Abstract
Purpose
We investigated the effects of testosterone replacement therapy (TRT) on the Fibrosis-4 (FIB-4) index among hypogonadal patients who were extracted from a randomized controlled study in Japan (the EARTH study).
Materials and Methods
Data of 186 patients (88 in the TRT group; 98 in the control group) were collected. The patients in the TRT group received intramuscular administration of testosterone enanthate (250 mg) every 4 weeks for 12 months. The patients’ background information such as current medical history and lifestyle habits were collected. Waist circumference, body mass index, and body fat volume were measured at baseline and 12-month visit. Fasting blood sugar (FBS), hemoglobin A1c, total cholesterol, triglyceride (TG), and high-density lipoprotein cholesterol levels were collected at baseline and 12-month visit. The FIB-4 index was calculated according to age, aspartate aminotransferase, alanine transaminase, and platelet count.
Results
Except for serum FBS values, most of baseline characteristics were comparable between the TRT and control groups. When comparing the changes of each variable from baseline at 12-month visit in both groups, significant differences were found in waist circumference (p=0.00248), fat volume (p=0.00812), and platelet counts (p=0.0478), whereas a FIB-4 index did not change. On the contrary, in a subanalysis including only patients with a FIB-4 index ≥1.30 at baseline, a significant difference in a FIB-4 index (−0.10±0.39 vs. 0.04±0.44; p=0.0311) was observed with significant decreases in waist circumference, body fat volume, and TG levels, and an increase in platelet counts. The FIB-4 index was significantly decreased by TRT from 1.98±0.52 to 1.87±0.60 (p=0.0277).
Conclusions
TRT for 12 months improved the FIB-4 index among hypogonadal men with a higher baseline FIB-4 index.
Keywords: Fibrosis, Hypogonadism, Liver cirrhosis, Metabolic syndrome, Testosterone
INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver diseases, and its global prevalence is estimated to be 25% in adult [1]. NAFLD is strongly involved in lifestyle-related diseases such as obesity, dyslipidemia, diabetes mellitus (DM), and hypertension, as well as metabolic syndrome, and can ultimately result in liver cirrhosis and hepatocellular carcinoma [2]. NAFLD is divided into two conditions; nonalcoholic fatty liver, which is a non-progressive condition in which fat simply accumulates in the liver, and nonalcoholic steatohepatitis (NASH), which may lead to lever fibrosis and scarring, eventually to cirrhosis and cancer [2]. Some large cohort studies demonstrated that liver fibrosis was the most important predictive factor to determine not only liver-related disease prognosis but also the mortality of patients with NAFLD [3,4]. For the patients with NASH, accurate identification and inhibition of liver fibrosis are considered to be important to prevent serious complications.
In older men, age-related decreases in serum testosterone levels are significantly associated with lifestyle-related diseases such as obesity, hypertension, dyslipidemia, and insulin resistance, and these clinical manifestations are referred as late-onset hypogonadism (LOH) syndrome [5,6]. In addition, testosterone deficiency plays a significant role in the development and progression of cardiovascular diseases [7]. Testosterone replacement therapy (TRT) can improve many symptoms and clinical conditions associated with LOH syndrome [8].
Several studies have demonstrated a potential relationship between testosterone and NAFLD [9,10,11]; low testosterone levels were significantly correlated with NAFLD in men. Moreover, NAFLD with metabolic syndrome in hypogonadal men are at a risk of all-cause mortality, including liver-specific and cardiovascular death [12]. Therefore, whether TRT can prevent the incidence and progression of NAFLD among hypogonadal men is likely an interesting issue. However, studies examining whether TRT can have beneficial effects on the progression of NAFLD and liver fibrosis have been extremely limited.
We performed a randomized controlled study (the EARTH study [13]) to evaluate efficacy of TRT for hypogonadal men. The EARTH study [13] was conducted between December 2007 and October 2010, and included 334 Japanese patients with LOH syndrome who were randomly assigned to the TRT (n=169) or control groups (n=165). TRT for 12 months had some beneficial effects on the physical subdomain of the role of the SF-36 scale, the voiding sub-score of International Prostate Symptom Scores, and question no.2 of the International Index of Erectile Function-5, and then significantly improved waist circumference, muscle volume, and serum triglyceride (TG) levels. The present study was conducted to investigate the effects of TRT on the Fibrosis-4 (FIB-4) index, a clinical biomarker of liver fibrosis, among study population extracted from the EARTH study [13].
