Abstract
Malocclusion may lead to the development of occlusal trauma, which can exacerbate periodontal disease. Here, we present a skeletal Class II adult patient with occlusal traumatic periodontitis of upper incisors, who was treated with a two-phased orthodontic treatment. In the first phase, a Twin Block appliance (TBA) was used to increase the vertical dimension of the posterior teeth, to eliminate the anterior occlusal trauma. In addition, TBA also improved mandibular retrusion by forwarding the mandible. In the second phase of fixed orthodontics, occlusion was fine-tuned with infrazygomatic crest (IZC) miniscrews and Class II intermaxillary elastics. At the end of treatment, anterior occlusal trauma was eliminated, periodontal conditions of upper incisors were improved, a stable occlusion and a harmonious profile were obtained. The successful two-phased orthodontic treatment showed that the TBA can effectively eliminate anterior occlusal trauma through restoration of posterior vertical dimension, and can improve mandibular retrusion by forwarding mandible and reconstructing stable occlusion in adult patient.
Keywords: Occlusal trauma, Periodontitis, Adult, Twin block appliance, Orthodontics
Introduction
Primary occlusal trauma was defined as an injury to the attachment apparatus or tooth as a result of excessive occlusal forces. Common indications for clinical diagnosis of occlusal trauma include persistent occlusal discomfort, progressive tooth mobility and migration, fremitus during occlusion, and radiographic evidence of wedge-shaped widening of the periodontal space and blurring or loss of the bony plate [1]. Occlusal trauma is thought to be a synergistic factor that can aggravate periodontitis, and teeth with significant supportive periodontal tissue loss are especially prone to occlusal trauma, which has been defined as secondary occlusal trauma. Thus, occlusal trauma and periodontitis corporately consist a vicious cycle, and periodontitis associated with occlusal trauma poses a great challenge for clinical treatment of these teeth. In order to gain a better prognosis of such patients, the interdisciplinary therapy is strongly recommended, which requires the cooperation among periodontists, prosthetists, and orthodontists [2].
Orthodontic treatment is generally not recommended for patients with advanced periodontitis that has progressed to a certain degree, especially in patients with moderate to severe resorption of the alveolar bone. Tooth movement during the orthodontic treatment of periodontopathic patients may lead to tooth loosening which cannot be fixed in target positions, resulting in undesirable and failed treatment. However, when periodontitis is accompanied with occlusal trauma, orthodontic treatment would be necessary to eliminate occlusal trauma by proper alignment and movement of teeth, achieving a better therapeutic effect than periodontic treatment alone [3, 4].
Anterior teeth, especially anterior upper teeth, often suffer from occlusal trauma as a result of excessive occlusal forces, and is defined as “anterior hyperfunction”, which normally results from decreased vertical support from posterior teeth [5]. The most common clinical manifestations are flaring migration of anterior upper teeth and spacing between them, accompanied with periodontitis of various degrees [5]. These are also the main complaints of patients seeking treatment. The principles of treatment for such patients are reestablishments of posterior vertical dimension, which are normally achieved through conventional removable prostheses [6] and implant-supported prostheses [7, 8]. Twin Block appliance (TBA) has been widely applied in orthodontic treatment of adolescents with retrusive mandible. Notably, the guided eruption of posterior teeth rebuilds the vertical dimension of occlusion during TBA therapy, and effectively improve the deep overbite and overjet of anterior teeth. However, to the best of our knowledge, there were no clinical reports conducting orthodontic treatment of patients with anterior teeth occlusal trauma through using TBA.
Here, we present the case of an adult patient with upper anterior teeth occlusal trauma and periodontitis, who was orthodontically treated with a TBA combined with a fixed appliance. The final therapeutic result was acceptable, regarding to aesthetic changes of profile, neutral posterior occlusion and anterior periodontal restoration with elimination of occlusal trauma.
Case report
A 29-year-old female patient, distressed herself with the protruding and loose upper incisors, as well as unaesthetic facial profile. We observed that her periodontal condition was terrible, and upon being questioned, she replied that she had been diagnosed with gingivitis as an elementary school student. The palatal gingiva of her upper anterior teeth had been bitten frequently by her lower anterior teeth, but she had paid no attention to these injuries. It was not until her periodontal condition worsened in recent years that she sought periodontal treatment one year prior to her visit to our department, and her periodontal condition was currently stable.
