Dynamic Changes in Metabolic Status Are Associated With... : Journal of Neuro-Ophthalmology (original) (raw)

Metabolic syndrome (MetS) is a combination of conditions including insulin resistance, hypertension, dyslipidemia, and obesity. MetS is known to be a risk factor for various diseases, including Type 2 diabetes mellitus and cardiovascular disease.1,2 The importance of MetS comes from the fact that it can be changed over time by changing lifestyle or receiving treatment for underlying diseases.3,4 Dynamic changes in Mets status over time have been shown to affect the risk of diabetes or cardiovascular events.2 For patients with multiple risk factors, prioritizing lifestyle changes can be overwhelming. By comparing the risk of a disease according to changes in MetS status, we can infer the preventive effect controlling metabolic syndrome.

Acquired third, fourth, and sixth cranial nerve palsies (ocular motor CNPs) occur fairly commonly in the elderly population. CNP might cause significant disability due to diplopia accompanied by paralytic strabismus. Known risk factors of acquired ocular motor CNP include diabetes, hypertension, and dyslipidemia, which are major components of MetS.5–7 Previously, we have suggested that obesity and metabolic syndrome are risk factors for acquired ocular motor CNP.8,9 In this article, we aimed to investigate the risk of ocular motor CNP according to the dynamic status of MetS using the Korean National Health Insurance Service (NHIS)-National Sample Cohort database.

METHODS

Data Source and Study Population

Korean National Health Insurance (NHI) is a national insurer that covers approximately 97% of the 50 million Korean population. The NHI offers a national health screening program (NHSP) for all beneficiaries aged 20 years or older at least biennially. The medical provider must submit claims for reimbursement from the NHIS for medical expenses. In this way, the NHIS gathers all health care utilization information including demographics, medical treatment, procedures, and disease diagnoses using codes from the International Classification of Diseases, 10th Revision, Clinical Modifications (ICD-10-CM).

In this study, a customized NHIS database cohort was used. It included 40% of the Korean population who were selected by stratified random sampling to ensure that the sample was representative of the entire population. Adults (aged 20 years or older) who received NHSP from the NHIS in 2009 and 2011 were screened. Those with an identifiable MetS status in 2009 and 2011 health examinations were included. Those who had missing information needed to identify their MetS status or baseline laboratory results were excluded. Those who had a history of ocular CNP or new CNP diagnosis or death within 1 year after the date of their last health examinations were also excluded. We used a 1-year time lag in sensitivity analysis to avoid the problem of reverse causation. Therefore, eligible individuals were followed up for CNP cases from 1 year after the date of their health examination (the 1-year time lag) until December 31, 2011.

This study adhered to the tenets of the Declaration of Helsinki. It was approved by the Institutional Review Board (IRB) of Samsung Medical Center (IRB No. SMC 2020-09-050). The requirement for informed consent from individual patients was waived because data used were public and anonymized under confidentiality guidelines.

Definition of Ocular Motor Cranial Nerve Palsy, Metabolic Syndrome, and Metabolic Syndrome Change

Ocular motor CNP was diagnosed based on ICD-10-CM code H49.0 (third CNP) or H49.1 (fourth CNP) or H49.2 (sixth CNP), excluding anyone with comorbid dysthyroid exophthalmos (H05.2), thyrotoxicosis (E05), or myasthenia gravis (G70.0). MetS was defined based on the modified criteria of the National Cholesterol Education Program Adult Treatment Panel III, with waist circumference (WC) cutoff modified for Asians.10,11 Individuals with at least 3 of the following components were diagnosed with MetS: (i) WC ≥ 90 cm for men or ≥85 cm for women; (ii) serum triglycerides ≥1.70 mmol/L or treatment with lipid-lowering medication; (iii) serum HDL-C < 1.04 mmol/L for men or <1.30 mmol/L for women or treatment with lipid-lowering medication; (iv) systolic BP (SBP) ≥ 130 mm Hg, diastolic BP (DBP) ≥ 85 mm Hg, or treatment with antihypertensive medication; and (v) fasting plasma glucose ≥5.55 mmol/L or the use of hypoglycemic agents.

