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Background: The purpose of this study is to analyze changes in mandibular width and frontal view ramus inclination using cone beam CT in patients with skeletal class III malocclusion who underwent BSSRO, with the removal of bone interference between segments., Methods: For all 20 subjects, cone-beam CT imaging was performed prior to surgery (T1), immediately post-surgery (T2), and 6 months after surgery (T3). Reorientation was performed using R2GATE software (MegaGen, Seoul, Korea). The gonion and antegonial notch were used as reference points in the sagittal view, and the most lateral point of the condyle head was used as the reference point in the frontal view. All measurements were recorded in the frontal view., Results: Inter-gonial width decreased by 2.64 mm at T3-T2 (P < .001) and by 2.58 mm at T3-T1 (P < .05). Inter-antegonial width decreased by 1.75 mm at T3-T2 (P < .05) and by 3.5 mm at T3-T1 (P < .001). In the frontal view, the right ramus inclination based on the gonion increased by 2.07° at T3-T1 (P < .05). The left ramus inclination based on gonion increased by 2.45° at T2-T1 (P < .05) and by 3.94° at T3-T1 (P < .001). The right ramus inclination based on antegonial notch increased by 2.35° at T2-T1 (P < .05) and by 3.04° at T3-T1 (P < .01). The left ramus inclination based on antegonial notch increased by 2.73° at T2-T1 (P < .001) and by 3.18° at T3-T1 (P < .001)., Conclusions: During bilateral sagittal split osteotomy, removing bone interference between the proximal and distal segments results in a reduction of postoperative mandibular width and an increase in frontal view ramus inclination., (© 2024. The Author(s).)

Ubiquitination is a crucial posttranslational modification required for the proper repair of DNA double-strand breaks (DSBs) induced by ionizing radiation (IR). DSBs are mainly repaired through homologous recombination (HR) when template DNA is present and nonhomologous end joining (NHEJ) in its absence. In addition, microhomology-mediated end joining (MMEJ) and single-strand annealing (SSA) provide backup DSBs repair pathways. However, the mechanisms controlling their use remain poorly understood. By using a high-resolution CRISPR screen of the ubiquitin system after IR, we systematically uncover genes required for cell survival and elucidate a critical role of the E3 ubiquitin ligase SCF cyclin F in cell cycle-dependent DSB repair. We show that SCF cyclin F -mediated EXO1 degradation prevents DNA end resection in mitosis, allowing MMEJ to take place. Moreover, we identify a conserved cyclin F recognition motif, distinct from the one used by other cyclins, with broad implications in cyclin specificity for cell cycle control.

Background: The emergence of high-priced potential cures has sparked significant health policy discussions in South Korea, where the healthcare system is funded through a single-payer National Health Insurance model. We conducted focus group interviews (FGIs) and accompanying surveys with diverse stakeholders to comprehensively understand related issues and find better solutions to the challenges brought by these technologies., Methods: From October to November 2022, 11 FGIs were conducted with stakeholders from various sectors, including government payers, policy and clinical experts, civic and patient organisations, and the pharmaceutical industry, involving a total of 25 participants. These qualitative discussions were supplemented by online surveys to effectively capture and synthesise stakeholder perspectives., Results: Affordability was identified as a critical concern by 84% of stakeholders, followed by clinical uncertainty (76%) and limited value for money (72%). Stakeholders expressed a preference for both financial-based controls and outcome-based pricing strategies to mitigate these challenges. Despite the support for outcome-based refunds, payers raised concerns about the feasibility of instalment payment models, whether linked to outcomes or not, due to the specific challenges of the Korean reimbursement system and the potential risk of 'cumulative liabilities' from ongoing payments for previously administered treatments. In addition, the FGIs highlighted the need for clear budgetary limits for drugs with high uncertainties, with mixed opinions on the creation of special silo funds (64.0% agreement). Less than half (48%) endorsed the use of external reference pricing, currently applied to such essential drugs in South Korea. A significant majority (84%), predominantly non-pharma stakeholders, advocated for addressing cost-effectiveness uncertainty through re-assessment once long-term clinical data become available., Conclusions: This study uncovers a broad agreement among stakeholders on the need for more effective value assessment methodologies for high-priced potential cures, stressing the importance of more robust and comprehensive re-assessment supported by long-term data collection, rather than primarily relying on external reference pricing. Each type of stakeholders exhibited a cautious approach to their specific uncertainties, suggesting that new funding strategies should accommodate these uncertainties with predefined guidelines and agreements prior to the initiation of managed entry agreements., (© 2024. The Author(s).)

