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Background: Screening and treating healthcare workers (HCWs) for latent tuberculosis infection (LTBI) are essential for tuberculosis (TB) infection control. Adverse drug reactions (ADRs) to anti-TB drugs present challenges to patient safety and treatment completion. Objective: This study investigated the association between human leukocyte antigen (HLA) alleles and the risk of ADRs, especially drug hypersensitivity (DHS) and hepatotoxicity, in HCWs with LTBI receiving isoniazid (INH) and rifampin (RIF) therapy. Methods: Korean HCWs with LTBI who received a 3 month INH and RIF regimen were included in this study. HLA genotyping was performed on HCWs who experienced ADRs during treatment, as well as the control group consisted of individuals who did not develop ADRs. Results: Of the 67 patients, 29 (43.2%) experienced ADRs during INH and RIF therapy. The HLA-A *11:01 allele was more frequent in patients with DHS without hepatotoxicity (DSH+/H-) compared to the control group (DHS-/H-) (4/9, 44.4% vs. 3/38, 7.9%; odd ratio [OR], 8.554; 95% confidence interval [CI], 1.415-59.869; p = 0.018). Conversely, HLA-DPB1 *05:01 was associated with an increased risk of hepatotoxicity regardless of DHS (10/20, 50% vs. 5/38, 13.2%; OR, 5.323; 95% CI, 1.493-21.518; p = 0.011). In the DHS with hepatotoxicity group (DHS+/H+), HLA-DPB1 *05:01 was present in a higher proportion (3/5, 60% vs. 5/38, 13.2%; OR, 8.912; 95% CI, 1.110-92.993; p = 0.037), whereas HLA-A *11:01 was not observed in this group. Conclusions: The HLA-A *11:01 allele was associated with an increased risk of DHS without hepatotoxicity, whereas the HLA-DPB1 *05:01 allele was associated with an increased risk of hepatotoxicity.

Background: A healthcare system's collapse due to a pandemic, such as the coronavirus disease 2019 (COVID-19), can expose healthcare workers (HCWs) to various mental health problems. This study aimed to investigate the impact of the COVID-19 pandemic on the depression and anxiety of HCWs., Methods: A nationwide questionnaire-based survey was conducted on HCWs who worked in healthcare facilities and public health centers in Korea in December 2020. Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) were used to measure depression and anxiety. To investigate factors associated with depression and anxiety, stepwise multiple logistic regression analysis was performed., Results: A total of 1,425 participating HCWs were included. The mean depression score (PHQ-9) of HCWs before and after COVID-19 increased from 2.37 to 5.39, and the mean anxiety score (GAD-7) increased from 1.41 to 3.41. The proportion of HCWs with moderate to severe depression (PHQ-9 ≥ 10) increased from 3.8% before COVID-19 to 19.5% after COVID-19, whereas that of HCWs with moderate to severe anxiety (GAD-7 ≥ 10) increased from 2.0% to 10.1%. In our study, insomnia, chronic fatigue symptoms and physical symptoms after COVID-19, anxiety score (GAD-7) after COVID-19, living alone, and exhaustion were positively correlated with depression. Furthermore, post-traumatic stress symptoms, stress score (Global Assessment of Recent Stress), depression score (PHQ-9) after COVID-19, and exhaustion were positively correlated with anxiety., Conclusion: In Korea, during the COVID-19 pandemic, HCWs commonly suffered from mental health problems, including depression and anxiety. Regularly checking the physical and mental health problems of HCWs during the COVID-19 pandemic is crucial, and social support and strategy are needed to reduce the heavy workload and psychological distress of HCWs., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Background and Aims: High-risk human papillomavirus (HR-HPV) infection-a well-established risk factor for cervical cancer-has associations with cardiovascular disease (CVD). However, its relationship with CVD mortality remains uncertain. This study examined the associations between HR-HPV infection and CVD mortality., Methods: As part of a health examination, 163 250 CVD-free Korean women (mean age: 40.2 years) underwent HR-HPV screening and were tracked for up to 17 years (median: 8.6 years). National death records identified the CVD mortality cases. Hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD mortality were estimated using Cox proportional hazard regression analyses., Results: During 1 380 953 person-years of follow-up, 134 CVD deaths occurred, with a mortality rate of 9.1 per 105 person-years for HR-HPV(-) women and 14.9 per 105 person-years for HR-HPV(+) women. After adjustment for traditional CVD risk factors and confounders, the HRs (95% CI) for atherosclerotic CVD (ASCVD), ischaemic heart disease (IHD), and stroke mortality in women with HR-HPV infection compared with those without infection were 3.91 (1.85-8.26), 3.74 (1.53-9.14), and 5.86 (0.86-40.11), respectively. The association between HR-HPV infection and ASCVD mortality was stronger in women with obesity than in those without (P for interaction = .006), with corresponding HRs (95% CI) of 4.81 (1.55-14.93) for obese women and 2.86 (1.04-7.88) for non-obese women., Conclusions: In this cohort study of young and middle-aged Korean women, at low risks for CVD mortality, those with HR-HPV infection had higher death rates from CVD, specifically ASCVD and IHD, with a more pronounced trend in obese individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Chronic hepatitis B virus (HBV) infection is associated with a reduced risk of dyslipidaemia. Using a human faecal microbiota transplantation (FMT), we compared changes in gut microbiota and lipid profiles in mice transplanted with human faeces from HBV-infected and non-infected individuals., Approach and Results: A total of 19 mice received human FMT from four HBV-infected individuals and were categorised into the HBV-positive mice group, while 20 mice received FMT from four HBV-non-infected individuals into the HBV-negative one. In the analysis of gut microbiota in FMT mice, we observed a robust increase in alpha diversity and abundance of Akkermansia muciniphila in HBV-positive mice, compared to that in HBV-negative. Functional inference analysis revealed that the pathways involved in glycerolipid metabolism were more enriched in HBV-positive mice. At 5 weeks of FMT, the reduced triglyceride (TG) level was predominantly observed in HBV-positive mice., Conclusions: Altered gut microbiota accompanied by HBV infection was associated with a robust increase in alpha diversity and butyrate producers, which resulted in a reduced level of TG at 5 weeks post-FMT. This indicates that the reduced risk of dyslipidaemia in chronic HBV infection may be due to the altered gut microbiota accompanied by HBV infection., Competing Interests: Declaration of competing interest All authors have nothing to declare., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused the death of thousands of patients worldwide. Although age is known to be a risk factor for morbidity and mortality in COVID-19 patients, critical illness or death is occurring even in the younger age group as the epidemic spreads. In early 2022, omicron became the dominant variant of the COVID-19 virus in South Korea, and the epidemic proceeded on a large scale. Accordingly, this study aimed to determine whether young adults (aged ≤ 50 years) with critical COVID-19 infection during the omicron period had different characteristics from older patients and to determine the risk factors for mortality in this specific age group., Methods: We evaluated 213 critical adult patients (high flow nasal cannula or higher respiratory support) hospitalized for polymerase chain reaction-confirmed COVID-19 in nine hospitals in South Korea between February 1, 2022 and April 30, 2022. Demographic characteristics, including body mass index (BMI) and vaccination status; underlying diseases; clinical features and laboratory findings; clinical course; treatment received; and outcomes were collected from electronic medical records (EMRs) and analyzed according to age and mortality., Results: Overall, 71 critically ill patients aged ≤ 50 years were enrolled, and 142 critically ill patients aged over 50 years were selected through 1:2 matching based on the date of diagnosis. The most frequent underlying diseases among those aged ≤ 50 years were diabetes and hypertension, and all 14 patients who died had either a BMI ≥ 25 kg/m² or an underlying disease. The total case fatality rate among severe patients (S-CFR) was 31.0%, and the S-CFR differed according to age and was higher than that during the delta period. The S-CFR was 19.7% for those aged ≤ 50 years, 36.6% for those aged > 50 years, and 38.1% for those aged ≥ 65 years. In multivariate analysis, age (odds ratio [OR], 1.084; 95% confidence interval [CI], 1.043-1.127), initial low-density lipoprotein > 600 IU/L (OR, 4.782; 95% CI, 1.584-14.434), initial C-reactive protein > 8 mg/dL (OR, 2.940; 95% CI, 1.042-8.293), highest aspartate aminotransferase > 200 IU/L (OR, 12.931; 95% CI, 1.691-98.908), and mechanical ventilation implementation (OR, 3.671; 95% CI, 1.294-10.420) were significant independent predictors of mortality in critical COVID-19 patients during the omicron wave. A similar pattern was shown when analyzing the data by age group, but most had no statistical significance owing to the small number of deaths in the young critical group. Although the vaccination completion rate of all the patients (31.0%) was higher than that in the delta wave period (13.6%), it was still lower than that of the general population. Further, only 15 (21.1%) critically ill patients aged ≤ 50 years were fully vaccinated. Overall, the severity of hospitalized critical patients was significantly higher than that in the delta period, indicating that it was difficult to find common risk factors in the two periods only with a simple comparison., Conclusion: Overall, the S-CFR of critically ill COVID-19 patients in the omicron period was higher than that in the delta period, especially in those aged ≤ 50 years. All of the patients who died had an underlying disease or obesity. In the same population, the vaccination rate was very low compared to that in the delta wave, indicating that non-vaccination significantly affected the progression to critical illness. Notably, there was a lack of prescription for Paxlovid for these patients although they satisfied the prescription criteria. Early diagnosis and active initial treatment was necessary, along with the proven methods of vaccination and personal hygiene. Further studies are needed to determine how each variant affects critically ill patients., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Background: Despite highly effective machinery for the maintenance of genome integrity in human embryonic stem cells (hESCs), the frequency of genetic aberrations during in-vitro culture has been a serious issue for future clinical applications., Method: By passaging hESCs over a broad range of timepoints (up to 6 years), the isogenic hESC lines with different passage numbers with distinct cellular characteristics, were established., Result: We found that mitotic aberrations, such as the delay of mitosis, multipolar centrosomes, and chromosome mis-segregation, were increased in parallel with polyploidy compared to early-passaged hESCs (EP-hESCs) with normal copy number. Through high-resolution genome-wide approaches and transcriptome analysis, we found that culture adapted-hESCs with a minimal amplicon in chromosome 20q11.21 highly expressed TPX2, a key protein for governing spindle assembly and cancer malignancy. Consistent with these findings, the inducible expression of TPX2 in EP-hESCs reproduced aberrant mitotic events, such as the delay of mitotic progression, spindle stabilization, misaligned chromosomes, and polyploidy., Conclusion: These studies suggest that the increased transcription of TPX2 in culture adapted hESCs could contribute to an increase in aberrant mitosis due to altered spindle dynamics., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The appropriate use of carbapenem is a critical concern for patient safety and public health, and is a national priority. We investigated the nationwide status of carbapenem prescription in patients within their last 14 days of life to guide judicious-use protocols from the previous study comprised of 1350 decedents. Carbapenem use was universally controlled through computerised authorisation system at all centres during the study period. Carbapenem prescribing patterns and their optimality were evaluated. A total of 1201 patients received antimicrobial agents within the last two weeks of their lives, of whom 533 (44.4%) received at least one carbapenem. The median carbapenem treatment duration was seven days. Of the 533 patients receiving carbapenems, 510 (95.7%) patients had microbiological samples drawn and 196 (36.8%) yielded carbapenem-resistant pathogens. A total of 200 (37.5%) patients were referred to infectious disease (ID) specialists. Of the 333 patients (62.5%) who did not have ID consultations, 194 (58.2%) were assessed as "not optimal", 79 (23.7%) required escalation, 100 (30.0%) required de-escalation, and 15 (4.5%) were discontinued. Notwithstanding the existing antibiotic restriction program system, carbapenems are commonly prescribed to patients in their last days of life.