Photographs taken before treatment showed an acceptable facial symmetry, but she had inadequate skin length on her upper lip, giving rise to an everted lip, with exposed anterior teeth and tense mentalis when her mouth was closed. A convex facial profile along with an underdeveloped chin were revealed lateral photographs. A Class II Division 1 malocclusion was present in her case (bilateral full Class II relationships of molars and canines). Mild crowding in both the maxillary and mandibular arches was observed, along with mesial inclination of the posterior teeth. The maxillary anterior teeth were severely protruded, resulting in a deep overjet up to 11 mm, while the mandibular anterior teeth were biting on the palatal mucosa, forming an impinging overbite. The upper midline was significantly shifted to the left (Figs. 1 and 2).
Fig. 1.
Pretreatment facial and intraoral photographs
Fig. 2.
Pretreatment dental cast
Lateral cephalometric analysis confirmed that she had a skeletal Class II-tendency jaw relationship with a retrognathic mandible. The inclination angle of upper incisor was increased to 120.4°, and the incisal internal angle was reduced to 113.0° (Fig. 3A). A panoramic radiograph revealed horizontal obstruction of the mandibular third molar on the left side and vertical impaction on the right, along with a bilateral asymmetric condylar morphology (Fig. 3B).
Fig. 3.
Radiographs before treatment. (A) Lateral cephalometric radiographs and tracing; (B) Panoramic radiograph
Cone-beam computed tomography (CBCT) imaging revealed a severe labial tilt of the maxillary anterior teeth with thin labial bone cortex. The maxillary anterior teeth had root resorption and crown-root ratio close to 1:1. A moderate decrease in the length of the mandibular anterior alveolar bone was observed, which was up to 1/2 − 1/3 of the root. The root apices of the incisors were round and obtuse (Fig. 4).
Fig. 4.
CBCT showing root and alveolus resorption before treatment. (a) Maxillary right central incisor (b) Maxillary left central incisor. (c) Maxillary right lateral incisor (d) Maxillary left lateral incisor
Accordingly, the patient was diagnosed with Angle Class II Division 1, a skeletal Class II, and secondary occlusal traumatic periodontitis.
Treatment objectives
The objectives of the first-phase treatment included (1) increasing the vertical dimension of occlusion to relieve occlusal trauma of the anterior teeth; and (2) correcting the retrognathic mandible to improve facial aesthetics; The objectives of the second-phase treatment included (1) aligning the dentition and retracting the maxillary anterior teeth; and (2) achieving neutral occlusion of the canines and the molars, as well as optimal overbite and overjet, to obtain a good and stable occlusal relationship.
Treatment alternatives
Three treatment options were provided to the patient. Orthodontic-orthognathic surgical treatment was the first option. Moreover, due to chin underdevelopment, genioplasty might be performed to improve the facial profile. Orthognathic surgery combined with orthodontic treatment was considered the most effective option for improving facial aesthetics. However, high therapy expense and uncertainty about eliminating occlusal trauma make the patient deny this option.
Traditional fixed orthodontic treatment was the second option, necessitating the extraction of maxillary first premolars and all third molars prior to treatment. For patients with aggravated overjet due to occlusal trauma, reverting to a normal occlusal relationship through traditional fixed orthodontic treatment is highly challenging.
The third treatment option was a two-phase orthodontic treatment. In the first phase, the TBA was used to increase the vertical occlusal support and decrease the occlusal force in the anterior teeth, thus diminishing occlusal trauma. In the second phase, fixed orthodontic appliance was used for arches alignment and levelling, and miniscrews were surgically inserted into bilateral infrazygomatic crest (IZC) to ensure strong sagittal anchorage for maximum retraction of maxillary anterior teeth after the occlusal trauma in the anterior had been eliminated.
Finally, considering the disadvantages of orthognathic surgery and traditional fixed orthodontic treatment, the third option was finally approved by both the patient and doctors.
Materials and methods
The first phase TBA was made according to the following procedures: (1) occlusal recording of the mandibular relocation; (2) arrow clasps and arm clasps were made by 0.7 mm stainless steel to increase the retention of TBA; (3) selfcuring acrylic resin were used to form the body of upper and lower plates of TBA. The patient was instructed to wear the TBA continuously. The appointment intervals were every 4–6 weeks. The height of the upper block was gradually abraded to allow eruption of lower molars. This phase lasted for 13 months.
