Cardiovascular safety of evogliptin dual and triple therapy in patients with type 2 diabetes: a nationwide cohort study.

OBJECTIVE: To investigate the risk of cardiovascular events associated with commonly used dual and triple therapies of evogliptin, a recently introduced dipeptidyl peptidase-4 inhibitor (DPP4i), for managing type 2 diabetes in routine clinical practice. DESIGN: A retrospective cohort study. SETTING: Korean Health Insurance Review and Assessment database. PARTICIPANTS: Patients who initiated metformin-based dual therapy and metformin+sulfonylurea-based triple therapy in South Korea from 2014 to 2018. INTERVENTIONS: Initiation of combination therapy with evogliptin. PRIMARY AND SECONDARY OUTCOME MEASURES: Hazards of cardiovascular events, a composite endpoint of myocardial infarction, heart failure and cerebrovascular events, and its individual components. Cox proportional hazards model with propensity score-based inverse probability of treatment weighting were used to estimate HRs and 95% CIs. RESULTS: From the dual and triple therapy cohorts, 5830 metformin+evogliptin users and 2198 metformin+sulfonylurea+evogliptin users were identified, respectively. Metformin+evogliptin users, as compared with metformin+non-DPP4i, had a 29% reduced risk of cardiovascular events (HR 0.71, 95% CI 0.62 to 0.82); HRs for individual outcomes were cerebrovascular events (0.71, 95% CI 0.53 to 0.95), heart failure (0.70, 95% CI 0.59 to 0.82), myocardial infarction (0.89, 95% CI 0.60 to 1.31). Metformin+sulfonylurea+evogliptin users, compared with metformin+sulfonylurea+non-DPP4i, had a 24% reduced risk of cardiovascular events (0.76, 95% CI 0.59 to 0.97); HRs for individual outcomes were myocardial infarction (0.57, 95% CI 0.27 to 1.19), heart failure (0.74, 95% CI 0.55 to 1.01), cerebrovascular events (0.96, 95% CI 0.61 to 1.51). CONCLUSIONS: These findings suggest that dual or triple therapies of evogliptin for the management of type 2 diabetes in routine clinical practice present no cardiovascular harms, but could alternatively offer cardiovascular benefits in this patient population.

Adverse Events Following COVID-19 Vaccination in Adolescents: Insights From Pharmacovigilance Study of VigiBase.

BACKGROUND: During coronavirus disease 2019 (COVID-19) pandemic, several COVID-19 vaccines were licensed with fast-track procedures. Although these vaccines have demonstrated high immunogenicity, there has been concerns on the serious adverse events (AEs) following COVID-19 vaccination among adolescents. We aimed to analyze comparative safety of COVID-19 vaccination in adolescents. METHODS: In this pharmacovigilance study, we performed a disproportionality analysis using VigiBase, the World Health Organization's global individual case safety report (ICSR) database. To compare serious AEs reported following COVID-19 vaccines vs. all other vaccines in adolescents aged 12-17 years, ICSRs following any vaccines on adolescents aged 12-17 years were included, defining cases as reports with the AEs of interest, with all other AEs as non-cases. The AEs of interest were myocarditis/pericarditis, multisystem inflammatory syndrome/Kawasaki disease (MIS/KD), anaphylaxis, Guillain-Barré syndrome (GBS), and immune thrombocytopenia (ITP). We conducted a disproportionality analysis to estimate reporting odds ratio (ROR) with 95% confidence interval (CI) for each AE of interest, adjusted for sex by using logistic regression. RESULTS: Of 99,735 AE reports after vaccination in adolescents, 80,018 reports were from COVID-19 vaccinated adolescents (52.9% females; 56.3% America). The AEs of interest were predominantly reported as serious AE (76.1%) with mRNA vaccines (99.4%). Generally, higher reporting odds for the AEs were identified following COVID-19 vaccination in adolescents; myocarditis/pericarditis (2,829 reports for the COVID-19 vaccine vs. 35 for all other vaccines, adjusted ROR [aROR], 19.61; 95% CI, 14.05-27.39), and MIS/KD (104 vs. 6, aROR, 4.33; 95% CI, 1.89-9.88). The reporting odds for anaphylaxis (515 vs. 165, aROR, 0.86; 95% CI, 0.72-1.02), GBS (94 vs. 40, aROR, 0.64; 95% CI, 0.44-0.92) and ITP (52 vs. 12, aROR, 1.12; 95% CI, 0.59-2.09) were not significantly higher following COVID-19 vaccination. CONCLUSION: In this study, there were disproportionate reporting of immune-related AEs following COVID-19 vaccination. While awaiting definitive evidence, there is a need to closely monitor for any signs of immune-related AEs following COVID-19 vaccination among adolescents.

