Search

Intestinal neuropeptides and neurotrophins as endocrine messengers play a key role in the bidirectional gut-brain interaction both in health and disease status. Their alterations in several neurological disorders have been reported, but whether a remarkable change occurs in Parkinson disease (PD) remains unexplored. In this study, we aimed to investigate the levels of 13 neuropeptides and 4 neurotrophins in the intestine of neurotoxin-induced PD mice. The PD mice were obtained by chronic injection of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) or MPTP/probenecid (MPTP/p). The levels of mRNA and protein expression in mouse intestines were measured by using real-time reverse transcription polymerase chain reaction and Western blotting, respectively. We found that the mRNA expression of 2 neuropeptides (cholecystokinin [CCK] and dynorphin A [Dyn A]) and 2 neurotrophins (brain-derived neurotrophic factor [BDNF] and neurotrophin-5) was significantly decreased in the colon of MPTP group compared to the vehicle-treated group. The protein levels of CCK, Dyn A, and BDNF were reduced in the colon of MPTP- or MPTP/p-treated mice compared to those of the vehicle-treated group. These data suggest that the intestinal expression of CCK, Dyn A, and BDNF was significantly reduced in PD animal models, and may play a role in the gut-brain axis in PD., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

Skin photoaging occurs due to chronic exposure to solar ultraviolet radiation (UV), the main factor contributing to extrinsic skin aging. Clinical signs of photoaging include the formation of deep, coarse skin wrinkles and hyperpigmentation. Although melanogenesis and skin wrinkling occur in different skin cells and have different underlying mechanisms, their initiation involves intracellular calcium signaling via calcium ion channels. The ORAI1 channel initiates melanogenesis in melanocytes, and the TRPV1 channel initiates MMP-1 production in keratinocytes in response to UV stimulation. We aimed to develop a drug that may simultaneously inhibit ORAI1 and TRPV1 activity to help prevent photoaging. We synthesized nootkatol, a chemical derivative of valencene. TRPV1 and ORAI1 activities were measured using the whole-cell patch-clamp technique. Intracellular calcium concentration [Ca 2+ ]i was measured using calcium-sensitive fluorescent dye (Fura-2 AM). UV-induced melanin formation and MMP-1 production were quantified in B16F10 melanoma cells and HaCaT cells, respectively. Our results indicate that nootkatol (90 μM) reduced TRPV1 current by 94% ± 2% at -60 mV and ORAI1 current by 97% ± 1% at -120 mV. Intracellular calcium signaling was significantly inhibited by nootkatol in response to ORAI1 activation in human primary melanocytes (51.6% ± 0.98% at 100 μM). Additionally, UV-induced melanin synthesis was reduced by 76.38% ± 5.90% in B16F10 melanoma cells, and UV-induced MMP-1 production was reduced by 59.33% ± 1.49% in HaCaT cells. In conclusion, nootkatol inhibits both TRPV1 and ORAI1 to prevent photoaging, and targeting ion channels may be a promising strategy for preventing photoaging.

Global coupled chemistry-climate models underestimate carbon monoxide (CO) in the Northern Hemisphere, exhibiting a pervasive negative bias against measurements peaking in late winter and early spring. While this bias has been commonly attributed to underestimation of direct anthropogenic and biomass burning emissions, chemical production and loss via OH reaction from emissions of anthropogenic and biogenic volatile organic compounds (VOCs) play an important role. Here we investigate the reasons for this underestimation using aircraft measurements taken in May and June 2016 from the Korea-United States Air Quality (KORUS-AQ) experiment in South Korea and the Air Chemistry Research in Asia (ARIAs) in the North China Plain (NCP). For reference, multispectral CO retrievals (V8J) from the Measurements of Pollution in the Troposphere (MOPITT) are jointly assimilated with meteorological observations using an ensemble adjustment Kalman filter (EAKF) within the global Community Atmosphere Model with Chemistry (CAM-Chem) and the Data Assimilation Research Testbed (DART). With regard to KORUS-AQ data, CO is underestimated by 42% in the control run and by 12% with the MOPITT assimilation run. The inversion suggests an underestimation of anthropogenic CO sources in many regions, by up to 80% for northern China, with large increments over the Liaoning Province and the North China Plain (NCP). Yet, an often-overlooked aspect of these inversions is that correcting the underestimation in anthropogenic CO emissions also improves the comparison with observational O 3 datasets and observationally constrained box model simulations of OH and HO 2 . Running a CAM-Chem simulation with the updated emissions of anthropogenic CO reduces the bias by 29% for CO, 18% for ozone, 11% for HO 2 , and 27% for OH. Longer-lived anthropogenic VOCs whose model errors are correlated with CO are also improved, while short-lived VOCs, including formaldehyde, are difficult to constrain solely by assimilating satellite retrievals of CO. During an anticyclonic episode, better simulation of O 3 , with an average underestimation of 5.5 ppbv, and a reduction in the bias of surface formaldehyde and oxygenated VOCs can be achieved by separately increasing by a factor of 2 the modeled biogenic emissions for the plant functional types found in Korea. Results also suggest that controlling VOC and CO emissions, in addition to widespread NO x controls, can improve ozone pollution over East Asia., Competing Interests: Competing interests. The authors declare that they have no conflict of interest.

We investigated locking behaviors of coupled limit-cycle oscillators with phase and amplitude dynamics. We focused on how the dynamics are affected by inhomogeneous coupling strength and by angular and radial shifts in coupling functions. We performed mean-field analyses of oscillator systems with inhomogeneous coupling strength, testing Gaussian, power-law, and brain-like degree distributions. Even for oscillators with identical intrinsic frequencies and intrinsic amplitudes, we found that the coupling strength distribution and the coupling function generated a wide repertoire of phase and amplitude dynamics. These included fully and partially locked states in which high-degree or low-degree nodes would phase-lead the network. The mean-field analytical findings were confirmed via numerical simulations. The results suggest that, in oscillator systems in which individual nodes can independently vary their amplitude over time, qualitatively different dynamics can be produced via shifts in the coupling strength distribution and the coupling form. Of particular relevance to information flows in oscillator networks, changes in the non-specific drive to individual nodes can make high-degree nodes phase-lag or phase-lead the rest of the network.

In hematopoietic stem cell transplant recipients, the incidence of tuberculosis in positive interferon-γ release assay (IGRA) without isoniazid prophylaxis (3.58/100 person-years) was higher than in negative or indeterminate IGRA (1.15/100 person-years; P = .01) and in positive IGRA with isoniazid prophylaxis (0/100 person-years; P = .09). The number needed to treat was 22 (95% confidence interval, 12-99) with positive IGRA results., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the conversion of oncogenic prostaglandin E 2 to non-tumerigenic 15-keto prostaglandin E 2 . In the present study, we found that curcumin, a yellow coloring agent present in the rhizome of Curcuma longa Linn (Zingiberaceae), induced expression of 15-PGDH at the both transcriptional and translational levels in normal rat gastric mucosal cells. By using deletion constructs of 15-PGDH promoter, we were able to demonstrate that activator protein-1 (AP-1) is the principal transcription factor responsible for regulating curcumin-induced 15-PGDH expression. Curcumin enhanced the expression of c-Jun and c-Fos that are functional subunits of AP-1, in the nuclear fraction of cells. Silencing of c-Jun suppressed curcumin-induced expression of 15-PGDH. Moreover, the chromatin immunoprecipitation assay revealed curcumin-induced binding of c-Jun to the AP-1 consensus sequence present in the 15-PGDH promoter. Curcumin increased phosphorylation of ERK1/2 and JNK, and pharmacologic inhibition of these kinases abrogated the curcumin-induced phosphorylation of c-Jun and 15-PGDH expression. In contrast, tetrahydrocurcumin which lacks the α,β-unsaturated carbonyl group failed to induce 15-PGDH expression, suggesting that the electrophilic carbonyl group of curcumin is essential for its induction of 15-PGDH expression. Curcumin restored the expression of 15-PGDH which is down-regulated by Helicobacter pylori through suppression of DNA methyltransferase 1. In addition, oral administration of curcumin increased the expression of 15-PGDH and its regulators such as p-ERK1/2, p-JNK, and c-Jun in the mouse stomach. Taken together, these findings suggest that curcumin-induced upregulation of 15-PGDH may contribute to chemopreventive effects of this phytochemical on inflammation-associated gastric carcinogenesis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Colistin is an important antibiotic currently used to manage infections caused by multidrug-resistant pathogens in both humans and livestock animals. A new mobile colistin-resistance ( mcr-9 ) gene was recently discovered; this discovery highlighted the need for rigorous monitoring of bacterial resistance against colistin. Salmonella is one of the major pathogens responsible for foodborne illnesses; however, there is minimal information regarding the presence of mcr genes in foodborne Salmonella strains. The aim of this study was to investigate the presence of mcr genes among 178 Salmonella strains isolated from chicken meat in Korea. Antimicrobial susceptibility was measured using the broth microdilution method. Bioinformatics characterization of colistin-resistant strains and genetic environment of the mcr-9 gene were analyzed using next-generation sequencing. Transferability of the mcr-9 carrying colistin-resistant Salmonella strain was tested using broth-mating conjugation. Thirteen of the 178 Salmonella isolates showed colistin resistance, but only one strain, Salmonella Dessau ST14 (KUFSE-SAL043) from a traditional chicken market in Korea, carried an mcr family gene, mcr-9 . This strain also carried other acquired antimicrobial resistance genes such as bla TEM-1B , qnrS1 , and aac(6')-Iaa . Only the IncX1 plasmid replicon type was detected in this strain. In the strain KUFSE-SAL043, the mcr-9 gene was located between two insertion sequences, IS 903B and IS 26 , followed by the downstream regulatory genes qseB -like and qseC -like, which were located between IS 1R and Δ IS 1R . Conjugation tests revealed that the mcr-9 gene was successfully transferred to Escherichia coli J53 at a mean frequency of 2.03 × 10 -7 . This is the first report of a transferable mcr-9 gene in Salmonella isolated from chicken meat in Korea, highlighting the possibility of transfer of colistin resistance. Therefore, the wide use of colistin should be reconsidered, and a One Health perspective should be adopted to monitor the antimicrobial resistance of Enterobacteriaceae strains in humans, livestock, and the environment.