Objective: Heritability of stroke is assumed not to be low, especially in the young stroke population. However, most genetic studies have been performed in highly selected patients with typical clinical or neuroimaging characteristics. We investigated the prevalence of 15 Mendelian stroke genes and explored the relationships between variants and the clinical and neuroimaging characteristics in a large, unselected, young stroke population., Methods: We enrolled patients aged ≤55 years with stroke or transient ischemic attack from a prospective, nationwide, multicenter stroke registry. We identified clinically relevant genetic variants (CRGVs) in 15 Mendelian stroke genes (GLA, NOTCH3, HTRA1, RNF213, ACVRL1, ENG, CBS, TREX1, ABCC6, COL4A1, FBN1, NF1, COL3A1, MT-TL1, and APP) using a customized, targeted next generation sequencing panel., Results: Among 1,033 patients, 131 (12.7%) had 28 CRGVs, most frequently in RNF213 (n = 59), followed by ABCC6 (n = 53) and NOTCH3 (n = 15). The frequency of CRGVs differed by ischemic stroke subtypes (p < 0.01): the highest in other determined etiology (20.1%), followed by large artery atherosclerosis (13.6%). It also differed between patients aged ≤35 years and those aged 51 to 55 years (17.1% vs 9.3%, p = 0.02). Only 27.1% and 26.7% of patients with RNF213 and NOTCH3 variants had typical neuroimaging features of the corresponding disorders, respectively. Variants of uncertain significance (VUSs) were found in 15.4% patients., Interpretation: CRGVs in 15 Mendelian stroke genes may not be uncommon in the young stroke population. The majority of patients with CRGVs did not have typical features of the corresponding monogenic disorders. Clinical implications of having CRGVs or VUSs should be explored. ANN NEUROL 2023;93:768-782., (© 2022 American Neurological Association.)

Background: Antimicrobial prescriptions for serious chronic or acute illness nearing its end stages raise concerns about the potential for futile use, adverse events, increased multidrug-resistant organisms, and significant patient and social cost burdens. This study investigated the nationwide situation of how antibiotics are prescribed to patients during the last 14 days of life to guide future actions., Methods: This nationwide multicenter retrospective cohort study was conducted at 13 hospitals in South Korea from November 1 to December 31, 2018. All decedents were included in the study. Antibiotic use during the last two weeks of their lives was investigated., Results: A total of 1,201 (88.9%) patients received a median of two antimicrobial agents during the last two weeks of their lives. Carbapenems were prescribed to approximately half of the patients (44.4%) in the highest amount (301.2 days of therapy per 1,000 patient-days). Among the patients receiving antimicrobial agents, 63.6% were inappropriate and only 327 patients (27.2%) were referred by infectious disease specialists. The use of carbapenem (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.13-2.03; P = 0.006), underlying cancer (OR, 1.56; 95% CI, 1.20-2.01, P = 0.047), underlying cerebrovascular disease (OR, 1.88; 95% CI, 1.23-2.89, P = 0.004), and no microbiological testing (OR, 1.79; 95% CI, 1.15-2.73; P = 0.010) were independent predictors for inappropriate antibiotic prescribing., Conclusion: A considerable number of antimicrobial agents are administered to patients with chronic or acute illnesses nearing their end-of-life, a high proportion of which are prescribed inappropriately. Consultation with an infectious disease specialist, in addition to an antimicrobial stewardship program, may be necessary to induce the optimal use of antibiotics., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

During the coronavirus disease 2019 (COVID-19) pandemic, frontline healthcare workers (HCWs) suffered more distress from the possibility of contracting the virus, quarantine, social stigma, and prejudice against their families. Many studies have investigated the impact of the pandemic on HCWs; however, studies or guidelines presenting strategies to overcome these challenges are lacking. As part of a 2020 research project supported by the Ministry of Health and Welfare, titled "Health impact assessment of healthcare workers undertaking coronavirus disease 2019 treatment and management in Korea: Identifying problems and researching effective solutions" (HC20C0003), we created guidelines to respond to serious problems posed by infection control. and burnout among HCWs during COVID-19 response measures throughout the extended pandemic period. We formulated the guidelines by means of a systematic review and collated them with the latest literature. The guidelines will highlight the gravity and impact of infection control and burnout among HCWs responding to COVID-19 and include potential prevention strategies, and they can be used as a reference in the event of another emerging infectious disease outbreak in the future., Competing Interests: No conflict of interest., (Copyright © 2023 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS.)