Study Groups

Study participants were divided into 4 groups according to MetS status: MetS-free (those who were consistently free from MetS during 2009 and 2011 NHSP), MetS-chronic (those who had MetS throughout the 2 health examinations), MetS-developed (those who newly developed MetS [absence of MetS in 2009 but presence of Mets in 2011]), and MetS-recovery (those who recovered from MetS [presence of MetS in 2009 but absence of MetS at 2011]).

Assessment

Standardized self-reported questionnaires were used to collect general health behavior and lifestyle information at the time of enrollment. Height (cm) and weight (kg) were measured using an electronic scale in the medical institutions during health examinations. WC (cm) was measured at the middle point between the rib cage and iliac crest by trained examiners. Body mass index (BMI) was calculated as body weight (kg) divided by height (m) squared. General obesity was defined as a BMI ≥25 kg/m2 based on the World Health Organization recommendations for Asian populations.12 Abdominal obesity was defined as a WC of ≥90 cm for men and ≥85 cm for women according to the Asian-specific WC cutoff for abdominal obesity.13

Blood samples were drawn after overnight fasting. Serum levels of glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, hemoglobin, serum creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (γ-GTP) were then measured.

Baseline comorbidities were identified based on the combination of medical history with clinical and pharmacy codes of the ICD-10-CM.

Statistical Analysis

Baseline characteristics of study participants according to the status of MetS are presented as mean ± SD for continuous variables and number (percentage) for categorical variables. Values were compared by analysis of variance for continuous variables or the chi-squared test for categorical variables. Incidence rates of ocular motor CNP were calculated by dividing the number of events by 1,000 person-years. We performed multivariable Cox proportional hazards regression analysis to evaluate the association of MetS change with incident ocular motor CNP and calculated hazard ratios (HRs) with 95% confidence interval (CIs). Model 1 was unadjusted. Model 2 was adjusted for age and sex. Model 3 was additionally adjusted for smoking status, alcohol consumption, and physical activity. We also conducted subgroup analyses according to age group and calculated P values for the interactions between MetS and subgroups in the development of ocular motor CNP using Cox regression analysis. All statistical analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC).

RESULTS

Study Population

Among 4,233,273 individuals older than 20 years who participated in NHSP in 2009, 2,883,947 also participated in the 2011 examination. After excluding those who had missing information (n = 152,930), those who had a history of CNP (n = 2,408), and those who had a new CNP diagnosis or death within one year after the date of their health examination (n = 6,695), a total of 2,721,914 eligible individuals were finally identified for the cohort (Fig. 1). These study participants were followed up until December 31, 2018, with an average follow-up duration of 6.33 ± 0.62 years. A total of 1,549,111 (56.91%) men and 2,684,162 (43.09%) women were included in our study cohort. Their mean age, BMI, and WC were 46.96 years (SD: 13.55 years at 2009 health check-up), 23.74 kg/m2 (SD: 3.15 kg/m2), and 80.33 cm (SD: 9.28 cm), respectively. Baseline characteristics according to dynamic MetS status are summarized in Table 1. For all variables, P values were significant (P < 0.001). This seemed to result from the very large sample size.

FIG. 1.:

Selection flow of study population.

