Efficacy of ossiculoplasty in patients with chronic otitis media with severe to profound hearing loss

Abstract

Chronic otitis media (COM) is treated medically and/or surgically. Ossiculoplasty for COM with severe-to-profound hearing loss has not been recommended because the severity of hearing loss before surgery is negatively associated with postoperative hearing improvement. Our study assessed the effectiveness of ossiculoplasty for severe-to-profound hearing loss and identified prognostic factors associated with favorable outcomes. We retrospectively reviewed the medical records of 182 patients with severe-to-profound hearing loss who underwent ossiculoplasty with tympanoplasty and mastoidectomy for COM between January 2017 and December 2018. Air conduction, bone conduction, and air-bone gap significantly improved compared to baseline values. Univariate analysis revealed that high ossiculoplasty outcome parameter staging (OOPS) or middle ear risk index (MERI) scores, obstructed Eustachian tube status, or computed tomography (CT) findings with sclerotic mastoid or soft tissue density (STD) of the retrotympanic space were associated with a lower odds ratio for air gain ≥ 20 dB at 12 months postoperatively. Multivariate analysis revealed that a high OOPS score and obstructed Eustachian tube significantly predicted poorer outcomes. In conclusion, ossiculoplasty can be considered for selected patients with COM, such as those with a low OOPS index, aerated middle ear, or no STD of the retrotympanic space on CT, before cochlear implantation even if they had severe-to-profound hearing loss and high bone conduction threshold.

Introduction

Chronic otitis media (COM) is an important disease associated with hearing loss. The prevalence of COM in the USA is less than 1%, whereas that in South Korea is 3.8%^1,2. In South Korea, the number of COM cases requiring surgery is moderately increasing, despite improvements in hygiene and medical care³. This may be associated with an aging population and an increase in various comorbidities, such as diabetes mellitus or hypertension. Although COM is initially treated with antibiotics, surgical treatments such as tympanoplasty and/or mastoidectomy are often required in many cases⁴. However, if the ossicular chain is eroded or fixed due to COM, ossiculoplasty should be considered with the aim of restoring hearing.

Indicators such as the Eustachian tube status, inflammation extension, and smoking are well-known prognostic factors for predicting hearing recovery after surgical therapy^5–7. Other studies have developed scoring systems, such as ossiculoplasty outcome parameter staging (OOPS) or middle ear risk index (MERI) scores^6,7. Among these prognostic factors, severity of hearing loss before surgery is strongly associated with hearing recovery after operation⁸. In patients with COM who present with severe-to-profound hearing loss and poor bone conduction—commonly associated with sensorineural hearing loss—surgical interventions, such as ossiculoplasty, are generally not recommended as they typically fail to achieve satisfactory hearing restoration beyond infection control^9,10. These patients can undergo simultaneous or staged cochlear implantation; however, hearing rehabilitation using hearing aids can be advised considering the cost or complication risks associated with cochlear implantation^9,10.

However, some studies have shown that bone conduction may either remain unaffected postoperatively, or improved after middle ear surgery for COM^8,11. Some patients may show high bone conduction, resulting from overestimated bone conduction due to infection or fixed ossicular chain¹². This also may occur in older individuals in whom there is a decreased reliability of hearing tests¹³. In selected patients, the reduction of inflammation or infection after medical/surgical therapy for COM may contribute to hearing recovering. In addition, ossiculoplasty can be performed simultaneously with middle ear surgery^8,10,11, reducing the needs for additional surgery after treatment of COM. This study aimed to verify the efficacy of ossiculoplasty for severe-to-profound hearing loss and identify the prognostic factors associated with favorable outcomes.

Materials and methods

Patient selection

We retrospectively reviewed the medical charts of 216 patients with severe-to-profound hearing loss who underwent ossiculoplasty with tympanoplasty/mastoidectomy for COM at a tertiary medical center between January 1, 2017, and December 12, 2018. In our study, participants with severe or profound hearing loss had preoperative air conduction (AC) > 70 dB and preoperative bone conduction (BC) > 40 dB. There is no standardized numerical cutoff for high bone conduction, as definitions vary among studies. In our study, high bone conduction was defined as a threshold of 40 dB or more, based on the concept that a bone conduction level of 40 dB or more is regarded as moderate hearing loss, which falls outside the range of serviceable hearing.