Impact of National Public-Private Mix and Medical Expense Support Program for Control Tuberculosis in South Korea: An Interrupted Time Series Analysis.

Tuberculosis (TB) remains a major threat to global public health, various measures at national level have been implemented to control TB and no evidence with long-term effectiveness has yet been evaluated on TB control programs. We confirmed the long-term effectiveness of the TB control programs in reducing overall burden in South Korea using interrupted time series analysis. Along with the Public-Private Mix, our finding suggests that relieving the economic burden of people with TB may further complement in achieving the End TB strategy. For countries currently developing strategies for TB control, results may provide important insights in effective TB control.

Association between proton pump inhibitors use and risk of asthma in Korea: A prevalent new-user cohort study.

There have been conflicting mechanisms that proton pump inhibitors (PPIs) may promote or prevent asthma development. However, the evidence on the association of PPI use with the risk of asthma and its exposure-response relationship has been limited. We aim to identify the association between the use of PPIs and the incidence of asthma, compared with use of histamine 2 receptor antagonists (H2RAs). A nationwide, prevalent new-user cohort study was conducted using Korea's National Sample Cohort database. Patients were defined as PPI or H2RA users between 2003 and 2019. PPI users matched to H2RA users based on time-conditional propensity score. Cox proportional hazards model was used to estimate adjusted hazard ratios with 95% confidence intervals of incident asthma associated with PPI use by duration of use, cumulative dose, and average dose per duration. Among the 250,041 pairs, PPI users (51.3% male; mean [SD] age, 42.6 [16.5]; mean follow-up, 6.7 years) showed a higher incidence rate of asthma (7.94 events per 1000 person-year) compared to H2RA users (3.70 events per 1000 person-year) with adjusted hazard ratio of 2.15 (95% confidence interval = 2.08-2.21). The risk of asthma was significantly increased across all observed groups of duration of use, cumulative dose, and average dose per duration. This study suggested that PPI use is associated with an increased risk of developing asthma compared to H2RA use.

Breastfeeding and impact on childhood hospital admissions: a nationwide birth cohort in South Korea.

Benefits of breastfeeding for both the mother and the child are well established, but a comprehensive and robust study to investigate the protective effect of breastfeeding and attenuated time effect stratified by cause of morbidity are lacking. This study is based on the nationwide birth cohort in Korea that includes data on all infants born from 2009 to 2015. Of 1,608,540 children, the median follow-up period was 8.41 years (interquartile range, 6.76-10.06). When compared to children with fully formula feeding, the hospital admission rate was 12% lower in those with partially breastfeeding and 15% lower in those with exclusive breastfeeding. The apparent protective effect of breastfeeding was reduced with increasing age. Our study provides potential evidence of the beneficial association of breastfeeding on subsequent hospital admissions. The protective effect declined over time as the children grew older. Encouraging any breastfeeding for at least the first 6 months among infants is an important public health strategy to improve overall child health.

Cost-Effectiveness of All-Oral Regimens for the Treatment of Multidrug-Resistant Tuberculosis in Korea: Comparison With Conventional Injectable-Containing Regimens.