Background: Antimicrobial stewardship programs (ASPs) aim to optimize antimicrobial use by minimizing the spread of antimicrobial resistance. The core elements for implementing ASPs in healthcare facilities have been developed by the World Health Organization, international research group and government agencies of various countries. However, to date, there is no documented core elements for implementation of ASP in Korea. This survey aimed to establish a national consensus on a set of core elements and their related checklist items for the implementation of ASPs in Korean general hospitals., Materials and Methods: The survey was conducted from July 2022 to August 2022 by the Korean Society for Antimicrobial Therapy with support from the Korea Disease Control and Prevention Agency. A literature review was conducted by searching Medline and relevant websites to retrieve a list of core elements and checklist items. These core elements and checklist items were evaluated by a multidisciplinary panel of experts using a structured modified Delphi consensus procedure, using two-step survey included online in-depth questionnaires and in-person meeting., Results: The literature review identified 6 core elements (Leadership commitment, Operating system, Action, Tracking, Reporting, and Education) and 37 related checklist items. Fifteen experts participated in the consensus procedures. Ultimately, all 6 core elements were retained, and 28 checklist items were proposed, all with ≥80% agreement; in addition 9 items were merged into 2 items, 2 items were deleted, and 15 items were rephrased., Conclusion: This Delphi survey provides useful indicators for the implementation of ASP in Korea and suggests national policy improvement about the barriers ( e.g. , shortage of staffing and financial support) existing in Korea for optimal implementation of ASPs., Competing Interests: BWE and HBK are editorial board of Infect Chemother; however, they did not involve in the peer reviewer selection, evaluation, and decision process of this article. Otherwise, no potential conflicts of interest relevant to this article was reported., (Copyright © 2023 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS.)

Burnout is a form of negative emotional and physical response to job stress. This study aimed to investigate the prevalence of burnout among healthcare workers responding to the coronavirus disease 2019 (COVID-19) outbreak in Korea and to explore correlates of burnout among healthcare workers. A nationwide questionnaire-based survey was conducted from December 1, 2020, to January 29, 2021 on 1425 healthcare workers who worked in one of the 16 healthcare facilities designated for COVID-19 care, in public health centers, or as paramedics in Korea. Burnout was assessed using 16 Korean-adapted items based on the Oldenburg Burnout Inventory (OLBI). Data were collected using a structured questionnaire and analyzed using the R version 4.1.1 software program. OLBI results indicate clinically exhaustion in 84.5% (1204/1425) and clinically disengagement in 91.1% (1298/1425), and 77.3% (1102/1425) met the score criteria for both the exhaustion and disengagement subscales for burnout. Burnout rate was significantly increased in the group with chronic fatigue symptoms (Fatigue Severity Scale ≥ 3.22) after the outbreak of COVID-19 (OR, 3.94; 95% CI 2.80-5.56), in the female group (OR, 2.05; 95% CI 1.46-2.86), in the group with physical symptoms (Patient Health Questionnaire-15 ≥ 10) after the outbreak of COVID-19 (OR, 2.03; 95% CI 1.14-3.60), in the group with a higher Global Assessment of Recent Stress scale (OR, 1.71; 95% CI 1.46-2.01), in the group with post-traumatic stress symptoms (Primary Care Post-Traumatic Stress Disorder-5 ≥ 2) (OR, 1.47; 95% CI 1.08-2.01), and in the younger age group(OR, 1.45; 95% CI 1.22-1.72). The chronic fatigue symptoms were correlated with cumulative days of care (OR, 1.18; 95% CI 1.02-1.37). The physical symptoms were correlated with average contact hours with COVID-19 patients per day (OR, 1.34; 95% CI 1.17-1.54), and cumulative days of care (OR, 1.21; 95% CI 1.06-1.38). Most Korean healthcare workers suffered from burnout related to excessive workload during the COVID-19 pandemic. During a widespread health crisis like COVID-19, it is necessary to regularly check the burnout status in healthcare workers and reduce their excessive workload by supplementing the workforce and providing appropriate working hours sufficient rest hours., (© 2023. The Author(s).)

Importance: The impact of non-diabetic hyperglycaemia and insulin resistance on infection-related mortality risk remains unknown., Objective: We investigated the association of glycaemic status and insulin resistance with infection-related mortality in individuals with and without diabetes., Design: Cohort study based on Kangbuk Samsung Health Study and national death records., Participants: About 666 888 Korean adults who underwent fasting blood measurements including glucose, glycated haemoglobin (HbA1c), and insulin during health-screening examinations were followed for up to 15.8 years., Main Outcome and Measures: Infection-related mortality, therefore we used Cox proportional hazards regression analyses to estimate hazard ratios (HRs) and 95% CIs for infection-related mortality. Vital status and infection-related mortality were ascertained through national death records. Variable categories were created based on established cut-offs for glucose and HbA1c levels and homeostatic model assessment of insulin resistance (HOMA-IR) quintiles., Results: During a median follow-up of 8.3 years, 313 infectious disease deaths were dentified. The associations of glucose and HbA1c levels with infection-related mortality were J-shaped (P for quadratic trend<.05). The multivariable-adjusted HR (95% CIs) for infection-related mortality comparing glucose levels <5, 5.6-6.9, and ≥7.0 mmol/L to 5.0-5.5 mmol/L (the reference) were 2.31 (1.47-3.64), 1.65 (1.05-2.60), and 3.41 (1.66-7.00), respectively. Among individuals without diabetes, the multivariable-adjusted HR for infection-related mortality for insulin resistance (HOMA-IR ≥75th centile versus <75th centile) was 1.55 (1.04-2.32)., Conclusions and Relevance: Both low and high glycaemic levels and insulin resistance were independently associated with increased infection-related mortality risk, indicating a possible role of abnormal glucose metabolism in increased infection-related mortality., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Genetic alterations have been reported for decades in most human embryonic stem cells (hESCs). Survival advantage, a typical trait acquired during long-term in vitro culture, results from the induction of BCL2L1 upon frequent copy number variation (CNV) at locus 20q11.21 and is one of the strongest candidates associated with genetic alterations that occur via escape from mitotic stress. However, the underlying mechanisms for BCL2L1 induction remain unknown. Furthermore, abnormal mitosis and the survival advantage that frequently occur in late passage are associated with the expression of BCL2L1, which is in locus 20q11.21. In this study, we demonstrated that the expression of TPX2, a gene located in 20q11.21, led to BCL2L1 induction and consequent survival traits under mitotic stress in isogenic pairs of hESCs and human induced pluripotent stem cells (iPSCs) with normal and 20q11.21 CNVs. High Aurora A kinase activity by TPX2 stabilized the YAP1 protein to induce YAP1-dependent BCL2L1 expression. A chemical inhibitor of Aurora A kinase and knockdown of YAP/TAZ significantly abrogated the high tolerance to mitotic stress through BCL2L1 suppression. These results suggest that the collective expression of TPX2 and BCL2L1 from CNV at loci 20q11.21 and a consequent increase in YAP1 signaling promote genome instability during long-term in vitro hESC culture., (© 2022. The Author(s).)

Background: Despite recent advances in the treatment of drug reaction with eosinophilia and systemic symptoms (DRESS), the mainstay of treatment involves discontinuing the culprit drugs and administering topical or systemic corticosteroid., Objective: The clinical use of a tumor necrosis factor (TNF)-alpha inhibitor was rarely explored in treatment of DRESS., Methods: We present a case of corticosteroid-induced DRESS that was successfully treated with a TNF-alpha inhibitor without sequalae., Results: This is the first case report that showed the clinical use of a TNF alpha inhibitor in treating corticosteroids- induced DRESS and immediate hypersensitivity reactions. The HLA-B*5801 was identified as a possible genetic factor associated with a corticosteroid-induced DRESS., Conclusions: A TNF-alpha inhibitor could be a primary option in treating DRESS, especially in patients with hypersensitivity reaction to corticosteroids.