The second phase of fixed orthodontics was conducted through the bonding Damon brackets (standard torque, Ormco corporation) to the patient upper and lower teeth. A sequences of Nickel titanium and stainless-steel arch wires were applied according to requirement. The miniscrews (12 mm*1 mm, Ormco corporation) were implanted in the IZC zones. Intermaxillary elastics of various types and forces were applied according to requirement. Occlusion was fine-tuned during this phase, which lasted for 37 months.
The baseline periodontal measurements and evaluations of occlusal trauma were made according to the following: The clinical parameters obtained from the periodontist before and after orthodontic treatment included probing pocket depths (PPD), bleeding on probing and dental mobility. The clinical crown length (CCL) was measured by vernier caliper according to the pre-treatment and post-treatment casts. In addition, the pre-treatment and post-treatment casts of the patient were scanned and analyzed for the occlusal contact area and strength by the i-align invisible appliance company.
Other measurements from panoramic radiographs were performed using the computer’s built-in measurement tool [9]: (1) the apex-to-marginal bone level distance (MBL); (2) the bone defect radiological dimension (BDRD), calculated as the triangular area bounded by the defect base, the most coronal point of the interproximal bone crest, and its vertical projection onto the root surface; and (3) the root length (RL), defined as the linear measurement from the root apex to the cementoenamel junction. (4) Periodontal ligament space width (PDLW), measured as the mean radiolucent space between the root surface and adjacent alveolar bone, recorded from three equidistant points along the middle third of the root.
The criteria for determining treatment success were defined as follows: (1) elimination of anterior incisor occlusal trauma and improved periodontal conditions; (2) normal anterior overjet and overbite; (3) Class I molar and canine relationships; (4) improved profile of patient.
Treatment progress
The first therapy phase lasted for 13 months, during which the TBA was used to increase the vertical height of the posterior teeth to establish occlusal support, and to forward the mandible to improve the profile (Fig. 5). During the second month of wearing the TBA, lingual buttons were bonded to the maxillary second premolars, and buccal tubes were bonded to the maxillary second molars, mandibular first and second molars. Then, vertical intermaxillary elastics were applied (Fig. 6) to accelerate lower posterior teeth elongation, thus elevating the vertical support of posterior teeth and eliminating occlusal trauma of upper anterior teeth.
Fig. 5.
Phase 1 treatment with Twin Block appliance
Fig. 6.
Vertical intermaxillary tractions were applied to assist the eruption of posterior teeth
Once posterior occlusal contact was established between the upper and lower second molars(Fig. 7), the second phase of fixed orthodontic therapy was initiated. Early alignment and leveling were achieved with archwire sequencing for 10 months. Meanwhile, the deep overbite, which was greatly improved during the first phase, was further corrected by using bite pads on the lingual side of upper anterior teeth, along with leveling of lower arch and class II elastics. At the 11th month, two 2.0 × 12-mm miniscrews were implanted on infrazygomatic crest (IZC) regions of both sides, which provided strong anchorage to distalize upper premolars and molars.
Fig. 7.
Facial and intraoral photographs after phase 1 treatment
Finally, the maxillary anterior teeth were retracted and deep overjet was corrected using sliding mechanics in 0.018 × 0.018-in stainless steel wire. Attention was given to torque control and midline alignment during the fixed orthodontic treatment phase. After fine occlusal adjustment, the fixed orthodontic appliance was debonded. The duration of the second phase was 37 months, and the overall treatment lasted for 51 months. The patient was instructed to wear retainers for two years and was advised to revisit the periodontist for maintaining periodontal condition.
Treatment results
At the end of the full course of treatment, the patient’s mandible was stabilized in a forward position, and the protruded profile was greatly improved (Fig. 8). The class II canine and molar relationships had been corrected to class I relationships on both left and right sides, accompanied with significant improvement in overbite and overjet.
Fig. 8.