BACKGROUND: Regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB) have been changed from injectable-containing regimens to all-oral regimens. The economic effectiveness of new all-oral regimens compared with conventional injectable-containing regimens was scarcely evaluated. This study was conducted to compare the cost-effectiveness between all-oral longer-course regimens (the oral regimen group) and conventional injectable-containing regimens (the control group) to treat newly diagnosed MDR-TB patients. METHODS: A health economic analysis over lifetime horizon (20 years) from the perspective of the healthcare system in Korea was conducted. We developed a combined simulation model of a decision tree model (initial two years) and two Markov models (remaining 18 years, six-month cycle length) to calculate the incremental cost-effectiveness ratio (ICER) between the two groups. The transition probabilities and cost in each cycle were assumed based on the published data and the analysis of health big data that combined country-level claims data and TB registry in 2013-2018. RESULTS: The oral regimen group was assumed to spend 20,778 USD more and lived 1.093 years or 1.056 quality-adjusted life year (QALY) longer than the control group. The ICER of the base case was calculated to be 19,007 USD/life year gained and 19,674 USD/QALY. The results of sensitivity analyses showed that base case results were very robust and stable, and the oral regimen was cost-effective with a 100% probability for a willingness to pay more than 21,250 USD/QALY. CONCLUSION: This study confirmed that the new all-oral longer regimens for the treatment of MDR-TB were cost-effective in replacing conventional injectable-containing regimens.

Validating an approach to overcome the immeasurable time bias in cohort studies: a real-world example and Monte Carlo simulation study.

BACKGROUND: Immeasurable time bias arises from the lack of in-hospital medication information. It has been suggested that time-varying adjustment for hospitalization may minimize this potential bias. However, whereas we examined this issue in one case study, there remains a need to assess the validity of this approach in other settings. METHODS: Using a Monte Carlo simulation, we generated synthetic immeasurable time-varying hospitalization-related factors of duration, frequency and timing. Nine scenarios were created by combining three frequency scenarios and three duration scenarios, where the empirical cohort distribution of hospitalization was used to simulate the 'timing'. We used Korea's healthcare database and a case example of ß-blocker use and mortality among patients with heart failure. We estimated the gold-standard hazard ratio (HR) with 95% CI using inpatient and outpatient drug data, and that of the pseudo-outpatient setting using outpatient data only. We assessed the validity of adjusting for time-varying hospitalization in nine different scenarios, using relative bias, confidence limit ratio (CLR) and mean squared error (MSE) compared with the empirical gold-standard estimate across bootstrap resamples. RESULTS: With the real-world gold standard (HR 0.73; 95% CI 0.67-0.80) as the reference estimate, adjusting for time-varying hospitalization (0.71; 0.63-0.80) effectively reduced the immeasurable time bias and had the following performance metrics across the nine scenarios: relative bias (range: -7.08% to 0.61%), CLR (1.28 to 1.36) and MSE (0.0005 to 0.0031). CONCLUSIONS: The approach of adjusting for time-varying hospitalization consistently reduced the immeasurable time bias in Monte Carlo simulated data.

Comparative safety of bedaquiline and delamanid in patients with multidrug resistant tuberculosis: A nationwide retrospective cohort study.

BACKGROUND/PURPOSE(S): Bedaquiline and delamanid were recently approved for multidrug resistant tuberculosis (MDR-TB). Bedaquiline carries a black box warning of increased risk of death compared to the placebo arm, and there is a need to establish the risks of QT prolongation and hepatotoxicity for bedaquiline and delamanid. METHODS: We retrospectively analyzed data of MDR-TB patients retrieved from the South Korea national health insurance system database (2014-2020) to assess the risks of all-cause death, long QT-related cardiac event, and acute liver injury associated with bedaquiline or delamanid, compared with conventional regimen. Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Stabilized inverse probability of treatment weighting based on propensity score was used to balance characteristics between the treatment groups. RESULTS: Of 1998 patients, 315 (15.8%) and 292 (14.6%) received bedaquiline and delamanid, respectively. Compared with conventional regimen, bedaquiline and delamanid did not increase risk of all-cause death at 24-month (HR 0.73 [95% CI, 0.42-1.27] and 0.89 [0.50-1.60], respectively). Bedaquiline-containing regimen increased risk of acute liver injury (1.76 [1.31-2.36]), while delamanid-containing regimen increased risk of long QT-related cardiac events (2.38 [1.05-3.57]) within 6 months of treatment. CONCLUSION: This study adds to the emerging evidence refuting the higher mortality rate observed in the bedaquiline trial population. Association between bedaquiline and acute liver injury needs careful interpretation considering for other background hepatotoxic anti-TB drugs. Our finding on delamanid and long QT-related cardiac events suggest careful risk-benefit assessment in patients with pre-existing cardiovascular disease.