Objectives: This study aimed to explore the public view on priority-setting criteria for healthcare resource allocation. Specifically, it investigates how the value of a quality-adjusted life year (QALY) varies depending on patient characteristics., Methods: A discrete choice experiment was conducted using an online sample of the general South Korean population. Respondents were presented with two competing treatment scenarios. The attributes of the scenarios were age at disease onset, life expectancy without treatment, life-years gain with treatment, health-related quality of life (HRQoL) without treatment, and HRQoL gains with treatment. Two hundred choice sets were generated and randomly allocated into 20 blocks. A conditional logit model was used to estimate the factors affecting the respondents' choices., Results: A total of 3,482 respondents completed the survey. The larger the QALY gain, the more likely it was that the scenario would be chosen but with a diminishing marginal value. Respondents prioritized 40-year-old patients over 5-year-olds and 5-year-olds over 70-year-olds and prioritized baseline HRQoL of 40% and 60% over 20%. Patients at the end of life were not preferred to those with a longer life expectancy., Conclusion: Overall, respondents preferred health-maximizing options without explicit consideration for end-of-life patients or those with poor health. In addition, they revealed a kinked preference for patient age, prioritizing middle-aged patients over children and older people., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background/objectives: Atopic dermatitis (AD) is a chronic disease with an increasing incidence globally; therefore, there is a growing demand for natural compounds effective in treating dermatitis. In this study, the protective effects of Lycium barbarum leaves with and without chlorophyll (LLE and LLE[Ch-]) on AD were investigated in animal models of AD and HaCaT cells. Further, we investigated whether LLE and LLE(Ch-) show any differences in physiological activity., Materials/methods: AD was induced by 2,4-dinitrochlorobenzene (DNCB) for three weeks, while NC/Nga mice were fed LLE or LLE(Ch-) extracts for 7 weeks. Serum immunoglobulin E (IgE) and cytokine (tumor necrosis factor [TNF]-α, interleukin [IL]-6, and IL-4) concentrations and the degree of DNA fragmentation in lymphocytes were examined. A histopathological examination (haematoxylin & eosin staining and blue spots of toluidine) of the dorsal skin of mice was performed. To elucidate the mechanism of action, the expression of the thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) were measured in HaCaT cells., Results: Serum IgE and cytokines (TNF-α and IL-6) levels as well as DNA fragmentation of lymphocytes were significantly decreased in AD-induced mice treated with LLE or LLE(Ch-) compared to those of the control group. The epidermal thickness of the dorsal skin and mast cell infiltration in the LLE group significantly reduced compared to that in the control group. The LLE extracts showed no cytotoxicity up to 1,000 µg/mL in HaCaT cells. LLE or LLE(Ch-)-treated group showed a reduction of TARC and MDC in TNF-α-and IFN-γ-stimulated HaCaT cells., Conclusions: These results suggest that LLE potentially improves inflammation by reducing the expression of chemokines that inhibit T helper 2 cell migration. LLE(Ch-) showed similar effects to LLE on blood levels of IgE, TNF-α and IL-6 and protein expression in HaCat cells, but the ultimate effect of skin improvement was not statistically significant. Therefore, both LLE and LLE(Ch-) can be used as functional materials to alleviate AD, but LLE(Ch-) appears to require more research to improve inflammation., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interests., (©2023 The Korean Nutrition Society and the Korean Society of Community Nutrition.)

Objectives: This study aimed to compare appraisal decisions about anticancer drugs between the health technology assessment (HTA) agencies in Korea and England, and investigate whether the decisions and supporting evidence are comparable., Methods: This study identified 49 anticancer drugs listed by the Korean Ministry of Health and Welfare between January 2014 and December 2019. Of those, 46 anticancer drugs for 58 indications were included for analysis. Official appraisal documents from both countries for 58 drug-indication pairs were compared and assessed in terms of clinical and economic evidence. Evidence items and their groups for analysis were predefined., Results: Three-quarters of cases were recommended with managed entry agreements (MEAs) in England and three-fifths in Korea. Finance-based MEA types were most common in both countries. Korean and English authorities made consistent decisions in 48 cases (83%) when classifying decisions as 'recommended' and 'not recommended', while the degree of agreement lowered to 16 cases (28%) when subdividing decisions according to MEA types. When the evidence base was identical, their decisions were more likely to be consistent. Regarding clinical evidence, while the majority of cases referred to the same pivotal studies, differences between the committees' recognized comparators and the appraisal date caused discrepancies in decisions. Economic evidence, including incremental cost-effectiveness ratio (ICER) estimates, was identical in only 12 cases (21%), which contributed to discrepancies., Conclusion: England relies on economic evaluation, with increasing use of data collection agreements, in contrast with Korea's new procedure exempting companies from providing economic evaluation. While there is possibility for international cooperation in the assessment of clinical evidence, transferability issues exist, particularly with regard to economic evidence., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

A measles outbreak with 20 confirmed cases occurred at a local children's hospital in Daejeon from March 28 to April 21, 2019. The index patient was a 7-month-old girl with a recent history of travel to Vietnam. Contact tracing, active surveillance, and post-exposure prophylaxis were conducted by health authorities. Among the 20 patients, 11 (55%) were infants (0-11 months of age), three (15%) were aged 1-3 years, one (5%) was aged 4 years, and five (25%) were adults. Fifteen (75%) patients did not have a history of measles vaccination, and five (25%) had received only one vaccine dose. This study described the importance of prompt application of infection control measures in susceptible environments, including hospitals. Age-appropriate vaccination and providing information on infectious diseases to international travelers and multicultural families in Korea is vital., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Objectives: Recognition of sepsis frequently occurs in emergency departments. To evaluate the appropriateness of empiric antibiotic use in the setting of suspected sepsis in emergency department, the percentages of bacterial infection and antibiotic-related adverse drug effects were quantified in an emergency department at an academic medical center., Methods: We retrospectively reviewed electronic medical records of adults who presented to the emergency department between January 2018 and June 2018 with suspected sepsis (defined as having ≥2 systemic inflammatory response syndrome [SIRS] criteria) and received ≥1 dose of intravenous broad-spectrum antibiotic., Results: In total, 218 patients were included in the final analysis. Moreover, 19.3% of these patients had confirmed bacterial infections; 44.5% had suspected bacterial infections; and 35.9% did not have bacterial infection. Elevated SIRS score (ie, ≥2) and Quick Sequential Organ Failure Assessment (qSOFA) score (ie, ≥2) were not associated with the presence of bacterial infections. We identified 90-day Clostridioides difficile infections in 7 patients and drug-resistant organism infections in 6 patients, regardless of the presence of bacterial infections., Conclusions: A high number of patients received intravenous broad-spectrum antibiotics in the emergency department without confirmed or suspected bacterial infections that were supported by microbiologic cultures, radiographic imaging, or other symptoms of infections. Most patients who were initially admitted to the emergency department with suspected sepsis were discharged home after receiving 1 dose of intravenous antibiotic. Patients who were initially screened using SIRS score and who received broad-spectrum antibiotics in the emergency department were without confirmed or suspected bacterial infection., (© The Author(s) 2022.)