Hearing loss was quantitatively defined as a four-frequency pure-tone average calculated using the following formula: ([500 Hz + 1000 Hz + 2000 Hz + 3000 Hz]/4)¹⁴. After excluding patients aged < 18 years (n = 5) and those with incomplete data (n = 29), 182 participants were included in the study. This study was approved by the institutional review board of Kyungpook National University Hospital (KNUH 2020-07-001). Due to the retrospective nature of the study, Kyungpook National University Hospital (KNUH 2020-07-001) waived the need of obtaining informed consent. All methods were performed in accordance with relevant guidelines and regulations.

Clinical variables

The following clinical data were collected before surgery: age at surgery, sex, presence of diabetes mellitus or hypertension, smoking status, primary diagnosis, otorrhea, perforation of the tympanic membrane, presence of cholesteatoma, ossicular status, status of the middle ear or mucosa, previous surgery, smoking status, presence/type of mastoidectomy, and preoperative CT findings.

OOPS and MERI scores were calculated as previously described^6,7. Briefly, OOPS included otorrhea, perforation of the tympanic membrane, presence of cholesteatoma, ossicular or middle ear status, previous surgery, and smoking status. The MERI included otorrhea, ossicular or mucosal status, previous surgery, and presence/type of mastoidectomy. We performed temporal bone CT without enhancement and evaluated the presence of mastoid sclerosis as an indirect indicator to predict Eustachian tube function. Furthermore, as soft tissue density of the retrotympanic space on CT findings can affect the results of ossiculoplasty and inflammation recurrence, we evaluated the soft tissue density of the retrotympanic space based on CT findings. Placement of the intact graft at the correct location was also examined and defined as a condition without tympanic membrane perforation, extrusion of the prosthesis, or postoperative inflammation. The graft was evaluated using endoscopy at 2 weeks and, 1, 3, 6, and 12 months postoperatively.

Audiometric methods

Pre- and postoperative AC, pre- and postoperative BC, pre- and postoperative speech discrimination test (SDT), postoperative air-bone gap (ABG), and air gain (AG) were evaluated. Hearing data were measured 1d before surgery and at 3 and 12 months after surgery. Pure-tone air and bone conduction thresholds were measured at 0.5, 1, 2, 3, 4, 6, and 8 kHz. The AC and BC values are defined as the mean values of the thresholds at four frequencies: 0.5, 1, 2, and 3 kHz. Postoperative ABG was defined as the difference between postoperative AC and preoperative BC. The AG was calculated as the difference between the preoperative and postoperative AC values.

Hearing rehabilitation

The patient’s predicted hearing rehabilitation method was decided according to the clinician’s opinion based on bilateral hearing and the status of the tympanic membrane and EAC. Hearing loss was quantitatively defined as a four-frequency pure-tone average calculated using the following formula: ([500 Hz + 1000 Hz + 2000 Hz + 3000 Hz]/4)¹⁴. On average, a patient’s hearing loss is categorized as mild, moderate, moderately severe, severe, or profound as defined by the WHO (mild, 26 to 35dB; moderate, 35 to 50 dB; moderately severe, 50 to 65 dB; severe, 65 to 80 dB; profound, 80 to 95 dB)¹⁵. The final hearing rehabilitation method was confirmed by reviewing the patient’s chart.

Statistical analyses

Data were analyzed using SPSS version 21 (IBM Corp., Armonk, NY, USA). Categorical data are expressed as frequencies and percentages, and continuous data are expressed as means ± standard deviation. Categorical data were compared using the chi-squared test, and continuous data were compared using the paired t-test or one-way analysis of variance. Receiver operating characteristic (ROC) curves were used to calculate the probability of predicting success, cutoff values, sensitivity, and specificity. MedCalc version 11.6.1.0. (MedCalc, Mariakerke, Belgium) was used for ROC analysis. Logistic regression analysis was performed to identify independent variables that predicted hearing recovery, and multivariate analysis was performed using the backward conditional method. A P-value < 0.05 was considered statistically significant.