MATERIALS AND METHODS
1. Study subjects
This retrospective subanalysis included patients with a diagnosis of LOH syndrome who had enrolled in the EARTH study [13]. Hypogonadal symptoms of LOH syndrome were screened according to the Aging Male Symptoms scale. Hypogonadism was diagnosed based on the Japanese criteria; serum free testosterone (FT) level <11.8 pg/mL [14]. FT levels were measured by radioimmunoassay (RIA) (DPC-free testosterone kit, Mitsubishi Kagaku).
The exclusion criteria were as follows: obvious alcohol consumption (self-reported alcohol intake of >30 g per day); viral hepatitis; autoimmune liver diseases; any other obvious liver diseases in the EARTH study [13]. Finally, we collected data of 186 patients (88 in the TRT group; 98 in the control group) (Fig. 1).
Fig. 1. Flow chart of the eligible patients in this study is presented. The EARTH study is refereed to reference [13]. TRT: testosterone replacement therapy, FIB-4: Fibrosis-4, TE: testosterone enanthate.
2. Ethics statement
This study was approved by our Institutional Review Board (Approval no. 2023-333), and was performed in accordance with the Ethical Guidelines for Medical and Health Research. Informed consent was submitted by all subjects when they were enrolled.
3. Study protocol
Initially, patients’ background information such as current medical history and lifestyle habits at the initial visit were collected. Waist circumference, body mass index (BMI), and body fat volume were measured at baseline and 12-month visit. In addition, blood biochemical data, including platelet counts, aspartate aminotransferase (AST), alanine transaminase (ALT), fasting blood sugar (FBS), hemoglobin A1c (HbA1c), total cholesterol, TG, and high-density lipoprotein cholesterol (HDL-Chol), were collected at baseline and 12-month visit. The FIB-4 index was calculated according to the following formula: age (years)×AST (U/L)/platelets (×109/L)×√ALT (U/L) [15]. In cases with a FIB-4 index of <1.30, the negative predictive value for liver advanced fibrosis was 90%, whereas a positive predictive value of approximately 80% at a high cut off value of 2.67 [15]. A FIB-4 index <1.30 was also acceptable for excluding advanced fibrosis in Japan [16], and in patients with a FIB-4 index of ≥1.30, careful examination at a specialized medical institution is recommended.
The patients in the TRT group received intramuscular administration of testosterone enanthate (250 mg) every 4 weeks for 12 months, whereas no treatment was performed in the control group.
4. Statistical analysis
Student’s t-test was used for comparing backgrounds of patients in the TRT and control groups. The changes of each variable from baseline at 12-month visit in both groups were compared using the Mann–Whitney U-test. In addition, all patients were divided into two groups based on a FIB-4 index at baseline (≥1.30 and <1.30), and a similar analysis was performed. Wilcoxon’s signed rank test was used to compare a FIB-4 index at baseline and study end in both groups. All statistical procedures were performed using SPSS version 25 (IBM Corp.). The statistical significance was considered at p-values <0.05.
RESULTS
Baseline characteristics of included patients are presented in Table 1. Although FBS values was significantly higher in the TRT group (p=0.0397), the other baseline characteristic was comparable between the TRT and control groups. There were 59 patients with a FIB-4 index ≥1.30 at baseline in the TRT group and 67 in the control group.
Table 1. Baseline patients’ characteristicus in the TRT and control groups.
