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Athletic performance is a multifactorial trait influenced by environmental and genetic factors. Previous studies have identified various genes associated with athletic performance, including the β2-adrenergic receptor (ADRB2) gene, which has been consistently shown to be linked with elite athletic performance in diverse populations. The ADRB2 gene is known to play a key role in various biological systems, including cardiovascular, pulmonary, metabolic, and musculoskeletal functions. It acts by interacting with adrenaline. In particular, the ADRB2 rs1042713 (A > G) polymorphism has been associated with cardiovascular and respiratory functions. In addition, the association between the ADRB2 rs1042713 polymorphism and athletic performance has been reported. Thus, we conducted a case-control study to analyze the genetic association with ADRB2 rs1042713 polymorphism with 150 elite athletes, 116 college athletes, and 145 controls (control I) in the Korean population. The genotypes were determined by PCR-RFLP. As a result, we found significant differences in the distributions of genotype (p = 0.005) and allele (p = 0.002) frequencies between elite athletes and the control Ⅱ (control I + college athletes). We also found that the ADRB2 rs1042713 G/G genotype [odds ratio (OR) 2.42, 95% CI 1.384-4.235, p = 0.002] and the G allele (OR 1.58, 95% CI 1.184-2.098, p = 0.002) were significantly associated with elite athletic performance. Additionally, we observed a gender-specific association in female elite athletic performance (p = 0.0002 and p = 0.0002, respectively). In conclusion, our results suggest that the ADRB2 rs1042713 polymorphism may be associated with elite athletic performance in the Korean population. To validate these findings, additional studies with larger samples, including elite athletes from various sports types and diverse ethnic origins are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Digital therapeutics (DTx) are therapeutic interventions driven by software and directly provided to patients, allowing them to manage their health with ease in any setting. A growing interest in DTx has spurred a discussion concerning their reimbursement pathways. However, DTx are still at a premature stage, with insufficient evidence on effectiveness, efficiency, and safety. Currently, although industries desire to quickly enter the market, especially by getting their products reimbursed by the National Health Insurance (NHI) fund, the NHI is cautious about DTx due to their uncertainties. Thus, public discussion and social consensus are crucial in deciding whether to reimburse DTx by the NHI fund., Objective: This study examined multiple stakeholders' awareness and attitudes toward DTx and perceptions of regulatory pathways for adopting DTx., Methods: In-depth interviews were conducted with 11 stakeholders in South Korea (industry: n=4, health care: n=3, academia: n=2, and consumer: n=2) using semistructured guidelines. They were purposively sampled to identify individuals with expertise in DTx and NHI policies. The interviews were conducted either in person or via a videoconference for 45-70 minutes. Qualitative data were analyzed using directed content analysis, which uses interview guidelines as an analytical framework., Results: Findings were divided into three categories: (1) awareness and attitude toward DTx, (2) perception of whether DTx are worth entering the market and being reimbursed by the NHI fund, and (3) perception of how to enter the market and how to reimburse DTx by the NHI fund if they are worth it. Although consumer stakeholders were not familiar with the basic concept of DTx, the other stakeholders understood it thoroughly. However, all participants showed positive attitudes and acceptance of DTx. Most of them responded that DTx are worth entering the market, but they could not reach an agreement on the pathways for DTx to enter the market. Although participants were in favor of the reimbursement of DTx in principle, they responded that a conservative approach is required due to insufficient clinical evidence for DTx., Conclusions: We found that stakeholders in South Korea had positive attitudes toward DTx, perceived them as worth using, and agreed to allow them to enter the market. The main issue was not the problem of the technology itself but the difference in opinion as to the pathways for reimbursement. Therefore, this study concluded that the NHI fund, which is operated very conservatively, is insufficient to quickly adopt and implement DTx. Various reimbursement methods, including tax-based financing, raising innovation funds for new technologies, and pilot studies using the NHI fund, should be used to rapidly generate clinical evidence and reduce the uncertainties of DTx to secure a stable market., (© Boram Sim, Jin Han Ju, Byungsoo Kim, Jin Yong Lee. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org).)

Background: Attention deficit hyperactivity disorder (ADHD) is a common childhood neurodevelopmental disorder, and the prevalence of ADHD among Korean children has attained about 8.5%. Various genetic factors can contribute to the etiology of the disease. Synaptophysin (SYP) regulates neurotransmitter release and synaptic plasticity. According to previous studies, several genetic polymorphisms on SYP were risk factors for ADHD., Objective: We investigated the effect of the SYP gene polymorphisms (rs2293945 and rs3817678) on ADHD in Korean children., Methods: In this study, we examined the case-control study in 150 ADHD cases and 322 controls. The genotyping of SYP gene polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)., Results: Significant associations in the genotype and genetic models of SYP rs2293945 polymorphism between girls with ADHD and control girls were found. The girls with ADHD having the C/T genotype were significantly associated with ADHD. In the dominant model of rs3817678, C/T + T/T genotypes were significantly associated with ADHD. The haplotype analyses showed significant associations from haplotypes of rs2293945 T-rs3817678 G and rs2293945 C-rs3817678 A., Conclusion: Our results imply that the SYP rs2293945 C/T polymorphism in female participants may provide a possible effect on the genetic etiology of ADHD., (© 2023. The Author(s) under exclusive licence to The Genetics Society of Korea.)

