J Neurogastroenterol Motil 2024; 30(2): 220-228  https://doi.org/10.5056/jnm23029
Effect of Trimebutine and Rifaximin on Breath Hydrogen and Methane by Glucose Breath Test in Patients With Functional Bloating: A Randomized Double-blind Clinical Trial
Ik Hyun Jo,1 Chang-Nyol Paik,1* Ji Min Lee,1 Do Seon Song,1 and Yeon-Ji Kim2
1Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Gyeonggi-do, Korea; and 2Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Gyeonggi-do, Korea
Correspondence to: *Chang-Nyol Paik, MD, PhD
Division of Gastroenterology, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, 93 Jungbu-daero, Paldal-gu, Suwon, Gyeonggi-do 16247, Korea
Tel: +82-31-881-8582, E-mail: cmcu@catholic.ac.kr
Received: February 23, 2023; Revised: August 22, 2023; Accepted: September 12, 2023; Published online: April 30, 2024
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Drugs that stabilize intestinal motility may improve the efficacy of nonabsorbable antibiotics, such as rifaximin, against small intestinal bacterial overgrowth (SIBO). We compared the efficacy of rifaximin alone with that of its combination with trimebutine maleate against SIBO.
We performed a randomized double-blind placebo-controlled trial (https://cris.nih.go.kr, no. KCT0004836) that included patients with functional bloating, no constipation, and SIBO using the hydrogen (H2)–methane (CH4) glucose breath test (GBT). Patients were randomized into 2 groups in a 1:1 ratio, namely rifaximin (1200 mg/day) + trimebutine maleate (600 mg/day) group and rifaximin + placebo group, for 2 weeks. Patients completed a symptom questionnaire and underwent a GBT at baseline and at 1 month after treatment withdrawal. The primary outcome was SIBO eradication. The secondary outcomes included changes in the concentrations of exhaled gases, symptoms, and presence of adverse events.
The complete eradication rate of SIBO was 35.9% (14/39) in the rifaximin group, and 34.1% (14/41) in the combined group with no significant differences. In both groups, no significant differences were observed in GBT profiles before and after the treatment, respectively. However total breath H2 and CH4 concentration were conspicuously decreased in the combined group after treatment. The combined group exhibited substantial relief of bloating. The adverse events were similar in the 2 groups.
While the combination therapy was not superior over rifaximin alone for SIBO eradication, it improves the symptom of bloating with numerically reducing the concentration of breath H2/CH4.
Keywords: Breath tests; Dysbiosis; Functional gastrointestinal disorder; Rifaximin; Trimebutine

Abdominal bloating is one of the most frequent gastrointestinal complaints and affects up to 15.9% of adults.1 Recently, small intestinal bacterial overgrowth (SIBO) was suggested as an etiologic factor in patients with abdominal bloating, regardless of the presence of irritable bowel syndrome (IBS).2,3 Several factors, such as weakened intestinal motility, anatomical abnormalities, and reduced secretion of gastric acid or antibacterial substance, can predispose individuals to the occurrence of SIBO.4

Oral antibiotics, such as rifaximin, are widely accepted as the main treatment modality for SIBO,5,6 since they are both effective and safe.7 Rifaximin is poorly absorbed in the gastrointestinal tract, where it attains very high concentrations, and is excreted unchanged in the feces.8 Thus, it provides an effective targeted therapy against enteric pathogens, with a low risk of adverse events.5,6,9 However, in the case of rapid intestinal transit, rifaximin in the intestines could be quickly excreted in the stool, which might reduce its duration of action and potentially affect the efficacy against enteric bacteria.

Trimebutine maleate [3,4,5-trimethoxybenzoic acid 2-(dimethylamino)-2-phenylbutyl ester maleate] is a well-known drug used for the treatment of complex symptoms related to functional gastrointestinal disorders.10,11 The drug can exhibit dual action, regulating both hypo- and hyper-motility of the gastrointestinal tract, depending on the enkephalin receptor subtype activated.12 Trimebutine maleate could be effective as an adjuvant therapy to improve the efficacy of nonabsorbable oral antibiotics against SIBO by stabilizing small bowel motility. However, information regarding the effect of trimebutine maleate on SIBO is still lacking. The aim of this study is to compare the efficacy of the combination of rifaximin and trimebutine maleate with rifaximin alone in SIBO treatment.