Data regarding extraintestinal Clostridioides difficile infections (ECDIs) remain scarce and anecdotal. We conducted a retrospective cohort study to investigate characteristics and prognostic factors in patients with ECDI. From January 1997 through December 2018, 60 patients were enrolled and divided into three groups as follows: group A (gastrointestinal [GI] disruption caused by malignancy, n = 13); group B (GI disruption from causes other than malignancy, n = 25); group C (no GI disruption, n = 22). GI disruption was defined as compromised integrity of the GI tract caused by abdominal surgery, perforation, malignancy, enterocolitis, or bleeding. The incidence of ECDI was 2.53 per 100,000 admissions. The most common specimens yielded C. difficile were blood (36.7%), peritoneal fluid (20.0%), and abscesses (16.7%). Six patients (10.0%) had confirmed C. difficile enterocolitis, and 36 patients (60.0%) had a polymicrobial infection. C. difficile bacteremia was significantly more common in group A patients than those in groups B or C (53.8% vs. 48.0% vs. 13.6%, p = 0.02), as was the 30-day mortality rate (69.2% vs. 12.0% vs. 18.2%, respectively; p < 0.001). In multivariate analysis, group A (adjusted odds ratio [aOR], 17.32; 95% confidence interval [CI], 2.96-101.21; p = 0.002) and an age of > 65 years (aOR, 7.09; 95% CI, 1.31-38.45; p = 0.02) were independent risk factors for 30-day mortality. ECDI was uncommonly associated with C. difficile enterocolitis. Two factors, GI disruption caused by malignancy, and old age, were associated with significantly poorer short-term outcomes.

Burkholderia cepacia complex (BCC) is an emerging pathogen of nosocomial infection in chronic or critically ill patients without cystic fibrosis (CF). The objective was to evaluate the management and outcomes of BCC bacteremia in patients without CF. We conducted a retrospective study of non-CF adult patients with BCC bacteremia between January 1997 and December 2016 at 4 tertiary hospitals in South Korea. A total of 216 non-CF patients with BCC bacteremia were identified. Most cases were hospital-acquired (79.2%), and the most common source was a central venous catheter (CVC) (42.1%). The rates of susceptibility to trimethoprim-sulfamethoxazole and piperacillin-tazobactam of BCC isolates were high as 92.8% and 90.3%, respectively. The rates of susceptibility to ceftazidime, meropenem, and levofloxacin were 75.5%, 72.3%, and 64.1%, respectively. The 14-day, 30-day, and in-hospital mortality rate was 19.4%, 23.1%, and 31.0%, respectively. Female (OR = 3.1; 95% CI, 1.4-6.8), liver cirrhosis (OR = 6.2; 95% CI, 1.6-16.6), septic shock (OR = 11.2; 95% CI, 5.1-24.8), and catheter-related infection (OR = 2.6, 95% CI, 1.2-5.8) were the independent risk factors for 30-day mortality. The outcome did not differ according to type of antibiotics used. Among 91 patients with CVC-related BCC bacteremia, delayed CVC removal (> 3 days) had a higher rate of persistent bacteremia (54.5 vs. 26.1%; P = 0.03) and lower rate of clinical response (49.0 vs. 71.9%; P = 0.04), compared with early CVC removal (within 3 days). BCC bacteremia occurring in non-CF patients was mostly hospital-acquired and CVC-related. Early removal of the catheter is crucial in treatment of CVC-related BCC bacteremia.

The Korean Society of Laryngology, Phoniatrics and Logopedics appointed a task force to establish clinical practice guidelines for the management of unilateral vocal fold paralysis (UVFP). These guidelines cover a comprehensive range of management-related factors, including the diagnosis and treatment of UVFP, and provide in-depth information based on current, up-to-date knowledge. Detailed evidence profiles are provided for each recommendation. The CORE databases, including OVID Medline, Embase, the Cochrane Library, and KoreaMed, were searched to identify all relevant papers, using a predefined search strategy. When insufficient evidence existed, expert opinions and Delphi questionnaires were used to fill the evidence gap. The committee developed 16 evidence-based recommendations in six categories: initial evaluation (R1-4), spontaneous recovery (R5), medical treatment (R6), surgical treatment (R7-14), voice therapy (R15), and aspiration prevention (R16). The goal of these guidelines is to assist general otolaryngologists and speech-language pathologists who are primarily responsible for treating patients with UVFP. These guidelines are also intended to facilitate understanding of the condition among other health-care providers, including primary care physicians, nurses, and policy-makers.

High levels of iron in the peritoneal cavity during menstruation have been implicated in the pathogenesis of endometriosis. However, whether iron directly affects the growth or migration of human endometriotic cells is poorly understood. This study demonstrated the presence of increased levels of the iron storage protein, ferritin, in the endometriotic tissues of patients with endometriosis. Furthermore, iron treatment stimulated the migration and epithelial-mesenchymal transition (EMT), but not growth, of 12Z human endometriotic cells. The expression of matrix metalloproteinase (MMP)-2/-9 was markedly increased through iron treatment in 12Z cells. Interestingly, intracellular reactive oxygen species (ROS) levels were significantly increased by iron in 12Z cells, and N-acetyl-L-cysteine significantly reduced iron-induced migration and MMP-2/-9 expression. Additionally, iron stimulated the activation of the NFκB pathway, and the activation was associated with iron-induced migration and MMP-2/-9 expression in 12Z cells. Moreover, iron markedly increased EMT and MMP-2/-9 expression in endometriotic lesions in an endometriosis mouse model. Taken together, these results suggest that iron may contribute to the migration abilities of human endometriotic cells via MMP expression through the ROS-NFκB pathway.

Background: Protective mechanical ventilation using low tidal volume has been introduced to surgical patients to reduce the incidence of postoperative pulmonary complications. We investigated the effects of protective ventilation (PV) techniques on anesthesia-induced atelectasis identified via lung ultrasonography in patients undergoing abdominal surgery., Methods: A total of 42 adult patients who were scheduled for open abdominal surgery with an expected duration > 2 hours were included in the study. Patients were randomized to receive either conventional ventilation (CV; tidal volume of 9-10 mL/kg predicted body weight [PBW] with no positive end-expiratory pressure [PEEP]) or PV (tidal volume of 6-8 mL/kg PBW and 5 cmH₂O PEEP) via pressure-controlled ventilation with volume guaranteed. Lung ultrasonography was performed at four predefined time points to assess perioperative atelectasis by dividing each hemithorax into six quadrants based on a modified lung ultrasound (LUS) scoring system., Results: The tidal volume delivered to patients was 9.65 ± 1.65 mL/kg PBW in the CV group and 6.31 ± 0.62 mL/kg PBW in the PV group. Ventilation using low tidal volume led to similar LUS scores in all lung areas and at all time points compared to ventilation using high tidal volume. There was no significant difference between the groups in the number of patients requiring recruitment maneuvers at the end of surgery., Conclusion: Ventilation with low tidal volume combined with 5 cmH₂O PEEP did not cause further loss of aeration compared to ventilation with high tidal volume. Low tidal volume ventilation can be used in patients without lung injury based on lung assessment by bedside lung ultrasonography., Trial Registration: Clinical Research Information Service Identifier: KCT0003746., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)