Background: The COVID-19 pandemic has a substantial impact on the physical and mental health status of patients with COVID-19. This study's objective was to evaluate the factors associated with mental health in patients isolated with COVID-19., Methods: It is a retrospective, cross-sectional study. One hundred and two patients discharged from COVID-19 hospitalization in Korea were analyzed. The primary outcome was the correlation between psychological problems such as anxiety, depression, and fear of stigma and physical symptoms such as respiratory symptoms, gastrointestinal symptoms, headache, and fever. Mental and physical symptoms were ascertained using closed and multiple-choice questions. The secondary outcome was the correlation between mental issues, demographic factors, and disease severity. Hypoxia and the need for oxygen therapy, a need for remdesivir antiviral treatment, and indications of pneumonia progression on chest x-ray were confirmed through a review of medical records and used to measure disease severity., Results: Patients with COVID-19 indicated feelings of depression (48.1%), anxiety (49.1%), and fear of stigma (60.45%), and some continued to experience physical symptoms even after discharge. Logistic regression revealed that gastrointestinal symptoms positively correlated with depression (p &lt; .05) and headache positively correlated with fear of stigma (p &lt; .05), while the other factors were not statistically significant (p &gt; .05)., Conclusions: This study showed that psychological symptoms persisted even after discharge. Gastrointestinal symptoms and headache were influential factors in predicting depression and fear of stigma. Based on this, dedicated COVID-19 hospitals should provide mental health support and preventive management., Competing Interests: Conflict of interest No commercial party having a direct financial interest in the results of the research supporting this article has or will confer any benefit upon the authors or upon any organization with which the authors are associated., (Copyright © 2022 Australasian College for Infection Prevention and Control. Published by Elsevier B.V. All rights reserved.)

Lycium barbarum and scopoletin are widely used in oriental Eastern medicine and are often consumed as teas. In this study, proinflammatory cytokines expressed in human keratinocytes (HaCaT) were induced by skin diseases caused by 2,4-dinitrochlorobenzene (DNCB) and tumor necrosis factor alpha (TNF- α )/interferon gamma (IFN- γ ). The inhibitory activity of L. barbarum EtOH extract (LBE) and scopoletin on proinflammatory cytokines and chemokines was investigated. In the DNCB-induced animal model, oral administration of LBE inhibited skin lesions and proinflammatory cytokines and chemokines and showed inhibitory effects in vitro . Additionally, as a result of examining the efficacy of scopoletin isolated from L. barbarum , scopoletin in HaCaT cells showed inhibitory effects on proinflammatory cytokines and chemokines. It shows promise in the treatment of chronic skin diseases., Competing Interests: The authors have declared that there is no conflict of interest., (Copyright © 2022 Seon Gyeong Bak et al.)

The first version of the pharmacoeconomic (PE) guidelines was published in South Korea in 2006. Despite its first revision in 2011, there were still ambiguities in its interpretation. Moreover, methodologies for estimating effectiveness and costs have also evolved since then. Under these circumstances, the Health Insurance Review and Assessment Service published the third version in January 2021. This article reviews the revision process and major changes made in the new edition of the PE guidelines. The revision was processed through reviews of the previous 50 PE submissions, international guidelines, academic literature, and surveys and advisory meetings to obtain stakeholders' opinions. The analysis perspective has changed from a limited societal perspective to a healthcare system perspective. In addition to the drug with the highest market share, drugs used in clinical trials can be selected as comparators under certain conditions. The discount rate decreased from 5% to 4.5%. Furthermore, the revised guidelines provide more detailed and specific instructions for items including non-inferiority margin, extrapolation, utility elicitation, and uncertainty. Treatment switch and co-dependent technology guidelines are newly included; the budget impact analysis guideline is deleted. Through this revision, transparency and consistency of decision-making is expected to improve., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: We aimed to describe the types of uncertainties examined in the economic evaluations submitted for reimbursement in Korea and their impact on the incremental cost-effectiveness ratio (ICER). Method: Fifty dossiers were submitted by pharmaceutical companies to the economic subcommittee of the Pharmaceutical Benefit Coverage Advisory Committee (PBCAC) from January 2014 to December 2018. The types of uncertainties were categorized as structural and parametric, and the frequencies of the sensitivity analysis per variables were analyzed. The impact of uncertainties was measured by the percent variance of the ICER relative to that of the base case analysis. Results: Of the 50 submissions, varying discount rate (44 submissions), followed by time horizon (38 submissions) and model assumptions (29 submissions), were most frequently used to examine structural uncertainty, while utility (42 submissions), resource use (41 submissions), and relative effectiveness (26 submissions) were used to examine parametric uncertainty. A total of 1,236 scenarios (a scenario corresponds to a case where a single variable is varied by a single range) were presented in the one-way sensitivity analyses, where parametric and structural sensitivity analyses comprised 679 and 557 scenarios, respectively. Varying drug prices had the highest impact on ICER (median variance 19.9%), followed by discount rate (12.2%), model assumptions (11.9%), extrapolation (11.8%), and time horizon (10.0%). Conclusions: Variables related to long-term assumptions, such as model assumptions, time horizon, extrapolation, and discounting rate, were related to a high level of uncertainty. Caution should be exercised when using immature data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bae, Lee and Bae.)