High-Intensity Statin Reduces the Risk of Mortality Among Chronic Liver Disease Patients With Atherosclerotic Cardiovascular Disease: A Population-Based Cohort Study.

Background 2018 American Heart Association/American College of Cardiology cholesterol guideline recommends statin in patients with chronic and/or stable liver disease for secondary prevention of atherosclerotic cardiovascular disease yet remains equivocal on the adequate intensity of statin for patients with chronic liver disease (CLD). We aimed to assess the association between statin intensity and mortality among patients with CLD with atherosclerotic cardiovascular disease. Methods and Results We conducted a population-based cohort study in South Korea. We assessed the risk of survival and clinical outcomes using inverse probability of treatment-weighted Cox proportional hazards regression. We also estimated the absolute risk difference between treatment groups based on the Poisson distribution. During an average of 2.35 person-years, 10 442 patients with CLD with atherosclerotic cardiovascular disease were identified. Among those patients, 5515 (52.8%) received high-intensity statin, and 4927 (47.2%) received low/moderate-intensity statin. High-intensity statin was associated with lower risk for all-cause mortality (hazard ratio [HR], 0.83 [95% CI, 0.75-0.92]), cardiovascular-cause mortality (HR, 0.85 [0.71-1.01]), liver-cause mortality (HR, 0.72 [0.54-0.97]) compared with low/moderate-intensity statin. Although both hospitalizations for recurrent myocardial infarction and stroke were shown to be increased among high-intensity statin users, effect estimate was homogeneous in the absolute scale (myocardial infarction: HR, 1.12 [1.04-1.19], risk difference, 7.57 [-0.69 to 15.84] per 1000 person-years; stroke: HR, 1.11 [0.97 to 1.27]; risk difference, -1.70 [-5.19 to 1.78]). Conclusions Among patients with CLD with atherosclerotic cardiovascular disease, high-intensity statin was significantly associated with a lower risk of mortality. These findings herein support the guidelines for statin use in patients with CLD while demonstrating potential benefit of optimal intensity use.

Immeasurable Time Bias in Self-controlled Designs: Case-crossover, Case-time-control, and Case-case-time-control Analyses.

BACKGROUND: Impact of immeasurable time bias (IMTB) is yet to be examined in self-controlled designs. METHODS: We conducted case-crossover, case-time-control, and case-case-time-control analyses using Korea's healthcare database. Two empirical examples among elderly patients were used: 1) benzodiazepines-hip fracture; 2) benzodiazepines-mortality. For cases, the date of hip fracture diagnosis or death was defined as the index date, and the inherited date of their matched cases for controls or future cases. Exposure was assessed in the 1-30 day (hazard) and 61-90 day (control) windows preceding the index date. A non-missing exposure setting included in- and outpatient prescriptions and the pseudo-outpatient setting included only the outpatients. Conditional logistic regression was done to estimate odds ratios (ORs) with 95% confidence intervals (CIs), where the relative difference in OR among the two settings was calculated to quantify the IMTB. RESULTS: The IMTB had negligible impacts in the hip fracture example in the case-crossover (non-missing exposure setting OR 1.27; 95% CI, 1.12-1.44; pseudo-outpatient setting OR 1.21; 95% CI, 1.06-1.39; magnitude 0.05), case-time-control (OR 1.18; 95% CI, 0.98-1.44; OR 1.13; 95% CI, 0.92-1.38; 0.04, respectively), and case-case-time-control analyses (OR 0.99; 95% CI, 0.80-1.23; OR 0.94; 95% CI, 0.75-1.18; 0.05, respectively). In the mortality example, IMTB had significant impacts in the case-crossover (non-missing exposure setting OR 1.44; 95% CI, 1.36-1.52; pseudo-outpatient setting OR 0.72; 95% CI, 0.67-0.78; magnitude 1.00), case-time-control (OR 1.38; 95% CI, 1.26-1.51; OR 0.68; 95% CI, 0.61-0.76; 1.03, respectively), and case-case-time-control analyses (OR 1.27; 95% CI, 1.15-1.40; OR 0.62; 95% CI, 0.55-0.69; 1.05, respectively). CONCLUSION: Although IMTB had negligible impacts on the drug's effect on acute events, as these are unlikely to be accompanied with hospitalizations, it negatively biased the drug's effect on mortality, an outcome with prodromal phases, in the three self-controlled designs.

