Biportal Endoscopic Techniques for Severe Dural Ossification in Thoracic Ossification of the Ligamentum Flavum: Insights From Preoperative Imaging
Article information
Abstract
Objective
This study evaluates surgical strategies based on preoperative computed tomography (CT) findings during unilateral biportal endoscopic (UBE) surgery for thoracic ossification of the ligamentum flavum (OLF) with dural ossification.
Methods
This retrospective study included patients undergoing posterior thoracic laminectomy via UBE surgery to treat symptomatic thoracic stenosis due to OLF. Clinical outcomes were assessed using visual analogue scale (VAS) and Japanese Orthopaedic Association (JOA) scores, alongside analyses of preoperative CT and intraoperative videos for dural ossification characteristics.
Results
A total of 34 patients participated, showing significant improvements in VAS and JOA scores postoperatively. All focal dural ossifications exhibiting the tram-track sign were effectively excised without significant dural defects. The circumferential floating technique was employed for cases with the bridge sign, whereas wide excision was warranted for those with the comma sign.
Conclusion
UBE surgery effectively manages progressive thoracic OLF associated with dural ossification. Preoperative CT imaging is essential for assessing dural involvement and guiding surgical techniques. Microscopic surgery is recommended for inexperienced surgeons requiring wide dural excision.
INTRODUCTION
Endoscopic posterior thoracic approaches have been employed to treat thoracic myelopathy caused by ossification of the ligamentum flavum (OLF) [1-8]. However, endoscopic methods have limitations in addressing severely progressed thoracic OLF, particularly in cases with extensive dural ossification. In such instances, microscopic surgery is preferred, often requiring a wide laminectomy and additional instrumentation [3,4,9-11].
To minimize injury to surrounding structures, we are exploring the use of the unilateral biportal endoscopic (UBE) system for treating advanced thoracic OLF with extensive dural ossification. UBE employs independent 2-handed techniques like those in microscopic surgery, while significantly enhancing surgical visibility [8,12-15]. By leveraging the advantages of UBE surgery, we successfully manage the various types of dural ossification [16] associated with thoracic OLF according to preplanned surgical strategies based on preoperative imaging.
This study aims to present surgical strategies informed by preoperative computed tomography (CT) findings during UBE thoracic OLF surgery, while also evaluating the concordance between preoperative CT images and intraoperative video observations.
MATERIALS AND METHODS
1. Study Patients
This retrospective study was approved by the Public Institutional Bioethics Committee (P01-202502-01-038). The study included patients who underwent posterior thoracic laminectomy using a biportal endoscopic system to treat thoracic symptomatic stenosis due to OLF between January 2023 and August 2024 at a single center. All procedures were performed by a single surgeon with 7 years of experience in biportal endoscopic spine surgery.
All patients who met the following inclusion criteria were included in this study:
(1) Thoracic stenotic symptoms in the back and legs that did not respond to conservative treatments (symptoms of thoracic stenosis included chronic mid and lower back pain, radiating pain throughout the legs, and tingling in the lower legs. Myelopathic symptoms, such as numbness in the soles and lower legs, gait instability, and urinary dysfunction, were criteria for surgery).
(2) Thoracic stenosis confirmed by magnetic resonance imaging (MRI) and identification of OLF on CT, regardless of whether spinal cord signal changes were observed.
(3) Surgical intervention involving 1 or 2 consecutive levels.
(4) A follow-up duration of more than 6 months.
(5) Patients who underwent preoperative CT, pre- and postoperative MRI, and had intraoperative videos recorded.
2. Surgical Procedures
Patients underwent surgery under general anesthesia in the prone position using a radiolucent Wilson frame. Two paramedian skin incisions were made at the medial border of the involved-level pedicles under C-arm image guidance. A biportal endoscopic system (4 mm, 0° endoscope) and a toolkit, including a scope retractor and working sheath [17,18], were utilized. Bony drilling was performed with round-type and Match Head-type diamond burrs (3 mm and 4 mm) and a slim handpiece (Primado 2, NSK/Nakanish Inc., Tochigi-ken, Japan) [2,13].