Results

Baseline characteristics

Our cohort predominantly comprised women with a mean age of 60.9 ± 10.4 years (Table 1). The proportion of patients with diabetes mellitus and hypertension was 151 (83.0%) and 126 (69.2%), respectively. Most patients were nonsmokers, and the mean follow-up duration was 31.1 ± 19.8 months. The number of patients with an eroded malleus, incus, and stapes was 104 (57.1%), 132 (72.5%), and 80 (40.0%), respectively. Most patients underwent columella reconstruction as an ossiculoplasty, and canal wall-down as a mastoidectomy. Although many patients had cholesteatomas, ossiculoplasty was performed concurrently with cholesteatoma removal, and no patients underwent second-look procedure. Titanium and autologous incus were the most commonly used ossicles. Preoperative MERI or OOPS scores were 8.0 ± 2.2 and 6.1 ± 1.9, respectively. On temporal bone CT, the numbers of patients with sclerotic mastoid or soft tissue density(STD) of the retrotympanic space were 160 (87.9%) and 86 (47.3%), respectively. Six patients had postoperative complication during follow-up (prosthesis extrusion in 3, re-perforation in 2, and postoperative inflammation in 1).

Table 1.

Baseline characteristics.

Variables	n = 182
Age (years)	60.9 ± 10.4
Sex (men)	80 (44.0%)
Diabetes mellitus	151 (83.0%)
Hypertension	126 (69.2%)
Smoker
Non-smoker	162 (89.0%)
Ex-smoker	9 (4.9%)
Current smoker	11 (6.0%)
Primary diagnosis
Non-specific chronic otitis media	81 (44.5%)
Congenital cholesteatoma	1 (0.5%)
Acquired cholesteatoma	71 (39.0%)
Adhesive otitis media	29 (15.9%)
Mean follow-up duration (months)	31.1 ± 19.8
Laterality (right)	83 (45.6%)
Presence of cholesteatoma	105 (57.7%)
Edematous/fibrotic mucosa	140 (76.9%)
Tympanic membrane perforation	122 (67.0%)
Obstructed Eustachian tube	80 (44.0%)
Drainage
Dry up	91 (50.0%)
Occasionally wet	56 (30.8%)
Persistently wet	35 (19.2%)
Ossicle status
Eroded malleus	104 (57.1%)
Eroded incus	132 (72.5%)
Eroded stapes	80 (44.0%)
Revision operation	56 (30.7%)
Operation type
Type 3	117 (64.3%)
Type 4	65 (35.7%)
Mastoidectomy
None	28 (15.4%)
Canal wall up;	40 (22.0%)
Canal wall down	114 (62.6%)
Ossiculoplasty
Columella reconstruction	165 (90.7%)
Interposition	17 (9.3%)
Ossiculoplasty material
Autologous ossicles	65 (36.2%)
Artificial material	116 (63.8%)

Data are expressed as numbers (percentage) for categorical data and mean ± SD for continuous data.

Changes in hearing outcomes after ossiculoplasty

AG improved after ossiculoplasty (Table 2). Air conduction, bone conduction, and ABG significantly improved compared to baseline values. At 12 months postoperatively, the numbers of patients with AG ≥ 20 or ≥ 30 dB were 38 (20.9%) and 21 (11.5%), respectively, and those with ABG < 20 dB were 61 (33.5%).

Table 2.

Changes in hearing outcomes after ossiculoplasty.

	Preoperative	3 months	12 months	P-value
Air gain	–	6.8 ± 14.7	8.0 ± 14.7	0.025
Air conduction	88.9 ± 10.5	82.2 ± 17.7*	80.9 ± 17.2*	< 0.001
Bone conduction	56.7 ± 8.9	54.5 ± 16.8#	54.0 ± 12.2*	0.013
Air-bone gap	32.2 ± 9.2	25.5 ± 15.6*	23.8 ± 16.9*	< 0.001

Data are expressed as mean ± SD. *P < 0.001 vs. preoperative values;^#P < 0.05 vs. preoperative values.

Statistical analyses are performed using the repeated measures analysis of variance. Each values at 3 months or 12 months compared to preoperative values were compared using paired t-test.

For 38 patients with postoperative air gain ≥ 20 dB, air conduction at preoperative, 3 or 6 months after operation were 90.1 ± 10.0, 63.3 ± 15.6, and 59.6 ± 13.7 dB, respectively (P < 0.001 for values at 3 months or 12 months vs. baseline values). Bone conduction preoperative and 3 and 6 months after operation was 55.2 ± 8.5. 44.6 ± 12.0, and 43.3 ± 12.2 dB, respectively. SDT results at preoperative, 3 and 6 months after operation were 67.2 ± 34.6, 79.3 ± 29.1, and 83.8 ± 22.8, respectively. Air conduction, bone conduction, and SDT values at 3 or 12 months postoperatively significantly improved compared with baseline values (P < 0.001 for values at 3 months or 12 months vs. baseline values).