| Variable | TRT group (n=88) | Control group (n=98) | p-value | |
|---|---|---|---|---|
| Age (y) | 65.8±8.8 | 67.2±9.1 | 0.160 | |
| Free testosterone (pg/mL) | 7.43±2.17 | 7.21±2.04 | 0.234 | |
| Weist circumference (cm) | 85.8±9.7 | 86.4±8.5 | 0.338 | |
| BMI (kg/m2) | 23.8±4.7 | 23.6±3.1 | 0.375 | |
| Fat volume (kg) | 22.9±6.9 | 23.2±7.0 | 0.386 | |
| Platelet (1,000/µL) | 210±46 | 210±58 | 0.476 | |
| AST (IU/L) | 24.3±9.0 | 24.3±13.3 | 0.482 | |
| ALT (IU/L) | 25.0±13.2 | 23.2±13.9 | 0.185 | |
| FBS (mg/dL) | 137±40 | 127±36 | 0.0397 | |
| HbA1c (%) | 6.3±1.0 | 6.2±0.9 | 0.131 | |
| T-Chol (mg/dL) | 184±26 | 186±31 | 0.318 | |
| TG (mg/dL) | 122±81 | 109±50 | 0.0936 | |
| HDL-Chol (mg/dL) | 56±14 | 55±14 | 0.310 | |
| FIB-4 index | 1.66±0.63 | 1.70±0.60 | 0.357 | |
| Diabetes mellitus | 64 (72.7) | 70 (71.4) | 0.884 | |
| Dyslopidemia | 35 (39.8) | 38 (38.8) | 0.889 | |
| Hypertension | 42 (47.7) | 40 (40.8) | 0.343 | |
| FIB-4 index | ||||
| <1.30 | 29 (32.9) | 31 (31.6) | 0.847 | |
| ≥1.30 and <2.67 | 54 (61.4) | 60 (61.2) | ||
| ≥2.67 | 5 (5.7) | 7 (7.2) | ||
Values are presented as mean±standard deviation or number (%).
TRT: testosterone replacement therapy, BMI: body mass index, AST: aspartate aminotransferase, ALT: alanine transaminase, FBS: fasting blood sugar, HbA1c: hemoglobin A1c, T-Chol: total cholesterol, TG: triglyceride, HDL-Chol: high-density lipoprotein cholesterol, FIB-4: Fibrosis-4.
Overall, when comparing the changes of each variable from baseline at 12-month visit in both groups, significant differences were found in waist circumference (−0.5±3.1 vs. 1.0±8.4; p=0.00248), fat volume (−1.0±4.3 vs. 0.5±4.0; p=0.00812), and platelet counts (1.5±31.6 vs. −6.2±30.8; p=0.0478) (Table 2). The other parameter including FIB-4 index showed no significant differences.
Table 2. Comparisons of changes in each variable from baseline at 12-month visit in the TRT and control groups.
| Variable | TRT group (n=88) | Control group (n=98) | p-value |
|---|---|---|---|
| Weist circumference (cm) | -0.5±3.1 | 1.0±8.4 | 0.00248 |
| BMI (kg/m2) | 0.1±0.8 | 0.1±1.0 | 0.443 |
| Fat volume (kg) | -1.0±4.3 | 0.5±4.0 | 0.00812 |
| Platelet (1,000/µL) | 1.5±31.6 | -6.2±30.8 | 0.0478 |
| AST (IU/L) | 0.5±8.7 | 0.9±8.9 | 0.386 |
| ALT (IU/L) | 0.8±8.4 | 23.8±13.9 | 0.161 |
| FBS (mg/dL) | 0.8±45.0 | 8.5±42.9 | 0.121 |
| HbA1c (%) | 0.0±0.5 | 0.0±0.4 | 0.308 |
| T-Chol (mg/dL) | -1.3±22.3 | -3.0±26.4 | 0.324 |
| TG (mg/dL) | -8.4±73.0 | 4.9±42.1 | 0.0639 |
| HDL-Chol (mg/dL) | -1.7±7.8 | -1.4±7.2 | 0.381 |
| FIB-4 index | -0.02± 0.36 | 0.06±0.07 | 0.0599 |
Values are presented as mean±standard deviation.
TRT: testosterone replacement therapy, BMI: body mass index, AST: aspartate aminotransferase, ALT: alanine transaminase, FBS: fasting blood sugar, HbA1c: hemoglobin A1c, T-Chol: total cholesterol, TG: triglyceride, HDL-Chol: high-density lipoprotein cholesterol, FIB-4: Fibrosis-4.
In a subanalysis including the patients with a FIB-4 index ≥1.30 at baseline, significant differences in a FIB-4 index (−0.10±0.39 vs. 0.04±0.44; p=0.0311) and TG levels (−14.4±48.6 vs. 3.6±40.0; p=0.0127) were also observed in addition to waist circumference, fat volume, and platelet counts (Table 3). The FIB-4 index was significantly decreased by TRT from 1.98±0.52 to 1.87±0.60 (p=0.0277) (Fig. 2). Thus, TRT for 12 months could significantly decreased a FIB-4 index along with a decrease in waist circumference, fat volume, and TG levels and an increase in platelet counts.