This study aimed to determine the policy implications for drug management by identifying the prescription trends of potentially inappropriate medications (PIMs) in older outpatients. Considering the Drug Utilization Review and Korean version of the standards for PIMs based on the Beers Criteria, 141 ingredients were selected that spanned over 7 years of health insurance claims data analysis. During the study period, the number of patients and claims related to PIMs increased. Although the number of health insurance claims decreased in 2020 owing to coronavirus disease (COVID-19), it increased again in 2021. Tamsulosin was the most frequently prescribed drug for male patients, followed by alprazolam and zolpidem. For female patients, eperisone was the most frequently prescribed drug, followed by alprazolam, zolpidem, and etizolam. In Korea, health insurance claims for PIMs decreased in 2020 owing to the COVID-19 pandemic. However, an overall increasing trend was observed from 2015 to 2021. Moreover, during this period, the prescription trend of benzodiazepine-type drugs and zolpidem increased in both male and female patients. Therefore, management policies regarding PIMs and drug ingredients, such as benzodiazepines and zolpidem, are required., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Attention deficit hyperactivity disorder (ADHD) is a common and heritable neurodevelopmental disorder. Particularly, ADHD is known to be related to the dopaminergic system. ADHD symptoms can appear when the dopamine binding affinity diminishes due to dopamine receptor abnormalities, such as the dopamine D 2 receptor (D 2 R). This receptor interacts with the adenosine A 2A receptor (A 2A R). The A 2A R acts as an antagonist of D 2 R, that is, the increased binding of adenosine with A 2A R inhibits the D 2 R activity. Furthermore, it is found that the single nucleotide polymorphisms of the adenosine A 2A receptor gene (ADORA2A) revealed a significant relationship with ADHD in various populations. Therefore, we examined the genetic relationship between ADORA2A polymorphisms (rs2297838, rs5751876, and rs4822492) and Korean ADHD children. A case-control study was performed for 150 cases and 322 controls. Genotyping of ADORA2A polymorphisms was conducted by PCR-RFLP. The results demonstrated that the rs5751876 TC genotype was associated with children with ADHD (p = 0.018). The rs2298383 CC genotype was significantly associated with children with ADHD/HI (p = 0.026). However, when Bonferroni correction was used, the significance vanished (p adjusted  = 0.054 and p adjusted  = 0.078, respectively). Haplotype analysis showed that TTC, TCC, and CTG demonstrated a significant difference between ADHD/C children and control groups (p adjusted  = 0.006, p adjusted  = 0.011, and p adjusted  = 0.028, respectively). In conclusion, we propose a possible association between ADORA2A polymorphisms with Korean children having ADHD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Heat waves are generally known to deteriorate air quality. However, the impacts of heat waves on air quality can substantially vary depending on the characteristics of heat waves. In this study, we examine air quality changes in Seoul during heat waves and their associations with large-scale atmospheric patterns. For this, air quality data from 25 stations and meteorological data from 23 weather stations and reanalysis datasets during July and August of 2001-2021 are used. Under heat waves, the mean daily PM 10 , NO 2 , and CO concentrations decrease by 7.9 %, 6.1 %, and 4.6 %, respectively, whereas the mean daily PM 2.5 , O 3 , and SO 2 concentrations increase by 4.1 %, 17.2 %, and 2.9 %, respectively. The atmospheric circulation under heat waves is less favorable for long-range transport of air pollutants to Seoul. The PM 2.5 /PM 10 ratio increases under heat waves, indicating that the secondary formation of aerosols becomes more important under heat waves. 37 % of the heat wave days are accompanied by severe O 3 pollution exceeding the O 3 concentration standard in South Korea. There is a significant variability of air quality in Seoul within heat waves. The heat wave days with higher concentrations of PM 2.5 , PM 10 , O 3 , NO 2 , and CO than their non-heat wave means exhibit a prominent difference in large-scale atmospheric pattern from the heat wave days with lower concentrations. This difference is characterized by a zonal wave-like pattern of geopotential height, which is similar to the circumglobal teleconnection pattern known as one of the major patterns for heat waves in South Korea. This zonal wave-like pattern produces more stagnant conditions over Seoul., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Attention deficit hyperactivity disorder (ADHD) is a major neurodevelopmental disorder including multiple environmental and biological causes. It is generally reported that the prevalence of ADHD is 4-fold higher in boys than in girls. Previous studies have reported that the Y-linked genes have been significantly associated with neuropsychiatric disorders. Furthermore, several Y chromosome haplogroups have been reported to be related to the development of ADHD symptoms. Therefore, we analyzed the genetic correlation between the Y chromosome haplogroups and ADHD in the Korean boys. Our results showed that the Y chromosome haplogroup O2b (xO2b1) (p = 0.053) and O3a3c1 (p = 0.050) has a trend of borderline statistical significance. In subtype analysis, a significant association was observed between haplogroup O3a3c1 and the ADHD/C [odds ratio (OR), 3.43; 95 % confidence interval (CI), 1.336 - 8.782; p = 0.007]. However, this association could not pass the Bonferroni correction for multiple testing. In conclusion, our results showed a lack of association between Y chromosome haplogroups and the occurrence of ADHD in Korean boys., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In South Korea, there are few studies to understand the current status of pulmonary rehabilitation in clinical practice and develop it. This study aimed to assess the current status and annual changes in the number and pattern of prescriptions for pulmonary rehabilitation before and after its insurance coverage. The trends of pulmonary rehabilitation before and after its insurance coverage commencement were evaluated using the data of 24,380 patients during the 3-year period from 2016 to 2018 that were archived by the National Health Information Database of the Health Insurance Review and Assessment Service in South Korea. The annual total number of patients who received pulmonary rehabilitation was stratified by the type of prescription, sex, age, type of insurance, medical institution, and region. In addition, the frequencies of pulmonary rehabilitation for various diagnoses were investigated using the major codes of the Korean Standard Classification of Disease. The patients who received pulmonary rehabilitation increased by approximately 2 times from 5936 in 2016 (before insurance coverage) to 10,474 in 2019. Before 2017, most patients underwent simple pulmonary rehabilitation coded as MM290. However, since the insurance coverage of rehabilitation exercise for pulmonary disease (MM440), the proportions of patients receiving them increased. Men underwent pulmonary rehabilitation more often than women, and >70% of the patients were aged >60 years. Most patients received pulmonary rehabilitation at tertiary hospitals in Seoul. In 2016, pulmonary rehabilitation was prescribed more frequently for cerebral infarction; after 2017, it was prescribed more frequently for lung cancer. This study summarized the current status and trends of pulmonary rehabilitation in South Korea before and after National Health Insurance Service coverage, which commenced on January 1, 2017. A significant increase in the number of pulmonary rehabilitations was confirmed after the insurance coverage., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Attention deficit hyperactivity disorder (ADHD) is a common and heritable childhood psychiatric disorder. Recently, many studies reported a down-regulated hypothalamus-pituitary-adrenal axis (HPA-axis) with low cortisol levels in children with ADHD. The FK506 binding protein 5 or FKBP5 gene regulates the negative feedback of the HPA-axis, and genetic variants in this gene showed an association with ADHD. We investigated the genetic association between FKBP5 gene polymorphisms and susceptibility to ADHD in Korean children. We conducted a case-control study with 150 ADHD children and 322 controls. Genotyping of FKBP5 rs9394309 and rs7748266 was performed by using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). Our results showed that rs7748266 polymorphism has significant genotype (p = 0.021) and allele (p = 0.009) frequency differences between children with ADHD and the control group. CT genotype [odds ratio (OR) 1.70, 95 % confidence interval (CI) 1.134-2.540, p = 0.010] and T allele (OR 1.54, 95 % CI 1.114-2.117, p = 0.009) were associated with increased risk of ADHD. In addition, dominant (p = 0.006) and over-dominant genetic (p = 0.016) models showed significant associations with ADHD. In the stratified analysis, a significant result was obtained from the girl samples (p = 0.048). The OR of the girls with ADHD with CT genotype was 2.29 (95 % CI 1.170-4.469, p = 0.014). In contrast to rs7748266 polymorphism, rs9394309 polymorphism did not show any significant result (p > 0.05). Haplotype analysis also revealed a significant difference of the TG haplotype for rs7748266 - rs9394309 (p = 0.028, global haplotype association p-value of 0.0091). Conclusively, we confirmed that FKBP5 gene polymorphisms were associated with ADHD in Korean children. These results suggested that FKBP5 may factor in the development of ADHD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Replacement with nonvaccine serotypes (NVTs) among invasive pneumococcal diseases (IPDs) after the introduction of extended-valency pneumococcal conjugate vaccines varies in predominant serotypes across countries. This study analyzed changes in serotype distribution through serotyping, multilocus sequence typing, and antimicrobial susceptibility testing of 168 pediatric IPD isolates obtained from a multihospital-based surveillance system during 2014-2019 in South Korea. Vaccine serotypes (VTs) accounted for 16.1% (19A, 10.1%; 6A, 1.8%; and 19F 1.8%), 82.1% were NVTs (10A, 23.8%; 15A, 8.3%; 12F, 6.5%; 15C, 6.5%; and 15B, 6.0%), and three (1.8%) were nontypeable. Serotype 10A was the most common serotype, with a significant increase from 11.5% in 2014 to 33.3% in 2019 (p < 0.05 for the trend). Other NVTs decreased from 70.4% to 41.7% between 2015 and 2019, most notably in serotype 12F (from 14.8% to 0%). Almost all (95.0%) serotype 10A isolates were ST11189, which were multidrug resistant., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The folate metabolism that converts homocysteine to methionine is closely related to the accumulation of homocysteine. Increased homocysteine levels lead to an impaired antithrombotic function of the vascular endothelium and uterine-placental circulation, resulting in abnormal pregnancy outcomes. Previous studies have reported that gene polymorphisms in folate metabolism are associated with the development of preterm birth (PTB) in various populations., Objective: we performed a case-control study to evaluate the association between five polymorphisms in folate metabolic genes (MTHFR, MTR, MTRR, TCN2) and PTB., Methods: In this study, a total of 254 subjects were analyzed (111 patients with PTB and 143 women at ≥ 38 weeks of gestation). Genotype and allele frequency differences between patients and control groups and the Hardy-Weinberg equilibrium were assessed using a Chi-square test. For evaluation indicators, odds ratios (ORs) of 95% confidence intervals (CI) were estimated. In addition, we analyzed the combined genotype frequencies of SNPs of folate-metabolizing genes to measure gene-gene interactions for PTB., Results: Our results showed that the MTR rs1805087 GG (p = 0.031), and TCN2 rs1801198 CG genotype (OR 0.53, 95% CI 0.288-0.980, p = 0.042) were significantly associated with PTB. The MTHFR rs4846049 AA showed a marginal trend toward significance (OR 0.15, 95% CI 0.018-1.205, p = 0.041). In particular, the combined genotypes, including MTHFR rs1537514 CC-MTRR rs1801394 GG, MTHFR rs1537514 CC-TCN2 rs1801198 CG, and MTR rs1805087 AA-TCN2 rs1801198 CG, have significant interactions with PTB (OR 0.49, 95% CI 0.248-0.992, p < 0.05)., Conclusion: The polymorphisms of folate metabolic genes may have a genetic association with the development of PTB in Korean women. A larger sample set and functional studies are required to further elucidate our findings., (© 2021. The Genetics Society of Korea.)