The outside-in en bloc removal technique, as described by Kim et al. [1,2], was employed to decompress the spinal canal. Bilateral bony drilling was conducted along the medial pedicular lines at the cranial and caudal ends of the OLF, and the bulky OLF was thinned using a layer-by-layer drilling technique with a high-speed diamond burr. We use a pressure-controlled water pump, maintaining the pressure below 30 mmHg to reduce stress on the spinal cord from the infusing saline. Additionally, the en bloc removal of the OLF flap as the final surgical step remarkably decreases the duration of dural exposure, also reducing unnecessary pressure on the spinal cord.
Surgical methods for managing dural ossification were determined based on its characteristics and implemented according to the following steps. Dural ossification [16] was identified based on the extent of the ossification process, as well as the presence of specific signs, including the tram-tract sign, bridge sign, and comma sign.
1) Focal dural ossification exhibiting the ‘tram-tract sign’
Before removing the OLF mass from the dural ossification zone, the OLF mass should be drilled to reduce its size, facilitating more efficient manipulation (Fig. 1A–C). After confirming the dura mater at the proximal or distal drilled border, the OLF is thinned until it resembles thin paper, reaching a surface comparable to that of the exposed dura mater. This technique enables clear visualization of the dissection plane, allowing for the safe removal of both the dural ossification and the OLF as a cohesive unit.
Surgical methods for managing focal dural ossification showing the tram-tract sign. (A) Bilateral focal dural ossification. (B) When the dural ossification is not fused to the ossification of the ligamentum flavum (OLF), the thinned OLF can be completely removed while maintaining the ossified dura in situ. (C) In cases where dural ossification is fused to the OLF mass, the ossified dura can be floated with the thinned OLF (left) or removed along with the outer dura mater while preserving the inner layer of the dura mater (right). (D, E) Exposed inner dura mater (dotted circle) after the removal of the ossified outer layer of the dura mater. (F) Exposed ossified dura after removing the OLF (black asterisk), with remaining OLF fragments attached to the ossified dura after floating (yellow asterisk). (G) Preoperative computed tomography showed focal dural ossification (red arrowhead) with bilateral OLF. (H) Preoperative magnetic resonance imaging (MRI) is shown. (I) Postoperative MRI demonstrated a sufficiently expanded dural sac without any dural defect. SAP, superior articular process; Sup, superior; Inf, inferior; CL, contralateral; IL, ipsilateral.
When the dural ossification is not fused to the OLF mass, the thinned OLF can be completely removed while maintaining the ossified dura in situ (Fig. 1B and G–I). In cases where dural ossification is fused to the OLF mass, the ossified dura can either be floated while still attached to the thinned OLF (Fig. 1C and F) or removed along with the outer dura mater, while preserving the inner layer of the dura mater (Fig. 1C–E).
We recommend utilizing the focal floating technique for ossified dura rather than incising the mass when the entire dural layer is ossified and completely fused to the OLF (Fig. 1F). This approach facilitates adequate dural expansion while minimizing the risk of unnecessary dural defects. Once the outer layer of dura is peeled away, applying Tachosil to seal the inner dural layer effectively protects against potential delayed dural tears (Supplementary Video Clips 1 and 2).
2) Central dural ossification exhibiting the ‘Bridge sign’
The bilateral dorsal portion of the dura mater is ossified and fused at the midline; however, the lateral portion of the dural sac, which has the potential for adequate expansion, remains intact (Fig. 2A–C). In this context, floating the ossified dura facilitates sufficient expansion of the dural sac, thereby alleviating spinal cord compression (Fig. 2H–K).
Circumferential floating technique for managing dural ossification with bridge sign. (A) Centrally fused dural ossification is observed involving the dorsal dura mater. (B) The ossification of the ligamentum flavum (OLF) is removed circumferentially while preserving the thin layer of OLF that is fused to the ossified dura. (C) The ossified dura is floated by expanding the bilateral lateral portion of dural sac. (D) An intraoperative photo shows the “squeezing drilling technique,” which safely drills out the OLF mass. The OLF mass is drilled out using side-by-side compressive force between the scope retractor and diamond burr. (E, F) The ossified dural flap is detached from the bilateral superior articular processes (E: ipsilateral, F: contralateral). (G) After the removal of the OLF mass, the cranial end of the dural ossification and the free dural border are exposed. (H, I) Preoperative computed tomography and magnetic resonance imaging (MRI) revealed centrally fused dural ossification in the dorsal portion of dural sac (red arrowhead). (J) Following the circumferential floating technique, the remaining ossified dura is elevated as the dural sac expands (yellow arrowhead). (K) Postoperative MRI demonstrated a sufficiently expanded dural sac. SAP, superior articular process; Sup, superior; Inf, inferior; CL, contralateral; IL, ipsilateral.