Association between ranitidine use with potential NDMA impurities and risk of cancer in Korea.

N-Nitrosodimethylamine (NDMA) detected above the acceptable level in ranitidine products has been a great global concern. To examine the risk of cancer among people treated with ranitidine, we conducted a cohort study using the National Health Insurance Service-National Sample Cohort data (2002-2015) of South Korea. Patients were aged 40 or above as of January 2004 and began receiving ranitidine or other histamine-2 receptor antagonist (H2RA), active comparator, without a history of H2RAs prescription during the prior 2-years. The lag time was designated up to 6 years. The outcomes were an overall incident cancer risk and the risk of major single cancers during the follow-up. The association between ranitidine use and cancer risk was examined by Cox regression model. After exclusion and propensity score matching, 25,360 patients were available for analysis. The use of ranitidine was not associated with the overall cancer risk and major individual cancers [overall cancer: incidence rate per 1000 person-years, 2.9 vs 3.0 among the ranitidine users and other H2RAs users, respectively; adjusted hazard ratio (HR) and 95% confidence interval (95% CI) for all cancers, 0.98 (0.81-1.20)]. The higher cumulative exposure to ranitidine did not increase the cancer risk. Given the insufficient follow-up period, these findings should be interpreted carefully.

Challenges in evaluating treatments for COVID-19: The case of in-hospital anticoagulant use and the risk of adverse outcomes.

Anticoagulants are a potential treatment for the thrombotic complications resulting from COVID-19. We aimed to determine the association between anticoagulant use and adverse outcomes among hospitalized patients with COVID-19. We used data from the COVID-19 International Collaborative Research Project in South Korea from January to June 2020. We defined exposure using an intention-to-treat approach, with person-time classified as use or non-use of anticoagulants at cohort entry, and a time-varying approach. The primary outcome was all-cause, in-hospital mortality; the secondary outcome was a composite including respiratory outcomes, cardiovascular outcomes, venous thromboembolism, major bleeding, and intensive care unit admission. Cox proportional hazards models estimated adjusted hazard ratios (HRs) of the outcomes comparing use versus non-use of anticoagulants. Our cohort included 2,677 hospitalized COVID-19 patients, of whom 24 received anticoagulants at cohort entry. Users were older and had more comorbidities. The crude incidence rate (per 1,000 person-days) of mortality was 5.83 (95% CI: 2.80, 10.72) among anticoagulant users and 1.36 (95% CI: 1.14, 1.59) for non-users. Crude rates of the composite outcome were 3.20 (95% CI: 1.04, 7.47) and 1.80 (95% CI: 1.54, 2.08), respectively. Adjusted HRs for mortality (HR: 1.12, 95% CI: 0.48, 2.64) and the composite outcome (HR: 0.79, 95% CI: 0.28, 2.18) were inconclusive. Although our study was not able to draw conclusions on anticoagulant effectiveness for COVID-19 outcomes, these results can contribute to future knowledge syntheses of this important question. Our study demonstrated that the dynamic pandemic environment may have important implications for observational studies of COVID-19 treatment effectiveness.

Real-world treatment patterns for atopic dermatitis in South Korea.

The phenotypes of atopic dermatitis (AD) are diverse, and ethnic differences have been suggested. To date, few studies have explored large-scale national data on the treatment patterns of AD in Asians. Therefore, we aimed to examine real-world treatment patterns for AD, including the probability of discontinuation of AD treatment and restart after discontinuation. A retrospective observational study was conducted using the nationwide healthcare database in South Korea between January 1, 2016 to July 31, 2020. We identified 944,559 pediatric patients and 1,066,453 adults with AD. Topical corticosteroids and antihistamines were the most commonly prescribed medications in all age groups. The frequency of topical corticosteroid prescription decreased as the age increased. Although immunosuppressive drugs were not widely used in both children and adults, cyclosporine was the most frequently prescribed immunosuppressant, particularly among those aged 12 years or more (1-2%). Pediatric patients were more likely to discontinue treatment than adult patients. Treatment restart for moderate-to-severe AD was earlier than that for overall AD. In conclusion, significant differences were observed in the treatment patterns of AD between pediatric and adult patients. These findings will improve our understanding of the latest treatment patterns for AD, which may contribute to decision-making in clinical practice.