Objectives: The aims of this study were to identify whether the site of acquisition or the underlying carbapenem-resistant Enterobacteriaceae (CRE) resistance mechanism was associated with clinical outcomes, and to evaluate risk factors for 14-day mortality in patients with CRE bacteremia., Materials and Methods: A retrospective cohort study was conducted at a 2700-bed tertiary center. All adult patients with monomicrobial carbapenem-resistant Escherichia coli or Klebsiella pneumoniae bacteremia from 2011 to 2018 were included. All blood isolates collected were tested with a modified carbapenem inactivation method for phenotypic detection of carbapenemase., Results: Of 133 patients with monomicrobial CRE bacteremia, 63 (47.4%) were infected with carbapenemase-producing CRE (CP-CRE), and 70 (52.6%) with non-CP-CRE. Patients with community-onset infection (COI) were more likely to present with biliary or urinary tract infections, less likely to have ineradicable or non-eradicated foci and to receive appropriate empirical therapy, and marginally more likely to have CP-CRE compared with those with hospital-acquired infection (HAI). However, 14-day mortality was significantly lower in COI than HAI (7% vs 29%, P = 0.01). Patients who died were more likely to have had a higher APACHE II score, ineradicable or non-eradicated foci, and a lower chance of having received appropriate antibiotic treatment. Multivariate analysis revealed that HAI, high APACHE II score, and inappropriate antibiotic treatment were independent risk factors for mortality. Carbapenemase production did not affect mortality., Conclusions: The results of this study indicate that timely, appropriate treatment is essential for managing CRE bacteremia, regardless of carbapenemase production, particularly in critically ill patients with hospital-acquired bacteremia., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Staphylococcus aureus is a virulent gram-positive organism, which rarely involves the biliary tract. This study aimed to analyze the clinical characteristics and outcomes of S. aureus bacteremia (SAB) originating from the biliary tract by comparing them with those of catheter-related SAB and biliary Klebsiella pneumoniae bacteremia. A matched case-control study within a prospective observational cohort of patients with SAB was conducted. Biliary SAB was defined as the isolation of S. aureus from blood cultures with symptoms and signs of biliary infection. Biliary SAB patients were matched (1:3) with the control groups: patients with catheter-related SAB and biliary Klebsiella pneumoniae bacteremia. Out of 1818 patients with SAB enrolled in the cohort, 42 (2%) had biliary SAB. Majority of these patients had solid tumors involving the pancreaticobiliary tract or liver, biliary drainage stent, and/or recent broad-spectrum antibiotic exposure. Patients with biliary SAB were more likely to have community-onset SAB, solid tumors, and lower APACHE II score than those with catheter-related SAB. They were less likely to have community-acquired infection and solid tumors and more likely to have lower Charlson comorbidity index and higher APACHE II score as compared with biliary K. pneumoniae bacteremia. The 12-week mortality in the biliary SAB group was higher than those in other control groups (60% vs. 20% and 14%). After adjusting for confounding factors, biliary SAB was independently associated with higher mortality. Biliary SAB is relatively rare. When it is clinically suspected, early aggressive treatment should be considered due to high mortality.

Aim: To evaluate the outcomes and complications of hybrid Descemet membrane endothelial keratoplasty (H-DMEK) using a Descemet stripping automated endothelial keratoplasty (DSAEK) pull-through donor inserter and donor stroma as carrier., Methods: This was a retrospective interventional case series of eyes with bullous keratopathy (BK) and Fuchs endothelial corneal dystrophy (FECD), which underwent H-DMEK, performed using a bimanual pull-through technique using DSAEK-prepared donor stroma as carrier and the EndoGlide Ultrathin DSAEK donor insertion device. Complex cases with tube shunts, trabeculectomy, aphakia, aniridia, previous vitrectomy, keratoplasty or combined with intraocular lens exchange, were also included. The outcome measures were intraoperative and postoperative complications, best corrected visual acuity (BCVA) and endothelial cell loss after surgery., Results: Of the 85 eyes from 79 patients, 43.5% (n=37) had BK, 28.2% (n=24) had FECD while 24.7% (n=21) had failed grafts. DMEK was performed in 37 complex eyes (43.5%). Four eyes (4.7%) required rebubbling for graft detachment and two cases of graft failure were observed. A BCVA of 20/25 or better was attained in 44.7% and 57.1% of eyes without pre-existing ocular pathology at 6 and 12 months, respectively. The overall endothelial cell loss was 32.2%±20.5% at 6 months, which improved from 37.2%±20.9% to 24.2%±17.5%, comparing the first 40 and last 45 cases (p=0.012)., Conclusion: Hybrid DMEK offers a controlled 'pull-through' technique of donor insertion in the 'endothelium-in' configuration, which may be useful especially in complicated eyes. More studies are needed to confirm the long-term endothelial cell loss and graft survival associated with this technique., Competing Interests: Competing interests: DT: Patent of EndoGlide (royalties to Network Medical), (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The purpose of this study was to investigate the differences in CT characteristics and disease spread patterns between ROS1-rearranged adenocarcinomas and epidermal growth factor receptor (EGFR)-mutant or anaplastic lymphoma kinase (ALK)-rearranged adenocarcinomas. Patients with stage IIIb/IV adenocarcinoma with ROS1 rearrangement, EGFR mutations, or ALK rearrangement were retrospectively identified. Two radiologists evaluated CT features and disease spread patterns. A multivariable logistic regression model was applied to determine the clinical and CT characteristics that can discriminate between ROS1-rearranged and EGFR-mutant or ALK-rearranged adenocarcinomas. A cohort of 169 patients was identified (ROS1 = 23, EGFR = 120, and ALK = 26). Compared to EGFR-mutant adenocarcinomas, ROS1-rearranged adenocarcinomas were less likely to have air-bronchogram (p = 0.011) and pleural retraction (p = 0.048) and more likely to have pleural effusion (p = 0.025), pericardial metastases (p < 0.001), intrathoracic and extrathoracic nodal metastases (p = 0.047 and 0.023, respectively), and brain metastases (p = 0.017). Following multivariable analysis, age (OR = 1.06; 95% CI: 1.01, 1.12; p = 0.024), pericardial metastases (OR = 10.50; 95% CI: 2.10, 52.60; p = 0.005), and nodal metastases (OR = 8.55; 95% CI: 1.14, 62.52; p = 0.037) were found to be more common in ROS1-rearranged tumors than in non-ROS1-rearranged tumors. ROS1-rearranged adenocarcinomas appeared as solid tumors and were associated with young age, pericardial metastases and advanced nodal metastases relative to tumors with EGFR mutations or ALK rearrangement.

There are limited long-term data on the trends in incidence and characteristics of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (MRSAB) in intensive care units (ICUs) in which infection control measures have been adopted. We evaluated the trend of incidence and changes in characteristics of MRSA bacteremia in ICUs at a tertiary-care hospital over 10 years using prospective cohort data. ICU-acquired bacteremia was defined as S. aureus bacteremia (SAB) that occurred 48 h or more after ICU admission. MRSA isolates were collected and subjected to microbiological and genotypic analyses. A total of 529 SAB episodes were identified among 367,175 ICU patients. Of these episodes, 288 (54.4%) were ICU acquired, 238 (82.6%) of which were MRSAB. The incidence density of ICU-acquired MRSAB decreased from 1.32 per 1,000 patient-days to 0.19 per 1,000 patient-days (a decrease of 20% annually; P <  0.001 for trend), whereas that of non-ICU-acquired MRSAB fluctuated and did not decrease significantly. The decline in ICU-acquired MRSAB was due to lower catheter-related infection and less pneumonia. Rates of persistent bacteremia and 12-week mortality also fell significantly. A total of 183 isolates were collected from 238 ICU-acquired MRSAB cases. There were no significant changes in the geometric means of vancomycin MICs, vancomycin heteroresistance, or the sequence types of MRSA isolates over time. Chlorhexidine MICs decreased ( P <  0.001 for trend) in association with a decline in frequency of the qacA or qacB gene that was related to reductions in specific spa types. The incidence of MRSAB in ICUs has decreased dramatically over time, but most of the microbiological and genotypic characteristics of MRSA isolates have not changed., (Copyright © 2020 American Society for Microbiology.)