Currently, antimicrobial resistance (AMR) is a major threat to global public health. The antimicrobial stewardship program (ASP) has been proposed as an important approach to overcome this crisis. ASP supports the optimal use of antimicrobials, including appropriate dosing decisions, administration duration, and administration routes. In Korea, efforts are being made to overcome AMR using ASPs as a national policy. The current study aimed to develop core elements of ASP that could be introduced in domestic medical facilities. A Delphi survey was conducted twice to select the core elements through expert consensus. The core elements for implementing the ASP included (1) leadership commitment, (2) operating system, (3) action, (4) tracking, (5) reporting, and (6) education. To ensure these core elements are present at medical facilities, multiple departments must collaborate as teams for ASP operations. Establishing a reimbursement system and a workforce for ASPs are prerequisites for implementing ASPs. To ensure that ASP core elements are actively implemented in medical facilities, it is necessary to provide financial support for ASPs in medical facilities, nurture the healthcare workforce in performing ASPs, apply the core elements to healthcare accreditation, and provide incentives to medical facilities by quality evaluation criteria., Competing Interests: BWE is editorial board of Infect Chemother; however, he did not involve in the peer reviewer selection, evaluation, and decision process of this article. Otherwise, no potential conflicts of interest relevant to this article was reported., (Copyright © 2022 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS.)

Gliomas are the most common primary tumors in the brain and spinal cord. In previous GWASs, SNPs in epidermal growth factor receptor (EGFR) have been reported as risk loci for gliomas. However, EGFR variants associated with gliomas in the Korean population remain unstudied. This study explored the association of EGFR SNPs with the risk of glioma. We genotyped 13 EGFR exon SNPs in a case-control study that included 324 Korean patients diagnosed with glioma and 480 population-based controls. Statistical analyses of the association between EGFR SNPs and glioma risk were conducted using logistic regression. Both stepwise analysis and conditional logistic analysis were performed to identify independent associations among genotyped variants. We confirmed that two SNPs (rs2227983, rs1050171) were significantly associated with glioma (rs2227983: odds ratio = 1.42, P corr  = 0.009; rs1050171: odds ratio = 1.68, P corr  = 0.005). Additionally, the stepwise analysis and conditional logistic analysis indicated that both SNPs created variants with independent genetic effects. This study is the first to show evidence that functional variants of EGFR, namely, rs2227983 (K521R) and rs1050171 (Q787Q), are associated with an increased risk of glioma in the Korean population. Future work should confirm the functional association between EGFR variants and glioma., (© 2022. The Author(s).)

Background: Previous genomewide association studies (GWASs), single nucleotide polymorphisms (SNPs) on cyclin-dependent kinase inhibitor 2 A (CDKN2A), cyclin-dependent kinase inhibitor 2B (CDKN2B), and cyclin-dependent kinase inhibitor 2B antisense RNA1 (CDKN2B-AS1) were reported as risk loci for glioma, a subgroup of the brain tumor. To further characterize this association with the risk of brain tumors in a Korean population, we performed a fine-mapping association study of CDKN2A, CDKN2B, and CDKN2B-AS1., Methods and Results: A total of 17 SNPs were selected and genotyped in 1,439 subjects which were comprised of 959 patients (pituitary adenoma 335; glioma 324; meningioma 300) and 480 population controls (PCs). We discovered that a 3'untranslated region (3'UTR) variant, rs181031884 of CDKN2B (Asian-specific variant), had significant association with the risk of pituitary adenoma (PA) (Odds ratio = 0.58, P = 0.00003). Also, rs181031884 appeared as an independent causal variant among the significant variants in CDKN2A and CDKN2B, and showed dose-dependent effects on PA., Conclusions: Although further studies are needed to verify the impact of this variant on PA susceptibility, our results may help to understand CDKN2B polymorphism and the risk of PA., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

The contaminated healthcare environment plays an important role in the spread of multidrug-resistant organisms (MDROs) and Clostridioides difficile. This study aimed to evaluate the antimicrobial effects of ozone generated by a dielectric barrier discharge (DBD) plasma reactor on various materials that were contaminated by vancomycin-resistant Enterococcus faecium (VRE), carbapenem-resistant Klebsiella pneumoniae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Acinetobacter baumannii (CRAB) and C. difficile spores. Various materials contaminated by VRE, CRE, CRPA, CRAB and C. difficile spores were treated with different ozone concentrations and exposure times. Atomic force microscopy (AFM) demonstrated bacterial surface modifications following ozone treatment. When an ozone dosage of 500 ppm for 15 min was applied to VRE and CRAB, about 2 or more log 10 reduction was observed in stainless steel, fabric and wood, and a 1-2 log 10 reduction in glass and plastic. Spores of C. difficile were more resistant to ozone than were all other tested organisms. On AFM, the bacterial cells, following ozone treatment, were swollen and distorted. The ozone generated by the DBD plasma reactor provided a simple and valuable decontamination tool for the MDROs and C. difficile spores, which are known as common pathogens in healthcare-associated infections., (© 2022. The Author(s).)

Purpose: We retrospectively investigated NTM musculoskeletal infections to understand the clinical characteristics as well as the diagnostic performance of molecular tests as a useful supplementary test., Methods: A retrospective cohort study was conducted from January 2016 to December 2019. Intraoperative specimens for culture and pathological analysis were obtained during surgery under sterile conditions. AdvanSure TB/NTM real-time PCR (LG Life Sciences, Seoul, Korea) and PCR-reverse blot hybridization assay (REBA, REBA Myco-ID; YD Diagnostics, Yongin, Republic of Korea) was performed directly from tissue specimens for the rapid and accurate identification of 20 mycobacterial species., Results: A series of 24 patients was identified during the study period. Agricultural/aquatic exposure were predisposing factors in 9 patients, trauma in 4 patients, but no predisposing host factor was identified for 11 patients. Twenty-two patients presented with tenosynovitis and two with arthritis with substantial delays between initial presentation of symptoms and microbiologic diagnosis, with a median of 147 days (range 5-396 days). Pathologic tissue examination of musculoskeletal NTM infections was positive for chronic granulomatous inflammation in 18 cases. Fifteen were positive in the culture study, and nine were positive only in the molecular study using tissue specimens. All 6 M. ulcerans/M. marinum isolates were identified only by PCR., Conclusions: This study is an important reminder that NTM infections should be a part of the differential diagnosis in patients with chronic musculoskeletal infections refractory to regular treatment. Although molecular test cannot replace the conventional smear and culture methods, it can be used as a useful supplementary test especially in diagnosing M. marinum infection., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Numerous patients around the globe are dying from coronavirus disease 2019 (COVID-19). While age is a known risk factor, risk analysis in the young generation is lacking. The present study aimed to evaluate the clinical features and mortality risk factors in younger patients (≤ 50 years) with a critical case of COVID-19 in comparison with those among older patients (> 50 years) in Korea., Methods: We analyzed the data of adult patients only in critical condition (requiring high flow nasal cannula oxygen therapy or higher respiratory support) hospitalized with PCR-confirmed COVID-19 at 11 hospitals in Korea from July 1, 2021 to November 30, 2021 when the delta variant was a dominant strain. Patients' electronic medical records were reviewed to identify clinical characteristics., Results: During the study period, 448 patients were enrolled. One hundred and forty-two were aged 50 years or younger (the younger group), while 306 were above 50 years of age (the older group). The most common pre-existing conditions in the younger group were diabetes mellitus and hypertension, and 69.7% of the patients had a body mass index (BMI) > 25 kg/m². Of 142 younger patients, 31 of 142 patients (21.8%, 19 women) did not have these pre-existing conditions. The overall case fatality rate among severity cases was 21.0%, and it differed according to age: 5.6% (n = 8/142) in the younger group, 28.1% in the older group, and 38% in the ≥ 65 years group. Age (odds ratio [OR], 7.902; 95% confidence interval [CI], 2.754-18.181), mechanical ventilation therapy (OR, 17.233; 95% CI, 8.439-35.192), highest creatinine > 1.5 mg/dL (OR, 17.631; 95% CI, 8.321-37.357), and combined blood stream infection (OR, 7.092; 95% CI, 1.061-18.181) were identified as independent predictors of mortality in total patients. Similar patterns were observed in age-specific analyses, but most results were statistically insignificant in multivariate analysis due to the low number of deaths in the younger group. The full vaccination rate was very low among study population (13.6%), and only three patients were fully vaccinated, with none of the patients who died having been fully vaccinated in the younger group. Seven of eight patients who died had a pre-existing condition or were obese (BMI > 25 kg/m²), and the one remaining patient died from a secondary infection., Conclusion: About 22% of the patients in the young critical group did not have an underlying disease or obesity, but the rate of obesity (BMI > 25 kg/m²) was high, with a fatality rate of 5.6%. The full vaccination rate was extremely low compared to the general population of the same age group, showing that non-vaccination has a grave impact on the progression of COVID-19 to a critical condition. The findings of this study highlight the need for measures to prevent critical progression of COVID-19, such as vaccinations and targeting young adults especially having risk factors., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2022 The Korean Academy of Medical Sciences.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused health problems and distress among healthcare workers (HCWs), so supportive measures to promote their health and relieve distress are needed., Materials and Methods: We conducted two rounds of Delphi surveys with 20 COVID-19-related frontline healthcare professionals and public officials. The surveys evaluated means of supporting HCWs' health by improving health care systems and working environments in terms of effectiveness and urgency. The validity of the measures was assessed by calculating the content validity ratio., Results: The top-priority measures to support HCWs were "secure isolation units capable of treating severe cases" in the facility infrastructure category, "secure nursing staff dedicated for patients in the intensive care units" in the personnel infrastructure category, "improve communication between central office and frontline field" in the cooperation system category, "support personal protective equipment and infection control supplies" in the aid supplies category, and "realization of hazard pay" in the physical/mental health and compensation category., Conclusion: There was consensus among the experts on the validity and priorities of policies in the facility, personnel, cooperation, supplies, and compensation categories regarding measures to promote COVID-19 related HCWs' health., Competing Interests: No conflict of interest., (Copyright © 2022 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS.)