Background: Interstitial lung diseases (ILDs) are chronic, parenchymal lung diseases with a variable clinical course and a poor prognosis. Within various clinical courses, acute exacerbation (AE) is a devastating condition with significant morbidity and high mortality. The aim of this study was to investigate the role of interleukin-6 (IL-6) to predict AE and prognosis in patients with ILD., Methods: Eighty-three patients who were diagnosed with ILD from 2016 to 2019 at the Haeundae Paik Hospital, Busan, South Korea, were included and their clinical data were retrospectively analyzed., Results: The median follow-up period was 20 months. The mean age was 68.1 years and 65.1% of the patients were men with 60.2% of patients being ever-smokers. Among ILDs, idiopathic pulmonary fibrosis was the most common disease (68.7%), followed by connective tissue disease-associated ILD (14.5%), cryptogenic organizing pneumonia (9.6%), and nonspecific interstitial pneumonia (6.0%). The serum levels of IL-6 were measured at diagnosis with ILD and sequentially at follow-up visits. During the follow-ups, 15 (18.1%) patients experienced an acute exacerbation (AE) of ILD and among them, four (26.7%) patients died. In the multivariable analysis, high levels of IL-6 (OR 1.014, 95% CI: 1.001-1.027, p = 0.036) along with lower baseline saturations of peripheral oxygen (SpO2) were independent risk factors for AE. In the receiver operating characteristic curve analysis, the area under the curve was 0.815 (p < 0.001) and the optimal cut-off value of serum IL-6 to predict AE was 25.20 pg/mL with a sensitivity of 66.7% and specificity of 80.6%. In the multivariable Cox analysis, a high level of serum IL-6 (HR 1.007, 95% CI: 1.001-1.014, p = 0.018) was only an independent risk factor for mortality in ILD patients., Conclusions: In our study, a high level of serum IL-6 is a useful biomarker to predict AE and poor prognosis in patients with ILD., Competing Interests: The authors have declared that no competing interests exist.

The inactivated trivalent influenza vaccine (TIV) offers limited protection when two influenza B lineages co-circulate or when there is a vaccine mismatch (i.e., discordance in the predominant circulating B strain and WHO-recommended B strain). Inactivated quadrivalent influenza vaccine (QIV) may reduce the burden of influenza. Here, we report the results of a phase 3 clinical trial that evaluated the immunogenicity and safety of a novel QIV, GC3110A, in Korean children aged 6-35 months, which has been approved and is currently in use in Korea. The study involved two parts. In Part 1, the safety of GC3110A was evaluated in 10 subjects. After none of the subjects reported grade 3 adverse events (AEs), we proceeded to Part 2. Part 2 was a randomized, double-blind, multicenter phase 3 trial wherein we compared the immunogenicity and safety of GC3110A with those of a licensed control TIV. Immunogenicity was evaluated by measuring hemagglutination inhibition titers. The 200 participants enrolled in Part 2 were randomized in a 4:1 ratio to receive GC3110A or control TIV. The study vaccine group met both primary (i.e., the lower limit of 95% confidence interval [CI] of the seroconversion rate exceeds 40% for four strains) and secondary (i.e., the lower limit of 95% CI of the seroprotection rate exceeds 70% for four strains) immunogenicity endpoints. There was no significant between-group difference in the seroconversion rate, seroprotection rate, and geometric mean titer for the shared strains. However, the study vaccine group demonstrated significantly higher immunity for the additional strain B/Yamagata. In the safety analysis, there was no significant between-group difference in the proportion of participants with solicited local AEs, solicited systemic AEs, and unsolicited AEs. In conclusion, the results indicate that GC3110A has comparable immunogenicity and safety to those of TIV. Clinical Trial Registry Number: NCT03285997., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JH Kang’s institution has received research grants from GC Pharma (Yoingin, Korea). Except that, they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Immunization is the most effective preventive strategy against varicella. While the Oka strain is commonly used for varicella vaccination worldwide, Korea widely uses the MAV/06 strain. A new live attenuated MAV/06 strain varicella vaccine (MG1111), which uses the new cell line Medical Research Council-5 for better viral propagation, was developed. MG1111 was approved by Korean health authorities. Here, we report the results of phase III, randomized, double-blind, multicenter study conducted in Korea and Thailand, which compared the immunogenicity and safety profiles of MG1111 versus the control vaccine, Varivax TM . In total, 515 healthy children (12 month-12 years) were randomized 1:1 to receive either the MG1111 or control vaccine (MG1111: 258, Control: 257). The seroconversion rate (SCR) and geometric mean titer (GMT) were measured using the fluorescent antibody to membrane antigen (FAMA) test. The MG1111 group achieved a SCR of 97.9% (95% CI: 95.2-99.3) after vaccination. The lower limit of 95% CI for SCR difference (MG1111-Varivax TM ) was -4.0%, which was higher than the specified non-inferiority margin of -10%. Further, the GMT of the MG1111 increased from 2.0 to 74.2 (95% CI: 65.0-84.8) and the lower limits of the 95% CI for post-vaccination GMT ratios (MG1111/Varivax TM ) were 0.55 higher than the specified parameter of 0.5. Therefore, the MG1111 group was not statistically inferior to the control vaccine group in terms of SCR and GMT. Furthermore, the MG1111 and control vaccine groups were not significantly different in the percentage of participants showing adverse events-solicited, local, or systemic during 43-day period of observation and serious adverse events during 6 month of observation. The present results indicate that MG1111was not immunologically inferior to Varivax TM , and safety profiles of MG1111 are similar to those of Varivax TM ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Since the 2000s, two lineages of the influenza B virus (influenza B/Victoria and influenza B/Yamagata) have been co-circulating. Information on the age distribution of patients infected by each influenza B virus lineage may be helpful for establishing differentiated influenza prevention and control strategies for each age group., Methods: Age distributions were compared between patients infected by influenza A and B viruses and between those infected by the influenza B virus when B/Victoria and B/Yamagata lineages circulated dominantly., Results: Between the 2014-2015 and 2018-2019 influenza seasons, 2,718 and 1,397 patients were diagnosed with influenza A and B virus infections, respectively. The median age of patients infected by the influenza B virus was lower than that of patients infected by the influenza A virus (8 vs 12 years, p < 0.001). In the Yamagata season, the median ages of patients infected by influenza A and B viruses were similar (12 vs 11 years, p = 0.732); however, in the Victoria season, the median age of patients infected by the influenza B virus was lower than that of patients infected by the influenza A virus (6 vs 10 years, p < 0.001). In patients infected by the influenza B virus, patients aged <6 years and those aged ≥6 years were more likely to be infected during the Victoria and Yamagata seasons, respectively ( p < 0.001)., Conclusion: The age distribution of patients infected by the influenza virus was different between the Yamagata and Victoria seasons. Different influenza prevention and control strategies should be considered on the basis of the predominantly circulating virus and the affected age group.

This study was conducted to assess the nasopharyngeal (NP) carriage and acute otitis media (AOM) occurrence in Korean children who received pneumococcal conjugate vaccines (PCVs). The longitudinal study was conducted through four consecutive visits. At each visit, NP aspirates were obtained and subjects were asked to visit if AOM occurred. A total of 305 subjects were enrolled and received PCV13 (n = 182) or PCV10 (n = 123). In the PCV13 group, the NP carriage of Streptococcus pneumoniae at each visit was 2.7%, 14.8%, 18.7%, and 15.9%, respectively. Non-typeable Haemophilus influenzae (NTHi) was 3.3%, 2.7%, 2.7%, and 5.5%, and that of Moraxella catarrhalis was 1.1%, 9.3%, 4.9%, and 0.5%. In the PCV10 group, the NP carriage of S. pneumoniae at each visit was 3.3%, 7.3%, 6.5%, and 4.1%, respectively. That of NTHi was 2.4%, 4.1%, 1.6%, and 0.8%, and that of M. catarrhalis was 4.1%, 0.8%, 0.8%, and 0.0%. AOM occurrence in the PCV13 group observed after the primary dose and before booster dose was 20.9%, occurrence after booster dose was 11.0%, and the incidence of two or more AOM was 11.0%. In the PCV10 group, AOM occurrence was 9.8%, 7.3%, respectively, and the incidence of two or more AOM was 2.4%. The predominant S. pneumoniae isolated were non-vaccine type (10A, 15A, and 15B). In this study, AOM occurrence was lower in the PCV10 group than in the PCV13 group. This seems to be related to ecological changes that lead to differences in NP carriage, especially S. pneumoniae and NTHi.

Background: Preterm birth (PTB) is a major adverse pregnancy outcome and largely contributes to increasing neonatal and maternal mortality. Genetic and environmental factors may play an important role in the development of PTB. Numerous studies have shown that immune genes related to the immune system, such as IL-6, IL-10, and TNFα, are associated with the occurrence of PTB., Objective: We examined genetic associations between IL-6 rs1800796, IL-10 rs1800872, and TNFα rs1800630 polymorphisms and PTB in Korean women., Methods: In this study, 115 PTB patients and 147 controls were analyzed. The genotyping of three SNPs was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)., Results: Our result showed that the rs1800872 polymorphism was significantly associated with the development of PTB in genotype frequency (odds ratio (OR) 1.71, 95% confidence interval (CI) 1.01-2.90, p = 0.046). We also found a significant association in an analysis of combined genotypes (rs1800796 CC, rs1800872 CA, and rs1800630 CA) (OR 7.43, 95% CI 2.06-26.84, p = 0.001). In a correlation analysis, rs1800630 A allele was significantly related with the increased birth weight (g) within PTB patients (p = 0.005)., Conclusion: Our results imply possible relationships between the rs1800796, rs1800872, and rs1800630 polymorphisms and the development of PTB.