TABLE 1. - Baseline characteristics of study population

| | Changes in MetS | | | | | | ----------------------------- | ------------------- | ---------------------- | ---------------------- | ---------------------- | | MetS-Free | MetS-Developed | MetS-Recovered | MetS-Chronic | | | Participants, n (%) | 1,914,080 (70.32) | 254,344 (9.3) | 184,796 (6.79) | 368,694 (13.55) | | Male, n (%) | 1,045,306 (54.61) | 161,843 (63.63) | 123,227 (66.68) | 218,735 (59.33) | | Age, yr | 44.2±12.91 | 51.3±12.94 | 51.56±12.99 | 56.03±12.01 | | BMI, kg/m2 | 22.9±2.77 | 25.08±2.91 | 25.43±2.97 | 26.33±3.19 | | WC, cm | 77.71±8.2 | 83.96±7.89 | 86.49±9.33 | 88.35±8.52 | | Diabetes, n (%) | 51,492 (2.69) | 24,188 (9.51) | 27,301 (14.77) | 118,598 (32.17) | | Hypertension, n (%) | 264,385 (13.81) | 92,861 (36.51) | 89,939 (48.67) | 267,214 (72.48) | | Dyslipidemia, n (%) | 153,268 (8.01) | 50,667 (19.92) | 66,244 (35.85) | 221,223 (60) | | Chronic kidney disease, n (%) | 186,849 (9.76) | 34,214 (13.45) | 25,072 (13.57) | 64,443 (17.48) | | SBP, mm Hg | 123.68 ± 266.36 | 129.95 ± 147.19 | 121.33 ± 138.71 | 117.79 ± 116.82 | | DBP, mm Hg | 119.01 ± 13.43 | 126.37 ± 14.24 | 131.65 ± 13.36 | 132.22 ± 14.8 | | Total cholesterol, mg/dL | 190.64 ± 36.45 | 207.94 ± 44.66 | 207.7 ± 46.33 | 205.63 ± 48.04 | | HDL-C, mg/dL | 74.49 ± 9.25 | 78.88 ± 9.56 | 81.77 ± 9.48 | 81.57 ± 10.18 | | LDL-C, mg/dL | 57.75 ± 31.64 | 54.05 ± 31.73 | 53.39 ±35.16 | 52.7 ± 36.33 | | Triglycerides,* mg/dL | 96.54 (96.47–96.62) | 134.29 (134.03–134.55) | 174.16 (173.76–174.57) | 174.16 (173.86–174.47) | | Smoking | | | | | | Never | 1,160,815 (60.65) | 134,428 (52.85) | 95,370 (51.61) | 208,280 (56.49) | | Former | 267,182 (13.96) | 44,405 (17.46) | 36,308 (19.65) | 71,862 (19.49) | | Current | 486,083 (25.4) | 75,511 (29.69) | 53,118 (28.74) | 88,552 (24.02) | | Drinking | | | | | | Nondrinker | 964,504 (50.39) | 124,355 (48.89) | 88,116 (47.68) | 199,574 (54.13) | | Light to moderate drinker† | 825,440 (43.12) | 103,425 (40.66) | 75,783 (41.01) | 130,288 (35.34) | | Heavy drinker | 124,136 (6.49) | 26,564 (10.44) | 20,897 (11.31) | 38,832 (10.53) | | Regular PA,‡ n (%) | 347,485 (18.15) | 52,288 (20.56) | 35,887 (19.42) | 78,169 (21.2) | | Income, low§ | 321,498 (16.8) | 41,930 (16.49) | 29,712 (16.08) | 60,597 (16.44) |

Data are presented as mean ± SD or number (%), unless otherwise noted.

*Geometric mean.

†Mild-to-moderate alcohol consumption was defined as <30 g of alcohol/day, and heavy alcohol consumption was defined as >30 g of alcohol/day.

‡Regular physical activity was defined as intense 20-min workouts ≥3 days weekly or moderate 30-min workouts ≥5 days weekly.

§The low-income level was defined as the lower one‐fifth of the entire population.

BMI, body mass index; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MetS, metabolic syndrome; PA, physical activity; SBP, systolic blood pressure; WC, waist circumference.

Ocular Motor Cranial Nerve Palsy Risk according to the Dynamic Metabolic Syndrome Status

The incidence rate of ocular motor CNP was the highest in the MetS-chronic group (811 events during 2,318,158 person-years of follow-up, incidence rate: 0.35 per 1,000 person-years; Table 2) throughout a mean follow-up of 6.3 years, followed by the MetS-recovered group (282 events during 1,163,127 person-years of follow-up, incidence rate: 0.24 per 1,000 person-years), MetS-developed group (385 events during 1,606,474 person-years of follow-up, incidence rate: 0.24 per 1,000 person-years), and MetS-free group (1,652 events during 12,135,574 person-years of follow-up, incidence rate: 0.13 per 1,000 person-years). In the analysis according to sex, the incidence rate of the male MetS-chronic group was 0.41 per 1,000 person-years while that of the female MetS-chronic group was 0.26 per 1,000 person-years.

TABLE 2. - Risk of acquired ocular motor cranial palsy according to the dynamic changes in metabolic syndrome

Model 1 was unadjusted. Model 2 was adjusted for age and sex. Model 3 was additionally adjusted for smoking status, alcohol consumption, and physical activity.

CNP, cranial nerve palsy; MetS, metabolic syndrome; Ref, reference.