Analytical Approaches to Reduce Selection Bias in As-Treated Analyses with Missing In-Hospital Drug Information.

INTRODUCTION: While much attention has focused on immeasurable time bias as a potential exposure misclassification bias, it may also result in potential selection bias in cohort studies using an as-treated (or per protocol) exposure definition in which patients are censored upon treatment discontinuation. METHODS: We examined analytical approaches to minimise informative censoring due to the absence of in-hospital drug data using a case study of ß-blocker use and mortality in heart failure. We conducted a cohort study using Korea's healthcare database, including inpatient and outpatient drug data. Using an as-treated exposure definition, patients were followed up until death, ß-blocker discontinuation (in the exposed), ß-blocker initiation (in the unexposed), or end of study period. In 'complete prescription' analysis using inpatient and outpatient drug data, we estimated hazard ratios (HR) and 95% confidence intervals (CI) using a Cox proportional hazard model. In outpatient drug-based analyses, we attempted to reduce the bias using stabilised inverse probability weighting (IPW) for treatment crossovers, hospitalisation, and all artificial censorings. RESULTS: An HR of 0.89 (95% CI 0.74-1.07) for ß-blocker use versus non-use for all-cause mortality was found in 'complete prescription' analysis. Benefits were exaggerated when follow-up was assessed using outpatient drug data only (HR 0.71; 95% CI 0.57-0.89). Weighting by stabilised IPW for treatment crossovers and hospitalisation reduced the bias. CONCLUSIONS: When using an as-treated exposure definition, missing in-hospital drug data induced selection bias in our case study. Using IPW for censoring mitigated bias from the hospitalisation-induced censorings.

Long-term clinical outcomes of oral antidiabetic drugs as fixed-dose combinations: A nationwide retrospective cohort study.

AIM: To compare treatment patterns and clinical outcomes of single-pill fixed-dose combination (FDC) and two-pill combination (TPC) therapies using real-world data. METHODS: We conducted a nationwide retrospective cohort study using South Korea's healthcare database (2002-2015). We identified two cohorts of incident patients with type 2 diabetes who initiated FDC or TPC therapy within 4 months of their first prescription for metformin or sulphonylurea. We examined persistence and adherence patterns and the clinical outcome of a composite endpoint of death or hospitalization for acute myocardial infarction, heart failure or stroke and compared the differences in treatment patterns and clinical outcomes using Cox models. RESULTS: Of 5143 and 10 973 patients who initiated FDC and TPC therapy, respectively, we identified 5143 patient pairs after propensity score matching. The FDC group exhibited greater median time to treatment discontinuation (163 vs. 146 days), and proportion of days covered at 12 months (mean 0.60 vs. 0.57, P < .0001) and at 24 months (0.53 vs. 0.51, P = .014) than the TPC group. The FDC group, compared with the TPC group, had reduced risks of the composite clinical outcome (hazard ratio 0.86, 95% confidence intervals 0.77-0.97) and hospitalization for stroke (0.80, 0.67-0.96). CONCLUSION: FDC therapy may provide favourable cardiovascular benefits, especially reducing the risk of hospitalization for stroke, and has better medication adherence among patients with type 2 diabetes.

Temporal trends of pharmacologic treatments for tuberculosis and multidrug resistant tuberculosis following dissemination of treatment guidelines in South Korea.