Materials and Methods

Study Subjects

This study was carried out at a teaching referral center with a prospective design. Patients aged 20 years to 80 years, who visited the hospital with functional bloating and no constipation, fulfilled the Rome IV criteria, and were diagnosed with SIBO using the glucose breath test (GBT), were enrolled between March 2020 and February 2021.

Patients who had taken medication that can affect gastric acid secretion (proton pump inhibitors or histamine-2 receptor antagonists), intestinal motility (prokinetics, laxatives, bulking agents, antidiarrheal drugs, and narcotics), or gut microbes (antibiotics and probiotics) during the preceding 3 months before the initiation of the study were excluded. Patients with connective tissue, thyroid, chronic liver, or major psychiatric diseases, or chronic renal disease were excluded. Another exclusion criterion was a history of gastrointestinal surgery other than laparoscopic appendectomy.13,14

Approval for this study was granted by the Institutional Research Ethics Board of St. Vincent’s Hospital, The Catholic University of Korea (Approval No. VC19MESI0159). The study complied with the Declaration of Helsinki guidelines, and written informed consent was obtained from all participants. This trial was registered on the International Clinical Trials Registry Platform (https://cris.nih.go.kr, No. KCT0004836).


Eligible patients were randomly assigned, in a 1:1 ratio, to one of the following 2 groups: rifaximin (Normix, Alfa Wassermann, Italy; 400 mg × 3 times daily) combined with trimebutine maleate (Polybutine, Samil Pharmaceutical Co, Ltd, Seoul, Korea; 200 mg × 3 times daily) (combined group) or rifaximin with placebo (rifaximin group). Duration of the treatment was 2 weeks.

Randomization was carried out with a computer-generated list of random numbers, and an impartial staff member assigned treatments based on consecutive numbers, which were then kept in sealed envelopes. The treatment allocation was blinded to all investigators as well as patients.

Fecal Calprotectin

A fecal calprotectin (FC) quantitative test was performed to evaluate and compare the status of intestinal inflammation between the 2 groups before the assigned treatments. Stool samples were collected (1-2 g per person) between 1 day to 3 days prior to drug administration, and stored at –20℃ until analysis. The ELISA kit (Bühlmann Laboratories AG, Schönenbuch, Switzerland) was used to determine the FC levels. The FC-ELISA kit had a measurement range of 10-1800 μg/g, with a calprotectin cut-off level of ≥ 50 μg/g as specified by the manufacturer. Laboratory personnel conducting the analyses were blinded to the clinical history of patients.

Glucose Breath Test

After fasting for at least 12 hours overnight, GBT was conducted with a gas chromatograph (BreathTracker SC; QuinTron Instrument Company, Milwaukee, WI, USA). Patients were instructed to follow a low-carbohydrate-restricted diet the day before the GBT and to rinse their mouth with 20 mL of 0.05% chlorhexidine 30 minutes before the breath test. Physical activity, sleeping, and smoking were prohibited for 2 hours before and during the test. The patients were made to ingest 75 g of glucose (DIASOL-S SOLN; Taejoon Pharm Co, Ltd, Seoul, Korea). End-expiratory breath samples were collected at baseline, before ingestion of the glucose solution. Additional breath samples were collected thereafter at every 10 minutes for 2 hours. The breath hydrogen (H2) and methane (CH4) concentrations were evaluated at each time point. Accordingly, H2 and CH4 concentrations were measured 13 times for each patient. Total breath H2 and CH4 concentrations over the 2-hour test time were assessed. The diagnosis of SIBO was determined by a positive GBT, which was defined as either (1) a baseline H2 or CH4 concentration exceeding 15 ppm or (2) an increase in H2 or CH4 concentration greater than 12 ppm above the baseline within 90 minutes of glucose solution ingestion.13-16 Positivity including both GBT (H2)+ and GBT (CH4)+ was classified as a GBT (mixed)+. GBT (H2) or GBT (CH4) positivity indicated positivity to H2 or CH4, respectively.