Objectives: We evaluated the effectiveness of IGRA-based isoniazid (INH) treatment with the diagnostic value of quantitative IGRA titer for post-transplant tuberculosis (TB) in kidney transplant (KT) recipients., Methods: All adult KT recipients were enrolled from January 2014 to December 2017. The development of TB after KT was observed, stratified by quantitative IGRA results as well as by IGRA results with/without INH treatment., Results: Of 1150 KT recipients, 322 (28%) revealed positive IGRA results (≥0.35 IU/mL) and 12 (1.0%) developed TB. Seven (3.2%) of 217 patients with positive IGRA without INH developed TB, whereas none of 105 patients with positive IGRA with INH developed TB (rate difference -1616 per 100,000 person-years, P = 0.016) and 5 (0.6%) of 828 patients with negative or indeterminate IGRA developed TB (rate difference -1388 per 100,000 person-years, P<0.001). Among the 217 positive IGRA patients without INH, 6 (6.4%) of 94 patients who had positive IGRA titer>2.96 IU/mL developed TB, whereas one (0.8%) of 123 patients who had positive IGRA titer≤2.96 IU/mL developed TB (rate difference 2964 per 100,000 person-years, P = 0.017)., Conclusions: IGRA-based INH treatment with risk stratification by quantitative IGRA results appears to be effective to prevent the development of TB in KT recipients., Competing Interests: Declaration of Competing Interest The authors of this manuscript have no conflicts of interest to disclose as described by the Journal of Infection., (Copyright © 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Granular corneal dystrophy type 2 (GCD2) is the most common form of transforming growth factor β-induced (TGFBI) gene-linked corneal dystrophy and is pathologically characterized by the corneal deposition of mutant-TGFBIp. The defective autophagic degradation of pathogenic mutant-TGFBIp has been shown in GCD2; however, its exact mechanisms are unknown. To address this, we investigated lysosomal functions using corneal fibroblasts. Levels of cathepsins K and L (CTSK and CTSL) were significantly decreased in GCD2 cells, but of cathepsins B and D (CTSB and CTSD) did not change. The maturation of the pro-enzymes to their active forms (CTSB, CTSK and CTSL) was inhibited in GCD2 cells. CTSL enzymes directly degraded both LC3 (autophagosomes marker) and mutant-TGFBIp. Exogenous CTSL expression dramatically reduced mutant-TGFBIp in GCD2 cells, but not TGFBIp in WT cells. An increased lysosomal pH and clustered lysosomal perinuclear position were found in GCD2 cells. Transcription factor EB (TFEB) levels were significantly reduced in GCD2 cells, compared to WT. Notably, exogenous TFEB expression improved mutant-TGFBIp clearance and lysosomal abnormalities in GCD2 cells. Taken together, lysosomal dysfunction in the corneal fibroblasts underlies the pathogenesis of GCD2, and TFEB has a therapeutic potential in the treatment of GCD2., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Epstein-Barr virus (EBV) is etiologically associated with ~ 10% of all gastric carcinomas. However, the molecular mechanisms and roles of EBV miRNAs in gastric carcinoma oncogenesis are yet to be elucidated., Methods: MicroRNA microarray and TaqMan quantitative real-time RT-PCR were conducted. RT-PCR and luciferase reporter assay for PIAS3, western blotting for 20 proteins, immunofluorescence for STAT3, transfection with miRBART5-5p-plasmid, STAT3-plasmid, miRBART5-5p mimic, or PIAS3-siRNA, and in vitro assays for biological effects of PD-L1 were implemented. In situ hybridization for EBV-encoded small RNAs and immunohistochemistry were performed on gastric carcinoma tissues., Results: Transfecting miR-BART5-5p into EBV(-) gastric carcinoma cell lines caused a decrease in PIAS3 3'-UTR reporter activity, PIAS3 downregulation, and subsequent STAT3 activation followed by PIAS3/pSTAT3-dependent PD-L1 upregulation. Interestingly, due to PD-L1 knockdown, apoptosis was increased, while the rate of cell proliferation, invasion capacity, and migration were decreased in miR-BART5-5p-transfected cells. In EBV(+) gastric carcinoma cells, anti-miR-BART5-5p reduced PD-L1 levels through PIAS3/pSTAT3 control. Among 103 patients with EBV-associated gastric carcinomas, overall survival was significantly shortened for those with PD-L1(+) tumors compared to those with PD-L1(-) tumors (P = 0.049)., Conclusions: Our findings imply that miR-BART5-5p directly targets PIAS3 and augments PD-L1 through miR-BART5/PIAS3/pSTAT3/PD-L1 axis control. This contributes to antiapoptosis, tumor cell proliferation, invasion and migration, as well as immune escape, furthering gastric carcinoma progression and worsening the clinical outcome, especially in the PD-L1(+) group of patients with EBV-associated gastric carcinomas. miR-BART5-5p may, therefore, be amenable to PD-1/PD-L1 immune checkpoint inhibitor therapy.

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) infection is associated with significant mortality, causing worldwide concern, yet there are limited data on contributing microbiological factors. This study aimed to identify the clinical and microbiologic risk factors for mortality in CRAB bacteremia., Methods: Adult patients with monomicrobial CRAB bacteremia in a 2700-bed tertiary hospital between December 2012 and December 2018 were retrospectively enrolled. Risk factors for 30-day mortality were evaluated. All isolates collected on the first day of bacteremia were subjected to colistin susceptibility testing by broth microdilution and to genotyping by multilocus sequence typing., Results: A total of 164 patients were enrolled, and 90 (55%) died within 30 days. The most common genotype among the isolates was ST191 (49%), and 12 isolates (7%) were resistant to colistin. Genotype, colistin minimum inhibitory concentration, and colistin resistance were not significantly associated with mortality, in contrast to several clinical factors. In multivariable analysis, ineradicable or not-eradicated focus (adjusted odds ratio [aOR], 4.92; 95% CI, 1.95-12.42; P = .001), septic shock (aOR, 4.72; 95% CI, 2.12-10.49; P < .001), and inappropriate antimicrobial therapy (aOR, 2.54; 95% CI, 1.05-6.16; P = .04) were independent risk factors for mortality. Among antibiotic strategies, colistin combined with tigecycline or other antibiotics were significantly associated with lower mortality after adjustment for confounding factors., Conclusions: Clinical factors such as the nature of the infection source and source control, severity of bacteremia, and appropriateness of antibiotics, rather than microbiological factors, contribute to mortality in CRAB bacteremia. A specific antibiotic combination may help improve outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: To evaluate the relationship between delay to computed tomography perfusion and estimated core infarct volumes in patients with large vessel occlusion (LVO)., Patients and Methods: A retrospective registry of consecutive adults >18 years old who underwent CTP in clinical practice for suspected LVO within 24 h of LKN at 3 academic hospitals was queried (06/2017 - 12/2017). CT and CTP findings were compared over time as a continuous variable, and dichotomized by ≤6 h or 6-24 h from LKN., Results: Of 410 screened patients, 75 had LVO, of whom 60 (14.6 %) met inclusion criteria (median age 78y [IQR 64-84], 36 were female [60 %]), and 39 (65.0 %) underwent thrombectomy. Thirty (50 %) presented in the extended window (6-24 h) and had lower ASPECTS scores compared to patients in the early window (median 7 vs. 9, p < 0.01). Perfusion core (rCBF <30 %) volumes were similar (median 8 vs. 25, p = 0.10). After adjustment for age, NIHSS, and thrombolysis, there was a trend for lower ASPECTS for every hour after LKN (proportional OR 0.92, 95 %CI 0.84-1.00, p = 0.06), but no change in perfusion core (p = 0.37) or T max >6 s volumes (p = 0.29), or mismatch ratios (p = 0.48) after adjusting for age, NIHSS, ASPECTS, and thrombolysis., Conclusion: As time progresses in anterior LVO, the unenhanced CT is more sensitive than CTP for detecting irreversibly damaged tissue. These results underscore the importance of carefully reviewing the unenhanced and perfusion CT when considering a patient for thrombectomy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Pulmonary mucormycosis (PM) represents a serious burden in terms of morbidity and mortality in immunocompromised patients. Studies of prognostic factors in patients with PM are limited and have involved small numbers of patients., Methods: Adult patients diagnosed with proven and probable PM according to the modified definitions of the EORTC/MSG 2008 in a tertiary hospital in Seoul, South Korea, between 2008 and 2019 were retrospectively enrolled., Results: A total of 49 patients including 31 (63%) with proven PM and 18 (37%) with probable PM were enrolled. The 90-day mortality rate was 49% (24/49). Neutropenia, thrombocytopenia, use of voriconazole at clinical suspicion, positivity of non-sterile culture, use of steroid and treatment without surgery were more common in fatal cases than non-fatal cases. Voriconazole use at clinical suspicion for invasive mould pneumonia (OR 6.91, P = .01) and prolonged neutropenia (OR 4.86, P = .03) were independent risk factors for mortality. Voriconazole use at clinical suspicion was associated with positive galactomannan (GM) assay (OR 5.93, P = .02) and history of invasive pulmonary aspergillosis (OR, 6.88, P = .05)., Conclusion: About half of the patients with PM died within 90 days of diagnosis, and fatal outcomes were common in patients with prolonged neutropenia and empirical voriconazole use. Caution is needed in using voriconazole even in patients with positive GM results and prior histories of invasive pulmonary aspergillosis in whom PM cannot be ruled out by differential diagnosis., (© 2020 Blackwell Verlag GmbH.)