Table 3. Comparisons of changes in each variable from baseline at 12-month visit in the patients with a higher FIB-4 index at baseline in the TRT and control groups.
| Variable | TRT group (n=59) | Control group (n=67) | p-value |
|---|---|---|---|
| Weist circumference (cm) | -0.8±3.2 | 0.8±3.7 | 0.00569 |
| BMI (kg/m2) | 0.0±0.9 | 0.0±1.1 | 0.476 |
| Fat volume (kg) | -1.3±4.9 | 0.5±3.7 | 0.0116 |
| Platelet (1,000/µL) | 9.3±29.6 | -0.6±22.9 | 0.0194 |
| AST (IU/L) | -0.9±6.8 | -0.5±9.2 | 0.387 |
| ALT (IU/L) | 0.2±8.9 | 1.0±11.3 | 0.324 |
| FBS (mg/dL) | -0.8±44.1 | 11.5±42.1 | 0.0588 |
| HbA1c (%) | -0.1±0.5 | 0.1±0.4 | 0.101 |
| T-Chol (mg/dL) | -3.3±21.2 | -3.5±24.0 | 0.481 |
| TG (mg/dL) | -14.4±48.6 | 3.6±40.0 | 0.0127 |
| HDL-Chol (mg/dL) | -1.5±7.5 | -1.5±7.5 | 0.490 |
| FIB-4 index | -0.10±0.39 | 0.04±0.44 | 0.0311 |
Values are presented as mean±standard deviation.
TRT: testosterone replacement therapy, BMI: body mass index, AST: aspartate aminotransferase, ALT: alanine transaminase, FBS: fasting blood sugar, HbA1c: hemoglobin A1c, T-Chol: total cholesterol, TG: triglyceride, HDL-Chol: high-density lipoprotein cholesterol, FIB-4: Fibrosis-4.
Fig. 2. In the patients with higher a Fibrosis-4 (FIB-4) index at baseline, the FIB-4 index was significantly decreased by testosterone replacement therapy (TRT) from 1.98±0.52 to 1.87±0.60 (p=0.0277) (Blue). A FIB-4 index was significantly increased by TRT from 1.03±0.24 to 1.13±0.24 (p=0.0312) (Red); however the change was within the normal range.
In the patients with a FIB-4 index <1.30 at baseline, TRT had some benefits for waist circumference (0.3±2.8 vs. 1.8±3.9; p=0.0475) and fat volume (−0.4±2.7 vs. 0.9±4.6; p=0.0264), whereas a FIB-4 index showed not significant difference between the two groups (p=0.0949) (Table 4). Although the FIB-4 index was significantly increased by TRT from 1.03±0.24 to 1.13±0.24 (p=0.0312), the change was within the normal range (Fig. 2).
Table 4. Comparisons of changes in each parameter from baseline among the patients with lower FIB-4 index (<1.30) at baseline in TRT and control groups.
| Variable | TRT group (n=29) | Control group (n=31) | p-value |
|---|---|---|---|
| Weist circumference (cm) | 0.3±2.8 | 1.8±3.9 | 0.0475 |
| BMI (kg/m2) | 0.1±0.7 | 0.3±1.0 | 0.126 |
| Fat volume (kg) | -0.4±2.7 | 0.9±4.6 | 0.0264 |
| Platelet (1,000/µL) | -8.0±32.8 | -18.6±41.1 | 0.138 |
| AST (IU/L) | 3.2±11.2 | 4.2±7.4 | 0.344 |
| ALT (IU/L) | 1.6±7.3 | 5.8±12.9 | 0.0619 |
| FBS (mg/dL) | 4.7±48.4 | 3.9±45.5 | 0.475 |
| HbA1c (%) | 0.0±0.5 | 0.0±0.4 | 0.198 |
| T-Chol (mg/dL) | 2.8±20.1 | -5.2±35.0 | 0.154 |
| TG (mg/dL) | 2.8±107.6 | 8.9±46.8 | 0.386 |
| HDL-Chol (mg/dL) | -2.2±8.3 | -1.0±6.8 | 0.263 |
| FIB-4 index | 0.09±0.21 | 0.20±0.27 | 0.095 |
Values are presented as mean±standard deviation.
TRT: testosterone replacement therapy, BMI: body mass index, AST: aspartate aminotransferase, ALT: alanine transaminase, FBS: fasting blood sugar, HbA1c: hemoglobin A1c, T-Chol: total cholesterol, TG: triglyceride, HDL-Chol: high-density lipoprotein cholesterol, FIB-4: Fibrosis-4.