Background: As the coronavirus disease 2019 (COVID-19) pandemic is ongoing, heavy workload of healthcare workers (HCWs) is a concern. This study investigated the workload of HCWs responding to the COVID-19 outbreak in South Korea., Methods: A nationwide cross-sectional survey was conducted from September 16 to October 15, 2020, involving 16 healthcare facilities (4 public medical centers, 12 tertiary-care hospitals) that provide treatment for COVID-19 patients., Results: Public medical centers provided the majority (69.4%) of total hospital beds for COVID-19 patients (n = 611), on the other hand, tertiary care hospitals provided the majority (78.9%) of critical care beds (n = 57). The number of beds per doctor (median [IQR]) in public medical centers was higher than in tertiary care hospitals (20.2 [13.0, 29.4] versus 3.0 [1.3, 6.6], P = 0.006). Infectious Diseases physicians are mostly (80%) involved among attending physicians. The number of nurses per patient (median [interquartile range, IQR]) in tertiary-care hospitals was higher than in public medical centers (4.6 [3.4-5] vs. 1.1 [0.8-2.1], P = 0.089). The median number of nurses per patient for COVID-19 patients was higher than the highest national standard in South Korea (3.8 vs. 2 for critical care). All participating healthcare facilities were also operating screening centers, for which a median of 2 doctors, 5 nurses, and 2 administrating staff were necessary., Conclusion: As the severity of COVID-19 patients increases, the number of HCWs required increases. Because the workload of HCWs responding to the COVID-19 outbreak is much greater than other situations, a workforce management plan regarding this perspective is required to prevent burnout of HCWs., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2022 The Korean Academy of Medical Sciences.)

Introduction: Cigarette smoking is a leading cause of death worldwide and is associated with various diseases. However, studies addressing its impact on infection-related deaths are limited. This study examined the relationship between smoking and infection-related mortality., Aims and Methods: A cohort of 583 034 South Korean adults who underwent annual or biennial health examinations were followed up for infection-related deaths using national records. Cox proportional hazards regression assessed hazard ratios (HRs) and 95% confidence intervals (CIs) for infection-related mortality., Results: The median follow-up was 9.1 years (maximum 18 years), and 335 infection-related deaths were identified. Current smoking, but not former smoking, was positively associated with an increased risk of infection-related mortality. After adjusting for possible confounders, the multivariable-adjusted HRs (95% CIs) for infection-related mortality comparing former and current smokers with never smokers were 0.94 (0.68-1.30) and 1.45 (1.05-2.02), respectively; and those for infection-related mortality by number of pack-years comparing 10-19.9 and ≥20 pack-years to <10 pack-years were 1.26 (0.81-1.96) and 1.47 (1.03-2.09), respectively, while those comparing 10-19 and ≥20 cigarettes/day to <10 cigarettes/day were 1.35 (0.86-2.11) and 1.54 (1.13-2.11), respectively (p for trend <.05). Individuals with ≥20 pack-years had a 2.06 times greater risk of infection-related mortality when changes in smoking status and confounders during follow-up were updated in the analysis as time-varying covariates., Conclusions: Current smoking status, intensity, and pack-years were associated with an increased risk of infection-related death, with the highest risk of infection-related mortality found consistently in individuals with ≥20 pack-years., Implications: In this large-scale cohort study of relatively young and middle-aged South Korean adults, current smoking, smoking intensity, and pack-years were associated with an increased risk of death due to infections; in particular, a significantly increased risk of infection-related mortality was consistently found in individuals with ≥20 pack-years. When appropriate, infection-related mortality should be included in smoking-attributable mortality burdens, and effective smoking control measures should be considered to improve infection-related mortality., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hepatitis B virus (HBV) infection is associated with a reduced risk of developing dyslipidemia and non-alcoholic fatty liver diseases. Given that the gut microbiota plays a significant role in cholesterol metabolism, we compared the differences in gut microbial diversity and composition between HBV-infected and uninfected subjects., Results: A prospective case-control study was designed comprising healthy controls (group A) and HBV-infected individuals (group B) in a 1:1 ratio (57 participants each; total = 114). The patients in group B were divided into two subgroups according to their HBV DNA loads: B1 < 2000 IU/mL (N = 40) and B2 ≥ 2000 IU/mL (N = 17). In a pairwise comparison of HBV-infected individuals and controls, higher alpha diversity was noted in group B, and the difference was significant only in patients in group B1. Alloprevotella and Eubacterium coprostanoligenes were predominant in group B1 compared to the control, whereas the abundance of Bacteroides fragilis and Prevotella 2 was lower., Conclusions: The gut microbiome in HBV-infected individuals with a low viral load is highly diverse and is dominated by specific taxa involved in fatty acid and lipid metabolism. To our knowledge, this is the first demonstration of a correlation between the presence of certain bacterial taxa and chronic HBV infection depending on the load of HBV DNA., (© 2021. The Author(s).)