Attention deficit hyperactivity disorder (ADHD) is a multifactorial disorder with multiple environmental and biological etiologies, including genetic factors. Until now, several genetic variants have been reported to be significantly associated with ADHD. Recently, the relationship between mitochondrial DNA (mtDNA) haplogroups and psychiatric disorders such as schizophrenia has also been reported. However, currently there are no reports pertaining to the genetic association between mtDNA haplogroups and ADHD. Therefore, we performed an mtDNA haplogroup analysis of a total of 472 Korean children (150 Children with ADHD and 322 controls). The 20 East Asian specific mtDNA haplogroups were determined using the SNaPshot assay. We also sequenced the displacement loop (D-loop) region, position 15,971-613. Our results showed that haplogroup B4 was significantly associated with ADHD (OR, 1.90; 95% CI, 1.055-3.429; p = 0.031). A marginally significant association was found in subjects with ADHD and haplogroup B5 (OR, 0.26; 95% CI, 0.059-1.139; p = 0.041). When stratified based on gender, an association was also observed between haplogroup B5 and boys diagnosed with ADHD (OR, 0.17; 95% CI, 0.022-1.340; p = 0.048). Compared with boys, girls with ADHD carried an excess of the haplogroup D4b (OR, 4.83; 95% CI, 1.352-17.272; p = 0.014). Stratified analysis of subtypes also showed significant results (combined: haplogroup B4, p = 0.007; inattentive: haplogroup F, p = 0.022). Our results showed a possible role of mtDNA haplogroups in the genetic etiology of ADHD and ADHD symptoms in Korean children., (Copyright © 2018 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Background and Objectives: The ACE gene encodes the angiotensin-converting enzyme (ACE), a component of the renin-angiotensin system. Increased ACE activity may cause abnormal regulation of placental circulation and angiogenesis, resulting in adverse pregnancy outcomes. Previous studies have reported that the insertion/deletion (I/D) polymorphism of the ACE gene is associated with the development of preterm birth (PTB). However, results of the association between ACE gene I/D and PTB are inconsistent in various populations. Therefore, we performed a case-control study and a meta-analysis to evaluate the association between ACE I/D polymorphism and PTB. Materials and Methods: We analyzed a total of 254 subjects (111 patients with PTB and 143 women at ≥38 weeks gestation) for the case-control study. For the meta-analysis, we searched Google Scholar, PubMed, and NCBI databases with the terms "ACE," "angiotensin-converting enzyme," "preterm birth," "preterm delivery," and their combinations. Results: Our results of the case-control study indicated that ACE I/D polymorphism is significantly associated with PTBs in the overdominant genetic model (odds ratio (OR) 0.57, 95% confidence interval (CI) 0.347-0.949, p = 0.029) and that the ID genotype of ACE I/D polymorphism has a protective effect for PTB (OR 0.57, 95% CI 0.333-0.986, p = 0.043). Similarly, the meta-analysis showed that the OR for the ACE gene ID genotype was 0.66 (95% CI 0.490-0.900, p < 0.01). Conclusion: The ACE gene ID genotype has a significant association with PTB and is a protective factor for PTB. A larger sample set and functional studies are required to further elucidate of our findings., Competing Interests: The authors declare no conflict of interest.

Purpose: Enterococci are a common cause of bacteremia in immunocompromised patients. Although the increase of vancomycin-resistant enterococci (VRE) makes appropriate antibiotic therapy difficult, clinical characteristics of enterococcal bacteremia and the impact of VRE infection on outcomes have rarely been reported in immunocompromised children., Methods: We enrolled children and adolescents (< 19 years of age) with underlying malignancies who were diagnosed with enterococcal bacteremia during febrile neutropenia between 2010 and 2017. Medical records of the enrolled children were retrospectively reviewed to evaluate the clinical characteristics of enterococcal bacteremia and impact of VRE infection on outcomes., Results: Thirty-six episodes of enterococcal bacteremia were identified in 30 patients. VRE infection was identified in 11 episodes (30.6%); the 7- and 30-day mortalities were 27.8% and 44.4%, respectively. Acute lymphoblastic leukemia (50.0%) and acute myeloid leukemia (30.6%) were the most common underlying disorders. Three (8.3%) of the patients were in complete remission, and palliative and reinduction chemotherapies were administered in 47.2% and 36.1% of episodes, respectively. Empirical antibiotic therapy was appropriate in 64.0% of patients with vancomycin-susceptible enterococcal infection and in none of the VRE-infected patients (p = 0.001). However, the 30-day mortality was not significantly different between the two patient groups (44.0% vs. 45.5%, p = 1.000)., Conclusions: Most episodes of enterococcal bacteremia occurred in advanced stages of underlying malignancies, and still showed high mortality. The prognosis seemed to be related to the underlying disease condition rather than vancomycin resistance of the isolated enterococci, although the number of enrolled patients was small.

Competing Interests: Disclosure: The authors have no potential conflicts of interest to disclose.

Several approved inactivated hepatitis A (HA) vaccines are available in Korea. These have been shown to be immunogenic and safe in European children; however, their immunogenicity and safety have not been investigated among Korean children. We aimed to compare the immunogenicity and safety of the most commonly used HA vaccines in ethnic Korean children aged 12 to 18 months.In this open-label, randomized, prospective, multicenter study, 108 children were enrolled and randomized to receive a pediatric form of Avaxim, Epaxal, or Havrix. The 2nd dose was administered after an interval of 6 months. Anti-HA virus (HAV) immunoglobulin (Ig) G was measured to assess geometric mean concentrations (GMCs) and seropositvity rates (≥20 mIU/mL anti-HAV IgG). To assess safety, local solicited adverse events (AEs), systemic solicited AEs, unsolicited AEs, and serious AEs (SAEs) were graded.Among the 108 participants enrolled, 37, 34, and 37 received Avaxim, Epaxal, and Havrix, respectively. After administration of 2 doses, the seropositivity rates in the Avaxim, Epaxal, and Havrix groups were all 100% (95% confidence intervals [CIs]: 99.0-100, 98.9-100, and 99.0-100, respectively; P < .001). The anti-HAV GMCs in the Avaxim, Epaxal, and Havrix groups were 5868.4 (95% CI: 4237.2-8126.6), 1962.1 (95% CI: 1298.0-2965.9), and 2232.9 mIU/mL (95% CI: 1428.4-3490.4), respectively, after administration of 2 doses (P < .001). There were no significant differences in the proportions of participants reporting local solicited AEs, systemic solicited AEs, unsolicited AEs, and SAEs among the 3 vaccine groups after the 1st and 2nd doses. All local solicited and unsolicited AEs were grade 1 or 2. Grade 3 systemic solicited AE occurred in 5.4% and 2.9% of the participants in the Havrix group after the 1st and 2nd doses, respectively. SAEs after the 1st and 2nd doses were reported in 2 participants and 1 participant, respectively, but none was assessed as being related to vaccination.The results indicate that these vaccines were safe and immunogenic in ethnic Korean children. The results have contributed to the establishing of an HA vaccination policy in Korea and will be informative to countries that plan to initiate vaccination programs against HAV.

Background : In South Korea, the one-dose varicella vaccine was included in the National Immunization Program for children aged 12-15 months in 2005, and the vaccine coverage reached >95%. The impact of varicella vaccination on varicella and herpes zoster (HZ) was investigated, accounting for demographic changes over time. Methods : We calculated the crude and age-sex standardized incidence rates (IRs) and age-specific IRs of varicella and HZ from 2003 to 2015, using the National Health Information Database including approximately 50 million Koreans. The annual incidence rate ratios (IRRs) were calculated using a negative binomial regression analysis, adjusting for age and sex. Results : The crude varicella IR steadily declined by 67%, from 5.70/1000 to 1.87/1000 person years (IRR per year: 0.91; 95% CI 0.89-0.93), but the adjusted IRs showed a significant decline only during 2010-2015 (adjusted IRR per year: 0.90; 95% CI 0.88-0.93). The greatest decline was found in children ≤4 years of age, whereas the IR increased until 2011 and then declined afterward in children aged 5-9 years, who represented the highest incidence age group in 2013-2015. The crude HZ IR increased from 2.67/1000 to 9.80/1000 person years (IRR per year: 1.12; 95% CI 1.10-1.15), and the adjusted IR also followed the same trend. A similar increasing trend was observed before and after universal vaccination. Conclusions : One-dose varicella vaccination was moderately effective in preventing varicella, but this strategy was insufficient to interrupt varicella transmission in children. Furthermore, the HZ incidence dramatically increased over this decade. The current vaccination strategy against varicella-zoster disease should be reconsidered.