Intestinal Symptom Questionnaire

The study questionnaire consisted of the Rome IV Diagnostic Questionnaire and supplementary questions regarding bowel symptom severity, previously validated and utilized in other studies.17,18 Additionally, participants were asked 13 questions about individual symptoms that occurred during the previous 4 weeks, including abdominal discomfort (including pain or cramps), hard or loose stool, strain, urgency, tenesmus, bloating, flatulence, chest discomfort (including heartburn), early satiety, frequent urination, and nausea. Symptom severity was determined by combining the symptom frequency and intrusiveness scores, both measured on a 7-point scale ranging from 0 (never) to 6 (always or extremely). The total symptom score was calculated by adding the frequency and bothersomeness scores for each symptom, with scores ranging from 0 to 12.

Outcome Measures

The primary objective was to determine the rate of SIBO eradication, defined as the negative conversion rate of GBT outcomes. Secondary objectives included evaluating the effects of treatment on total H2 and CH4 concentrations and symptom scores. The outcome measures were assessed 2 weeks after the completion of assigned treatment. Drug safety and tolerance were evaluated by recording adverse events, including their severity and duration. Patient compliance was determined by counting the doses and number of medications returned. Patients who took 90% of the prescribed medications were considered compliant.

Sample Size Calculation

Based on the findings of a previous study,15 the sample size, required to detect a 30% increase in the eradication rate in the combined group compared to that in the rifaximin group, was calculated. With an α value of 0.05 and a power of 80%, a total of 39 patients were required in each group. Considering a dropout rate of 10%, the final number of patients needed was 43 per group.

Statistical Methods

Continuous variables were presented as mean ± standard deviation, while categorical variables were presented as absolute values and percentages. The chi-square test or Fisher’s exact test was used to compare categorical variables. Changes from baseline were evaluated using the paired t test for symptom scores, and Wilcoxon’s signed-rank test for gas concentrations due to the skewed distribution of data. The statistical significance level was set at P < 0.05. All statistical analyses were conducted using SPSS version 20.0 for Windows (IBM Corp, Armonk, NY, USA).



In total, 86 patients were participated and randomly assigned receive rifaximin alone or its combination with trimebutine maleate. Eighty participants completed the study, excluding those lost during follow-up and those with poor adherence to the assigned treatment. Details of the study participant enrollment process are provided in Figure 1.

Figure 1. The flow diagram of the enrollment of study participants. SIBO, small intestinal bacterial overgrowth.

Demographic and basic characteristics of the study groups are presented in Table 1. There was no significant difference in characteristics, such as age, sex, body mass index, tobacco use, alcohol consumption, and comorbidities between the 2 groups. Among the enrolled patients, 20.0% (16/80) were included with a calprotectin level ≥ 50 µg/g. The mean values of FC and the proportion of higher FC (≥ 50 µg/g) were not significantly different between the groups. Most of the enrolled patients had a status of GBT (H2)+, with 92.3% (36/39) being in the rifaximin group and 82.9% (34/41) being in the combined group. No significant difference between the 2 groups was observed in the baseline results of GBT (Table 1).

Table 1 . Baseline Characteristics of the Study Population

(n = 39)
(n = 41)
Age (yr)53.56 ± 14.3254.32 ± 13.850.812
Sex: male20 (51.3)23 (56.1)0.666
BMI (kg/m2)24.13 ± 3.6123.86 ± 3.020.719
Alcohol consumption9 (23.1)18 (43.9)0.083
Smoking history7 (17.9)13 (31.7)0.245
Hypertension8 (20.5)11 (26.8)0.689
Diabetes5 (12.8)8 (19.5)0.612
Calprotectin (μg/g)31.69 ± 45.5047.63 ± 55.980.167
Calprotein ≥ 50 μg/g5 (12.8)11 (26.8)0.117
GBT profiles
H236 (92.3)34 (82.9)0.433
CH42 (5.1)4 (9.8)
Mixed1 (2.6)3 (7.3)
GBT (H2)b37(94.9)37 (90.2)0.432
GBT (CH4)c3 (7.7)7 (17.1)0.205
Total H2 (ppm)301.21 ± 163.56312.10 ± 226.790.807
59.28 ± 55.68108.71 ± 154.200.063

aRifaximin + trimebutine maleate.

bMixed + hydrogen (H2).

cMixed + methane (CH4).

BMI, body mass index; GBT, glucose breath test.

Data are presented as mean ± SD or n (%).