The OLF mass associated with dural ossification is thinned using a high-speed diamond drill and the ‘squeezing drilling technique’ (Fig. 2D). The OLF mass is stabilized with a scope retractor, and side drilling is performed from the contralateral side of the mass with counteractive force (Fig. 2D). This technique helps prevent spinal cord injury that may arise from drilling with compressive force. The OLF mass is incised along the bilateral medial pedicular line by drilling out the medial aspect of the superior articular process (SAP). Subsequently, the thinned OLF is elevated from the bilateral cut edges, and the residual dura in the lateral spinal canal is expanded as the dural ossification is floated (Fig. 2E and F). If the exposed dura becomes transparent due to erosion or manipulation, it is advis-able to cover it with a sealant patch to prevent delayed dural tears (Fig. 2G) (Supplementary Video Clip 3).
3) Aggressively extended dural ossification exhibiting the ‘Comma sign’
Dural ossification is extensively present at the lateral borders and the ventral portion of the dura mater, commonly accompanying an aggressively growing OLF mass (Fig. 3A and I). This type of ossification often extends to the cranial and caudal edges of the ligamentum flavum (Fig. 3J). In such cases, floating the dural ossification is not feasible due to the lack of an expandable portion in both the lateral and cranio-caudal dural sacs. To alleviate spinal cord compression, a broad excision of the ossified dura, followed by dural reconstruction, is required (Fig. 3B–D).
Circumferential wide excision of dural ossification and dural reconstruction for managing dural ossification with the comma sign. (A) The ossified dura extends widely to the lateral and ventral portion of dural sac, crossing the midline. (B) After drilling out the ossification of the ligamentum flavum (OLF) mass, the ossified dura is circumferentially excised using a diamond drill. (C) Although a wide dural defect occurred, the arachnoid membrane sealed the CSF, preventing leakage. (D) Dural reconstruction is performed with a dural substitute graft and a multilayered sealant patch. (E) Intraoperative photo: The ossified dura was completely fused to the OLF mass. During drilling out the OLF mass, the ossified dura was exposed, and the subdural space is visible through the patch hole of dural ossification (white asterisk). (F) Ossified dura is circumferentially cut (white asterisks) using an endoscopic drill. (G) A flap of dural ossification is removed. The arachnoid membrane (yellow asterisk) covers the spinal cord and prevents CSF leakage. (H) After dural reconstruction. (I) Preoperative computed tomography (CT) scans showed broad dural ossification, indicating the comma sign (red circle: head, curved line: tail). (J) The sagittal CT image further revealed extensive dural ossification (red arrowheads). (K) Preoperative magnetic resonance imaging (MRI) demonstrated the absence of dura in the head portion of the comma sign (yellow arrowhead). (L) One-year follow-up MRI revealed a sufficiently expanded dural sac without pseudomeninocele, with the arachnoid membrane indicated (red asterisk). SAP, superior articular process; Sup, superior; Inf, inferior; CL, contralateral; IL, ipsilateral.
Wide marginal drilling and layer-by-layer thinning of the OLF are conducted using a high-speed diamond drill, allowing the spinal cord to be faintly visible through the translucent dural ossification (Fig. 3E). The ossified dura is circumferentially incised 360° along the bilateral and cranio-caudal ends of the dural ossification (Fig. 3F). The secured flap of dural ossification is carefully elevated using a blunt hook to prevent injury to the arachnoid membrane (Fig. 3G). The elevated flap is then removed with forceps. The thickened arachnoid membrane, typically covering the spinal cord, aids in preventing significant cerebrospinal fluid (CSF) leakage. Subsequently, a dural substitute graft is placed over the area of the dural defect, and several layers of a sealant patch are applied to the graft (Fig. 3H). Sealing procedures should be conducted promptly to prevent the enlargement of the injured area of the arachnoid membrane. Preparation of the sealant patch and dural substitute grafts must be completed prior to the removal of the ossified flap. This sealing method facilitates reconstruction of the dural layer while reducing the risk of pseudomeninocele formation (Fig. 3I–L) (Supplementary Video Clip 4).