DISCUSSION
In this study, the FIB-4 index was significantly decreased by TRT among hypogonadal men with a relatively higher FIB-4 index (≥1.30) at baseline. Our results suggest that TRT may have some beneficial effects on the progression of liver fibrosis among hypogonadal men with a risk of hepatic steatosis.
NAFLD begins with the accumulation and infiltration of fat in the liver and can progress to NASH, and potentially lead to cirrhosis and hepatocellular carcinoma. The main cause of death in NAFLD cases is cardiovascular events, but liver fibrosis is the most important factor to determine disease prognosis [3,4]. The FIB-4 index is one of the noninvasive biomarkers for predicting liver fibrosis, and some previous studies demonstrated that the performance of the FIB-4 index in diagnosing progressive fibrosis in NAFLD was comparable with other noninvasive parameters [15,17]. In addition, the change in FIB-4 index was significantly correlated with change in fibrosis stage in the patients with NAFLD [16,18]. Currently, it has been suggested that the FIB-4 index may also be a surrogate tool for monitoring histological changes and may be a good index in the treatment of NAFLD.
It has been widely accepted that testosterone deficiency is significantly associated with sexual dysfunction, obesity, metabolic syndrome, and decrease in muscle mass and bone mineral density among older men [5,6,8]. Several studies have also demonstrated a potential correlation between testosterone deficiency and NAFLD [9,10,11,19]. A study showed that low serum total testosterone (TT) levels were independently correlated with NAFLD among 495 Korean men and revealed the odds ratio for patients in the lowest quintile of TT levels was found to be 5.12. [9]. In a cross-sectional and longitudinal study including 1944 men, TT levels were significantly involved in NAFLD diagnosed by ultrasonographic examinations [10]. However, current TT levels did not pose a risk progression of NAFLD in the future [10]. Another study demonstrated an inverse correlation between serum FT levels and a FIB-4 index (β=−0.28; p<0.0001) among 248 men with type 2 DM [11]. Furthermore, a most recent meta-analysis including 2,995 patients with NAFLD demonstrated that lower TT levels are significantly associated with the severity of NAFLD in men [19]. However, a limitation in most of these studies included a lack of direct evaluations of liver fibrosis, such as pathological examinations.
On the other hand, some studies have failed to find a relationship between testosterone and NAFLD. Hua et al. reported that serum TT levels were not involved with NAFLD; however, sex hormone-binding globulin (SHBG) levels were inversely correlated with NAFLD in 1,001 patients with type 2 DM [20]. Another cross-sectional study including 175 men with type 2 DM concluded that the severity of NAFLD was not directly linked to serum TT and FT levels [21]. Studies investigating the relationship between testosterone and NAFLD have been insufficient; therefore, to reach a more definite conclusion, further studies are required.
Some factors may explain how testosterone deficiency is associated with NAFLD development and progression. Testosterone deficiency potentially correlated with visceral obesity and metabolic syndrome, and visceral adipose tissue caused by a decrease in testosterone can result in the release of various inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α [22]. These inflammatory cytokines are a risk factor for the progression of NAFLD and cirrhotic states, and in particular, IL-6 induces insulin resistance and chronic inflammation in hepatocytes [23,24]. An experimental study demonstrated that castration caused liver inflammation in male mice [25]. On the contrary, TRT can improve obesity and metabolic syndrome in hypogonadal men [5,8], and this study also revealed that waist circumference and fat volume were improved by 12-month TRT. A possible mechanism is that the FIB-4 index could be improved by TRT through a decrease in visceral obesity. However, further studies are needed to confirm this hypothesis.
Evidence on the many clinical benefits of TRT on various metabolic factors such as obesity, lipid profile, and insulin resistance has been currently established; however, few studies have focused on liver fibrosis. A study showed that long-term TRT over 12 years could decrease fatty liver index, γ-glutamyl transpeptidase, bilirubin, and TG levels along with a reduction in waist circumference and BMI, although liver fibrosis was not investigated [26]. Moreover, only one study reported a protective role of TRT against NAFLD progression [27]. This prospective study included hypogonadal obese men (15 cases with TRT and 46 without TRT), and some markers of fat and liver functioning were assessed by liver and fat biopsies. In the TRT group, histopathological NAFLD activity, steatosis scores, and liver TG content were lower than in the control group, suggesting some protective effects of TRT against NAFLD progression. In this study, TRT failed to cause a significant decrease in the FIB-4 index. However, a subanalysis including only the patients with a FIB-4 index of ≥1.30 at baseline demonstrated that the FIB-4 index was significantly decreased in the TRT group compared to control group. Although the present findings do not necessarily demonstrate that TRT can have some beneficial effects on the progression of liver fibrosis, these may be evidence supporting our hypothesis.
