically.The D-type colonic uncovered stent and the Wallflex colonic uncovered stent are effective and safe for both palliative and preoperative bridging therapy used to treat acute malignant colonic obstruction.