The adjusted HR for the incidence of ocular motor CNP was 1.2 (95% CI: 1.069–1.343, model 3), 1.17 (95% CI: 1.026–1.331), and 1.42 (95% CI: 1.294–1.567) in MetS-developed, MetS-recovered, and MetS-chronic groups, respectively, compared with the MetS-free group after adjusting for age, sex, smoking, alcohol consumption, and regular exercise. Adjusted HRs according to sex showed similar trends, with men and women in the MetS-chronic group showing significantly increased the risk of ocular motor CNP by 1.57 (95% CI: 1.394–1.761) times and 1.19 (95% CI: 1.005–1.411) times, respectively.

The risk of ocular motor CNP according to dynamic changes in each component of MetS is summarized in Table 3.

TABLE 3. - Risk of acquired ocular motor cranial palsy by dynamic changes in metabolic syndrome components

| | N | CNP Events | Person-years | Incidence Rate | Hazard Ratio (95% Confidence Interval) | | | | | --------------------------- | ---------- | ------------ | -------------- | -------------------------------------- | ------------------- | ------------------- | ------------------- | | Model 1 | Model 2 | Model 3 | | | | | | | BMI pre/post | | | | | | | | | <25/<25 | 1,672,787 | 1,652 | 10,580,244.75 | 0.15614 | 1 (ref) | 1 (ref) | 1 (ref) | | <25/≥25 | 158,745 | 205 | 1,005,196.11 | 0.20394 | 1.306 (1.13–1.51) | 1.277 (1.104–1.476) | 1.278 (1.105–1.477) | | ≥25/<25 | 131,235 | 174 | 827,404.61 | 0.2103 | 1.347 (1.152–1.574) | 1.113 (0.952–1.301) | 1.114 (0.953–1.303) | | ≥25/≥25 | 759,147 | 1,099 | 4,810,490.27 | 0.22846 | 1.463 (1.356–1.579) | 1.322 (1.225–1.427) | 1.323 (1.226–1.428) | | Central obesity pre/post | | | | | | | | | No/No | 2,001,324 | 2003 | 12,675,734.08 | 0.15802 | 1 (ref) | 1 (ref) | 1 (ref) | | No/Yes | 200,986 | 242 | 1,270,739.27 | 0.19044 | 1.205 (1.054–1.377) | 0.991 (0.867–1.132) | 0.991 (0.867–1.133) | | Yes/No | 176,100 | 267 | 1,110,436.74 | 0.24045 | 1.521 (1.339–1.728) | 1.138 (1.001–1.294) | 1.139 (1.002–1.295) | | Yes/Yes | 343,504 | 618 | 2,166,425.65 | 0.28526 | 1.805 (1.649–1.975) | 1.324 (1.209–1.451) | 1.325 (1.209–1.451) | | HTN pre/post | | | | | | | | | No/No | 1,171,784 | 870 | 7,450,331.22 | 0.11677 | 1 (ref) | 1 (ref) | 1 (ref) | | No/Yes | 347,137 | 360 | 2,197,915.68 | 0.16379 | 1.403 (1.241–1.586) | 1.05 (0.928–1.189) | 1.015 (0.896–1.149) | | Yes/No | 296,020 | 318 | 1,874,636.45 | 0.16963 | 1.453 (1.278–1.652) | 1.111 (0.976–1.264) | 1.072 (0.941–1.221) | | Yes/Yes | 906,973 | 1,582 | 5,700,452.39 | 0.27752 | 2.376 (2.187–2.581) | 1.261 (1.154–1.378) | 1.177 (1.073–1.291) | | Hyperglycemia pre/post | | | | | | | | | No/No | 1,520,542 | 1,273 | 9,656,778.5 | 0.13182 | 1 (ref) | 1 (ref) | 1 (ref) | | No/Yes | 362,877 | 398 | 2,292,852.88 | 0.17358 | 1.317 (1.177–1.474) | 1.057 (0.944–1.184) | 1.037 (0.926–1.162) | | Yes/No | 327,064 | 343 | 2,068,323.05 | 0.16583 | 1.258 (1.117–1.418) | 1.028 (0.912–1.159) | 1.013 (0.899–1.142) | | Yes/Yes | 511,431 | 1,116 | 3,205,381.3 | 0.34816 | 2.643 (2.439–2.864) | 1.668 (1.536–1.813) | 1.607 (1.477–1.749) | | Low HDL pre/post | | | | | | | | | No/No | 2,265,397 | 2,309 | 14,337,818.82 | 0.16104 | 1 (ref) | 1 (ref) | 1 (ref) | | No/Yes | 167,499 | 268 | 1,060,973.04 | 0.2526 | 1.565 (1.379–1.776) | 1.118 (0.984–1.271) | 1.079 (0.95–1.227) | | Yes/No | 94,266 | 157 | 593,938.45 | 0.26434 | 1.64 (1.395–1.928) | 1.208 (1.027–1.421) | 1.169 (0.994–1.376) | | Yes/Yes | 194,752 | 396 | 1,230,605.42 | 0.32179 | 1.994 (1.793–2.219) | 1.229 (1.101–1.371) | 1.161 (1.04–1.297) | | High triglycerides pre/post | | | | | | | | | No/No | 1,423,436 | 1,277 | 9,013,980.32 | 0.14167 | 1 (ref) | 1 (ref) | 1 (ref) | | No/Yes | 348,289 | 435 | 2,205,439.56 | 0.19724 | 1.392 (1.248–1.552) | 1.142 (1.024–1.274) | 1.101 (0.987–1.229) | | Yes/No | 289,639 | 335 | 1,829,346.15 | 0.18313 | 1.293 (1.147–1.458) | 1.029 (0.912–1.161) | 0.982 (0.87–1.109) | | Yes/Yes | 660,550 | 1,083 | 4,174,569.71 | 0.25943 | 1.831 (1.688–1.985) | 1.32 (1.217–1.432) | 1.229 (1.128–1.338) |