Predictors of favorable hearing outcomes after ossiculoplasty

Table 3 shows the logistic regression analysis of the predictors of favorable hearing outcomes. On univariate analysis, for AG ≥ 20 dB at 12 months after operation as an independent variable, high OOPS or MERI scores, obstructed Eustachian tube status, or CT findings with sclerotic mastoid or STD of the retrotympanic space were associated with a lower odds ratio for AG ≥ 20 dB at 12 months after operation. On multivariate analysis, high OOPS score and obstructed Eustachian tubes were associated with a lower odds ratio for AG ≥ 20 dB at 12 months postoperatively.

Table 3.

Predictors of favorable hearing outcomes after operation.

	Univariate		Multivariate
	OR (95% CI)	P-value	OR (95% CI)	P-value
AG ≥ 20 dB at 12 months
Age (per increase 1 year)	1.01 (0.97–1.05)	0.614	–
Diabetes mellitus	1.13 (0.45–2.86)	0.798	–
Hypertension	1.22 (0.57–2.61)	0.606	–
OOPS (per increase 1 score)	0.62 (0.50–0.77)	< 0.001	0.69 (0.55–0.86)	0.001
MERI (per increase 1 score)	0.84 (0.72–1.00)	0.039	–
Obstructed E-tube	0.27 (0.11–0.62)	0.002	0.36 (0.15–0.88)	0.024
Sclerotic mastoid at CT	0.26 (0.10–0.65)	0.004	–
Retrotympanic STD at CT	0.32 (0.15–0.71)	0.005	0.44 (0.19–1.02)	0.055
AC < 50 dB at 12 months
Age (per increase 1 year)	1.05 (0.98–1.12)	0.174	–
Diabetes mellitus	1.69 (0.43–6.64)	0.452	–
Hypertension	2.40 (0.74–7.80)	0.145	–
OOPS (per increase 1 score)	0.53 (0.38–0.76)	< 0.001	0.53 (0.38–0.76)	< 0.001
MERI (per increase 1 score)	0.68 (0.52–0.88)	0.003	–
Obstructed E-tube	0.24 (0.05–1.11)	0.067	–
Sclerotic mastoid at CT	0.38 (0.09–1.52)	0.170	–
Retrotympanic STD at CT	0.35 (0.09–1.34)	0.124	–

Statistical analyses were performed using logistic regression, and multivariate analysis was performed using the backward conditional method.

Abbreviations: AG, air gain; AC, air conduction; OR, odds ratio; CI, confidence interval; OOPS, ossiculoplasty outcome parameter staging; MERI, middle ear risk index; E-tube; Eustachian tube; CT, computed tomography; STD, soft tissue density.

On univariate analysis when defining the independent variable as air conduction < 50 dB at 12 months postoperatively, high OOPS or MERI scores were associated with a lower odds ratio for outcomes. On multivariate analysis, a high OOPS score alone was associated with a lower odds ratio for air conduction < 50 dB at 12 months.

Furthermore, we evaluated the ROC curves for OOPS and MERI (Fig. 1). For prediction of AG ≥ 20 dB at 12 months after operation, ROC values of OOPS or MERI were 0.735 (95% CI, 0.665–0.798; P < 0.001) and 0.589 (95% CI, 0.513–0.661; P = 0.094). Sensitivity and specificity for prediction of air conduction < 50 dB at 12 months after operation using OOPS score ≤ 5 were 63.2% and 72.9%, respectively.

Fig. 1.

ROC curves for two indices for air gain ≥ 20 dB at 12 months after ossiculoplasty. MERI, middle ear risk index; OOPS, ossiculoplasty outcome parameter staging; ROC, receiver operating characteristic.