3. Analysis Clinical and Radiologic Parameters
Clinical parameters, including patient demographics, surgical level, operative time, length of hospital stay, and postoperative complications, were analyzed. Clinical outcomes were assessed using the visual analogue scale (VAS) for back and leg pain, as well as the Japanese Orthopaedic Association (JOA) score to evaluate disability before surgery, after surgery, and at the final follow-up. Although clinical data is analyzed retrospectively, we included this data to evaluate the efficacy and safety of the techniques demonstrated in this study. Preoperative CT and MRI were performed to confirm dural ossification and to classify the OLF according to the Sato classification. The Sato classification [19] describes the progression of ligamentous ossification as follows: (A) Lateral type refers to ossification confined to the capsular portion of the ligamentum flavum. (B) Extended type indicates ossification extending into the interlaminar portion. (C) Enlarged type is characterized by anteromedial thickening and enlargement of the ossification. (D) Fused type denotes the fusion of bilateral ossified masses at the midline. (E) Tuberous type refers to the anterior growth of the fused mass of ossification. Postoperative MRI was conducted to evaluate dural expansion and any complications.
Surgical videos were reviewed to analyze incidentally discovered dural ossifications and instances of dural injury. In cases where dural ossification was observed on preoperative CT, we conducted a thorough review of the operative videos, focusing on the characteristics of the dural ossifications and the surgical techniques employed. Statistical analysis was performed using SAS 9.4 (SAS Inc., USA).
RESULTS
We included 34 patients (14 men and 20 women) who underwent biportal endoscopic posterior thoracic laminectomy. The mean age of the patients was 68.1±9.1 years (Table 1). The mean follow-up period was 12.7±3.9 months, and the average length of hospital stay was 5.9±1.6 days (Table 1). A total of 41 segments were involved, with the operating spinal levels indicated in Table 1. The mean operative time per segment was 64.5±17.3 minutes.
Patient and surgical data (n=34)
Three patients demonstrated an epidural hematoma on postoperative MRI. One patient was successfully managed with conservative treatment, while 2 patients required microscopic hematoma removal due to severe pain at the surgical site and progression of neurological deficits in both legs. Following revision surgery, the acute symptoms were alleviated, and the patients recovered without any additional neurological deficits. One patient experienced a wrong-level surgery, which was identified on postoperative MRI, necessitating an additional procedure to address the targeted lesion. No serious intraoperative neurological injuries, such as those resulting from direct spinal cord contusion or high-pressure irrigation, were observed. Fur-thermore, segmental instability did not occur, despite most surgeries being performed in the lower thoracic and thoracolumbar junction areas.
VAS scores for back and leg pain showed significant improvement following surgery (Table 1). Neurological function was also restored, as evidenced by an increase in the JOA score (preoperative: 12.3±1.0; final follow-up: 15.4±0.7; Table 1).
Among the 41 operative levels, the OLF types were classified according to the Sato classification [19]: 14 levels were categorized as type A, 18 as type B, 5 as type C, 2 as type D, and 2 as type E (Table 1). Nine levels exhibited the ‘tram-track sign’ of dural ossification on preoperative CT images, indicating dural ossification (Table 2, Fig. 1). During the review of intraoperative videos for cases exhibiting the tram-track sign, focal dural ossification was observed to be fused to the OLF mass in 5 levels (1 classified as Sato type B and 4 as Sato type C); In 3 cases, the dural ossification located in the outer dural layer was removed together with the OLF mass by peeling it away from the inner layer of the dura mater (Supplementary Video Clip 1). Two levels demonstrated ossification of the entire dural layer, resulting in the ossified lesion being left intact and floated focally to facilitate dural expansion (Supplementary Video Clip 2). However, Dural ossification was not clearly visible in the surgical videos during the removal of the OLF mass in 4 levels exhibited the ‘tramtrack sign,’ all classified as Sato type B (Table 2); instead, only adhesive tissue was observed between the dura and the OLF mass. In these cases, it was suspected that the dural ossification was not fused to the OLF mass, allowing for clear separation of the OLF mass from the ossified dura. As a result, in all cases with dural ossifications exhibiting the tram-track sign, the OLF mass was successfully removed without resulting in any significant dural defects.
Surgical techniques for each type of dural ossification
One OLF case exhibiting the ‘bridge sign’ of dural ossification was classified as Sato type D (Table 2, Fig. 2). Intraoperative videos revealed that the dural ossification was located in the dorsal portion of the dural sac and was completely fused to the OLF mass; however, the ossified dura did not extend to the lateral dura mater (Supplementary Video Clips 3). Consequently, the circumferential floating technique was feasible for managing this type of dural ossification.