Model 1 was unadjusted. Model 2 was adjusted for age and sex. Model 3 was additionally adjusted for smoking status, alcohol consumption, and physical activity.

BMI, body mass index; CNP, cranial nerve palsy; HDL, high-density lipoprotein cholesterol; HTN, hypertension; Ref, reference.

Subgroup Analysis of the Risk of Ocular Motor Cranial Nerve Palsy According to Age Groups

The MetS status did not significantly increase the risk of ocular motor CNP in the age group of 20s and 30s. In the age group of 40s and 50s, risks of ocular motor CNP in the MetS-developed group, the MetS-recovered group, and the MetS-chronic group were increased by 1.19 times (95% CI: 1.003–1.421, Table 4), 1.24 times (95% CI: 1.017–1.504), and 1.59 times (95% CI: 1.373–1.841), respectively, compared with the risk in the MetS-free group. In the age group of 60s and older, MetS-developed and MetS-recovered groups showed no significant difference in the risk of ocular motor CNP compared with the MetS-free group, whereas the MetS-chronic group increased the risk significantly by 1.24 times (95% CI: 1.089–1.416).

TABLE 4. - Subgroup analysis of risk of acquired ocular motor CNP by dynamic changes in metabolic syndrome according to age group

CNP, cranial nerve palsy; MetS, metabolic syndrome; Ref, reference.

CONCLUSIONS

In this nationwide cohort study that included more than 2 million individuals, we demonstrated that the risk of ocular motor CNP was increased by 1.42 times in individuals with persistent MetS, 1.2 times in those who developed MetS, and 1.17 times in those who recovered from MetS, compared with those who remained free of MetS. This nationwide cohort study is the first to demonstrate the risk of ocular motor CNP associated with changes in MetS in the general population.

Previously, we have published that the existence of MetS significantly increases the risk of ocular motor CNP in the same cohort.9 However, the association between changes in MetS status and risk of ocular motor CNP has not been reported yet. MetS, a constellation of interrelated risk factors of metabolic origin, changes over time. This can be improved depending on the individual's lifestyle changes and active intervention.3,4 Analyzing the pattern of changes in metabolic syndrome over time and how these changes, especially the improvement of metabolic syndrome, alter the risk of developing CNP can provide us with clinically useful information.

In this study, the MetS-chronic group had the highest risk of ocular motor CNP, followed by MetS-developed and MetS-recovered groups compared with the MetS-free group. A previous study has shown that the risk of major adverse cardiovascular events, such as myocardial infarction and ischemic stroke, is associated with dynamic changes in MetS.14 The risk for major adverse cardiovascular events is higher in persons with chronic MetS than in those who have recovered from MetS. It has been concluded that the recovery from MetS is significantly associated with decreased risk for major adverse cardiovascular events. In the same manner, our decreasing trend in risk of ocular motor CNP was associated with recovery from MetS status.