Kawasaki disease (KD) refers to systemic vasculitis of medium-sized vessels accompanied by fever. The multifunctional protein apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) is a new biomarker for vascular inflammation. Here, we investigated the association between APE1/Ref-1 and KD. Three groups, including 32 patients with KD (KD group), 33 patients with fever (Fever group), and 19 healthy individuals (Healthy group), were prospectively analyzed. APE1/Ref-1 levels were measured, and the clinical characteristics of KD were evaluated. The mean age of all patients was 2.7 ± 1.8 years, but the Healthy group participants were older than the other participants. Fever duration was longer in the KD group than in the fever group. APE1/Ref-1 levels were significantly higher in the KD group ( p = 0.004) than in the other two groups, but there was no difference between the healthy and fever groups. APE1/Ref-1 levels did not differ according to fever duration or coronary arterial lesion but were higher in refractory KD cases than in non-refractory cases. APE1/Ref-1 levels were significantly higher during the acute phase of KD. We propose that APE1/Ref-1 could be a beneficial biological marker for the diagnosis and prognosis of KD, especially in refractory KD.

Pharmacoeconomic (PE) guidelines, first published in 2006 and later updated in 2011, were developed to guide the preparation and submission of PE data to the Health Insurance Review and Assessment Service (HIRA) for drug reimbursement decision making in South Korea. This study, which was conducted as part of a project for revision of the PE guideline, reviewed utility values used in the PE submissions processed at HIRA during 2014-2018 to identify aspects of the current guidelines that may need to be revisited. A total of 50 PE submissions were processed at HIRA over the 5 years. Of these, 47 submissions that used quality-adjusted life-years as an outcome measure were included in this review. Data were extracted from full copies of the manufacturer's initial submissions and committee documents provided by HIRA. Of the 47 submissions, nearly half (n = 23, 48.9%) used published sources to obtain health state utility values, followed by direct methods using time trade-off (n = 7) or standard gamble (n = 2) and indirect methods with patient-level data using the EQ-5D-3L (n = 4) or the EQ-5D-5L (n = 2). Mapping, using the EQ-5D-3L as a target measure, was also adopted in six submissions, although it was somewhat unfavourably described in the guideline. Notably, 52.2% of the submissions with published sources took utility values from different sources for different health states defined in a single model. In addition, details of utility measurement methods or mapping functions taken from published sources were relatively poorly reported. Moreover, the preferences of the Korean general public, preferred by the guideline, were rarely reflected in the utility values used in submissions relying on published sources (95.7% for foreign values only/mixed) and mapping (66.7%). While most submissions with direct and indirect methods used domestic preference values, the former was occasionally criticised by assessment committees because of health state descriptions. This review highlights a considerable amount of inconsistency in the measurement of utility values used in the PE submissions during 2014-2018, indicating a strong need for methodological standardisation., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: New drugs including cancer drugs and orphan drugs are becoming increasingly more expensive. Risk sharing arrangements (RSAs) could manage the risk based on both financial impact and the health outcome of new drugs if reimbursed. To improve patients' access to new drugs under uncertainties, many developed countries have adopted RSAs. In this study, we aimed to understand the effects of RSAs in South Korea on patients' access., Methods: We reviewed current status of RSA drugs in South Korea. The number of appraisals and time gap between market approval and reimbursement per RSA drug were considered to quantify improvement of patients' access as they showed how rapidly decisions on reimbursement of RSA drugs were derived. Then, we applied a comparative analysis to determine whether the RSA drugs in South Korea were reimbursed in the UK, Italy, and Australia. Most data for this study were obtained from websites of the governmental department/agencies responsible for appraisal of drug reimbursement in each country. And literatures related to RSAs were investigated as well., Results: The eligibility for Korean RSAs had two key components - drugs for cancer and rare diseases and not having other alternative treatments. As of the first half of 2019, there were 39 RSA drugs reimbursed in South Korea, the majority of which were financial-based schemes. Refund and expenditure cap were the representative types (89.7%). After introduction of RSAs, the time gap and number of appraisals were decreased. Based on the indications of RSA drugs, the level of drug coverage in South Korea was found lower than Italy, similar to the UK, and higher than Australia., Conclusions: RSAs in South Korea significantly enhanced patients' access to new drugs and led to the alleviation of patients' out-of-pocket expenses. The drug coverage of South Korea had a level comparable to that of other countries. This study provides implications for countries that have a dual mission of containing pharmaceutical expenditure and improving access to new drugs., (© 2021. The Author(s).)

The Korean government sought to include dental implant services for the elderly in the benefits package of the national health insurance. In 2014, the Citizens' Jury was held to discuss the topic, during which thirty jurors, randomly selected from the 2665 applicants, participated in a day-long deliberation process after having an information session on the topic by a team of experts. There was a substantial shift in opinion during the deliberation session toward a more cost-conscious view. Most jurors supported limiting the coverage of dental implant to only one tooth per individual given the extent of the financial burden that will be imposed on the population. They opposed covering implant services for the front teeth, given that the implant of front teeth generally serves aesthetic purposes rather than restoring mastication function. The government's final decision in 2014 was to offer coverage up to two teeth, regardless of tooth location. This scheme based on the jury's recommendations in 2014 has been implemented without policy failure to date, which shows that the lay public can meaningfully contribute to a decision-making process regarding controversial agendas such as benefits packages for expensive health services.