Two levels exhibited the ‘comma sign’ of dural ossification, classified as Sato type E (Table 2, Fig. 3). Surgical videos revealed that the broad ossified dura extended to both the lateral and ventral portions of the dura mater and was completely fused to the OLF mass (Supplementary Video Clip 4). The ossified dura was circumferentially excised to achieve neural decompression, followed by dural reconstruction. Both patients recovered neurological function without experiencing any instances of CSF leakage postoperatively.
DISCUSSION
In this study, the tram-track sign, indicative of focal dural ossification, was most frequently observed in preoperative CT scans. Focal dural ossification that is not fused to the OLF mass is visualized as the tram-track sign on preoperative CT images; however, completely fused ossified dura could not be confirmed through preoperative imaging. The detection of focal dural ossification on axial CT slices may be inaccurate, and the actual prevalence of unconfirmed focal dural ossification may exceed the findings noted in the preoperative scans.
Furthermore, upon reviewing intraoperative videos, only half of the levels displaying the tram-track sign were confirmed as distinct dural ossification, while 5 out of 9 levels exhibiting the sign did not show distinguishable dural ossification. Nonfused ossified dura could be smoothly separated from the OLF mass, but remaining focal dural ossification was not visualized during surgery. Conversely, fused ossified dura was identified through endoscopic visualization while elevating the OLF mass, irrespective of whether the outer dura was ossified or the entire dural layer was affected (Supplementary Video Clips 1 and 2). When operating on these cases, it is essential to anticipate the potential for dural involvement, and the management of dural ossification should be adapted to the intraoperative findings, either through removal of the outer dural layer or by employing a focal floating technique. The en bloc removal with a bisected flap technique is considered safer than a single-piece removal pattern, as it allows for direct confirmation of the space between the OLF and the dura mater.
All instances of focal dural ossification exhibiting the tramtrack sign were successfully managed without any dural defects or neurological injuries, irrespective of whether the ossified dura was fused to the OLF. Focal dural ossification may not indicate a significant risk for dural defects during thoracic OLF removal, particularly when associated with OLF classified as Sato type B. However, focal dural ossification in enlarged thoracic OLF (Sato type C) displayed invasive characteristics in the surgical videos (Supplementary Video Clip 2).
Extensive and aggressive dural ossification, indicated by the ‘comma sign’ and ‘bridge sign,’ is typically associated with aggressive thoracic OLF classified as Sato types D or E. A comprehensive understanding of the signs of dural ossification—particularly regarding their characteristics and the extent of dural involvement—enables us to effectively manage these challenging cases. The benefits of UBE surgery, such as enhanced visualization of the lesion and the use of a free 2-handed technique, can be leveraged in these situations [1].
The ‘bridge sign’ indicates ossification of the midline portion of the dura mater, which forms a connection between the bilateral OLF. This type of dural ossification typically did not extend to the lateral dura mater (Supplementary Video Clip 3). The ossified dura is completely fused to the OLF mass, making en bloc removal of the OLF mass infeasible without resulting in a significant dural defect. Therefore, floating the ossified dura attached to the thinned OLF—similar to an island in a vast lake—is a safer and more efficient approach than complete removal.
Most aggressive forms of dural ossification are indicated by the ‘comma sign,’ where the lateral and ventral dura mater is ossified as it crosses the midline. This type of dural ossification is commonly observed in OLF classified as type E, signifying anterior growth of the aggressive OLF. The comma sign encompasses the bridge sign of midline ossification; however, floating the dural ossification is not feasible due to the absence of expandable dura mater at the lateral dural borders. To achieve adequate neural decompression, it is essential to remove the dorsolateral portion of the dural ossification. A critical consideration when removing dural ossification associated with thoracic OLF is that no barrier exists between the OLF and the ossified dura. The spinal cord may be unexpectedly exposed during drilling of the OLF, and once widely exposed, further drilling becomes challenging due to the risk of direct spinal cord contusion or injury from the water pressure of infused saline [20,21]. Therefore, it is imperative to assess the extent of the ossified dura bilaterally and cranio-caudally using preoperative CT scans. Important anatomical landmarks include the bilateral facet joints. If the facet joint cartilage is not visualized during drilling, there is an increased risk of encountering the spinal cord. Once the facet joints are displayed, the lateral edge of the dural ossification can be secured along the medial pedicular line [4] (Supplementary Video Clip 4). The tip of the SAP extends to the neuroforamen, and the cranial end of the OLF is typically positioned at or slightly cranially to the neuroforamen. The extent of cranial drilling should be guided by the location of the SAP tip.