In the letter, Lai SW suggested that the cost-benefit of two-dose varicella vaccines should be considered since universal one-dose vaccination effectively reduced varicella incidence in Taiwan. However, the vaccination impact was different between South Korea and Taiwan. In South Korea, only a moderate reduction in varicella incidence was observed after implementing universal one-dose vaccination. Such difference possibly reflects the relatively high background varicella incidence in South Korea. As substantial variability in varicella epidemiology exists across countries, an optimal vaccination strategy may differ in each country. Despite the effectiveness of one-dose vaccine being moderate, primary vaccine failure and rapidly waning immunity are major concerns. Therefore, two-dose vaccination would be a reasonable choice for effectively preventing virus transmission in South Korea.

Background: Understanding the population genetics of pneumococci will allow detection of changes in the prevalence of circulating genotypes and evidence for capsular switching. We aimed to analyze the genetic structure of invasive pneumococcal isolates obtained from children before and after the use of pneumococcal conjugate vaccines (PCVs) in Korea., Methods: A total of 285 invasive pneumococcal isolates were analyzed using serotyping, multilocus sequence typing, and antimicrobial susceptibility testing. We classified the isolation year to pre-PCV7 (1995-2003; n = 70), post-PCV7 (2004-2010; n = 142), and post-PCV13 (2011-2013; n = 73) periods., Results: Of the 10 clonal complexes (CCs), antibiotic-resistant international clones, CC320 (31.6%), CC81 (14.7%), and CC166 (6.7%) were the main complexes. Serotype 19A was the main serotype of CC320 throughout the periods. Serotypes of CC81 mainly comprised of 23F (53.3%) in pre-PCV7 period and replaced by non-vaccine types (NVTs; 6C [10%], 13 [30%], 15A [40%], and 15B/C [20%]) in post-PCV13 period. The main serotype responsible for CC166 also changed from 9 V (80%) in pre-PCV7 to NVT 11A (50%) in post-PCV13 periods. Non-susceptibility to penicillin (42.3%) was the highest in CC320, increasing from 0 to 76%., Conclusion: The genetic structures of invasive pneumococcal isolates in Korean children have changed concomitantly with serotype after the implementation of PCVs.

Objective : Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. The genetic cause of ADHD is still unclear, but the dopaminergic, serotonergic, and noradrenergic pathways have shown a strong association. In particular, monoamine oxidase A (MAOA) plays an important role in the catabolism of these neurotransmitters, suggesting that the MAOA gene is associated with ADHD. Therefore, we evaluated the relationship between the MAOA gene polymorphisms (uVNTR and rs6323) and ADHD. Materials and methods : We collected a total of 472 Korean children (150 ADHD cases and 322 controls) using the Korean version of the Dupaul Attention Deficit Hyperactivity Disorder Rating Scales (K-ARS). Genotyping was performed by PCR and PCR-RFLP. The Behavior Assessment System for Children Second Edition (BASC-2) was used to evaluate the problem behaviors within ADHD children. Results : We observed significant associations between the rs6323 and ADHD in girls ( p < 0.05) and the TT genotype was observed as a protective factor against ADHD in the recessive model (OR 0.31, 95% CI 0.100⁻0.950, p = 0.022). The 3.5R-G haplotype showed a significant association in ADHD boys ( p = 0.043). The analysis of subtype also revealed that the 4.5R allele of uVNTR was a risk factor for the development of ADHD in the combined symptom among girls (OR 1.87, 95% CI 1.014⁻3.453, p = 0.031). In the BASC-2 analysis, the MAOA uVNTR polymorphism was associated with activities of daily living in ADHD boys ( p = 0.017). Conclusion : These results suggest the importance of the MAOA gene polymorphisms in the development of ADHD in Korean children. A larger sample set and functional studies are required to further elucidate of our findings.

Background: Invasive bacterial infections in apparently immunocompetent children were retrospectively analyzed to figure causative bacterial organisms in Korea., Methods: A total of 947 cases from 25 university hospitals were identified from 2006 to 2010 as a continuance of a previous 10-year period study from 1996 to 2005., Results: Escherichia coli (41.3%), Streptococcus agalactiae (27.7%), and Staphylococcus aureus (27.1%) were the most common pathogens in infants < 3 months of age. S. agalactiae was the most prevalent cause of meningitis and pneumonia and E. coli was the major cause of bacteremia without localizing signs in this group. In children 3 to 59 months of age, Streptococcus pneumoniae (54.2%), S. aureus (20.5%), and Salmonella spp. (14.4%) were the most common pathogens. S. pneumoniae was the leading cause of pneumonia (86.0%), meningitis (65.0%), and bacteremia without localizing signs (49.0%) in this group. In children ≥ 5 years of age, S. aureus (62.8%) was the predominant pathogen, followed by Salmonella species (12.4%) and S. pneumoniae (11.5%). Salmonella species (43.0%) was the most common cause of bacteremia without localizing signs in this group. The relative proportion of S. aureus increased significantly over the 15-year period (1996-2010) in children ≥ 3 months of age (P < 0.001), while that of Haemophilus influenzae decreased significantly in both < 3 months of age group (P = 0.036) and ≥ 3 months of age groups (P < 0.001)., Conclusion: S. agalactiae, E. coli, S. pneumoniae, and S. aureus are common etiologic agents of invasive bacterial infections in Korean children., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2018 The Korean Academy of Medical Sciences.)

Background: Tetanus-reduced dose diphtheria-acellular pertussis (Tdap) vaccination during adolescence was introduced in response to the resurgence of pertussis in various countries. A new Tdap vaccine was manufactured in Korea as a countermeasure against a predicted Tdap vaccine shortage. This study was performed to evaluate the immunogenicity, safety, and protection efficacy against Bordetella pertussis of the new Tdap vaccine in a murine model., Methods: Four-week-old BABL/c mice were used for assessment of immunogenicity and protection efficacy. A single dose of primary diphtheria-tetanus-acellular pertussis (DTaP) vaccine was administered, followed by a single dose of Tdap booster vaccine after a 12-week interval. Anti-pertussis toxin (PT), anti-filamentous hemagglutinin (FHA), and anti-pertactin (PRN) IgG titers were measured before primary vaccination, and before and after booster vaccination. An intranasal challenge test was performed after booster vaccination to determine protection efficacy. To assess safety, mouse weight gain test and leukocytosis promotion test were performed using 4-week-old ddY female mice., Results: Anti-PT and anti-FHA IgG titers after booster vaccination were significantly higher than those before booster vaccination with either the new vaccine or a commercially available Tdap vaccine (P = 0.01 for all occasions). After booster vaccination, no significant difference was observed between the two vaccines in antibody titers against pertussis antigens (P = 0.53 for anti-PT IgG, P = 0.91 for anti-FHA IgG, P = 0.39 for anti-PRN IgG). In the intranasal challenge test, inoculated B. pertussis was eradicated 7 days after infection. On days 4 and 7 after infection, colony counts of B. pertussis were not significantly different between the new and positive control vaccine groups (P = 1.00). Mean body weight changes and leukocyte counts of the new vaccine, positive control, and negative control groups were not significantly different 7 days after vaccination (P = 0.87 and P = 0.37, respectively). All leukocyte counts in the new vaccine group were within a mean ± 3 standard deviations range., Conclusions: A murine model involving a single dose primary DTaP vaccination followed by a single dose Tdap booster vaccination can be used for non-clinical studies of Tdap vaccines. The new Tdap vaccine manufactured in Korea exhibited comparable immunogenicity, protection efficacy, and safety with a commercially available Tdap vaccine.

Background: This prospective study was performed to evaluate serotype distribution, multilocus sequence typing, and antibiotic susceptibility of Streptococcus pneumoniae identified in Korean children with acute otitis media (AOM) after the introduction of a 7-valent pneumococcal conjugate vaccine (PCV7)., Methods: Nasopharyngeal aspirates were collected from children diagnosed with AOM in seven hospitals in Korea. The bacteria identified in these samples and the serotypes, sequence types (STs), and antibiotic susceptibilities of S. pneumoniae isolates were evaluated., Results: A total of 390 children were enrolled, and bacteria were identified in 376 (96.4%) children. S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were identified in 155 (39.7%), 127 (32.6%) and 86 (22.1%) children, respectively. Serotype 19A (22.4%) was the most common S. pneumoniae serotype, with serogroups 11 (14.7%) and 15 (13.5%) following. ST320 (23.5%) was the most common ST; ST166 (17.0%) and ST83 (8.5%) followed. The overall susceptibility rates of S. pneumoniae to oral penicillin V and amoxicillin/clavulanate were 2.6% and 53.2%, respectively. The susceptibility rate to cefditoren was 91.0%; however, the rates for other cephalosporins were less than 10.0%. Compared with other serogroups, S. pneumoniae serogroups 19, 11, and 15 showed significantly lower susceptibility rates to all the antibiotics tested., Conclusion: S. pneumoniae serotype 19A, serogroups 11 and 15 were the major nasopharyngeal-colonizing bacteria in Korean children with AOM after the introduction of PCV7. These relatively prevalent serotype/serogroups showed lower antibiotic susceptibility rates., (Copyright © 2016. Published by Elsevier Ltd.)