Objectives: Currently available interferon (IFN)-γ-release assays (IGRA) cannot discriminate active tuberculosis (TB) from latent TB infection (LTBI), and so have limited clinical utility for diagnosing active TB. Since numbers of tumour necrosis factor (TNF)-α-producing T cells are highly correlated with active TB, we hypothesized that detecting IFN-γ- and/or TNF-α-producing T cells would overcome this limitation of IGRA. This study evaluated the diagnostic performances of the IFN-γ and TNF-α dual release fluorospot assay for active TB., Methods: Adult patients with suspected TB including recent TB exposers were prospectively enrolled over a 28-month period. In addition to the conventional IGRA test (i.e. QuantiFERON-In-Tube), a fluorospot assay for detecting IFN-γ- and TNF-α-producing T cells was performed. The final diagnoses were classified by clinical category. Patients with confirmed or probable TB were regarded as active TB, and patients with not active TB were further classified as having not active TB with and without LTBI, based on the QuantiFERON-In-Tube results., Results: A total of 153 patients including 45 with active TB and 108 with not active TB (38 LTBI vs. 70 not LTBI) were finally analysed. The sensitivity and specificity of the QuantiFERON-In-Tube assay for active TB were 84% (95% confidence interval (CI), 70-93) and 70% (95% CI 61-79), respectively. The IFN-γ/TNF-α dual release assay by fluorospot had substantially higher diagnostic specificity (94%) for diagnosing active TB than the IFN-γ single release assay (72%, p < 0.001), without compromising sensitivity (84% vs. 89%, p 0.79)., Conclusions: The fluorospot-based IFN-γ/TNF-α dual release assay appears to be a simple and useful test for diagnosing active TB., (Copyright © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Bedside sonography of the inferior vena cava has been demonstrated to be a reliable tool for assessing intravascular volume status. Subclavian vein (SCV) assessment was proposed as a reasonable adjunct for measuring the inferior vena cava., Objective: We examined whether the preoperative diameter and collapsibility index of the SCV or the infraclavicular axillary vein could predict the incidence of hypotension after induction of general anaesthesia in patients undergoing laparoscopic cholecystectomy., Design: Prospective, observational study., Setting: Tertiary university hospital., Patients: Adults scheduled for laparoscopic cholecystectomy., Intervention: Sonographic evaluation of the SCV or the axillary vein (SCV-AV) before induction of anaesthesia., Main Outcome Measures: The main outcome was the association between the SCV-AV measurements (diameter an collapsibility index) and intra-operative hypotension (IOH) after induction of anaesthesia., Results: Patients who developed IOH had a higher collapsibility index of the SCV-AV during spontaneous breathing (P = 0.009) and deep inspiration (P = 0.002). After adjusting for confounding variables, the collapsibility index of the SCV-AV during spontaneous breathing was not a significant predictor of a decrease in mean arterial blood pressure (MAP) after inducing anaesthesia (P = 0.127), whereas the collapsibility index of the SCV-AV during deep inspiration was a significant predictor (P < 0.001)., Conclusion: The collapsibility index of the SCV-AV during deep inspiration was a significant predictor of IOH occurrence and the percentage decrease in MAP after inducing anaesthesia. Further studies in patients with higher collapsibility index are needed to confirm our findings, before the collapsibility index of the SCV-AV can be recommended unequivocally for clinical use., Trial Registration: This trial was registered on 8 September 2017 at the Clinical Trial Registry of Korea (https://cris.nih.go.kr/cris/index.jsp; Identifier: KCT0001078KCT0002457), and the first patient was enrolled on 14 October 2017.

Parainfluenza virus (PIV) infection is a significant cause of morbidity and mortality, especially in hematologic malignancy patients including hematopoietic stem cell transplantation (HCT) recipients. However, limited information is available for risk stratification in PIV-infected patients with hematologic malignancy with or without HCT. Patients with hematologic malignancy diagnosed with PIV from January 2009 to December 2018 were retrospectively included in a tertiary care hospital in Seoul, South Korea. Upper respiratory tract infection (URTI) was defined as the detection of PIV in a nasopharyngeal sample with URTI symptoms without new pulmonary infiltrates. Lower respiratory tract infection (LRTI) was defined as detection of PIV in either upper or lower respiratory tract samples with new pulmonary infiltrates, with or without hypoxia. PIV-associated mortality was defined as death with respiratory failure and persistent LRTI within 90 days after diagnosis. The study included 143 adult patients. Of these, 55 (38%) progressed to or initially presented with LRTI. Among these, 22 (40%) died from PIV-associated mortality. An immunodeficiency risk score was developed from associated risk factors using a multivariable Cox regression model. Patients were stratified into low (0-2), moderate (3-5), and high risk (6-8) groups with PIV-associated mortalities of 0%, 9%, and 67%, respectively (p < 0.005, Harrell's C-index = 0.84). PIV infection can result in substantial mortality in patients with hematologic malignancy if it progresses to LRTI. The immunodeficiency risk score presented here may be useful for distinguishing moderate and high risk groups that might benefit from antiviral therapy.

Staphylococcus aureus bacteremia is one of the most serious bacterial infections and may lead to worse clinical outcomes in patients with prolonged severe neutropenia. However, clinical data on S. aureus bacteremia in neutropenic patients with hematologic malignancies are limited. We conducted two case-control studies using a 10-year prospective cohort of patients with S. aureus bacteremia. Neutropenic and non-neutropenic hematologic malignancy patients were compared on clinical characteristics and treatment outcomes. An additional matched case-control study using solid tumor patients was conducted. Risk factors for 12-week mortality were analyzed. Of 1643 patients with S. aureus bacteremia, 64 (3.9%) neutropenic and 108 (6.6%) non-neutropenic patients with hematologic malignancies were included in the study. There were no significant differences in the incidence of metastatic infection between the two groups (17.2% vs. 17.6%, p = 0.95), in contrast with a previous study that observed no metastatic infection in neutropenic patients. Twelve-week mortality in neutropenic patients with hematologic malignancies tended to be lower than in non-neutropenic patients with hematologic malignancies (15.6% vs. 26.9%, p = 0.09) and was significantly lower than in neutropenic patients with solid tumors (15.6% vs. 45.8%, p = 0.003). Independent risk factors for mortality in hematologic malignancy patients with S. aureus bacteremia were high Charlson comorbidity score, high APACHE II score, and skin and soft tissue infection. Neutropenia was not independently associated with mortality. Our findings suggest that neutropenia in hematologic malignancies may not affect the incidence of metastatic infection or 12-week mortality of S. aureus bacteremia.

We isolated Japanese encephalitis virus genotype 5 from human specimens in South Korea. Whole-genome analysis showed 90.4% identity with other genotype 5 viruses from humans. This virus had a unique insertion in the NS4A gene. However, the envelope protein contained Lys 84, which was specific to strains of genotype 5 viruses from South Korea.

The increasing prevalence of antimicrobial resistance and the laborious development of novel antimicrobial agents have limited the options for effective antimicrobial therapy. The combination of previously used antimicrobial agents represents an alternative therapy for multidrug-resistant (MDR) pathogens. The objective of this study was to investigate the synergistic effect of a florfenicol (FFL)-based combination with other antimicrobial agents against MDR Escherichia coli isolates from livestock using checkerboard assays and murine infection models. The FFL/amikacin (AMK) and FFL/gentamicin (GEN) combinations showed synergy against 10/11 and 6/11 MDR E. coli isolates in vitro, respectively. The combination of FFL with aminoglycosides (AMK or GEN) exhibited a better synergistic effect against MDR E. coli isolates than the cephalothin (CEF)/GEN or FFL/CEF combinations. The combination of FFL with AMK or GEN could reduce the emergence of resistant mutants in vitro. The FFL/AMK combination showed a higher survival rate of mice infected with MDR E. coli isolates than FFL or AMK alone. In summary, the combination of FFL with aminoglycosides (AMK or GEN) is highly effective against MDR E. coli isolates both in vitro and in vivo. Our findings may contribute to the discovery of an effective combination regimen against MDR E. coli infections in veterinary medicine.

Background: Due to the low sensitivity of mould culture, clinicians usually depend on the histomorphologic diagnosis of invasive mould infection for empirical antifungal therapy. However, definite diagnosis is not always possible based on the mould morphology. We thus compared the histomorphologic diagnosis with immunohistochemistry (IHC)- and culture-based diagnosis. Methods: All adult patients who underwent tissue biopsy and in whom the histomorphologic diagnosis revealed invasive mould infection were enrolled at a tertiary hospital, Seoul, South Korea, between 1992 and 2014 (retrospectively) and 2015 and 2019 (prospectively). Their histomorphologic diagnoses were classified as two categories: (1) acute-angled branching, septate hyphae with parallel walls and a uniform width ('morphologic aspergillosis') and (2) right-angled branching pauciseptate, broader and ribbon-like hyphae with nonparallel walls ('morphologic mucormycosis'). Results: A total of 113 patients were finally analysed and their histomorphologic diagnoses were classified as follows: 51 (45%) with morphologic aspergillosis, 62 (55%) with morphologic mucormycosis. Of the 51 patients with morphologic aspergillosis, 46 (90%) received the same diagnosis based on culture and/or IHC, and the remaining five (10%) gave positive IHC result for mucormycosis. Of the 62 patients with morphologic mucormycosis, 60 (97%) had the same diagnosis based on culture and/or IHC, and the remaining two (3%) yielded a positive aspergillus culture or a positive IHC result for aspergillosis, respectively. Conclusions: The majority of histomorphologic diagnoses appear to be consistent with definitive diagnoses based on sterile culture and IHC tests. However, about 10% of 'morphologic aspergillosis' diagnoses were mucormycosis cases.