Aim: To validate six previously known primary open-angle glaucoma (POAG)-related loci in a Korean population., Methods: Representative POAG-related single-nucleotide polymorphisms (SNPs) from six loci ( cyclin-dependent kinase 4 inhibitor B antisense RNA 1 ( CDKN2B)-AS1, sineoculis homeobox homolog 1/sineoculis homeobox homolog 6 ( SIX1/SIX6 ) , a tonal BHLH transcription factor 7 ( ATOH7 ) , cell division cycle 7-transforming growth factor beta receptor 3, CAV1, transmembrane and coiled-coil domain family 1 ( TMCO1 ) were selected and genotyped from discovery (POAG=309, heathy=5400) and replication cohorts (POAG=310, healthy=5612 and POAG=221, healthy=6244, respectively). Data were analysed using logistic regression to calculate the OR for POAG risk associated with SNP., Results: From the discovery cohort, rs1900004 in ATOH7 (OR=1.29, p=0.0024); rs1063192 (OR=0.69, p=0.0006), rs2157719 (OR=0.63, p=0.0007) and rs7865618 (OR=0.63, p=0.0006) in CDKN2B-AS1 , and rs10483727 in SIX1/SIX6 (OR=0.68, p=7.9E-05) were nominally associated with the risk of POAG. The replication cohorts revealed nominal associations with rs2157719 (OR=0.72, p=0.0135), rs1063192 (OR=0.63, p=0.0007) and rs7865618 (OR=0.52, p=0.0004) in CDKN2B-AS1 . A mega-analysis from the entire Korean population revealed significance with rs1063192 (OR=0.77, p=6.0E-05), rs2157719 (OR=0.63, p=0.0007) and rs7865618 (OR=0.58, p=1.9E-06) in CDKN2B-AS1 and with rs10483727 in SIX1/SIX6 (OR=0.79, p=9.4E-05), with the same direction of effect between the discovery association and the replication sample., Conclusions: Variants near CDKN2B-AS1 and SIX1/SIX6 may require further investigation to obtain more genetic information on POAG development in a Korean population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Type 2 diabetes mellitus (T2DM) is associated with chronic hyperglycemia and lipid metabolism. A previous genome-wide association study revealed the TOMM40-APOE region as novel locus for T2DM susceptibility., Objective: This association study was conducted to determine the genetic effects of APOE single nucleotide polymorphisms (SNPs) on T2DM susceptibility and lipid profiles in a Korean population., Methods: A total of 6 tagging SNPs, including rs7412 and rs429358, were selected for ε genotype analysis and genotyped in 1436 subjects, consisting of 352 T2DM patients and 1084 unaffected controls., Results: Logistic regression analyses were conducted and there were no significant associations among the APOE 6 tagging SNPs, ε genotypes, and haplotypes with T2DM susceptibility. To investigate the association of the APOE tagging SNPs with the lipid profiles, a regression analysis was conducted. As a result, rs7412 was significantly associated with the total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) levels (P corr  = 2.30 × 10 -5 and 3.39 × 10 -13 , respectively) in the unaffected controls. The ε2 allele and ε3 allele were significantly associated with the TC (P corr  = 4.46 × 10 -6 and 0.02, respectively) and LDL levels (P corr  = 3.54 × 10 -14 and 0.0006, respectively) in the unaffected controls. Further analysis of only the unaffected controls was conducted. As a result, the APOE alleles ε2 and ε3 showed a significant association with the TC and LDL levels (P < 0.05)., Conclusion: The results of this study may help in understanding APOE polymorphisms and ε alleles and lipid profiles, which have been highly linked to T2DM, in a Korean population.

Background & Aims: Although coronavirus disease 2019 (COVID-19) is characterized by fever and respiratory symptoms, some patients have no or mild symptoms. Severe acute respiratory syndrome-coronavirus (SARS-CoV-2) has been detected in feces of patients. We investigated gastrointestinal symptoms and shedding of virus into feces of patients with asymptomatic or mild COVID-19., Methods: We collected data from 46 patients (median age, 26 y; 46% men) with asymptomatic or mild COVID-19 (without fever and pneumonia) and prolonged respiratory shedding of SARS-CoV-2, quarantined from April 4, 2020, through April 24, 2020, in Korea. Respiratory specimens included upper respiratory specimens (nasopharyngeal and oropharyngeal swabs) and lower respiratory specimens (sputum), and were collected twice per week. The median interval between COVID-19 diagnosis to the start of fecal sample collection was 37 days (range, 29-41 d); 213 stool specimens were collected from 46 patients. We used real-time reverse-transcription polymerase chain reaction to detect SARS-CoV-2 in the respiratory and fecal specimens., Results: Gastrointestinal manifestations were observed in 16 of the 46 patients (35%); diarrhea was the most common (15%), followed by abdominal pain (11%), dyspepsia (11%), and nausea (2%). Virus RNA was detected in feces from 2 patients without gastrointestinal symptoms (4%). Mean cycle threshold values from the time of quarantine to the time of fecal collection tended to be lower in patients with virus detected in fecal samples than in patients without virus in fecal samples (29.91 vs 33.67 in the first week, 29.47 vs 35.71 in the fifth week, respectively). Shedding of virus into feces persisted until day 50 after diagnosis; fecal samples began to test negative before or at approximately the time that respiratory specimens also began to test negative., Conclusions: In an analysis of fecal and respiratory specimens from patients with COVID-19 in quarantine in Korea, we found that the gastrointestinal tract could be a route of transmission of SARS-CoV-2 even in patients with asymptomatic or mild disease, with no gastrointestinal symptoms. The viral load of the respiratory specimens appears be related to shedding of the virus into feces in this group of patients., (Copyright © 2021. Published by Elsevier Inc.)

Background: Lung cancer is the leading cause of cancer-related deaths worldwide. Copy number variation (CNV) in several genetic regions correlate with cancer susceptibility. Hence, this study evaluated the association between CNV and non-small cell lung cancer (NSCLC) in the peripheral blood., Methods: Blood samples of 150 patients with NSCLC and 150 normal controls were obtained from a bioresource center (Seoul, Korea). Through an epigenome-wide analysis using the MethylationEPIC BeadChip method, we extracted CNVs by using an SVS8 software-supplied multivariate method. We compared CNV frequencies between the NSCLC and controls, and then performed stratification analyses according to smoking status., Results: We acquired 979 CNVs, with 582 and 967 copy-number gains and losses, respectively. We identified five nominally significant associations (ACOT1, NAA60, GSDMD, HLA-DPA1, and SLC35B3 genes). Among the current smokers, the NSCLC group had more CNV losses and gains at the GSDMD gene in chromosome 8 ( P =0.02) and at the ACOT1 gene in chromosome 14 ( P =0.03) than the control group. It also had more CNV losses at the NAA60 gene in chromosome 16 ( P =0.03) among non-smokers. In the NSCLC group, current smokers had more CNV gains and losses at the ACOT1 gene in chromosome 14 ( P =0.003) and at HLA-DPA1 gene in chromosome 6 ( P =0.02), respectively, than non-smokers., Conclusion: Five nominally significant associations were found between the NSCLC and CNVs. CNVs are associated with the mechanism of lung cancer development. However, the role of CNVs in lung cancer development needs further investigation.

Background: Hepatitis B is known to cause several forms of liver diseases including chronic hepatitis B (CHB), and hepatocellular carcinoma. Previous genome-wide association study of CHB risk has demonstrated that rs12614 of complement factor B (CFB) was significantly associated with CHB risk. In this study, fine-mapping study of previously reported GWAS single nucleotide polymorphism (SNP; CFB rs12614) was performed to validate genetic effect of rs12614 on CHB susceptibility and identify possible additional causal variants around rs12614 in a Korean population. This association study was conducted in order to identify genetic effects of CFB single nucleotide polymorphisms (SNPs) and to identify additional independent CHB susceptible causal markers within a Korean population., Methods: A total of 10 CFB genetic polymorphisms were selected and genotyped in 1716 study subjects comprised of 955 CHB patients and 761 population controls., Results: A non-synonymous variant, rs12614 (Arg32Trp) in exon2 of CFB, had significant associations with risk of CHB (odds ratio = 0.43, P = 5.91 × 10 - 10 ). Additional linkage disequilibrium and conditional analysis confirmed that rs12614 had independent genetic effect on CHB susceptibility with previously identified CHB markers. The genetic risk scores (GRSs) were calculated and the CHB patients had higher GRSs than the population controls. Moreover, OR was found to increase significantly with cumulative GRS., Conclusions: rs12614 showed significant genetic effect on CHB risk within the Korean population. As such rs12614 may be used as a possible causal genetic variant for CHB susceptibility.