Eradication rates

The negative conversion rates of GBT were 35.9% (14/39) in the rifaximin group and 34.1% (14/41) in the combined group (Table 2). In the GBT subtypes, negative conversion rates of the GBT (H2)+, GBT (CH4)+, GBT (mixed)+ in the rifaximin group were 33.5%, 50.0%, and 100.0%, respectively, whereas those in the combined group were 35.3%, 25.0%, and 0.0%, respectively (Table 2). Two groups showed similar overall eradication rates, as well as eradication rates by GBT subtypes.

Table 2 . Negative Conversion Rates of Glucose Breath Test Positivity According to the Treatment

(n = 39)
(n = 41)
Complete conversionb14/39 (35.9)14/41 (34.1)0.870
H212/36 (33.3)13/34 (35.3)0.162
CH41/2 (50.0)1/4 (25.0)
Mixed1/1 (100.0)0/3 (0.0)
GBT (H2)c13/37 (35.1)15/37 (40.5)e0.667
GBT (CH4)d2/3 (66.7)2/7 (28.6)e0.120

aRifaximin + trimebutine maleate.

bNegative conversion of both glucose breath test (GBT) (hydrogen [H2]) and methane (CH4) positivity.

cMixed + hydrogen (H2).

dMixed + methane (CH4).

ePartly conversion from 2 patients with mixed type to GBT (H2) group, and 1 patient to GBT (CH4) group, respectively.

GBT, glucose breath test.

Data are presented as n/N (%).

Glucose breath test profile

At baseline, there was no significant difference in total H2 or CH4 concentration between the 2 treatment groups (Table 1). Comparisons of the GBT profiles before and after treatment are shown in Table 3 and Figure 2. The mean total H2 or CH4 concentration and the mean H2 or CH4 in breath at the time points (Fig. 2B and 2D) numerically decreased after treatment in the combined group, but there were no significant differences between before and after treatment in the rifaximin or the combined groups, respectively.

Figure 2. The profiles of the glucose breath test before and after treatment: hydrogen (H2) concentrations in rifaximin group (A) and rifaximin plus trimebutine maleate group (B); methane (CH4) concentrations in rifaximin group (C) and rifaximin plus trimebutine maleate group (D).
ppm, parts per million.

Table 3 . Total Hydrogen-Methane Concentration of Pre- and Post-treatment During the Glucose Breath Test

Gas level (ppm)Rifaximin (n = 39)Combineda (n = 41)
H2301.21 ± 163.66316.67 ± 273.950.763312.10 ± 226.79253.10 ± 225.950.241
CH459.28 ± 55.6856.89 ± 55.130.850108.71 ± 154.2091.71 ± 119.510.578
Totalb360.49 ± 171.69373.56 ± 295.490.812420.80 ± 221.19344.80 ± 238.870.139

aRifaximin + trimebutine maleate.

bHydrogen (H2) + methane (CH4).

ppm, parts per million.

Data are presented as mean ± SD.

Bowel symptoms

At baseline, the total mean symptom scores were 48.00 ± 24.73 in the rifaximin group and 47.47 ± 23.41 in the combined group. There was no significant difference in the mean symptom scores for each symptom between the 2 treatment groups, either before or after the treatment. No significant difference in individual symptom scores was observed between the baseline scores and those after rifaximin treatment alone (Fig. 3A). In contrast, the mean score for bloating after combined treatment was significantly lower than the corresponding baseline score (Fig. 3B). For subgroup analyses, we categorized each treatment group based on the outcome of SIBO eradication. Consistent findings emerged: only in the combined treatment group did the bloating symptom score improve after treatment, irrespective of the success of SIBO complete conversion.

Figure 3. Changes in symptom scores after treatment with (A) rifaximin, or (B) rifaximin plus trimebutine maleate (*P < 0.05).

Adverse events

No serious adverse event was reported during the study. In total, 8 patients complained of minor adverse events. There was no significant difference between the 2 treatment groups in terms of types or frequencies of side effects (Table 4).

Table 4 . Adverse Events According to the Treatment Modality

Adverse eventsRifaximin
(n = 39)
(n = 41)
Total6 (15.4)2 (4.9)0.233
Serious adverse event0 (0.0)0 (0.0)1.000
Minor adverse event0.581
Diarrhea1 (2.6)0 (0.0)
Constipation1 (2.6)0 (0.0)
Bloating1 (2.6)0 (0.0)
Acid reflux1 (2.6)1 (2.4)
Abdominal discomfort2 (5.1)1 (2.4)

aRifaximin + trimebutine maleate.