Background: This study explored if Koreans consider the type of disease, rarity, and availability of alternative treatments as priority criteria in limited healthcare resource allocation., Materials and Methods: A web-based survey was conducted with a representative sample of 3,482 Korean adults. Participants were divided into six cohorts, differing in terms of the disease being compared and the cost and benefits of the treatments. Each cohort was asked two questions: 1) How to allocate a fixed budget into each of the two groups (cancer vs non-cancer, rare vs common, no other treatments available vs several treatments available), all else being equal; 2) allocation choices when conditions of two groups differed. The McNemar test was used to assess changes in responses between the two questions., Results: Under the control condition, the majority chose to treat an even number of patients with cancer and non-cancer diseases, and preferred to treat common diseases and those with no alternative treatments. However, when the treatment effects or costs of two comparison groups changed, choice shifted toward more effective or less costly treatment., Conclusions: While Koreans generally support the principle of health maximization, they also believe that priority should be given to diseases that previously did not have any treatments. However, no priority was given to cancer or rare diseases., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study, skin cream containing ziyuglycoside I isolated from Sanguisorba officinalis was manufactured and examined the protective effects of the skin cream against UVB-induced hairless mice. UVB-induced hairless mice were topically treated with the skin cream once a day for 5 weeks. Application of the skin cream did not exhibit side effect on body growth showing normal body weight and food efficiency in the mice. The skin cream treatment also was inhibited mRNA expression of interleukin (IL)-1β, matrix metalloproteinase (MMP)-2, MMP-9, and MMP-2 protein expression in the mice. Furthermore, the skin cream treatment inhibits epidermal wrinkle formation, wrinkle depth, wrinkle thickness, and collagen degradation in UVB-induced hairless mice. Therefore, the skin cream was able to play a role in the attenuation of photoaging caused by UVB irradiation via downregulation of mRNA expression of inflammatory cytokine IL-1β, MMP-2, MMP-9, and suppression of MMP-2 proteins expression.

South Korea is the first Asian country to mandate the submission of pharmacoeconomic data for reimbursement decision making. For a new drug to be listed, it must demonstrate its value in terms of comparative effectiveness and cost effectiveness. The Health Insurance Review and Assessment Service (HIRA) judges the submitted drug's value and decides whether its coverage is appropriate on the basis of the recommendation of the Pharmaceutical Benefit Coverage Assessment Committee. Once the drug has been accepted by HIRA, the National Health Insurance Service and the sponsoring company negotiate the price and expected sales volume. Even if HIRA acknowledges the value of the drug, it cannot be listed if the negotiation fails. In the off-patent market, generic and original branded drugs are treated equally in terms of pricing. Once generics enter the market, both drug prices should be lowered to 53.55% or less of the on-patent price. Since the current system was implemented, concerns have been raised about a decline in the accessibility of new drugs, especially for high-priced drugs used to treat serious diseases. In 2013, several measures had been introduced aimed at improving the accessibility of these drugs. A risk-sharing scheme and an increase in the maximum acceptable cost-effectiveness ratio were subsequently initiated. Although these schemes have been successful in improving access to high-priced drugs, they are often criticized for reducing transparency in pricing. Finding a balance between accessibility and efficiency is still a challenge in Korea., (Copyright © 2018. Published by Elsevier Inc.)

Background/objectives: Inflammatory Bowel Disease (IBD) has rapidly escalated in Asia (including Korea) due to increasing westernized diet patterns subsequent to industrialization. Factors associated with endoplasmic reticulum (ER) stress are demonstrated to be one of the major causes of IBD. This study was conducted to investigate the effect of Lycium barbarum ( L. barbarum ) on ER stress., Materials/methods: Mouse embryonic fibroblast (MEF) cell line and polarized Caco-2 human intestinal epithelial cells were treated with crude extract of the L. chinense fruit (LF). Paracellular permeability was measured to examine the effect of tight junction (TJ) integrity. The regulatory pathways of ER stress were evaluated in MEF knockout (KO) cell lines by qPCR for interleukin (IL) 6, IL8 and XBP1 spliced form (XBP1s). Immunoglobulin binding protein (BiP), XBP1s and CCAAT/enhancer-binding homologous protein (CHOP) expressions were measured by RT-PCR. Scanning Ion Conductance Microscopy (SICM) at high resolution was applied to observe morphological changes after treatments., Results: Exposure to LF extract strengthened the TJ, both in the presence and absence of inflammation. In polarized Caco-2 pretreated with LF, induction in the expression of proinflammatory marker IL8 was not significant, whereas ER stress marker XBP1s expression was significantly increased. In wild type (wt) MEF cells, IL6, CHOP and XBP1 spliced form were dose-dependently induced when exposed to 12.5-50 µg/mL extract. However, absence of XBP1 or IRE1α in MEF cells abolished this effect., Conclusion: Results of this study show that LF treatment enhances the barrier function and reduces inflammation and ER stress in an IRE1α-XBP1-dependent manner. These results suggest the preventive effect of LF on healthy intestine, and the possibility of reducing the degree of inflammatory symptoms in IBD patients., Competing Interests: CONFLICT OF INTEREST: The authors declare no potential conflicts of interest