Facial and intraoral photographs after phase 2 treatment
The occlusal trauma of upper incisors were successfully eliminated, and the periodontal conditions of the maxillary central incisors were improved (Tables 1 and 2; Fig. 9). The initial PPD of the right and left maxillary central incisors measured 7.30 mm and 7.10 mm, which decreased significantly to 3.50 mm and 3.20 mm after treatment. Notably, the MBL demonstrated increases of 1.36 mm (right) and 1.85 mm (left), suggesting enhanced intraosseous root support. The BDRD were reduced by approximately 3.6 mm² bilaterally, indicative of active marginal bone remodeling. RL exhibited minor decreases ranging from 0.35 mm to 0.6 mm, with no significant root resorption detected. In addition, BOP, PDLW, and dental mobility showed marked improvements, returning to physiologically normal ranges. The analysis of occlusal contact area and strength showed that central upper incisors had serious occlusal trauma, which was efficiently removed after treatment.
Table 1.
Pre- and posttreatment values and differences of PPD (probing pocket depth), CCL (clinical crown length), BOP (bleeding on probing) and dental mobility
| Pretreatment | Posttreatment | Δ | ||
|---|---|---|---|---|
| Maxillary right central incisor | PPD (mm) | 7.3 | 3.5 | -3.8 |
| CCL (mm) | 10.12 | 9.7 | -0.42 | |
| BOP | ++ | + | ||
| Dental mobility | II° | I° | ||
| Maxillary left central incisor | PPD (mm) | 7.1 | 3.2 | -3.9 |
| CCL (mm) | 9.92 | 9.67 | -0.25 | |
| BOP | ++ | + | ||
| Dental mobility | II° | I° |
Table 2.
Pre- and posttreatment values and differences of MBL (bone marginal level), BDRD (bone defect radiological dimension), RL (root length), and PDLW (periodontal ligament space width)
| Pretreatment | Posttreatment | ∆ | ||
|---|---|---|---|---|
| Maxillary right central incisor | MBL (mm) | 4.87 | 6.23 | 1.36 |
| BDRD (mm2) | 7.81 | 4.12 | -3.69 | |
| RL (mm) | 10.55 | 9.98 | -0.57 | |
| PDLW (mm) | 0.56 | 0.38 | -0.18 | |
| Maxillary left central incisor | MBL (mm) | 5.22 | 7.07 | 1.85 |
| BDRD (mm2) | 7.87 | 4.28 | -3.59 | |
| RL (mm) | 10.85 | 10.49 | -0.36 | |
| PDLW (mm) | 0.53 | 0.28 | -0.25 |
Fig. 9.
Evaluations of the occlusal trauma and periodontal parameters pre- and post-treatment. (A) Occlusal contact maps derived from pre-treatment and post-treatment digital model scans; (B) Measurements made on panoramic radiographs: MBL (marginal bone level), BDRD (bone defect radiological dimension), PDLW (periodontal ligament space width) and RL (root length)
The following changes were confirmed by lateral cephalogram measurements and analysis (Fig. 10; Table 3): ANB angle decreased from 4.6°to 3.6°; maxillary incisor labial inclination decreased from 120.2° to 100.3°, and the distances from the upper and lower lips to the E line decreased from 3.4 mm to 3.7 mm to 1.0 mm and 1.2 mm, respectively (Table). CBCT images after four years of therapy revealed that the roots of the maxillary anterior teeth returned to the middle of the alveolar bone of the maxilla (Fig. 11).
Fig. 10.
Radiographs after treatment. (A) Lateral cephalometric radiographs and tracing. (B) Panoramic radiograph
Table 3.