Visually guided decision-making requires integration of information from distributed brain areas, necessitating a brain-wide approach to examine its neural mechanisms. New tools in Drosophila melanogaster enable circuits spanning the brain to be charted with single cell-type resolution. Here, we highlight recent advances uncovering the computations and circuits that transform and integrate visual information across the brain to make behavioral choices. Visual information flows from the optic lobes to three primary central brain regions: a sensorimotor mapping area and two 'higher' centers for memory or spatial orientation. Rapid decision-making during predator evasion emerges from the spike timing dynamics in parallel sensorimotor cascades. Goal-directed decisions may occur through memory, navigation and valence processing in the central complex and mushroom bodies., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We investigated the colistin resistance of Klebsiella pneumoniae blood isolates from South Korea. Among 252 K. pneumoniae isolates, only 11 (4.4%) demonstrated colistin resistance, of which, one was resistant to all antibiotics but tigecycline. Multilocus sequence typing analysis revealed ten sequence types among the 11 colistin-resistant isolates, indicating independent occurrence of colistin resistance in K. pneumoniae. To understand the mechanism of colistin resistance, amino acid variations in PmrAB, PmrD, PhoPQ, and MgrB were investigated. Amino acid substitutions were identified in all the colistin-resistant K. pneumoniae isolates. Particularly, extensive alterations in the genes associated with colistin resistance were shared in four colistin-resistant isolates, suggesting recombination between these genes of unrelated isolates. Our results suggest that genetic recombination is responsible for colistin resistance in some K. pneumoniae isolates.

Primary open-angle glaucoma (POAG) can develop even within normal ranges of intraocular pressure, and this type of glaucoma (so-called 'normal-tension glaucoma [NTG]') is highly prevalent in East Asia including Korea and Japan. We conducted exome chip analysis to identify low-frequency and rare variants associated with POAG from the primary cohort (309 POAG patients and 5,400 control, all Koreans). For replication, Korean (310 POAG patients and 5,612 controls) and Japanese (565 POAG patients and 1,104 controls) cohorts were further investigated by targeted genotyping. SNP rs116121322 in LRRC27 showed nominally significant association with POAG in the discovery cohort (OR = 29.85, P = 2E-06). This SNP was validated in the Korean replication cohort but only in the NTG subgroups (OR = 9.86, P = 0.007). Japanese replication cohort did not show significant association with POAG (P .00.44). However, the meta-analysis in the entire cohort revealed significant association of rs116121322 with POAG (OR combined  = 10.28, P combined  = 1.4E-07). The LRRC27 protein expression was confirmed from human trabecular meshwork cells. For gene-based testing, METTL20 showed a significant association in POAG (P combined  = 0.002) and in the subgroup of NTG (P combined  = 0.02), whereas ZNF677 were significantly associated with only in the subgroup of high-tension glaucoma (P combined  = 1.5E-06). Our findings may provide further genetic backgrounds into the pathogenesis of POAG, especially for the patients who have lower baseline intraocular pressures.

Heteroresistance may pose a threat to the prognosis of patients following colistin treatment. We investigated colistin heteroresistance in Klebsiella pneumoniae isolates from South Korea. Among 252 K. pneumoniae blood isolates, 231 were susceptible to polymyxins. Heteroresistance to colistin was determined using population analysis profiles, disk diffusion assays, and E-test strip tests for the susceptible isolates. As a result, we identified three colistin-heteroresistant K. pneumoniae isolates belonging to separate clones (ST11, ST461, and ST3217) by multilocus sequence typing analysis. Two colistin-resistant subpopulations were selected from each heteroresistant isolate in either disk diffusion testing or E-testing. Two resistant subpopulations from the same isolate exhibited different amino acid substitutions in the two-component regulatory systems PmrAB and PhoPQ. An in vitro time-kill assay showed that meropenem combined with colistin had a 1× minimum inhibitory concentration bactericidal effect against a multidrug-resistant, colistin-heteroresistant isolate.

Our previous transcriptome study of cultured fibroblasts identified 178 genes that were differentially expressed by 8 idiopathic pulmonary fibrosis (IPF) fibroblasts compared with 4 controls. Here, we performed genome-wide DNA methylation analysis to evaluate the relationship of CpG methylation to differential gene expression. Among 485,577 loci, 5850 loci on 2282 genes showed significant differences between the 2 groups (delta-beta >10.21 and p -value <0.05). Among these, beta values of 80 CpGs (30 hypermethylated and 50 hypomethylated) were significantly correlated with mRNA expression of 34 genes (19.1%) of the 178 differentially expressed genes between the 2 groups (13 downregulated and 21 upregulated). Gene ontology enrichment of these genes included cell adhesion, molecule binding, chemical homeostasis, surfactant homeostasis, and receptor binding. One-third of them are involved in the known process of fibrosis; the others are novel genes with respect to pulmonary fibrosis. We identified relationships between the altered DNA methylation levels and about one-fifth of the corresponding changes in gene expression by lung tissue fibroblasts. Findings from this study provide new information on novel genes responsible for the pathogenesis of IPF under the control of CpG methylation changes in IPF lungs.

Lung cancer is a common form of cancer and the leading cause of cancer-related deaths worldwide. Early diagnosis using noninvasive biomarkers may play an important role in increasing the survival rate of patients with lung cancer. Biomarkers of DNA methylation in blood samples may improve the early diagnosis of lung cancer. Here, we used peripheral blood samples obtained from 150 patients diagnosed with non-small-cell lung cancer (NSCLC) and 150 healthy controls. The latter were selected by frequency matching with the 150 patients with NSCLC, based on age, sex, and smoking status. Genome-wide methylation profiles were obtained using a MethylationEPIC BeadChip Kit, which covers the 850k bp cytosine-phosphate-guanine site. This analysis showed two significant differentially methylated changes (cg12169243 [ DPH6 ] and cg25429010 [ IMP3 ]) associated with NSCLC in current smokers, six changes (cg09245319, cg17183999 [ USP7 ], cg06366994 [ CPE ], cg24992236 [ MEG9 ], cg22144719, and cg22448179 [epidermal growth factor receptor]) associated with epidermal growth factor receptor mutation in patients with adenocarcinoma, and four changes (cg25021476 [ RSL24D1 ], cg04989085 [ FAM113B ], cg20905681 [ CKAP4 ], and cg26379694) associated with advanced-stage NSCLC compared with stage I NSCLC. The validation of these DNA methylation changes and further research on the related genes may help develop easily accessible biomarkers for the early diagnosis or prognosis of NSCLC.

Gut dysbiosis is regarded as a pathogenetic factor of nonalcoholic fatty liver disease (NAFLD), but its role in NAFLD persistence is unknown. We investigated the influence of the gut microbiota on persistent NAFLD. This cohort study included 766 subjects with 16S ribosomal RNA (rRNA) gene sequencing data from fecal samples at baseline who underwent repeated health check-up examinations. Fatty liver was determined using ultrasound at baseline and follow-up. Participants were categorized into four groups: none (control), developed, regressed, or persistent NAFLD. The persistent NAFLD group had lower richness compared with the control group. Significant differences were also found in both non-phylogenic and phylogenic beta diversity measures according to NAFLD persistence. Pairwise comparisons indicated that taxa abundance mainly differed between the control and persistent NAFLD groups. A relative high abundance of Fusobacteria and low abundance of genera Oscillospira and Ruminococcus of the family Ruminococcaceae and genus Coprococcus of the family Lachnospiraceae were found in the persistent NAFLD group. Based on the functional predictions, pathways related to primary and secondary bile acid biosynthesis were highly detected in the persistent NAFLD group compared with the control group. These findings support that the composition of the gut microbiome associated with dysregulation of bile acid biosynthetic pathways may contribute to the persistence of NAFLD. This is the first cohort study to demonstrate the influence of microbiota on persistent NAFLD. Our findings may help identify potential targets for therapeutic intervention in NAFLD.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been the only treatment option for acute myeloid leukemia (AML) refractory to induction chemotherapy, with only 10-20% of patients achieving long-term survival. Certain donor genotypes may confer leukemia-clearing effects after allo-HSCT. We performed whole-exome sequencing of five pairs of the germ lines in AML patients who achieved long-term remission after allo-HSCT and in their donors, and found two significant variants: EGFR c.2982C > T and CDH11 c.945G > A. To validate the protective effects of these leukemia-clearing genotypes (LCGs), AML patients who received allo-HSCT in a complete-remission status were also analyzed. Twenty-two of 96 donors (22.9%) had LCGs in their genomes, and overall survival was significantly longer in patients who received allo-HSCT from donors with germ-line LCGs (hazard ratio=0.47, 95% confidence interval=0.24-0.94, p  = .033). These findings indicate that donor germ-line LCGs have phenotypically leukemia-clearing effects and are biomarkers for predicting clinical outcomes in allogeneic transplantation in AML patients.