Objectives: The South Korean government required the submission of economic evidence when it implemented the Positive-List System in December 2006. This study investigates the key factors that influenced actual public insurance reimbursement decisions, including the role of economic evidence, after 10 years of decision practice under compulsory health technology assessment (HTA) for new drugs., Method: Logistic regression analysis was used to estimate the impact of the variables involved, including cost-effectiveness ratio as a key variable, on reimbursement decisions. The latter were defined as "yes" or "no" at a submitted price and indication. Only cases (n = 91) that present a cost-effectiveness ratio, and that have been reviewed based on this ratio from January 2007 to December 2016, were included in the analysis., Results: Cases with higher cost-effectiveness ratios were less likely to be accepted. In addition, drugs that were used to treat severe diseases and drugs with no substitute were more likely to be recommended. The probability of acceptance declined along with the level of uncertainty in the submitted evidence. The acceptance rate for severe-disease drugs has increased since 2013, when the government introduced several policies that lowered the existing barriers to positive reimbursement. However, such an increase was not statistically significant., Conclusions: Cost-effectiveness is one of the most influential factors in drug-reimbursement decisions. However, inclusion of other explanatory variables, in addition to the cost-effectiveness ratio, predicted the results of decisions more accurately., Competing Interests: The authors have declared that no competing interests exist.

This study aims to identify the attributes that contribute to the value of medical devices and quantify the relative importance of them using a discrete choice experiment. Based on a literature review and expert consultation, seven attributes and their levels were identified-severity of disease (2), availability of substitutes (2), improvement in procedure (3), improvement in clinical outcomes (2), increase in survival (2), improvement in quality of life (3), and cost (4). Among 576 hypothetical profiles, optimal choice sets with 20 choices were developed and experts experienced in health technology assessment and reimbursement decision making in South Korea were surveyed. A total of 102 respondents participated in the survey. The results of the random-effect probit model showed that among the seven attributes, six, except for improvement in procedure, had a significant impact on respondents' choices on medical devices. Respondents were willing to pay the highest amount for devices that provided substantial improvements in quality of life, followed by increased survival, improved clinical outcome, treatment without substitutes, and technology for treating severe diseases. The findings of this experiment will inform decision-makers of the relative importance of the criteria and help them in reimbursement decision making of medical devices., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study describes the process and results of drug reimbursement decision-making in South Korea and evaluates its performance from the perspectives of the various stakeholders involved. Data were retrieved from the evaluation report posted on the Health Insurance Review and Assessment Service (HIRA) website. As of 2014, 253 new drugs had been submitted to the HIRA for appraisal. Of these, 175 (69.2%) were recommended in favor of listing and 78 (30.8%) were rejected. Furthermore, 68 of these drugs were deemed clinically improved relative to existing drugs. For those drugs that did not demonstrate clinical superiority (which was most of them), a simple price comparison to the existing drug was utilized as a gate toward listing. On top of the base-line analysis, 104 stakeholders from the industry, academia, public office, and civic society responded to a questionnaire designed to obtain their opinions on the South Korean positive list system (PLS). Stakeholders agreed that the consistency of reimbursement decision-making has improved since 2007, while accessibility to new drugs has apparently decreased. Respondents also indicated a preference toward improved public access to decision-making information. This examination of reimbursement decisions in South Korea will illuminate critical issues for countries that are considering the introduction of similar policies., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Phosphatase and tensin homolog (PTEN) loss or mutation consistently activates the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway, which contributes to the progression and invasiveness of prostate cancer. Furthermore, the PTEN/PI3-K/Akt and Ras/MAPK pathways cooperate to promote the epithelial-mesenchymal transition (EMT) and metastasis initiated from prostate stem/progenitor cells. For these reasons, the PTEN/PI3-K/Akt pathway is considered as an attractive target for both chemoprevention and chemotherapy. Herein we report that eupafolin, a natural compound found in common sage, inhibited proliferation of prostate cancer cells. Protein content analysis indicated that phosphorylation of Akt and its downstream kinases was inhibited by eupafolin treatment. Pull-down assay and in vitro kinase assay results indicated that eupafolin could bind with PI3-K and attenuate its kinase activity. Eupafolin also exhibited tumor suppressive effects in vivo in an athymic nude mouse model. Overall, these results suggested that eupafolin exerts antitumor effects by targeting PI3-K., (© 2014 Wiley Periodicals, Inc.)

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.

Endoplasmic reticulum (ER) stress is linked with development and maintenance of cancer, and serves as a therapeutic target for treatment of cancer. Verrucarin A, isolated from the broth of Fusarium sp. F060190, showed potential inhibitory activity on tunicamycin-induced ER stress in FaO rat liver cells. In addition, the compound decreased tunicamycin-induced GRP78 promoter activity in a dose dependent manner without inducing significant inhibition of luciferase activity and cell growth for 6 and 12 h. Moreover, the compound decreased the expression of GRP78, CHOP, XBP-1, and suppressed XBP-1, and reduced phosphorylation of IRE1α in FaO rat liver cells. This evidence suggests for the first time that verrucarin A inhibited tunicamycin-induced ER stress in FaO rat liver cells.