Cephalometric analysis from lateral radiographs
| Variables | Normal | Pretreatment | Posttreatment |
|---|---|---|---|
| Skeletal variables | |||
| SNA (º) | 82.7 ± 2.8 | 81.4 | 80.6 |
| SNB (º) | 80.7 ± 3.0 | 76.9 | 77.1 |
| ANB (º) | 2.0 ± 1.8 | 4.4 | 3.6 |
| Ptm-A (mm) | 46.3 ± 2.8 | 40.9 | 47.4 |
| Ptm-S (mm) | 16.9 ± 2.8 | 13 | 17.7 |
| PP-FH(º) | 5.2 ± 3.7 | 2.9 | 2 |
| FMA(º) | 25.0 ± 3.0 | 24.4 | 26.2 |
| MP-SN(º) | 32.0 ± 5.6 | 31.8 | 34.9 |
| S-Go/N-Me(%) | 68.5 ± 5.0 | 66.8 | 64.9 |
| ANS-Me/N-Me(%) | 55.0 ± 2.0 | 54 | 54 |
| Dental variables | |||
| U1-L1 (º) | 127.0 ± 9.0 | 113 | 122 |
| U1-SN (º) | 105.7 ± 6.3 | 120.4 | 100.9 |
| U1-NA (mm) | 5.1 ± 2.4 | 10 | 3.9 |
| U1-NA (º) | 22.8 ± 5.2 | 39 | 20.2 |
| L1-NB (mm) | 6.7 ± 2.1 | 4.6 | 4.8 |
| L1-NB (º) | 30.3 ± 5.8 | 23.6 | 34.3 |
| FMIA (º) | 57.0 ± 7.0 | 60.7 | 51.5 |
| Soft tissue variables | |||
| UL-E Line (mm) | -1.2 ± 1.6 | 3.4 | 1 |
| LL-E Line (mm) | 0 ± 2.1 | 3.7 | 1.2 |
Fig. 11.
CBCT showing root and alveolus resorption before treatment. (a) Maxillary right central incisor (b) Maxillary left central incisor. (c) Maxillary right lateral incisor (d) Maxillary left lateral incisor
Overall superimposition of the lateral cephalometric radiographs is shown in (Fig. 12). The superimposition illustrated forward and downward transition of the mandible, clockwise rotation of the occlusal plane, distalization of the maxillary molars, and clockwise rotation of the maxillary incisor. At the end of the treatment, the patient had no symptoms of TMJ discomfort.
Fig. 12.
Superimposed pretreatment and posttreatment cephalometric tracings. The overall superimposition was registered on SN at sella. Black line, pretreatment. Red line, posttreatment
Discussion
Occlusal trauma frequently occurs in patients with Class II dentofacial deformities, and impaired facial aesthetics and pathologic tooth migration are the main reasons that such patients are seeking clinical treatment [9, 10]. Occlusion plays a potential role in maintaining the homeostasis of periodontal supporting tissues, and malocclusions are assumed to be the risk factors of occlusal trauma and associated periodontitis [11, 12]. Consequently, the restoration of a normal occlusal relationship is crucial for patients with occlusal trauma and periodontitis.
Up until now, the clinical methods used for occlusal reconstruction include prosthodontics and orthodontics. For example, Se-Lim successfully treated a patient with anterior teeth occlusal trauma caused by loss of posterior teeth, through increasing the occlusal vertical dimension with provisional restorations [13]. In addition, there were other case reports that presented the orthodontic treatment of anterior teeth occlusal trauma and periodontitis [2–4, 14, 15]. In these cases, the anterior teeth were intruded, while the posterior teeth were extruded, through leveling arches during orthodontic treatment, thus eliminating the anterior teeth occlusal trauma and periodontitis. In the present case, we used the TBA-assisted orthodontic treatment to increase the vertical dimension of posterior occlusion, thus minimizing the occlusal contact and trauma of anterior teeth. Based on the final results, it is apparent that TBA can significantly facilitate occlusal reconstruction of adult patients, and effectively eliminate the anterior teeth occlusal trauma and periodontitis during treatment.
So far, the major application of TBA is to promote mandibular protrusion by forced relocation of mandible in a forward and downward position. Thus, it is an excellent appliance to correct the hypodevelopment of mandible and improve the profile of patients with such deformities. However, the application of TBA in elimination of anterior teeth occlusal trauma has not been reported. We proposed that the foundation of TBA in therapy of anterior teeth occlusal trauma is based on the effect of TBA in erupting the posterior teeth and elevating the posterior vertical height. This is reasonable, since diminished posterior support caused by extraction and abrasion of posterior teeth inevitably lead to excessive occlusal forces in the anterior region, which results in occlusal trauma [16]. In order to accelerate the eruptions of posterior teeth, buttons and tubes were bonded to the upper and lower molars of the patient, which facilitated the vertical elastics between upper and lower molars. By doing so, the occlusal trauma and periodontitis of upper incisors have been efficiently eliminated, as demonstrated by the indexes in Tables 1 and 2.