Purpose: A phase I clinical trial was conducted to evaluate the immunogenicity and safety of newly developed egg-cultivated trivalent inactivated split influenza vaccine (TIV) in Korea., Materials and Methods: The TIV was administered to 43 healthy male adults. Subjects with high pre-existing titers were excluded in a screening step. Immune response was measured by a hemagglutination inhibition (HI) assay., Results: The seroprotection rates against A/California/7/2009 (H1N1), A/Perth/16/2009 (H3N2) and B/Brisbane/60/2009 were 74.42% [95% confidence interval (CI): 61.38-87.46], 72.09% (95% CI: 58.69-85.50), and 86.05% (95% CI: 75.69-96.40), respectively. Calculated seroconversion rates were 74.42% (95% CI: 61.38-87.46), 74.42% (95% CI: 61.38-87.46), and 79.07% (95% CI: 66.91-91.23), respectively. There were 25 episodes of solicited local adverse events in 21 subjects (47.73%), 21 episodes of solicited general adverse events in 16 subjects (36.36%) and 5 episodes of unsolicited adverse events in 5 subjects (11.36%). All adverse events were grade 1 or 2 and disappeared within three days., Conclusion: The immunogenicity and safety of TIV established in this phase I trial are sufficient to plan a larger scale clinical trial., Competing Interests: The authors have no financial conflicts of interest.

Recommended infant vaccination in Korea includes DTaP-IPV and Hib vaccines administered as separate injections. In this randomized, open, controlled study we assessed the non-inferiority of immunogenicity of DTaP-IPV//Hib pentavalent combination vaccine (Pentaxim™) compared with licensed DTaP-IPV and Hib (PRP~T) vaccines. We enrolled 418 healthy Korean infants to receive either separate DTaP-IPV and Hib vaccines (n = 206) or the pentavalent DTaP-IPV//Hib (n = 208) vaccine at 2, 4, 6 months of age. Antibodies to all components were measured before the first vaccination and one month after the third, and safety was assessed after each vaccination including recording of reactions by parents. We confirmed the non-inferiority of DTaP-IPV//Hib compared with DTaP-IPV and Hib vaccines; 100% of both groups achieved seroprotection against D, T, IPV and PRP~T, and 97.5%-99.0% demonstrated seroresponses to pertussis antigens. Antibody levels were similar in both groups, except for those to the Hib component, PRP~T. In separate and combined groups geometric mean concentrations of anti-PRP~T antibodies were 23.9 and 11.0 μg/mL, respectively, but 98.3% and 97.4% had titers ≥ 1 μg/mL, indicative of long-term protection. All vaccines were well tolerated, with no vaccine-related serious adverse event. Both groups had similar safety profiles, but the combined vaccine group had fewer injection site reactions. The immunological non-inferiority and similar safety profile of DTaP-IPV//Hib vaccine to separate DTaP-IPV and Hib vaccines, with the advantage of fewer injections and injection site reactions, supports the licensure and incorporation of DTaP-IPV//Hib into the Korean national vaccination schedule (Clinical trial registry, NCT01214889).

Background: The rate of urinary tract infections (UTIs) due to extended-spectrum β-lactamase (ESBL)-producing bacterial strains requiring carbapenem therapy has been increasing in children. This study was conducted to evaluate the effect of non-carbapenem antibiotic therapy on childhood UTIs caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae., Methods: Medical records of children diagnosed with febrile UTIs due to E. coli or K. pneumoniae between 2010 and 2014 were retrospectively reviewed. The enrolled children were divided into two groups: the ESBL group and the non-ESBL group. Clinical characteristics and therapeutic responses were compared between the two groups., Results: A total of 211 episodes of UTI (204 caused by E. coli; seven caused by K. pneumoniae) were identified in 205 children. Twenty-two (10.4 %) episodes were categorized into the ESBL group. There was no significant difference in the type of antibiotic administered between the two groups. No carbapenems were administered; however, aminoglycosides were administered for 79.1 % of the total episodes. Although empirical antibiotics were appropriate for more episodes in the non-ESBL group compared with the ESBL group (100.0 % vs. 90.9 %, p = 0.011), there were no significant differences in the frequency of defervescence, bacterial eradication from the urine, acute pyelonephritis and vesicoureteral reflux or fever duration between the two groups., Conclusions: Non-carbapenem antibiotics showed favourable therapeutic effects on childhood UTIs caused by ESBL-producing strains. Aminoglycosides can be an alternative to carbapenems in such cases.

Rotavirus (RV) is one of the most important viral etiologic agents of acute gastroenteritis (AGE) in children. Although effective RV vaccines (RVVs) are now used worldwide, novel genotypes and outbreaks resulting from rare genotype combinations have emerged. This study documented RV genotypes in a Korean population of children with AGE 5 yr after the introduction of RVV and assessed potential genotype differences based on vaccination status or vaccine type. Children less than 5-yr-old diagnosed with AGE between October 2012 and September 2013 admitted to 9 medical institutions from 8 provinces in Korea were prospectively enrolled. Stool samples were tested for RV by enzyme immunoassay and genotyped by multiplex reverse-transcription polymerase chain reaction. In 346 patients, 114 (32.9%) were RV-positive. Among them, 87 (76.3%) patients were infected with RV alone. Eighty-six of 114 RV-positive stool samples were successfully genotyped, and their combinations of genotypes were G1P[8] (36, 41.9%), G2P[4] (12, 14.0%), and G3P[8] (6, 7.0%). RV was detected in 27.8% of patients in the vaccinated group and 39.8% in the unvaccinated group (P=0.035). Vaccination history was available for 67 of 86 cases with successfully genotyped RV-positive stool samples; RotaTeq (20, 29.9%), Rotarix (7, 10.4%), unvaccinated (40, 59.7%). The incidence of RV AGE is lower in the RV-vaccinated group compared to the unvaccinated group with no evidence of substitution with unusual genotype combinations.

Invasive pulmonary aspergillosis (IPA) is the most frequent form of invasive fungal diseases in immunocompromised patients. However, there are only a few studies on IPA in immunocompromised children in Korea. This study was designed to characterize IPA in Korean children with hematologic/oncologic diseases. Medical records of children with hematologic/oncologic diseases receiving antifungal therapy were reviewed. The enrolled children were divided into the IPA group (proven and probable IPA) and non-IPA group, and the clinical characteristics and prognosis were compared between the two groups. During the study period, 265 courses of antifungal therapy were administered to 166 children. Among them, two (0.8%) episodes of proven IPA, 35 (13.2%) of probable IPA, and 52 (19.6%) of possible IPA were diagnosed. More children in the IPA group suffered from neutropenia lasting for more than two weeks (51.4% vs. 21.9%, P<0.001) and showed halo signs on the chest computed tomography (78.4% vs. 40.7%, P<0.001) than in the non-IPA group. No other clinical factors showed significant differences between the two groups. Amphotericin B deoxycholate was administered as a first line antifungal agent in 33 (89.2%) IPA group episodes, and eventually voriconazole was administered in 27 (73.0%) episodes. Ten (27.0%) children in the IPA group died within 12 weeks of antifungal therapy. In conclusion, early use of chest computed tomography to identify halo signs in immunocompromised children who are expected to have prolonged neutropenia can be helpful for early diagnosis of IPA and improving prognosis of children with IPA.

Background: Invasive pulmonary aspergillosis (IPA) is the most common invasive fungal disease in immunocompromised patients, and it has a 30 % mortality rate despite appropriate antifungal therapy. This retrospective study was performed to determine risk factors for mortality in immunocompromised children with IPA., Methods: Medical records of 45 probable/proven IPA cases diagnosed in children with hematologic/oncologic diseases were reviewed. Selected cases were divided into the survival (n = 30) and fatality (n = 15) groups based on survival at 12 weeks after antifungal therapy. Clinical characteristics and serum galactomannan indices (GMIs) were compared between the two groups., Results: Significantly more children in the fatality group were male (p = 0.044), not in complete remission of the underlying malignancies (p = 0.016), and had received re-induction/salvage or palliative chemotherapy (p = 0.035) than those in the survival group. However, none of these factors was significantly associated with mortality in a multivariate analysis. Serum GMIs were higher in the fatality group than in the survival group during the entire period of antifungal therapy, and serum GMI at 1 week after antifungal therapy was most significantly associated with mortality. A serum GMI > 1.50 at 1 week after antifungal therapy exhibited a sensitivity and specificity of 61.5 % and 89.3 %, respectively, in predicting mortality within 12 weeks after antifungal therapy., Conclusions: Higher serum GMI in the early phase of antifungal therapy was associated with mortality in immunocompromised children with IPA. These children should receive more intensive care for IPA than others.