Data are presented as n (%).


SIBO is a clinical condition associated with functional gastrointestinal disorders1-3 and is characterized by an imbalance in the number and/or type of bacteria in the small bowel, which causes symptoms of bloating, abdominal discomfort, and malabsorption. Antibiotics are widely accepted as the primary treatment option for this imbalance. The non-absorbable oral antibiotic rifaximin has good efficacy and few adverse effects against SIBO compared to other systemic antibiotics.5,6 By stabilizing small bowel motility, trimebutine maleate might effectively improve the efficacy of nonabsorbable oral antibiotics, such as rifaximin, against SIBO. However, the effect of trimebutine maleate on the treatment of SIBO remains unclear. This study aimed to evaluate and compare the efficacy of rifaximin alone with that of its combination with trimebutine maleate for the treatment of SIBO. We performed a randomized double-blind placebo-controlled trial that included patients with functional bloating, no constipation, and SIBO, using the H2-CH4 GBT. Patients were randomized into rifaximin and combined groups for 2 weeks and made to complete a symptom questionnaire, followed by a GBT at baseline and at 1 month after treatment withdrawal. Primary outcome was the eradication rate of SIBO. Secondary outcomes included changes in the concentrations of exhaled gases, symptoms such as abdominal bloating, and presence of adverse events. The primary outcome of this study suggested that rifaximin combined with trimebutine maleate was not significantly more effective than rifaximin alone in eradicating SIBO. Nevertheless, the combination therapy could decrease breath H2 or CH4 concentration. The secondary outcomes revealed that bloating was significantly reduced in the combination group.

Enhancement of small bowel motility is considered to improve the efficacy of antimicrobial agents. Recently, few studies have suggested a potential role of prokinetics in the treatment of SIBO.7,19,20 A combination of antibacterial and prokinetic drugs theoretically can be expected to maximize the therapeutic efficacy against SIBO. In this study, both monotherapy with rifaximin and its combination with trimebutine maleate had similar eradication rates (approximately 35%), which were lower than some previously reported rates for rifaximin.21 In fact, similar to the results of our study, some studies have reported an insufficient eradication rate (approximately 30-40%).22,23 Furthermore, in a randomized clinical trial,24 the addition of prokinetics to rifaximin did not yield a satisfactory effect in eradicating SIBO, as compared to rifaximin treatment alone. Although the reasons are not yet clear, the pharmacodynamic interaction between prokinetics and rifaximin should be considered with caution. In addition, rifaximin itself is associated with the acceleration of intestinal transit.25 To eradicate intestinal microorganisms effectively, rifaximin requires an extended period of contact with the intestine in order to achieve the minimum inhibitory concentration. However, the use of prokinetics, which induce rapid intestinal transit, may impede this process.

While various prokinetics can be used for functional bloating, we specifically chose trimebutine as a combination drug with rifaximin for the treatment of patients presenting with bloating associated with SIBO. The primary reason for our selection of trimebutine is that the mode of action of trimebutine in the gastrointestinal tract is multifaceted.26-28 It has unique spasmolytic activity and displays significant non-selective agonist activity for intestinal opioid receptors µ and δ with an excitatory effect on gastrointestinal motility, and for κ subtypes with inhibitory effects. It also induces premature phase III of the migrating motor complex in the intestine. Trimebutine is a reliable modulator of gastrointestinal motility and a potential candidate for the treatment of both hyper- and hypo-motility intestinal disorders.29 Therefore, we hypothesized that trimebutine, acting as an intestinal motility stabilizer, might not only improve symptoms but also provide sufficient time for rifaximin, when used in combination, to eradicate enteric bacteria within the intestine. Another reason for choosing trimebutine is that several previous studies have shown trimebutine to have bacteriostatic and bactericidal activities against bacteria that frequently colonize the gastrointestinal tract.30,31