The clinical significance of long-term methicillin-resistant Staphylococcus aureus (MRSA) bacteremia remains unclear. We evaluated the clinical, microbiological characteristics, and clinical outcomes of long-term MRSA bacteremia. A nested case-control study was conducted in a prospective cohort of adult patients with MRSA bacteremia at a tertiary hospital between August 2008 and December 2017. Patients with long-term MRSA bacteremia (≥ 14 days) were compared with control patients, defined as having bacteremia that resolved in less than 3 days. The following variables were documented: heteroresistance phenotype, genotypes, agr dysfunction, and the presence of 41 virulence genes in isolates. Of the total 890 patients studied, 69 patients (7.8%) exhibited long-term MRSA bacteremia and 599 (67.3%) exhibited resolving bacteremia. The most common sources of long-term bacteremia were central venous catheter-related infection (39%) and osteomyelitis (19%). Independent risk factors for long-term MRSA bacteremia included male sex (adjusted odds ratio [aOR] = 2.43), community-acquired bacteremia (aOR = 2.93), the presence of a prosthetic device (aOR = 3.40), and osteomyelitis (aOR = 7.98). Metastatic infections developed more frequently in patients with long-term bacteremia than in those with resolving bacteremia (56.5% vs. 8.0%; P < 0.001). Although there were no significant differences in 30-day, 12-week, or in-hospital mortality rates between the two groups, infection-attributable mortality was higher in the long-term bacteremia group (23.2% vs. 11.5%; P = 0.01). Microbiological characteristics did not differ significantly between the two groups. Clinical factors, including community-acquired bacteremia, the presence of a prosthetic device, and osteomyelitis, appear to contribute to long-term MRSA bacteremia more than microbiological factors.

Background: Pneumocystis jirovecii pneumonia (PCP) is an important cause of morbidity and mortality in kidney transplant recipients (KTRs), and prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is recommended. The aim of this study was to investigate incidence and risk factors for PCP in KTRs after 6-month TMP-SMX prophylaxis., Methods: We conducted a case-control study of patients with PCP who received 6-month PCP prophylaxis with TMP-SMX after kidney transplantation (KT). In cases of rejection, PCP prophylaxis was provided for six additional months after anti-rejection therapy. Cytomegalovirus (CMV) infection was not considered an indication for PCP prophylaxis due to concerns of nephrotoxicity associated with TMP-SMX., Results: Among 3941 kidney or pancreas-kidney transplant recipients, 67 (1.7%) developed PCP after discontinuing TMP-SMX. A total of 47 patients with KT PCP and 94 controls were included. Duration of PCP prophylaxis was similar between cases and controls (median 6 months, P = .53). In multivariate analysis, rejection (OR 3.9; 95% CI 1.4-11.1) and CMV infection (OR 2.4; 95% CI 1.0-5.8) were independently associated with PCP development after TMP-SMX. Rejection or CMV infection was observed in 70% of patients with PCP. Time to PCP development after rejection (median [IQR] 6 [5-19] months) was slightly shorter than after CMV infection (median [IQR] 9 [5-12] months; P = .18)., Conclusion: Post-prophylaxis PCP occurred in <2% of KTRs, and about two-thirds of these experienced rejection or CMV infection. These data suggest that at least 6 to 9-month additional chemoprophylaxis may be needed to prevent PCP in KTRs with transplant rejection or CMV infection., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

As concerns arise that the vancomycin MIC of methicillin-resistant Staphylococcus aureus (MRSA) could be increased by concurrent colistin administration, we evaluated the effect of colistin on vancomycin efficacy against MRSA via in vitro and in vivo studies. Among MRSA blood isolates collected in a tertiary-care hospital, we selected representative strains from community-associated MRSA strains (CA-MRSA; ST72-MRSA-SCC mec IV) and hospital-acquired MRSA strains (HA-MRSA; ST5-MRSA-SCC mec II). USA CA-MRSA (USA300), HA-MRSA (USA100), N315 (New York/Japan clone), and a MRSA standard strain (ATCC 43300) were used for comparison. We performed checkerboard assays to identify changes in the vancomycin MIC of MRSA following colistin exposure and evaluated the effect of a vancomycin-colistin combination using time-kill assays. We also assessed the in vivo antagonistic effect by administering vancomycin, colistin, and a combination of these two in a neutropenic murine thigh infection model. In the checkerboard assays, vancomycin MICs of all MRSA strains except N315 were increased by from 0.25 to 0.75 μg/ml following colistin exposure. However, the time-kill assays indicated antagonism only against ST5-MRSA and USA100, when the vancomycin concentration was twice the MIC. In the murine thigh infection model with ST5-MRSA and USA100, vancomycin monotherapy reduced the number of CFU/muscle >1 log 10 compared to a combination treatment after 24 h in ST5-MRSA, indicating an antagonistic effect of colistin on vancomycin treatment. This study suggests that exposure to colistin may reduce the susceptibility to vancomycin of certain MRSA strains. Combination therapy with vancomycin and colistin for multidrug-resistant pathogens might result in treatment failure for concurrent MRSA infection., (Copyright © 2020 American Society for Microbiology.)

Sixteen of 45 patients with severe fever with thrombocytopenia (36%) were admitted to an intensive care unit; 9 (56%) developed invasive pulmonary aspergillosis (IPA) within a median of 8 days (range, 2-11). Mortality was higher in the IPA vs non-IPA patients and in those without vs with antifungal therapy., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: We evaluated the frequency of a positive result in follow-up blood cultures (FUBCs) and clinical outcome when FUBCs were not performed, in patients with a single Staphylococcus aureus -positive blood culture. Methods: We analyzed blood culture results in a prospective, observational cohort of patients with S. aureus bacteraemia (SAB) at a tertiary-care hospital. All adult patients with only a single positive blood culture set from at least two blood culture sets drawn at the initial SAB episode were enrolled in the study. We analyzed FUBC results performed within 5 days after bacteraemia onset and compared the characteristics and outcomes between patients with and without FUBCs. Results: Of 305 patients with a single S. aureus -positive blood culture, FUBCs were obtained in 274 (90%) and were positive in 15% (42/274), of whom 50% were afebrile. The rate of positivity of FUBCs was significantly higher in methicillin-resistant S. aureus (MRSA) than in methicillin-susceptible S. aureus (19% versus 9%, p = .03). In 190 patients with a single MRSA-positive blood culture, the demographic and clinical characteristics were similar between patients with and without FUBCs (167 versus 23). Although mortality was comparable between the two groups, relapse of SAB was significantly more frequent in patients in whom FUBCs were not performed (17% versus 2%, p = .008). Conclusions: Even if a patient has a single S. aureus -positive blood culture and no fever, FUBCs should be performed to manage the infection properly and to prevent SAB relapse.

Background/aims: We evaluated the usefulness in kidney transplant (KT) candidates of cytomegalovirus (CMV)-specific enzyme-linked immunospot (ELISPOT) assays for predicting the development of post-transplant CMV infections., Methods: All adult recipients admitted for living-donor KT between March 2014 and March 2015 were prospectively enrolled except donor CMV-seropositive and recipient seronegative (D+/R-) recipients. All the enrolled patients underwent CMV-specific ELISPOT assays before transplant, and a researcher blinded to the results of these assays examined the patients for CMV infection at least 6 months post-transplant., Results: Of 133 KT recipients, 44 (33%) developed CMV infections. When we used the cut-off determined by receiver operator characteristic curve, 16 of the 34 patients (47%) with negative pp65-specific ELISPOT results (< 11 spots/200,000 cells) developed CMV infections, whereas 28 of the 99 patients (39%) with positive pp65-specific ELISPOT results at baseline (≥ 11 spots/200,000 cells) developed CMV infections after KT (p = 0.02). Based on the multivariable Cox regression model, negative pp65-specific ELISPOT assay results was an independent risk factor for CMV infection (adjusted hazard ratio [AHR], 1.87; 95% confidence interval [CI], 1.01 to 3.46; p = 0.047) as well as age (AHR, 1.05; 95% CI, 1.01 to 1.08; p = 0.007)., Conclusion: Pre-transplant CMV-specific ELISPOT assay appears to predict the development of CMV infections after KT in recipients at moderate risk such as CMV-seropositive recipients (Clinical Trial Registration Number NCT02025335).