To investigate whether the value of the same drug is evaluated differently across jurisdictions, publicly available reimbursement recommendation data from the Health Insurance Review and Assessment Service (HIRA, Korea) from January 2007 until July 2012 were compared with reimbursement recommendation data from the Pharmaceutical Benefit Advisory Committee (PBAC) of Australia, and the Common Drug Review (CDR) and the pan-Canadian Oncology Drug review (pCODR) of Canada. The most recent guidelines from the three agencies regarding the recommended methods of economic evaluation and comparator selection were also compared. During the observation period, 25 products were evaluated by all three countries. No significant differences in the comparator(s)' selection or methods of economic evaluation were found, but the CDR was significantly less likely to positively recommend products compared with the other agencies (p=0.023). The agreement between agencies on selected comparator(s) was moderate to significant (kappa statistics=0.590-0.669), whereas the reimbursement decisions (kappa statistics=0.042-0.296) and the methods of economic evaluation (kappa statistics=0.138-0.525) showed slight to fair agreement. We illustrated that the divergence in reimbursement decisions across jurisdictions is less related to comparator selection or the level of clinical evidence considered and more related to country-specific issues., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

This retrospective study was conducted to evaluate clinical outcomes of bacteremia caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae and their antibiotic susceptibilities in febrile neutropenic children. Clinical characteristics, prognosis, and antibiotic susceptibilities were reviewed and compared between febrile neutropenic children with bacteremia caused by ESBL-producing and non-ESBL-producing E. coli and K. pneumoniae. A total of 61 episodes of E. coli and K. pneumoniae bacteremia, including 21 episodes (34.4%) due to ESBL-producing strains, were diagnosed. There was no significant factor associated with bacteremia by ESBL-producing strains. Empirical antibiotics were appropriate in 85.7% of the ESBL group and 95.0% of the non-ESBL group. In the entire study population, seven deaths (11.5%), including three deaths (4.9%) due to E. coli and K. pneumoniae bacteremia, occurred. The complication and mortality rates were not significantly different between the two groups. Antibiotic susceptibility rates were significantly lower in the ESBL group than in the non-ESBL group in most antibiotics. Although 52.4% and 66.7% of the ESBL-producing isolates were susceptible to piperacillin/tazobactam and cefepime, respectively, 96.7% of all the isolates and 90.5% of the ESBL-producing isolates were susceptible to piperacillin/tazobactam or cefepime in combination with aminoglycoside. In conclusion, the ESBL group did not show a significantly unfavorable outcome, and empirical therapy with piperacillin/tazobactam or cefepime in combination with aminoglycoside might be more useful for febrile neutropenic children, instead of β-lactam monotherapy in institutions with high prevalence of ESBL-producing E. coli and K. pneumoniae.

Background: This study was conducted to identify genetic polymorphisms associated with the prognosis of patients with early stage NSCLC., Materials and Methods: We genotyped 1,969 potentially functional single nucleotide polymorphisms (SNPs) of 1,151 genes involved in carcinogenesis in 166 NSCLC patients who underwent curative surgery, using the Affymetrix custom-made GeneChip. A replication study was performed in an independent cohort of 626 patients., Results: Fifty six SNPs which were associated with both overall survival (OS) and disease-free survival (DFS) with log-rank P values < 0.05 in discovery set were selected for validation. Among those, five SNPs (RACK1 rs1279736C>A and rs3756585T>G, C3 rs2287845T>C, PCAF rs17006625A>G, and PCM1 rs17691523C>G) were found to be significantly associated with survival in the same direction as the discovery set. In combined analysis, the rs1279736C>A and rs3756585T>G were most significantly associated with OS and DFS in multivariate analysis (P for OS = 4 × 10⁻⁵ and 7 × 10⁻⁵, respectively; and P for DFS = 0.003, both; under codominant model). In vitro promoter assay and electrophoretic mobility shift assay revealed that the rs3756585 T-to-G change increased promoter activity and transcription factor binding of RACK1., Conclusions: We identified five SNPs, especially RACK1 rs3756585T>G, as markers for prognosis of patients with surgically resected NSCLC.

Background: Decision makers in middle-income countries are using economic evaluations (EEs) in pricing and reimbursement decisions for pharmaceuticals. However, whilst many of these jurisdictions have local submission guidelines and local expertise, the studies themselves often use economic models developed elsewhere and elements of data from countries other than the jurisdiction concerned. The objectives of this study were to describe the current situation and to assess the challenges faced by decision makers in transferring data and analyses from other jurisdictions., Methods: Experienced health service researchers in each region conducted an interview survey of representatives of decision making bodies from jurisdictions in Asia, Central and Eastern Europe, and Latin America that had at least 1 year's experience of using EEs., Results: Representatives of the relevant organizations in twelve countries were interviewed. All twelve jurisdictions had developed official guidelines for the conduct of EEs. All but one of the organizations evaluated studies submitted to them, but 9 also conducted studies and 7 commissioned them. Nine of the organizations stated that, in evaluating EEs submitted to them, they had consulted a study performed in a different jurisdiction. Data on relevant treatment effect was generally considered more transferable than those on prices/unit costs. Views on the transferability of epidemiological data, data on resource use and health state preference values were more mixed. Eight of the respondents stated that analyses submitted to them had used models developed in other jurisdictions. Four of the organizations had a policy requiring models to be adapted to reflect local circumstances. The main obstacles to transferring EEs were the different patterns of care or wealth of the developed countries from which most economic evaluations originate., Conclusions: In middle-income countries it is commonplace to deal with the issue of transferring analyses or data from other jurisdictions. Decision makers in these countries face several challenges, mainly due to differences in current standard of care, practice patterns, or gross domestic product between the developed countries where the majority of the studies are conducted and their own jurisdiction.