Comparisons of hearing rehabilitation plan before and after ossiculoplasty

Hearing rehabilitation after surgery showed a significant change compared to hearing rehabilitation before surgery (Fig. 2). The number of patients in Group A increased from 74 to 119 (65.4%); none of the patients without hearing aids before surgery received additional instruments after surgery. Three patients were in Group B before surgery, two patients were in Group C, and 40 were in Group D. The number of patients in Group B increased from 12 to 28 (15.4%); one patient in Group C before surgery, 20 patients in Group D, and one patient in Group E. The number of patients in Group C increased from 10 to 24 (13.2%): one patient in Group B before surgery, 14 in Group D, and 2 in Group E. The number of patients in Group D decreased from 81 to 10 (5.5%), seven patients in Group D were still using hearing aids on both sides (Group D), and the hearing rehabilitation of 74 patients in Group D changed to Groups A-C. The number of patient in Group E decreased five to one (0.5%); hearing rehabilitation of all patients in Group E changed to Groups B-D. One patient in Group B was in Group E after surgery. The hearing rehabilitation methods expected before surgery significantly improved after surgery (P < 0.001).

Fig. 2.

Comparisons of hearing rehabilitation plan before and after ossiculoplasty. The alluvial diagram shows the distribution of hearing rehabilitation before surgery (left nodes) to after surgery (right nodes). Group A involved rehabilitation without a hearing aid; Group B used a hearing aid on the affected side; Group C used a hearing aid on the unaffected side; Group D used hearing aids on both sides; and Group E involved cochlear implantation.

Discussion

In our study, significant improvements in hearing outcomes were observed after ossiculoplasty in patients with COM and severe-to-profound hearing loss. AG, AC, BC, and ABG showed marked improvements compared to baseline values. At 12 months postoperatively, the numbers of patients with AG ≥ 20 dB or ≥ 30 dB were 38 (20.9%) and 21 (11.5%), respectively, and those with ABG < 20 dB were 61 (33.5%). Additionally, SDT preoperatively and at 3 and 6 months after operation were 67.2 ± 34.6, 79.3 ± 29.1, and 83.8 ± 22.8, respectively. These results led to significant changes in hearing rehabilitation. The number of patients without hearing aids or cochlear implantation as hearing rehabilitation after surgery increased 74 (40.7%) to 119 (65.4%) and the number of patients who need cochlear implantation for hearing rehabilitation decreased from 5 (2.7%) to 1 (0.5%).

The air conduction threshold, determined by the sound delivered through headphones, reflects the integrity of all the components involved in sound transmission. Thus, dysfunction in any part of the outer, middle, or inner ear can lead to an increase in the air conduction threshold¹⁰. The bone conduction threshold was assessed by positioning a bone oscillator on the mastoid to elicit movement in the skull. Any dysfunction in the inner ear may result in an elevation of the bone conduction threshold because bone conduction bypasses the outer or middle ear components¹⁰. In clinical practice, an increased bone conduction threshold indicates sensorineural dysfunction, suggesting that this problem likely lies beyond the middle ear. Consequently, the bone conduction threshold is typically not improved following middle ear surgery¹⁰, such as ossiculoplasty, because ossiculoplasty is a surgical procedure aimed at restoring the mechanism of sound transmission within the middle ear by reestablishing the process of sound energy transmission from the tympanic membrane to the stapes footplate¹⁶. In cases of severe-to-profound hearing loss with significant damage to the inner ear or auditory nerve, the efficacy of ossiculoplasty may be limited because the underlying sensory structures responsible for sound processing are compromised. Therefore, alternative treatment options, such as cochlear implantation, may be considered for patients with severe-to-profound hearing loss and a high bone conduction threshold¹⁷.

Despite the different routes to the cochlea, air conduction and bone conduction lead to similar movements of the basilar membrane, which in turn activate the same auditory sensory cells responsible for sound perception¹⁰. When measuring bone conduction, transmission through dermal layers, soft tissues, and bodily fluids also play a role in bone conduction hearing¹⁰. There are five contributors to bone conduction¹⁸; (1) generation of sound pressure in the ear canal, (2) relative motion of the middle ear ossicles caused by inertial effects from the mass of the ossicles, (3) inertial forces acting on the inner ear fluid, (4) compression and expansion of the cochlear space, and (5) transmission of sound pressure to the skull interior. The inertia of the cochlear fluid is often considered the most important contributor to bone conduction hearing¹⁸. However, assessment of bone conduction does not necessarily provide an accurate indication of cochlear function¹⁹. Surendran et al. suggested that contralateral masking could worsen bone conduction thresholds by approximately 10 dB¹⁸. In patients with middle ear pathology, such as otosclerosis of the stapes, a bone conduction threshold around 2,000 Hz can differ by up to 20dB, which is explained by the “Carhart effect”²⁰.