Bcl2l10, also known as Diva, Bcl‑b and Boo, is a member of the Bcl2 family of proteins, which are involved in signaling pathways that regulate cell apoptosis and autophagy. Previously, it was demonstrated that Bcl2l10 plays a crucial role in the completion of oocyte meiosis and is a key regulator of Aurora kinase A (Aurka) expression and activity in oocytes. Aurka is overexpressed in several types of solid tumors and has been considered a target of cancer therapy. Based on these previous results, in the present study, the authors aimed to investigate the regulatory role of Bcl2l10 in A2780 and SKOV3 human ovarian cancer cells. The protein expression of Bcl2l10 was examined in human cancer tissues and cell lines, including the ovaries, using a tissue microarray and various human ovarian cancer cell lines. It was found that Bcl2l10 regulated the protein stability and activities of Aurka in ovarian cancer cells. Although apoptosis was not affected, the cell cycle was arrested at the G0/G1 phase by Bcl2l10 knockdown. Of note, cell viability and motility were markedly increased by Bcl2l10 knockdown. On the whole, the findings of this study suggest that Bcl2l10 functions as tumor suppressor gene in ovarian cancer.

Purpose: To describe the outcomes and complications of repeat anterior lamellar keratoplasty (ALK) after a failed primary ALK., Methods: This was a retrospective case series. Twenty-three eyes of 22 patients who underwent repeat ALK for optical indications from January 1, 1991, to December 31, 2017, were included. Clinical data were recorded from the Singapore Corneal Transplant Study database. Outcome measures were graft survival, best-corrected visual acuity (BCVA), and complications., Results: Of the 780 cases of ALK performed for optical indications during the study period, 23 cases (2.9%) underwent repeat ALK. Primary ALK comprised of 16 deep ALK and 7 automated lamellar therapeutic keratoplasty cases. After repeat ALK, 21 eyes had further dissection down to the descemetic or predescemetic plane, whereas 2 eyes had graft exchange for failed automated lamellar therapeutic keratoplasty. The graft survival of repeat ALK was 93.2%, 86.1%, and 78.3% at 1, 3, and 5 years, respectively. There were 4 cases of graft failure with a mean time to failure of 2.0 ± 1.7 years. After the repeat ALK procedure, 63.6% and 66.7% of eyes achieved a BCVA of LogMAR +0.3 (20/40) or better at 1 and 2 years, respectively. Five eyes (17.4%) had an intraoperative microperforation., Conclusions: In the case of a failed ALK graft for a range of optical indications, a repeat ALK procedure offers a viable and safe surgical option with good long-term graft survival and visual outcomes, while avoiding the various disadvantages of performing penetrating keratoplasty, especially the risk of allograft endothelial rejection.

Background: Combined spinal-epidural anesthesia (CSEA) can be performed with either a single-space technique or a double-space technique for cesarean section. We performed a double-blind randomized controlled study to compare the effect of the double-space technique with that of the single-space technique on sensory block level and side effects., Methods: Parturients undergoing elective cesarean section under regional anesthesia were randomized to receive CSEA with either the double-space technique (double group, n = 20) or the single-space technique (single group, n = 20). In the double group, an epidural catheter was inserted at the L1-2 interspace, and dural puncture was performed at the L3-4 interspace. In the single group, the procedure was performed at the L3-4 interspace using the needle-through-needle technique., Results: There were no differences in time to readiness or intraoperative level of sensory block between the two groups. The postoperative sensory level was maintained at a higher level in the double group than in the single group (1 h postoperatively, P = 0.029; 6 h postoperatively, P = 0.016). There was no difference between the two groups in terms of side effects. The parturient satisfaction scores 48 h postoperatively were significantly different between groups (9.5 in the double group vs. 8 in the single group, P = 0.004)., Conclusions: We conclude that there were no differences in intraoperative variables between the double-space technique and the single-space technique for CSEA. However, double-space CSEA for cesarean section may be beneficial for controlling postoperative pain and improving parturient satisfaction., Trial Registration: The study was retrospectively registered at https://cris.nih.go.kr under the trial ID KCT0002514. Date of registration: October 27, 2017.

A helmet is critical for preventing head injuries during motorcycle accidents. However, South Korean motorcyclists have a lower prevalence of wearing a helmet, compared to developed countries. Therefore, we aimed to evaluate whether helmet wearing was associated with the clinical outcomes in Korean motorcycle accidents. Data were obtained from the Emergency Department-based Injury In-depth Surveillance database 2011-2015. We considered the patients had experienced a motorcycle accident and were only diagnosed with a craniocerebral trauma (CCT). The primary outcome was mortality and the secondary outcomes were the severity and hospitalization duration. The patients were separated whether they were wearing a helmet and the outcomes were compared using multivariate logistic regression after propensity score matching (PSM). Among 1,254,250 patients in the database, 2,549 patients were included. After PSM, 1,016 patients in each group were matched. The univariate analyses revealed that helmet wearing was associated with lesser severity (P < 0.001) and shorter hospitalization (P < 0.001). The regression analysis revealed that mortality was also lower in a helmet-wearing group (odds ratio: 0.34, 95% confidence interval: 0.21-0.56). In conclusion, wearing a helmet may reduce the mortality from a CCT after a motorcycle accident and associated with lesser severity and shorter hospitalization., Competing Interests: The authors have declared that no competing interests exist.

Rationale: Extracorporeal membrane oxygenation (ECMO) in multiple trauma patients with post-traumatic respiratory failure can be quite challenging because of the need for systemic anticoagulation, which may lead to excessive bleeding. In the last decade, there is a growing body of evidence that veno-venous ECMO (VV-ECMO) is lifesaving in multiple trauma patients with acute respiratory distress syndrome, thanks to technical improvements in ECMO devices., Patient Concerns: We report a case of a 17-year-old multiple trauma patient who was drunken and had confused mentality., Diagnoses: She was suffered from critical respiratory failure (life-threatening hypoxemia and severe hypercapnia/acidosis lasting for 70 minutes) accompanied by cardiac arrest and trauma-induced coagulopathy during general anesthesia., Interventions: We decided to start heparin-free VV-ECMO after cardiac arrest considering risk of hemorrhage., Outcomes: She survived with no neurologic sequelae after immediate treatment with heparin-free VV-ECMO., Lessons: Heparin-free VV-ECMO can be used as a resuscitative therapy in multiple trauma patients with critical respiratory failure accompanied by coagulopathy. Even in cases in which life-threatening hypoxemia and severe hypercapnia/acidosis last for >1 hours during CPR for cardiac arrest, VV-ECMO could be considered a potential lifesaving treatment.

Methods for distinguishing catheter-related candidemia (CRC) from non-CRC before catheter removal remain limited. We thus evaluated the diagnostic performance of differential time to positivity (DTP) to diagnose CRC in neutropenic cancer patients with suspected CRC. Of the 35 patients enrolled, 15 (43%) with CRC (six definite and nine probable) and 17 (49%) with non-CRC were finally analyzed. Based on the receiver operating characteristic curve, the optimal cutoff value of DTP for diagnosing CRC was ≥1.45 hours with the sensitivity 80% (95% confidence interval [CI], 51-95) and specificity 100% (95% CI, 80-100), respectively., (© The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Candida auris was first identified in Japan from specimens obtained from the ear, but most reports since have reported invasive infections or non-ear based cases. We reviewed all the microbiology records from a single center in South Korea from February 2016 to July 2018. One hundred eleven isolates were positive for C. auris from 79 patients. All 79 patients positive for C. auris had positive ear discharge samples. All but one of the patients with C. auris had been to the otorhinolaryngology clinic. Symptom-driven ear culture was done for all but one patient, whose culture was performed for surveillance. Ear discharges were mostly purulent (60%) or serous (34%). We performed the environmental cultures at the otorhinolaryngology outpatient clinic to evaluate the environmental contamination of C. auris, but C. auris was not isolated from medical equipment and environmental surfaces., (© The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: The precise role of cytomegalovirus (CMV) in ulcerative colitis (UC) remains disputed. We evaluated the association of CMV-specific host immune responses and systemic or local viral replication with responses to systemic steroids in patients with moderate to severe UC., Methods: Patients who were hospitalized for moderate to severe UC between April 2015 and June 2016 were enrolled. At baseline, all enrolled patients underwent CMV-specific enzyme-linked immunospot assays, quantitative polymerase chain reaction (qPCR) analysis of blood and colonic tissue for CMV viral load, histopathological testing for CMV in colonic tissue by hematoxylin and eosin staining, and immunohistochemical (IHC) analysis. Clinical responses to steroid therapy based on the Oxford index were assessed on day 3., Results: Of the 80 patients evaluated, 28 (35.0%) had poor responses to steroid therapy on day 3 of intensive treatment. The presence of inclusion bodies (32.1%) and high-grade (≥3) positivity on IHC (50.0%), as well as colonic (mean 1440.4 copies/mg) and blood (mean, 3692.6 copies/mL) CMV viral load, were higher in steroid-refractory UC patients than the control group (13.5%, 1.9%, mean 429.2 copies/mg, and mean 231.2 copies/mL, respectively; P = .046, .009, .017, and .002, respectively). However, CMV-specific T-cell responses were not associated with steroid-refractory UC. Multivariate analysis revealed that a higher Mayo score (odds ratio [OR], 2.00; P = .002) and higher blood CMV viral load via qPCR analysis (OR, 3.58; P = .044) were independent risk factors for steroid-refractory UC., Conclusions: In patients with moderate to severe UC, higher Mayo score and blood CMV expression determined by qPCR are independently associated with steroid refractoriness., Clinicaltrialsgov Registration Number: NCT02439372., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The clinical characteristics and outcomes of Streptococcus dysgalactiae subspecies equisimilis (SDSE) bacteremia cases have not been adequately evaluated. We retrospectively enrolled consecutive adult patients with SDSE or S. agalactiae (group B streptococci, GBS) bacteremia at a tertiary care hospital (Republic of Korea) from August 2012 to December 2016. We compared the incidence, seasonality, clinical characteristics, and outcomes of 52 SDSE bacteremia cases with 151 GBS bacteremia cases. The incidence of SDSE and GBS bacteremia in these patients was 1.28/100,000 and 4.22/100,000 person-days, respectively. Most SDSE bacteremia cases were of community-onset infection (SDSE 94.2% vs GBS 83.4%; p = 0.052). Lancefield group G was the most common bacteria type among SDSE isolates (43/47; 91.5%). Patients with SDSE bacteremia were older (median, 68.0 years vs 61.0 years; p = 0.03). In both groups, solid tumor was the most common underlying disease, and more than half of the patients were immunocompromised (51.9% vs 54.3%; p = 0.77). Chronic kidney disease was more common in the SDSE group (19.2% vs 5.3%; p < 0.01). Cellulitis was the most common clinical syndrome of SDSE bacteremia and was more common in the SDSE group (59.6% vs 29.1%; p < 0.01). SDSE bacteremia cases occurred more frequently in the warm season compared with GBS bacteremia cases (65.4% vs 37.1%; p < 0.01); in-hospital mortalities were not significantly different between the groups (3.8% vs 10.6%; p = 0.17). In conclusion, SDSE bacteremia is commonly associated with cellulitis, especially in older and immunocompromised patients during the warm season.