The gold standard for the diagnosis of SIBO is the quantitative evaluation of bacterial concentration through jejunal aspirate culture obtained via endoscopy.32 While this provides a definitive diagnosis, it is difficult to routinely administer due to its invasive nature. In contrast, the glucose breath test is already recognized as a non-invasive diagnostic tool for SIBO and is extensively used in clinical settings for diagnosis and follow-up.33,34 Our study showed that the conversion rate of GBT positivity and breath H2-CH4 concentrations in the combination therapy group was not statistically different from those in the rifaximin group. However, the combination therapy numerically decreased the total concentration of breath H2-CH4 and also at different time points during the GBT (Table 3 and Fig. 1), contrary to rifaximin alone. Thus, combination of trimebutine and rifaximin might provide an additional benefit over rifaximin single treatment in the eradication of SIBO, particularly in patients with bloating without constipation. Nevertheless, further studies with larger number of participants would be required to confirm the effect.

We enrolled patients based on their intestinal symptoms, such as abdominal bloating. Previous studies have demonstrated that rifaximin has superior effect in improving abdominal bloating in patients with SIBO or IBS.35 In our data, only the combination regimen showed a significant improvement in bloating in SIBO patients compared to baseline. This alleviation of bloating might be attributed to a decrease in total gas concentration, irrespective of the eradication status of SIBO. Although we carried out the follow-up at least two weeks after discontinuing trimebutine to minimize its effects on GBT results and symptom scores, it remains unclear whether the observed improvement in bloating resulted from the eradication of intestinal bacteria or the pharmacological action of trimebutine itself. In future, clinical studies would need to focus on assessing the efficacy of trimebutine alone against symptoms of SIBO rather than on that of its combination with antibiotics.

Adverse event rates were similar between the 2 groups. Previous studies had demonstrated that both rifaximin and trimebutine are safe to use.21,36 Therefore, the combination therapy may be safely used in patients with SIBO.

Calprotectin is a non-invasive fecal biomarker. It is one of the best available surrogate markers for detecting the presence of mucosal inflammation, especially in inflammatory bowel disease.37-39 Recently, several studies have demonstrated a strong correlation between FC and SIBO.40,41 We preferred this method over endoscopy, despite the latter being a useful tool for assessing intestinal inflammation, since endoscopic evaluation has several drawbacks, such as lack of objective criteria, invasiveness, and the use of preparations that could affect the breath test. Overall, the advantage of this study was that the FC test was performed to objectively evaluate the baseline status of intestinal inflammation in the 2 randomized groups of patients. Using this test, we demonstrated that no difference in inflammatory status existed between the 2 groups before the initiation of treatment.

This study has several limitations. The first was lack of follow-up of FC after treatment. Second, some participants dropped out during the follow-up period, although we verified them within the predicted range (a dropout rate of 10%). Third, the total study population may not be sufficient to demonstrate the benefits of combination therapy over those of rifaximin alone. Fourth, the duration for which participants took trimebutine was only 2 weeks, limiting the analysis of the long-term effects of continued trimebutine use on gastrointestinal symptoms following combination treatment. Fifth, for the intestinal motility of each participant, we took a symptom-based approach rather than objective evaluations. We expect future studies to investigate the efficacy of treatment on SIBO, with patient selection based on objective motility evaluations. Finally, the effects of trimebutine alone on the eradication of SIBO or the reduction of bloating were not assessed. Therefore, a comparative study with a larger number of patients would be required in future.

In conclusion, the trial did not suggest superiority of rifaximin and trimebutine combination therapy for the eradication of SIBO over rifaximin alone. Nevertheless, the combination treatment could possibly be a safe option to help reduce H2 and CH4 concentrations in exhaled gas and improve bloating.


This study was supported by grants from Samil Pharmaceutical Co, Ltd, Seoul, Korea. The authors are solely responsible for the contents, and the content does not necessarily represent the official views of Samil Pharmaceutical Co, Ltd.

Financial support:

This work was supported by Samil Pharmaceutical Co, Ltd, Seoul, Korea (Grant No. D1PLBT19004).

Conflicts of interest


Author contributions

Ik Hyun Jo and Chang-Nyol Paik conceived and designed the analysis, collected the data, and performed the analysis and drafted the manuscript; Ji Min Lee, Do Seon Song, and Yeon-Ji Kim contributed to data acquisition; and Chang-Nyol Paik supervised all study processes and outcomes. All authors have revised and approved the final version of the manuscript.

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