In recent study by Kim et al. concerning the mechanism of improved bone conduction hearing after middle ear surgery, they reported that bone conduction hearing can be underestimated in patients with otosclerosis¹⁰. In addition, our study showed that the mean AG, AC, BC, and ABG values significantly improved after ossiculoplasty. Among patients with COM and severe-to-profound hearing loss, the proportions of improvement of AG ≥ 20 dB or 30 dB were 20.5% and 11.5%, respectively. In particular, bone conduction improves after ossiculoplasty, and overclosure refers to an apparent improvement in bone conduction hearing attributable to the Carhart effect²¹. The American Academy of Otolaryngology-Head and Neck Surgery(AAO-HNS) committee on Hearing and Equilibrium recommends reporting the ABG based on simultaneously determined air and bone conduction values, preferring this method over the former practice of comparing postoperative air-conduction thresholds with preoperative bone conduction thresholds²¹. On multivariate analysis, a high OOPS score and obstructed Eustachian tube were associated with a lower odds ratio for AG ≥ 20 dB at 12 months postoperatively. Although statistical significance was not achieved, the presence of STD of the retrotympanic space in CT image was associated with a lower odds ratio for AG ≥ 20 dB. STD in the middle ear on temporal bone CT indicates conditions such as inflammation, cholesteatoma, mass, or trauma resulting in bloody discharge²². Inflammation can lead to reduced mobility or fixation of ossicles²³. Given that the inertia of cochlear fluid is the most important contributor to bone conduction hearing¹⁸, reduced mobility or fixation of the ossicles may be one of the causes of high bone conduction. In addition, ossiculoplasty changed the hearing rehabilitation plan before and after the surgery. Even when hearing improvement is difficult, ossiculoplasty performed concurrently with middle ear surgery may provide patients with alternative hearing rehabilitation strategies. Therefore, evaluation of postoperative hearing and provision of additional rehabilitation plans are necessary.

Among the currently studied patients, 151 (83.0%) had diabetes mellitus and 126 (69.2%) had hypertension. Hypertension and diabetes mellitus are both associated with a high prevalence of chronic otitis media²⁴. Park et al. reported high ORs for COM associated with hypertension and diabetes mellitus²⁴. Diabetes mellitus is associated with delayed wound healing^25,26. Individuals with diabetes mellitus have an increased risk of infections owing to neutrophil dysfunction and compromised humoral immunity^25,26. Altered function and reduced number of macrophages can hinder or slow the healing process^25,26. Furthermore, considering that most patients with these underlying conditions were older adults in the current study, the reliability of the preoperative audiometric assessments may have been compromised.

This study has a few limitations. First, this was a retrospective single-center study and did not include data from other regions/centres or ethnicities. Second, our study did not include data for more precise methods, such as the auditory brainstem response or dynamic Eustachian tube test. Third, most patients had diabetes mellitus, and more than half of the patients had hypertension. Thus, we could not perform a subgroup analysis based on underlying comorbidities. In addition, the mean patients age was relatively high. It is difficult to identify whether hearing improvement after ossiculoplasty is associated with BC overestimation due to underlying conditions such as comorbidites or older age. Therefore, further studies with larger sample sizes, including patients with various characteristics or comorbidities, and more precise methods are required.

In conclusion, even if patients with COM have severe-to-profound hearing loss with high BC, ossiculoplasty may be applied to selected patients with COM, such as those with a low OOPS index, a well-aerated middle ear, or no STD of the retrotympanic space on CT before cochlear implantation.

Author contributions

KY Lee conceptualized the project and acquired the funding, while DJ Jung curated the data. The formal analysis was performed by DJ Jung and JG Son. KY Lee also developed the methodology. Project administration was handled by DJ Jung and KY Lee. DJ Jung created the visualizations and wrote the original draft, which was then reviewed and edited by DJ Jung and JG Son. The investigation, resource gathering, and software development were conducted by DJ Jung, HG Kwon, and EH Kwon. DJ Jung and KY Lee supervised the project, and HG Kwon and EH Kwon validated the results.

Funding

This work was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant No. HR22C1832).

Data availability

All data generated or analyzed in this study are included in this published article.

Declarations

Competing interests

The authors declare no competing interests.