BACKGROUND/PURPOSE(S): The World Health Organization (WHO) released treatment guidelines for multidrug resistant tuberculosis (MDR-TB) in 2008, with subsequent revisions in 2011; Korea disseminated corresponding guidelines in 2011 and 2014, respectively. Thus, we aimed to investigate the temporal trends of and the updated guideline's impact on the prescription patterns of anti-TB drugs. METHODS: We conducted a time-series study using Korea's nationwide healthcare database (2007-2015), where patients with TB or MDR-TB were included. Only anti-TB drugs prescribed during the intensive phase of treatment for TB (two months) or MDR-TB (eight months) were assessed. We estimated the annual utilization of TB treatment regimens and the relative difference (RD) in the proportion of MDR-TB treatment medications between the following periods: before the first Korean guideline (June 2008 to March 2011); between the first and revised guidelines (April 2011 to July 2014); after the revised guideline (August 2014 to December 2015). RESULTS: Of 3523 TB (mean age 54.1 years; male 56.8%) patients, treatment regimens for TB complied with guideline recommendations as >80% of patients received either quadruple (mean 66.8%) or triple (14.5%) therapy of first-line anti-TB drugs. Following the WHO's guideline update, prescription patterns changed accordingly among 111 MDR-TB (mean age 46.0 years; male 67.6%) patients, as use of pyrazinamide (RD +20.3%) and prothionamide (+11.5%) increased (recommended to be compulsory), and streptomycin (-43.1%) decreased (ototoxicity risks). CONCLUSIONS: Anti-TB drug prescription patterns for both TB and MDR-TB well reflected WHO's treatment guideline as well as corresponding domestic guidelines of South Korea.

Survival, Prognosis, and Clinical Feature of Refractory Myasthenia Gravis: a 15-year Nationwide Cohort Study.

BACKGROUND: Myasthenia gravis (MG) is a rare classic autoimmune disease where immunosuppressant therapies have been successful to reduce MG attributable mortality fairly well. However, patients with refractory MG (rMG) among the actively treated MG (aMG) are nonresponsive to conventional therapy and display high disease severity, which calls for further research. We aimed to determine survival, prognosis, and clinical feature of patients with rMG compared to non-rMG. METHODS: Retrospective nationwide cohort study using Korea's healthcare database between 2002 and 2017 was conducted. Patients with rMG (n = 47) and non-rMG (n = 4,251) who were aged > 18 years, followed-up for ≥ 1 year, and prescribed immunosuppressants within 2 years after incident MG diagnosis were included. Patients with rMG were defined as administered plasma exchange or intravenous immunoglobulin at least 3 times per year after receiving ≥ 2 immunosuppressants. All-cause mortality, myasthenic crisis, hospitalization, pneumonia/sepsis, and emergency department (ED) visits were measured using Cox proportional hazard models and pharmacotherapy patterns for rMG were assessed. RESULTS: The rMG cohort included a preponderance of younger patients and women. The adjusted hazard ratio was 2.49 (95% confidence interval, 1.26-4.94) for mortality, 3.14 (2.25-4.38) for myasthenic crisis, 1.54 (1.15-2.06) for hospitalization, 2.69 (1.74-4.15) for pneumonia/sepsis, and 1.81 (1.28-2.56) for ED visits for rMG versus non-rMG. The immunosuppressant prescriptions were more prevalent in patients with rMG, while the difference was more remarkable before rMG onset rather than after rMG onset. CONCLUSION: Despite the severe prognosis of rMG, the strategies for pharmacotherapeutic regimens were similar in those two groups, suggesting that intensive monitoring and introduction of timely treatment options in the early phase of MG are required.

Pre-validation of a Calu-3 epithelium cytotoxicity assay for predicting acute inhalation toxicity of chemicals.

Although in vivo inhalation toxicity tests have been widely conducted, the testing of many chemicals is limited for economic and ethical reasons. Therefore, we previously developed an in vitro acute inhalation toxicity test method. The goal of the present pre-validation study was to evaluate the transferability, reproducibility, and predictive capacity of this method. After confirming the transferability of the Calu-3 epithelium cytotoxicity assay, reproducibility was evaluated using 20 test substances at three independent institutions. Cytotoxicity data were analyzed using statistical methods, including the intra-class correlation coefficient and Bland-Altman plots for within- and between-laboratory reproducibility. The assay for the 20 test substances showed excellent agreement within and between laboratories. To evaluate the predictive capacity, 77 test substances were analyzed for acute inhalation toxicity. Accuracy was measured using a cutoff of 40%, and the relevance was analyzed as a receiver-operating characteristic (ROC) curve. An accuracy of 72.73% was obtained, and the area under the ROC curve was 0.77, indicating moderate performance. In this study, we found that the in vitro acute inhalation toxicity test method demonstrated good reliability and relevance for predicting the acute toxicity of inhalable chemicals. Hence, this assay has potential as an alternative test for screening acutely toxic inhalants.