We investigated the prevalence of pertussis in Korean adolescents and adults with persistent cough. Study population was adolescents (aged 11-20 yr) and adults (≥ 21 yr old) who showed persistent cough of 1-8 weeks' duration. Pertussis was diagnosed by culture, polymerase chain reaction (PCR), and serology. A total of 310 subjects participated in this study, and 76 cases (24.5%) met the criteria for laboratory-confirmed pertussis. The majority of the pertussis cases (66/76) were confirmed by serology, while 3 cases (1.0%) were diagnosed with culture, and 10 cases (3.2%) were detected with PCR. Of the 76 subjects diagnosed with pertussis, 20/86 cases were adolescents and 56/224 cases were adults. Neither adolescents nor adults received adolescent-adult booster against pertussis within the previous 5 yr. Pertussis can be a primary cause of persistent cough in Korean adolescents and adults.

Background: Attention deficit hyperactivity disorder (ADHD) is a common childhood neuropsychiatric disorder characterized by behavioral problems such as attention deficit, hyperactivity, and impulsivity. The brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain., Aims: The aim of the present study was to investigate the association between the genotype and alleles for the BDNF gene in Korean children with ADHD., Methods: The sample consisted of 180 ADHD children and 159 control children. We diagnosed ADHD according to the DSM-IV. ADHD symptoms were evaluated with Conners' Parent Rating Scales and Dupaul Parent ADHD Rating Scales. Blood samples were taken from the 339 subjects, DNA was extracted from blood lymphocytes, and polymerase chain reaction was performed for BDNF rs6265, rs11030101, rs10835210, rs7103873, and rs2030324 polymorphisms. Alleles and genotype frequencies were compared using the Chi-square test. We compared the allele and genotype frequencies of the BDNF gene polymorphism in the ADHD and control groups., Results: This study showed that there was a significant correlation among the allele frequencies of the rs11030101 and rs10835210 single nucleotide polymorphisms (SNPs) (odds ratio=0.61, 95% confidence interval=0.39-0.96, p=0.034), but the final conclusions are not definite. Follow-up studies with larger patient or pure subgroups are expected. These results suggest that the BDNF allelic structure may impact ADHD symptoms.

The present study was conducted to investigate Epstein-Barr virus (EBV) reactivation after hematopoietic cell transplantation (HCT) in Korean children living in an area of a high seroprevalence against EBV and to determine the impact of recipient age on EBV reactivation. Medical records of 248 children and adolescents who had received allogeneic HCT were retrospectively reviewed. The trends of EBV reactivation and post-transplant lymphoproliferative disorders (PTLDs) were evaluated and compared between younger (≤10 years old) and older (11-20 years old) groups. EBV reactivation occurred in 177 cases (71.4 %) and high-level EBV reactivation, defined as a virus DNA titer of 300,000 copies/mL or higher, occurred in 21 cases (8.5 %). PTLD was diagnosed in five cases (2.0 %), and one of these patients died. The EBV reactivation rate was not significantly different between the two age groups; however, high-level reactivation and PTLD were more significantly frequent in the older than in the younger group (P = 0.030 and P = 0.026, respectively). In conclusion, older children and adolescents are more likely to experience high-level EBV reactivation and PTLDs, and higher EBV DNA titers than those previously reported may be a predictor of PTLD in areas with a high seroprevalence against EBV.

Attention deficit hyperactivity disorder (ADHD) is a common disorder of the school-age population. ADHD is familial and genetic studies estimate heritability at 80-90%. The aim of the present study was to investigate the association between the genetic type and alleles for the monoamine oxidase (MAO) gene in Korean children with ADHD. The sample consisted of 180 ADHD children and 159 control children. We diagnosed ADHD according to DSM-IV. ADHD symptoms were evaluated with Conners' Parent Rating Scales and Dupaul Parent ADHD Rating Scales. Blood samples were taken from the 339 subjects, DNA was extracted from blood lymphocytes, and polymerase chain reaction was performed for MAO polymorphism. Allele and genotype frequencies were compared using the chi-square test. We compared the allele and genotype frequencies of MAO gene polymorphism in the ADHD and control groups. This study showed that there was a significant correlation among the frequencies of the rs5906883 (odds ratio [OR]=1.47, 95% confidence interval [CI]=1.08-2.00, p=0.014) and the rs3027407 (OR=1.41, 95% CI=1.03-1.91, p=0.029) alleles of MAO, but the final conclusions are not definite. Follow-up studies with larger patient or pure subgroups are expected. These results suggested that MAO might be related to ADHD symptoms.

This seroepidemiologic study was performed to evaluate the immune status against tetanus in Korean adolescents and adults and to provide evidence to develop strategies for tetanus prevention. Between July 2012 and December 2012, serum samples were collected from adults and adolescents 11 years of age and older, and serum anti-tetanus IgG titers were determined using a commercial ELISA kit. Subjects were divided into six age groups: 11-20 years, 21-30 years, 31-40 years, 41-50 years, 51-60 years, and ≥61 years. The mean anti-tetanus IgG titers and tetanus seroprevalence of the age groups were compared. A total of 1193 adults and adolescents were enrolled. Mean anti-tetanus IgG titer and tetanus seroprevalence of all subjects were 1.20 ± 3.58 IU/mL and 56.4%, respectively. The mean anti-tetanus IgG titer decreased with an increase in age (p < 0.001). Tetanus seroprevalence increased from 92.0% in the 11-20 year age group to 95.7% in the 21-30 year age group, and then decreased with a further increase in age (p < 0.001). These results reflected an appropriate Td booster vaccine coverage at 11-12 years of age. However, the tetanus seroprevalence of adults older than 41 years was as low as the levels in previous studies: therefore, adults should be more encouraged to acquire decennial Td booster vaccinations recommended by the National Immunization Program., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

This study was conducted to evaluate age-specific seroprevalence of pertussis in Korea and to formulate a strategy to prevent and reduce the incidence of pertussis. Residual serum samples of healthy adolescents and adults 11 yr of age or older were collected between July 2012 and December 2012, and anti-pertussis toxin (PT) IgG titers were measured using a commercial ELISA kit. We compared the mean anti-PT IgG titers and seroprevalence of pertussis of the six age groups: 11-20, 21-30, 31-40, 41-50, 51-60, and ≥ 61 yr. A total of 1,192 subjects were enrolled. The mean anti-PT IgG titer and pertussis seroprevalence were 35.53 ± 62.91 EU/mL and 41.4%, respectively. The mean anti-PT IgG titers and seroprevalence were not significantly different between the age groups. However, the seroprevalence in individuals 51 yr of age or older was significantly higher than in individuals younger than 51 yr (46.5% vs 39.1%, P = 0.017). Based on these results, a new pertussis prevention strategy is necessary for older adults.

A new live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) has been developed based on innovative technology to give protection against JE with an improved immunogenicity and safety profile. In this phase 3, observer-blind study, 274 children aged 12-24 months were randomized 1:1 to receive one dose of JE-CV (Group JE-CV) or the SA14-14-2 vaccine currently used to vaccinate against JE in the Republic of Korea (Group SA14-14-2). JE neutralizing antibody titers were assessed using PRNT50 before and 28 days after vaccination. The primary endpoint of non-inferiority of seroconversion rates on D28 was demonstrated in the Per Protocol analysis set as the difference between Group JE-CV and Group SA14-14-2 was 0.9 percentage points (95% confidence interval [CI]: -2.35; 4.68), which was above the required -10%. Seroconversion and seroprotection rates 28 days after administration of a single vaccine dose were 100% in Group JE-CV and 99.1% in Group SA14-14-2; all children except one (Group SA14-14-2) were seroprotected. Geometric mean titers (GMTs) increased in both groups from D0 to D28; GM of titer ratios were slightly higher in Group JE-CV (182 [95% CI: 131; 251]) than Group SA14-14-2 (116 [95% CI: 85.5, 157]). A single dose of JE-CV was well tolerated and no safety concerns were identified. In conclusion, a single dose of JE-CV or SA14-14-2 vaccine elicited a comparable immune response with a good safety profile. Results obtained in healthy Korean children aged 12-24 months vaccinated with JE-CV are consistent with those obtained in previous studies conducted with JE-CV in toddlers.