One case classified as Sato type D did not present clear evidence of dural ossification on preoperative CT; however, unilateral broad dural ossification was discovered during the surgical procedure. The unexpected presence of dural ossification resulted in a dural tear during the en bloc removal of the OLF mass [22]. The remaining dural ossification and attached OLF were floated, and the dural defect was subsequently repaired using a sealant patch. When dural ossification is completely fused to the bulky OLF mass, the signs of dural ossification may not be evident on the preoperative CT scan, particularly when the ossified dura is extensively located in the lateral dural area. Therefore, during the removal of OLF in cases classified as Sato types D and E, it is crucial to anticipate the potential presence of advanced dural ossification in all instances and to plan the surgical approach accordingly [7].
These surgical methods can assist endoscopic spine surgeons in safely performing thoracic OLF removal in cases with dural ossifications. Prior to the treatment of thoracic OLF, a preoperative CT scan should be conducted to confirm the presence of dural ossification and assess its characteristics. Making customized surgical plans based on the findings from the CT scan facilitates successful removal of the thoracic OLF and effective management of the dural ossification.
During endoscopic thoracic decompression surgery, inexperienced surgeons face an increased risk of insufficient decompression when confronting severe conditions [2]. Inadequate decompression of the spinal canal can result in delayed progression of myelopathy, potentially necessitating revision surgery [3]. Prioritizing adequate decompression and minimizing complications is more critical than achieving minimal invasiveness, regardless of whether microscopy or endoscopy is utilized. Therefore, I recommend that inexperienced endoscopic spine surgeons consider microscopic surgery when faced with aggressive OLF associated with the comma sign, given the elevated risk of spinal cord injury and the potential for complications due to inadequate decompression. Furthermore, intraoperative neuromonitoring can reduce the risk of spinal cord injury in these cases.
The study has limitations. We focused on the management methods of dural ossification during the removal of thoracic OLF, which means that details of pre- and postoperative symptoms were not thoroughly described. Furthermore, the cases of aggressive dural ossification are limited, and the shapes of dural ossifications vary significantly; thus, the application of the recommended techniques may have limitations. A study with a larger sample size, incorporating a more diverse range of dural ossification shapes, is needed to establish the efficacy of the techniques demonstrated in this study.
CONCLUSION
Progressive thoracic OLF accompanied by dural ossification can be effectively treated using UBE surgery. Localized dural ossification exhibiting the tram-track sign and bridge sign can typically be managed with the floating technique; however, wide excision is essential in cases where the bilateral lateral portion of the dural sac is ossified and presents with the comma sign. Microscopic surgery is recommended for inexperienced endoscopic surgeons when wide dural excision is necessary.
Supplementary Materials
Supplementary Video Clips 1-4 are available at https://doi.org/10.14245/ns.2550338.169.
Case of tram-tract sign of focal dural ossification during thoracic ossified ligamentum flavum removal using biportal endoscopic surgery at T9–10 on the left. The outer layer of the dura is removed along with the ossified ligamentum flavum.
Case of tram-tract sign of focal dural ossification involving the full layer of the dura mater. The ossified dura is exposed after the removal of the ossified ligamentum flavum during biportal endoscopic thoracic laminectomy at T10–11 on the left.
Case of bridge sign of central dural ossification. The dural ossification is circumferentially floated after the removal of the ossified ligamentum flavum during biportal endoscopic thoracic laminectomy at T10–11 on the left.
Case of comma sign of wide dural ossification extending to the ventral dura mater. The ossified dura is circumferentially excised, and dural reconstruction is performed during biportal endoscopic thoracic laminectomy at T10–11 on the left.
Notes
Conflict of Interest
The authors have nothing to disclose.
Funding/Support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Author Contribution
Conceptualization: JYK; Data curation: JYK, SYC; Formal analysis: JYK, SYC; Funding acquisition: JYK; Methodology: JYK, DCL; Project administration: JYK, DCL, HSK, DHH; Visualization: JYK, DCL, HSK, DHH; Writing – original draft: JYK, HSK, DHH; Writing – review & editing: SYC, DCL.