There’s been a debate on whether the TBA treatment on adult patients could be as stable as its application on adolescents. Even though the popular opinion is that TBA-induced mandibular reposition can be stable only in adolescents, more and more studies and cases displayed that adult patient could also be effectively treated by TBA. For examples, some modified twin-block appliances were invented to reposition the mandible, thus correcting facial deformities such as skeletal class III malocclusion resulted from mandibular protrusion and overclosure [17], as well as facial asymmetry caused by mandibular deviation [18]. The patient in the present case had a severely retruded mandible, which was improved greatly after treatment as demonstrated by decreased ANB angle and harmony profile. The common key procedures during orthodontic treatment of these adult patients using either TBA or modified TBA are rebuilding the posterior support and vertical height of occlusion. Therefore, these cases together with our present case, shed light on the value of TBA in treating adult patient with facial deformities, and proposed the critical procedures during the usage of TBA.
At the end of TBA treatment, the canine and molar relationships, as well as anterior overjet and overbite, had been significantly improved. In order to establish a better occlusal relationship, the second-phase treatment with fixed orthodontic appliances were initiated. With respect to tooth movement in periodontitis, attentions should be given to changes in the resistance center of the tooth. In addition, it is vital to employ gentle orthodontic forces within the adaptive capacity of the compromised periodontal tissues [19]. During the second-phase treatment, an upper inclined guiding plate and the Class II elastics were applied to keep the mandible repositioning. Meanwhile, IZC miniscrews were implanted to further retract the upper arch and incisors. At the end of the entire orthodontic treatment, no further periodontal aggravation was seen in upper incisors. Moreover, the feedback from periodontist confirmed that the periodontal condition had been greatly improved with the help of periodontal therapy. This indicated that optimal orthodontic treatment together with periodontal therapy could effectively treat periodontitis, which was consistent with similar published case reports [2, 3, 14, 15].
In spite of the acceptable result of the present case, there are still some limitations in this case report. The first limitation is the lack of control group of patients with similar oral conditions but treated without TBA. Considering the ethical problems, we could not treat such patients using other appliances with uncertain therapeutic effect. The second limitation is that only one case was reported in the present study, which makes it unable to popularize our therapeutic notion and method. However, with more and more patients being treated in such a untraditional way, the sample size will grow, and more details will be compared among these patients, in order to form a more specific and personalized therapeutic system.
Conclusions
In this case report, we presented that adult patients with skeletal Class II and severe anterior occlusal traumatic periodontitis due to decreased posterior vertical dimension can be treated through a novel TBA-based two-phase orthodontic treatment. The first phase utilized TBA to increase posterior vertical support and correct the sagittal skeletal Class II relationship, while the second phase of fixed orthodontics retracted the flaring anterior incisors and fine-tuned the occlusion to stabilize the mandible in the forward position (Fig. 13).
Fig. 13.
Summary of the entire treatment process. (A) Schematic illustration and timeline of two-phased orthodontic treatment. White numbers indicate treatment duration (in months) after the start of treatment; (B) Representative intraoral pictures of the process of two-phased orthodontic treatment
Acknowledgements
The authors thank all the researchers for their participation in this study and the Affiliated Hospital of Qingdao University for providing a good clinical working environment and equipment.
Author contributions
CL performed the major patient clinical operations, analyzed and interpreted the patient data and was a major contribution writing the manuscript. DR proposed and agreed with the patient clinical treatments and performed major patient clinical operations. XY took part in funding acquisition and writing-editing. All the authors have read and approved the final manuscript.
Funding
This work was supported by grants 11702154 and 32171303 from the National Natural Science Foundation of China.
Data availability
Data is provided within the manuscript or supplementary information files.
Declarations
Ethics approval and consent to participate
All clinical interventions were conducted in accordance with the Declaration of Helsinki.
Consent for publication
Written informed consent for publication of her clinical details and clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal. This case report has been approved by the Institutional Review Board of the Affiliated Hospital of Qingdao University with protocol number—QYFYWZLL28626. The ethics approval and the written informed consent included the permission of using the photos, radiographs and raw data of CT of the patient.
Competing interests
The authors declare no competing interests.
Clinical trial number
Not applicable.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Xiao Yuan, Email: yuanxiaoqd@qdu.edu.cn.
DaPeng Ren, Email: rendapeng@qdu.edu.cn.
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Data Availability Statement
Data is provided within the manuscript or supplementary information files.