Three saikosaponins were isolated from the MeOH extract of the roots of Bupleurum falcatum L.: saikosaponins B3 (1); B4 (2); and D (3). Of the three, compound 3 inhibited the interaction of selectins (E, L, and P) and THP-1 cells with IC50 values of 1.8, 3.0 and 4.3 µM, respectively. Also, the aglycone structure 4 of compound 3 showed moderate inhibitory activity on L-selectin-mediated cell adhesion. From these results, we suspect that compound 3 isolated from Bupleurum falcatum roots would be a good candidate for therapeutic strategies to treat inflammation.

Diffuse cutaneous mastocytosis, the most rare form of cutaneous mastocytosis, often manifests as bullous lesions. Although cutaneous mastocytosis should be included in a differential diagnosis for pruritic skin lesions in children, early diagnosis of the disease is not easy due to its rare occurrence. A 17-month-old boy presented with recurrent itchy bullous skin lesions. He had been treated as atopic dermatitis at other hospitals for about one year, however, he was eventually diagnosed with diffuse cutaneous mastocytosis through skin biopsy. Unlike adults, children with cutaneous mastocytosis usually improve with age and do not develop systemic mastocytosis. Therefore, early and accurate diagnosis of cutaneous mastocytosis in children is essential for appropriate care.

Introduction: It has been estimated that the proportion of never-smokers among females with lung cancer is 53% worldwide and 75% in Korea. We conducted a two-stage study to identify genetic factors responsible for lung cancer susceptibility in female never-smokers., Materials and Methods: In a discovery set, 1969 potentially functional single nucleotide polymorphisms (SNPs) of 1151 genes, which were related to cancer development and progression, were evaluated using the Affymetrix custom-made GeneChip in 181 female never-smokers with lung cancer and 179 controls. A replication study was performed on an independent cohort of 596 cases and 1194 healthy controls., Results: Sixteen SNPs with p < 0.05 for genotype distribution in the discovery set were enrolled in the replication study. Among 16 SNPs, three SNPs (colony-stimulating factor 1 receptor [CSF1R] rs10079250A>G, tumor protein p63 [TP63] rs7631358G>A, and corepressor interacting with RBPJ 1 [CIR1] rs13009079T>C) were found to be significantly associated with lung cancer in the same direction as the discovery set. Homology-based model for CSF1R indicated that the rs10079250A>G leads to increased positive charge of CSF-binding region of CSF1R, thereby increasing the chance of binding between CSF and CSF1R. In addition, this SNP was found to increase the phosphorylation of a mitogen-activated protein kinase, JNK., Conclusions: Our results suggest that the three SNPs, particularly CSF1R rs10079250, may contribute to lung cancer susceptibility in never-smoking females.

Unlabelled: Kikuchi-Fujimoto disease (KFD) is characterized by self-limiting regional lymphadenopathy with prolonged fever. Although the reported recurrence rate of KFD is known to be 3-4 %, this rate appears to be higher in our clinical experience, and rates up to 38.5 % have been previously reported. In this retrospective study, we reviewed medical records of children with pathologically confirmed KFD to investigate the factors associated with recurrent KFD. Enrolled children were divided into two groups according to the recurrence of KFD, and clinical and laboratory factors were compared between the two groups. The recurrence of KFD was determined based not on repeated pathologic confirmation but on the presence of clinical febrile lymphadenopathy. A total of 33 children with KFD, 26 boys (78.8 %) and 7 girls (21.2 %), with a median age of 12 years (9 months to 19 years), were enrolled. Thirty-one children (93.9 %) complained of fever, and most of the children (90.9 %) complained of cervical lymphadenopathy. Neutropenia (<1,500/μL) or lymphopenia (<1,500/μL) was observed in 51.5 %. Lactate dehydrogenase level, erythrocyte sedimentation rate, and C-reactive protein level were elevated in 90.9, 96.9, and 54.5 % of children, respectively. Fourteen children (42.4 %) experienced recurrent KFD, including ten children after biopsy and four children before and after biopsy. In a multivariate analysis, a past history of other systemic illnesses (p = 0.013) and a higher absolute lymphocyte count (p = 0.023) were significantly associated with recurrent KFD. These systemic illnesses were chronic idiopathic thrombocytopenic purpura, autoimmune thyroiditis, nephrotic syndrome, perinatal cytomegalovirus infection, and hemophagocytic lymphohistiocytosis., Conclusion: Our results suggest that recurrent KFD is more frequent than reported, and recurrent KFD should be considered in children with a history of other systemic illnesses such as immune disorders.

Varicella-zoster virus infection can lead to severe illness in immunocompromised patients. Further the mortality rate of disseminated varicella infection is extremely high particularly in immunocompromised children. We report a case of disseminated varicella infection in a child with acute lymphoblastic leukemia who was receiving chemotherapy, but was initially admitted with only for acute abdominal pain. The patient rapidly developed severe complications, including acute respiratory distress syndrome, acute hepatitis, disseminated intravascular coagulation, and encephalopathy. Acyclovir is a highly potent inhibitor of varicella-zoster virus infection. However, owing to rapid disease progression, it might not be sufficient to control a disseminated varicella infection, especially in immunocompromised patients. Immunoglobulin neutralize virus invasion and suppress viremia, acting synergistically with acyclovir. In this case, early administration of acyclovir and a high-dose of immunoglobulin, combined with mechanical respiratory support, proved adequate for treatment of this severe illness.

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.

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.