A few experimental studies have also demonstrated the significant benefits of TRT for liver fibrosis. Nikolaenko et al. reported that TRT could attenuate hepatocyte apoptosis in castrated rats fed a high-fat diet [28]. Another study reported that testosterone inhibited the formation of macrovesicular lipid droplets and promoted lipid export, contributing to the improvement of steatohepatitis induced by high-fat diet and castration in rats [29].
On the other hand, in the patients with a FIB-4 index <1.30 at baseline, there was no significant difference in FIB-4 index in the two groups, and then the FIB-4 index was significantly increased by TRT. However, these findings do not preclude a benefit of TRT. Indeed, TRT had some beneficial effects on waist circumference and fat volume. In addition, an increase in a FIB-4 index were within the normal range, which is likely to be not clinically significant. Further studies including long-term follow-up are also required to clarify the effects of TRT on a FIB-4 index.
Hypogonadism had been diagnosed based on serum FT levels in the EARTH study [13]. FT is a known to be an unreliable marker for proper and androgen levels, and TT or bioavailable testosterone (BAT) are widely used for a diagnosis of hypogonadism. This diagnostic criteria in Japan is significantly different from ones in other countries. A previous epidemiological study demonstrated that serum TT levels did not change with age, but serum FT levels showed a good inverse correlation with age in Japanese men [14]. Measurement of SHBG is not covered by Japanese health insurance system. On the other hand, FT levels measured by RIA were extremely highly correlated with calculated FT levels (r=0.706, p<0.0001) [30]. Therefore, FT had been commonly used as a convenient diagnostic tool of hypogonadism in Japan. However, patients with liver disease may have abnormalities in hepatic production of SHBG, which may have a significant impact on actual androgen levels. In this respect, BAT may have been a more accurate marker considering the impact of liver disease on hypogonadism.
This study has some limitations. Initially, this was a retrospective subanalysis of the EARTH study [13], and there were some differences in baseline characteristics between two groups. Indeed, FBS values was significantly higher in the TRT group. However, since there were no differences between the two groups and in the proportion of patients diagnosed with DM and in HbA1c levels, it is unlikely that this difference in FBS values had any effects on the results. Second, only a clinical marker was used as an assessment of risk for liver fibrosis, and this study lacks objective data such as imaging and pathological examinations. In addition, more patients had DM, dyslipidemia, and obesity; therefore, some medical interventions, except for TRT, might be performed, which might contribute to some degree improvements in the FIB-4 index. Furthermore, exogenous testosterone administration may adversely affect fertility, and no information about the fertility status was available in this study. Other limitations include the retrospective nature of the study, the insufficient number of participants, and limited geographic representativeness, which may limit the ability to generalize and replicate the results. Despite these limitations, this study is a subanalysis of the prospective randomized controlled trial, and then has a relatively large sample compared with the previous study [27], which is likely to be valuable as another preliminary study that assumed a clinical benefit of TRT for the protection against liver fibrosis. Thus, to obtain a better understanding of TRT, further prospective studies with various objective data on liver fibrosis are required.
CONCLUSIONS
TRT for 12 months improved the FIB-4 index among hypogonadal men with a higher FIB-4 index at baseline.
Acknowledgements
None.
Footnotes
Conflict of Interest: The authors have nothing to disclose.
Funding: None.
- Conceptualization: KS, YK, RS, SK.
- Data curation: KS, YK, RS, SK, TN, HK.
- Formal analysis: KS.
- Investigation: KS, RS.
- Methodology: KS, YK, RS.
- Project administration: KS, YK.
- Supervision: KI, MN, AM.
- Validation: KS, MN, AM.
- Visualization: KS, MN, AM.
- Writing – original draft: KS.
- Writing – review & editing: KI, AM.
Data Sharing Statement
The data required to reproduce these findings cannot be shared at this time due to legal and ethical reasons.
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Data Availability Statement
The data required to reproduce these findings cannot be shared at this time due to legal and ethical reasons.