Severe fever with thrombocytopenia syndrome (SFTS) and scrub typhus are the most common tick-borne diseases in South Korea. However, few studies have systematically examined the simultaneous presence of the two diseases. We found that two (4.9%) of 41 patients with suspected and confirmed SFTS had evidence of coinfection with scrub typhus. In addition, two (3.6%) of 55 suspected and confirmed scrub typhus patients were identified to have coinfection with SFTS. Our data suggest that diagnostic evaluation for coinfection in patients with tick-borne illness and empirical doxycycline treatment in patients with SFTS may be warranted in areas endemic for both diseases until coinfection with scrub typhus is ruled out.

There are no surrogate markers for the development of postherpetic neuralgia (PHN) in patients with herpes zoster (HZ). All patients with HZ were prospectively enrolled to evaluate the associations of saliva varicella zoster virus (VZV) DNA persistence and VZV-specific cell-mediated immunity (CMI) with the development of PHN. Slow clearers were defined if salivary VZV DNA persisted after day 15. Salivary VZV was detected in 60 (85.7%) of a total of 70 patients with HZ on initial presentation. Of 38 patients for whom follow-up saliva samples were available, 26 (68.4%) were classified as rapid clearers and 12 (31.6%) as slow cleares. Initial VZV-specific CMI was lower in slow clearers than rapid clearers (median 45 vs 158 spot forming cells/10 6 cells, P = .02). Of the 70 patients with HZ, 22 (31.4%) eventually developed PHN. Multivariate analysis showed that slow clearers (OR, 15.7, P = .01) and lower initial VZV-specific CMI (OR, 13.8, P = .04) were independent predictors of the development of PHN, after adjustment for age and immunocompromised status. Initial low VZV CMI response and persistence of VZV DNA in saliva may be associated with the development of PHN., (© 2019 Wiley Periodicals, Inc.)

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by SFTS virus (SFTSV) which involves multiple organ systems, including lungs. However, there is limited data on lung involvement of SFTS. Therefore, the present study investigated the chest radiographic findings of SFTS, including computed tomography (CT), and compared these with those of scrub typhus, which is the most common tick-borne illness in South Korea and share risk factors and occur in similar settings.Medical records of patients with confirmed SFTS and scrub typhus in a tertiary hospital in Seoul (South Korea), between January 2014 and June 2018, were reviewed. Initial chest radiography and CT were reviewed by 2 experienced radiologists.A total of 39 patients with SFTS and 101 patients with scrub typhus were analyzed. All patients except 3 patients with scrub typhus in both groups received chest radiography. Cardiomegaly (90%) and patchy consolidation with ground glass opacity (GGO) pattern (31%) were more common in SFTS group than scrub typhus group (20%, P < .001 and 2%, P < .001, respectively). About half of each group received chest CT. Consolidation (29%) and pericardial effusion (24%) were more common in SFTS group than scrub typhus group (6%, P = .02 and 4%, P = .008, respectively). Interstitial thickening in chest radiography (58%) and chest CT (65%) was more frequent in scrub typhus group than SFTS group (18%, P < .001 and 19%, P < .001, respectively).Cardiomegaly with/without pericardial effusion and patchy consolidation with GGO pattern were more frequent in SFTS group, whereas interstitial thickening was more frequent in scrub typhus group. These findings will assist the early differentiation of SFTS from scrub typhus.

Objective: To investigate the accuracy of immunohistochemistry (IHC) tests for distinguishing between mucormycosis and aspergillosis and compare the clinical characteristics of mucormycosis patients according to galactomannan (GM) results., Methods: We evaluated diagnostic performance of IHC test with tissue sections of patients with culture-proven invasive fungal infection. In addition, we conducted PCR assay with tissue sections of mucormycosis patients with positive GM results to evaluate the possibility of co-infection., Results: In culture-proven mucormycosis (n = 13) and aspergillosis (n = 20), the sensitivity and specificity of IHC test were both 100% for mucormycosis and 85% and 100%, respectively, for aspergillosis. Among the 53 patients who met the modified criteria for proven mucormycosis and had GM assay results, 24 (45%) were positive. Compared with those with negative GM results (n = 29), mucormycosis patients with positive GM results had significantly higher incidence of gastrointestinal tract infections (6/24 [25%] vs 0/29 [0%], P = .006) and were more likely to be histomorphologically diagnosed as aspergillosis (7/24 [29%] vs 2/29 [7%], P = .06). PCR assay amplified both Aspergillus- and Mucorales-specific DNA in 6 of these 24 cases., Conclusions: Immunohistochemistry tests seem useful for compensating for the limitations of histomorphologic diagnosis in distinguishing between mucormycosis and aspergillosis. Some proven mucormycosis patients with positive GM results had histopathology consistent with aspergillosis and gastrointestinal mucormycosis. In addition, about one quarter of these patients revealed the evidence of co-infection with aspergillosis by PCR assay., (© 2019 Blackwell Verlag GmbH.)

Purpose: To compare the long-term graft survival outcomes and complications of patients who underwent Descemet membrane endothelial keratoplasty (DMEK), Descemet stripping automated endothelial keratoplasty (DSAEK), and penetrating keratoplasty (PK) for Fuchs endothelial corneal dystrophy (FECD) and bullous keratopathy (BK)., Design: Retrospective comparative cohort study., Methods: Patients with FECD and BK who underwent DMEK (121 eyes), DSAEK (423 eyes), or PK (405 eyes) from the prospective cohort from the Singapore Corneal Transplant Registry were included. A Kaplan-Meier survival analysis was conducted to compare the survival probabilities of the 3 groups. The main outcome measure was graft survival., Results: The DMEK group had the best overall cumulative graft survival of 97.4%, compared to DSAEK (78.4%) and PK (54.6%) (P < .001). In eyes with FECD, the DMEK group had the best graft survival of 98.7% compared to DSAEK (96.2%) and PK (73.5%) (P = .009). The graft survival in eyes with BK was poorer overall; however, the DMEK group still had the best graft survival of 94.7%, compared to DSAEK (65.1%) and PK (47.0%, P = .001). Eyes that underwent DMEK had the lowest rate of graft rejection (1.7% vs DSAEK 5.0% vs PK 14.1%, P < .001) and postoperative elevation of intraocular pressure (11.6% vs DSAEK 23.6% vs PK 22.5%, P = .015)., Conclusions: Patients who underwent DMEK for FECD and BK had better graft survival compared to DSAEK and PK. Eyes that underwent DMEK also had a significantly lower rate of graft rejection and elevated intraocular pressure compared to DSAEK and PK for the same indications., (Copyright © 2019 Elsevier Inc. All rights reserved.)