No cohort studies have evaluated the effect of obesity on the risk of cellulitis according to metabolic health status. We investigated an association of BMI and metabolic health status with the development of cellulitis. We conducted a cohort study of 171,322 Korean adults who underwent a health checkup examination and were followed from 2011 to 2016 for cellulitis and hospital admission related to cellulitis, which were ascertained through the linkage to the Health Insurance and Review Agency database. Being metabolically healthy was defined as not having any metabolic syndrome component and having a homeostasis model assessment of insulin resistance <2.5. During 638,240.4 person-years of follow-up, 14,672 cases of incident cellulitis were identified with 225 cases of cellulitis-related admission. After adjustment for possible confounders, the multivariable-adjusted hazard ratios (95% CI) for incident cellulitis comparing BMIs 23-24.9, 25-29.9, and ≥30 with a BMI of 18.5-22.9 kg/m 2 as the reference were 1.07 (1.02-1.11), 1.09 (1.04-1.13), and 1.19 (1.08-1.31), respectively, whereas the corresponding multivariable-adjusted hazard ratios (95% CI) for cellulitis-related admission were 1.55 (1.05-2.3), 2.47 (1.73-3.53), and 4.8 (2.86-8.05), respectively. These associations were consistently observed in both metabolically healthy and unhealthy individuals with no significant interaction. In a large cohort of apparently healthy adults, increased BMI was associated with an increased risk of cellulitis and hospitalization for cellulitis in both metabolically healthy and unhealthy individuals. Obesity appears to be an independent risk factor for cellulitis regardless of metabolic phenotype., Competing Interests: The authors declare no conflict of interest.

Purpose: Previous studies have revealed that PHLDB1 single-nucleotide polymorphisms (SNPs) are associated with glioma risk. Nonetheless, the association between PHLDB1 SNPs and the risk of pituitary adenoma has not been studied. The present study evaluated the association of PHLDB1 SNPs with the risk of pituitary adenomas., Methods: We genotyped 27 PHLDB1 tagging and exon SNPs in a case-control study that included 148 patients who got a diagnosis of nonfunctional pituitary adenoma (NFPA) and 375 normal controls within the Korean population. Statistical analyses of the association between PHLDB1 SNPs and the NFPA risk were conducted using logistic regression., Results: We detected an association between a PHLDB1 SNP and the risk of NFPA in the Korean population. Rs67307131 in intron 2 was significantly associated with NFPA (odds ratio [OR] = 2.15, 95% confidence interval [CI] 1.44-3.20; P = 0.0002 in the dominant model). In the referent analysis, a higher OR and stronger association (lower P value) were observed among patients with the "C/T" genotype (OR = 2.39, 95% CI 1.60-3.58; P = 0.00002). In a functional analysis with a SNP annotation tool, this SNP was predicted to be a CpG site and copy number variant; these properties are associated with susceptibility to diseases., Conclusions: Our findings suggest that genetic variation of PHLDB1 may be associated with the risk of NFPA. This is the first report of an association between PHLDB1 variants and NFPA. Further research is needed to confirm the impact of this SNP on NFPA susceptibility.

Rationale: Until now, no cohort studies have evaluated the relationship between high-risk human papillomavirus (HPV) infection and new-onset cardiovascular diseases (CVD)., Objective: We investigated an association between high-risk HPV infection and the development of CVD., Methods and Results: We conducted a cohort study of 63 411 women aged 30 or older without CVD at baseline who underwent a high-risk HPV test and were followed annually or biennially from 2011 to 2016. CVD was ascertained through the linkage to the Health Insurance and Review Agency database. A Cox-proportional hazards regression model was used to estimate adjusted hazard ratios (HRs) with 95% CIs of incident CVD. The prevalence of high-risk HPV infection was 7.6%. During 261 598.9 person-years of follow-up, 1122 cases of new-onset CVD were identified (incidence rate of 4.3 per 10 3 person-years). High-risk HPV infection was significantly associated with incident CVD. After adjustment for possible confounders, and high sensitivity C-reactive protein, a significant association between high-risk HPV infection and incident CVD was still observed, with a corresponding HR (95% CI) of 1.25 (1.03-1.52). This association was stronger among individuals with obesity and those with metabolic syndrome. Multivariable-adjusted HR (95% CI) for incident CVD comparing high-risk HPV-positive- to high-risk HPV-negative participants was 1.10 (0.87-1.39) in the nonobese, whereas corresponding HR (95% CI) was 1.73 (1.19-2.51) in those with obesity ( P for interaction by obesity=0.02). Similarly, multivariable-adjusted HR (95% CI) for incident CVD comparing high-risk HPV-positive- to high-risk HPV-negative participants was 1.09 (0.87-1.36) in those without metabolic syndrome and 1.99 (1.28-3.08) in those with MetS ( P for interaction=0.05)., Conclusion: In this large cohort, high-risk HPV infection was significantly associated with an increased risk of developing CVD, especially in obese individuals and those with MetS, indicating that high-risk HPV might affect CVD risk with possible effect modification by obesity and MetS.

The changes in the gut microbiota of healthy hepatitis B virus (HBV) carriers, including asymptomatic and non-cirrhotic subjects, have been rarely scrutinized. From 1463 faecal samples in health examinees, in total 112 subjects, including 36 hepatitis B surface antigen (HBsAg)-positive and 76 control subjects, were included. Twenty-eight of 36 HBsAg-positive individuals (78%) showed normal alanine aminotransferase (ALT) levels (normal ALT group), whereas eight subjects exhibited elevated ALT levels (22%, high ALT group). By using 16S rRNA gene sequencing, the distance between normal and high ALT groups among HBsAg-positive subjects showed a significant separation after the pairwise comparison of weighted UniFrac distance (permutational analysis of variance q -value = 0.039), when compared with the distances to the control group. In comparison with the control group, the normal ALT group had Anaerostipes as a significant taxon that showed a positive association (Coefficient ( Coef. ) = 0.028, q = 0.039). Desulfovibrio ( Coef. = 0.54, q = 0.014) and Megasphaera ( Coef. = 1.41, q = 0.030) showed positive correlations, and Acidaminococcus ( Coef. = -1.31, q = 4.15 × 10 -75 ) exhibited a negative correlation with high ALT level. Gut microbial composition was different according to HBV-induced serum ALT levels, indicative of a potential link between gut and liver metabolism.

Chronic hepatitis B (CHB) is a precursor to liver cirrhosis and hepatocellular carcinoma, caused by a Hepatitis B viral infection. Genome-wide association studies (GWASs) have been conducted to find genes associated with CHB risk. In previous GWAS, EHMT2 was identified as one of the susceptibility genes for CHB. To further characterize this association and discover possible causal variants, we conducted an additional association study. A total of 11 EHMT2 single-nucleotide polymorphisms (SNP) were selected and genotyped in 3902 subjects (1046 CHB patients and 2856 controls). An additional eight imputed SNPs were also included in further analysis. As a result, rs35875104 showed a strong association with the CHB, along with the previously reported genetic marker for CHB risk, rs652888 (odds ratio (OR) = 0.53, P = 2.20 × 10 -8 at rs35875104 and OR = 1.58, P = 9.90 × 10 -12 at rs652888). In addition, linkage disequilibrium and conditional analysis identified one SNP (rs35875104) as a novel genetic marker for CHB susceptibility. The GRSs (genetic risk scores) were calculated to visualize the combined genetic effects of all known CHB-associated loci, including EHMT2 rs35875104, which was additionally identified in this study. The findings from the present study may be useful for further understanding of the genetic etiology of CHB.