We analyzed the variation of eighteen miniSTR loci in 411 randomly chosen individuals from Korea to increase the probability that a degraded sample can be typed, as well as to provide an expanded and reliable population database. Six multiplex PCR systems were developed (multiplex I: D1S1677, D2S441 and D4S2364; multiplex II: D10S1248, D14S1434 and D22S1045; multiplex III: D12S391, D16S3253 and D20S161; multiplex IV: D3S4529, D8S1115 and D18S853; multiplex V: D6S1017, D11S4463 and D17S1301; multiplex VI: D5S2500, D9S1122 and D21S1437). Allele frequencies and forensic parameters were calculated to evaluate the suitability and robustness of these non-CODIS miniSTR systems. No significant deviation from Hardy-Weinberg equilibrium expectations were observed, except for D4S2364, D5S2500 and D20S161 loci. A multidimensional scaling plot based on allele frequencies of the six miniSTR loci (D1S1677, D2S441, D4S2364, D10S1248, D14S1434 and D22S1045) showed that Koreans appeared to have most genetic affinity with Chinese and Japanese than to other Eurasian populations compared here. The combined probability of match calculated from the 18 miniSTR loci was 2.902 × 10(-17), indicating a high degree of polymorphism. Thus, the 18 miniSTR loci can be suitable for recovering useful information for analyzing degraded forensic casework samples and for adding supplementary genetic information for a variety of analyses involving closely related individuals where there is a need for additional genetic information., (Copyright © 2013 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Japanese encephalitis virus is a common cause of encephalitis in Asian children; therefore, maintenance of immunity against Japanese encephalitis virus is essential. Although many countries recommend booster vaccination, some trials have concluded that administration of one or two vaccinations is sufficient. The current study was conducted to evaluate immunogenicity and safety after a booster vaccination with live attenuated vaccine. For 68 study subjects, measurement of antibody titer was performed before and at 4-6 weeks after administration of a booster dose. Adverse reactions occurring at the injection site and systemic adverse reactions were documented. The percentages of subjects with seroprotective neutralizing antibody titers was 100% before and after booster vaccination, and the geometric mean titer increased after booster vaccination. Thus, we predict that immunity will be maintained for a long time by an amnestic response. Low percentages of adverse reactions indicated the safety of the immunizations.

Unlabelled: Rotavirus gastroenteritis is the leading cause of severe acute gastroenteritis in children worldwide and is associated with high hospitalization and mortality rates in children younger than 5 years of age. Vaccination is necessary to prevent rotavirus infection. Two live attenuated and orally administered rotavirus vaccines became commercially available in Korea. The aim of this study is to describe epidemiological changes in rotavirus gastroenteritis after the introduction of rotavirus vaccines in Korea. The medical records of 11,199 children younger than 5 years of age and hospitalized for acute gastroenteritis from August 2007 to July 2010 in eight Korean hospitals were reviewed. Rotavirus was detected in stool samples obtained from 2,959 children (26.42 %). The authors evaluated the percentage of rotavirus gastroenteritis among all acute gastroenteritis hospitalizations in eight hospitals located in different geographical areas and analyzed epidemiological changes in rotavirus gastroenteritis according to age, geographical area, and season. According to the findings, the percentage of rotavirus gastroenteritis showed a decrease in children eligible for vaccination during the study period. After introduction of the vaccine, reduced rates of rotavirus detection were observed in all of the geographical areas, and the greatest reduction was observed in Seoul. In Seoul, there was a marked delay of the rotavirus season., Conclusion: Epidemiologic changes in Korea after the introduction of rotavirus vaccine are consistent with changes observed in other countries.

Haemophilus influenzae frequently colonizes the nasopharynx of children and adults, which can lead to a variety of infections. We investigated H. influenzae carriage in the nasopharynx of 360 children, in terms of (1) the prevalence of strains with decreased susceptibility, and (2) the presence of amino acid substitutions in PBP3. One hundred twenty-three strains were isolated (34.2%, 123/360), 122 of which were classified as nontypable H. influenzae (NTHi). Of these, β-lactamase-nonproducing ampicillin-susceptible strains accounted for 26.2%, β-lactamase-producing-ampicillin-resistant strains for 9.0%, β-lactamase-nonproducing ampicillin-resistant (BLNAR) strains for 40.2%, and β-lactamase-producing amoxicillin-/clavulanic acid-resistant (BLPACR) for 24.6%, respectively. Pulsed field gel electrophoresis (PFGE) patterns were so diverse that they were clustered into 41 groups. The amino acid substitutions in the transpeptidase domain (292 amino acids) of ftsI in BLNAR isolates showed that group IIb accounted for 30.6%, IIc for 8.2%, IId for 16.3%, III for 32.7%, and the others for 12.2%. Moreover, groups IIb (56.7%; 17/30) and III (23.3%; 7/30) were prevalent among BLPACR strains. They were subclassified into more diverse sequence subtypes by analysis of the entire PBP3 (610 amino acids). Groups IIb, IIc, IId, and III exhibited 13, four, six, and four sequence subtypes, respectively. Such a genetic diversity is likely indicative of significant potential for decreased antimicrobial susceptibility in nasopharyngeal-colonizing NTHi strains.

In 2009, the first outbreak of hand, foot and mouth disease (HFMD) or herpangina (HP) caused by enterovirus 71 occurred in the Republic of Korea. This study inquired into risk factors associated with complications of HFMD or HP. A retrospective medical records review was conducted on HFMD or HP patients for whom etiologic viruses had been verified in 2009. One hundred sixty-eight patients were examined for this investigation. Eighty patients were without complications while 88 were accompanied by complications, and 2 had expired. Enterovirus 71 subgenotype C4a was the most prevalent in number with 67 cases (54.9%). In the univariate analysis, the disease patterns of HFMD rather than HP, fever longer than 4 days, peak body temperature over 39℃, vomiting, headache, neurologic signs, serum glucose over 100 mg/dL, and having an enterovirus 71 as a causative virus were significant risk factors of the complications. After multiple logistic analysis, headache (Odds ratio [OR], 10.75; P < 0.001) and neurologic signs (OR, 42.76; P < 0.001) were found to be the most significant factors. Early detection and proper management of patients with aforementioned risk factors would be necessary in order to attain a better clinical outcome.

A recent resurgence of pertussis has raised public health concerns even in developed countries with high vaccination coverage. The aim of this study was to describe the clinical characteristics of infant pertussis, and to determine the relative importance of household transmission in Korea. The multicenter study was prospectively conducted from January 2009 to September 2011. We identified the demographic and clinical data from these patients and performed the diagnostic tests for pertussis in their household contacts. Twenty-one patients with confirmed pertussis were included in the analysis. All infections occurred in infants younger than 6 months of age (mean age, 2.5 months) who had not completed the primary DTaP vaccination except for one patient. Infants without immunization history had a significant higher lymphocytosis and longer duration of hospital stay compared to those with immunization. All were diagnosed with PCR (100%), however, culture tests showed the lowest sensitivity (42.9%). Presumed source of infection in household contacts was documented in 85.7%, mainly parents (52.6%). Pertussis had a major morbidity in young infants who were not fully immunized. Household members were responsible for pertussis transmission of infants in whom a source could be identified. The control of pertussis through booster vaccination with Tdap in family who is taking care of young infants is necessary in Korea.

We investigated serotype distribution and antimicrobial resistance of pneumococcal carriage isolates from children after optional immunization with the 7-valent pneumococcal conjugate vaccine (PCV7) in Korea. From June 2009 to June 2010, 205 (16.5%) pneumococcal isolates were obtained from 1,243 nasopharyngeal aspirates of infants and children at Seoul National University Children's Hospital, Korea. Serotype was determined by Quellung reaction and antibiotic susceptibility was tested by E-test. The results were compared to previous studies done in the pre-PCV7 period. In this study, the most common serotypes were 6A (15.3%), 19A (14.7%), 19F (10.2%), 35B (7.3%), and 6D (5.6%). The proportion of PCV7 serotypes decreased from 61.9% to 23.8% (P < 0.001). The overall penicillin nonsusceptibility rate increased from 83.5% to 95.4% (P = 0.001). This study demonstrates the impact of optional PCV7 vaccination in Korea; the proportion of all PCV7 serotypes except 19F decreased while antimicrobial resistant serotypes 6A and 19A further increased.

The majority of Korean patients with pandemic influenza A (H1N1) during the 2009 epidemic were under 20 yr of age. The limited data on the clinical characteristics of these children led us to conduct a case note-based investigation of children admitted to 6 university hospitals with 2009 H1N1 influenza. A total of 804 children was enrolled. The median age was 5 yr; 63.8% were males; and 22.4% had at least one chronic underlying disease. Ninety-five of the patients (11.8%) were critically ill and they suffered more from shortness of breath, dyspnea and lymphopenia than the other patients. Among all the patients, 98.8% were treated with antivirals and 73% received treatment within 48 hr of illness onset. All the enrolled patients are alive and appear to have had good outcomes, probably due to the early intervention and antiviral treatment. This study deals with hospitalized children whose diagnoses of influenza A (H1N1) were confirmed, and therefore provides important new information about the clinical patterns of children with influenza A (H1N1) in Korea.