Notably, the hazard ratio of ocular motor CNP in men of the MetS-chronic group was 1.57 while that in women of the MetS-chronic group was 1.19 compared with the MetS-free group. Gender differences in prevalence, risk factors, and cardiovascular adverse outcomes of MetS have been noticed.15–17 The prevalence of MetS in men and women has been reported to vary by age, ethnicity, and definition used. In Korea, the prevalence of MetS was higher in men than in women.15 However, the risk of cardiovascular adverse events was higher in women with MetS than in men with MetS.16 These differences between men and women might have come from different body fat distribution and sex hormone.18 Our result may imply that men with chronic MetS have a higher risk of developing ocular motor CNP than women with chronic MetS. On the contrary, men with MetS may have more benefit from recovery from MetS than women with MetS.

It was also interesting that the risk of ocular motor CNP depending on dynamic MetS status varied by age group. For those in their 20s and 30s, the incidence of ocular motor CNP was low. The risk of ocular motor CNP did not vary significantly depending on the MetS status. For those in their 40s and 50s, risks of ocular motor CNP in MetS developed, MetS-recovered, and MetS-chronic groups were significantly higher than in the MetS-free group. For those in their 60s and older, incidence rates of ocular motor CNP were relatively higher in all MetS statuses compared with other age groups. In this age group, only the MetS-chronic group showed increased risk of ocular motor CNP by 1.24 times compared with the MetS free group. The risk of ocular motor CNP was not significantly increased in MetS-recovered or MetS-developed group compared with the MetS-free group for those in their 60s and older. Based on the results of this study, we can presume that management of MetS status, especially for patients in their 40s or older, will significantly reduce the risk of ocular motor CNP.

Although causes of acquired ocular motor CNP are diverse, the most common cause is presumed to be microvascular ischemia.5,19 This microvascular ischemia occurs frequently in an older patient with cardiovascular risk factors such as diabetes, hypertension, and dyslipidemia, which are all factors of MetS.17 Microvascular ischemia might be the link between the association of MetS status and the risk of ocular motor CNP found in this study. The insignificant association of MetS status with ocular motor CNP at a young age (20s and 30s) is understandable considering that inflammation and neoplasm comprise a large portion of ocular motor CNP in early adulthood.20 It is also meaningful that the recovery from MetS has lower or not significant risk of ocular motor CNP in the middle or older age group compared with those with chronic MetS. We can presume that thorough management of MetS in the middle or older age group can significantly decrease ocular motor CNP risk.

Several limitations should be mentioned regarding our study. First, our study used insurance data comprised diagnostic codes. Thus, there was a possibility of misdiagnosis. Second, our study design could only show an association between MetS and ocular motor CNP. It could not show the causation relationship or the underlying possible mechanisms Third, owing to the limitations of using only the factors included in NHIS health screening, we were not able to analyze some potentially valuable factors such as HbA1C in our study. Finally, our data were comprised mostly Koreans. Thus, these results may need to be qualified to apply to other ethnicities. However, this study was a population-based, large-scale nationwide cohort study, which might offset the aforementioned limitations. In addition, our study showed the effect of MetS status on the development of ocular motor CNP in the general population for the first time.

In conclusion, we found that the dynamic MetS status was significantly associated with the risk of ocular motor CNP in our population-based, large-scale nationwide cohort. This association was more prominent in men and middle or older age groups. Future prospective studies are warranted to confirm benefits of controlling the MetS status to reduce the risk of ocular motor CNP.

STATEMENT OF AUTHORSHIP

Conception and design: D.D. Choi, K. Han, K.-A. Park, S.Y. Oh; Acquisition of data: K. Han; Analysis and interpretation of data: D.D. Choi, K. Han, K.-A. Park. Drafting the manuscript: D.D. Choi; Revising the manuscript for intellectual content: D.D. Choi, K. Han, K.-A. Park, S.Y. Oh. Final approval of the completed manuscript: D. D. Choi, K.-A. Park, S.Y. Oh.

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