Efficacy of clear aligners on mandibular molar distalization: A retrospective study

Jie Han; Nan Ning; Hongjiang Du; Mengqi Zhou; Chaoying Cai; Yaya Hong; Yi Zhou; Xuepeng Chen

doi:10.4103/digm.digm_30_21

ORIGINAL ARTICLE

Year : 2021 | Volume : 7 | Issue : 1 | Page : 1

Efficacy of clear aligners on mandibular molar distalization: A retrospective study

Jie Han¹, Nan Ning², Hongjiang Du³, Mengqi Zhou⁴, Chaoying Cai⁴, Yaya Hong⁴, Yi Zhou⁵, Xuepeng Chen⁴
¹ Department of Pediatric Dentistry, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Zhejiang, China
² MeiQi Technology, China
³ Department of Stomatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, China
⁴ Department of Orthodontics, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Zhejiang, China
⁵ Department of Implantation, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Zhejiang, China

Date of Submission	25-Jul-2021
Date of Decision	16-Aug-2021
Date of Acceptance	06-Oct-2021
Date of Web Publication	07-Dec-2021

Correspondence Address:
Xuepeng Chen
Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310006
China
Yi Zhou
Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310006
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/digm.digm_30_21

Abstract

Background: Clear aligners (CAs) can distalize mandibular molars. The present study aimed to study the efficiency and influencing the factors of CAs for mandibular molar distalization and to provide guidance for clinical design. Materials and Methods: The present study evaluated 32 adult orthodontic patients who needed mandibular molar distalization and were treated with CAs between September 2018 and September 2020 at the school of medicine. The cone-beam computed tomography images of T₀ (before orthodontic treatment) and T₁ (after mandibular molars were fully distalized) were collected, and the actual movements of mandibular molars were measured and compared with the expected movements. The efficiency of mandibular molar distalization during treatment was comprehensively evaluated, and the relevant factors were analyzed. Results: For mandibular first molar distalization, the average efficiency of the crown was 67.19% 9swn. 13%, and that of the root was 37.87% 7stn. 72%. There was a significant difference between the achieved movement amount and the expected amount (P < 0.05). For mandibular second molars, the average efficiency of the crown was 58.47% 7swn. 07%, and that of the root was 57.03% 3stn. 48%. There was a statistically significant difference between the achieved movement amount and the expected amount (P < 0.05). There was a significant negative correlation between the expected movement and the efficiency of the crown. Conclusions: CAs can achieve mandibular molar distalization, and the movement pattern of molars is mainly a tipping movement. To accomplish bodily movement, overcorrection should be fully considered. In addition, it is suggested that close attention should be given to observing root movement during molar distalization.

Keywords: Clear aligner, Efficiency, Mandible superimposition, Mandibular molar distalization

How to cite this article:
Han J, Ning N, Du H, Zhou M, Cai C, Hong Y, Zhou Y, Chen X. Efficacy of clear aligners on mandibular molar distalization: A retrospective study. Digit Med 2021;7:1

How to cite this URL:
Han J, Ning N, Du H, Zhou M, Cai C, Hong Y, Zhou Y, Chen X. Efficacy of clear aligners on mandibular molar distalization: A retrospective study. Digit Med [serial online] 2021 [cited 2023 Mar 24];7:1. Available from: http://www.digitmedicine.com/text.asp?2021/7/1/0/331950

Introduction

In the clinic, mandibular molar distalization is one of the main methods to increase the length of the lower dental arch to obtain space. Clear aligners (CAs) have been widely used because of their esthetics and comfort.^[1] Molar distalization is one of the tooth movement methods with a high expression rate.^{[2],[3],[4],[5],[6]} Zheng proposed that CAs have advantages in molar distalization.^[7]

The CA technique can display an animation of tooth movement in the design stage. However, there is a difference between the actual correction effect and the expected correction effect of the CA technique, which cannot be 100% achieved in the clinic.^{[8],[9],[10],[11],[12]} Many doctors have found that it may be necessary to restart during the treatment process or to adjust when the treatment is over to achieve the final treatment goal.^[10],[11] It extends chair time and reduces the trust of patients in CA technology. To clarify this clinical problem, research on the efficiency of CAs has been a hotspot in recent years.

At present, the expression rate of molar distalization in CAs is mostly focused on the upper jaw.^{[12],[13],[14]} However, recent practice has proven that CAs can effectively distalize mandibular molars.^[15]

An and Jang used the anatomical structures of the mandible to superimpose the lower dental models of 10 adults.^[16] They proposed that the mandibular tori can be used as a reliable registration structure. However, the incidence of mandibular tori differs among different populations, ranging from 9.8% to 37.8%.^{[17],[18],[19],[20]} Therefore, the use of mandibular tori for superimposition is limited to specific groups of people.

Some scholars proposed that the upper dental model can be superimposed with the stabilization structure of the palate, and then, the lower dental model can be registered through the occlusal relationship.^{[21],[22],[23]} However, the occlusion changes as the tooth moves, and the position of the mandible will also change accordingly, which affects the measurement of tooth movement. Dai proposed that mandibular rotation and translation can be measured by lateral cephalograms to calibrate the changes in mandibular position, eliminating the influence of occlusal changes on superimposition.^[24] However, the steps were complicated, and there was a horizontal error in the anterior tooth area.

According to the long-term follow-up study of implants by Bjürk,^[25],[26] the stable structures of the mandible include the inner cortical structure to the inferior border of the mandibular symphysis. Based on the stable structures, it is not difficult to superimpose nongrowing patients' serial cone-beam computed tomography (CBCT) models.

Ruellas^{[22],[27],[28]} proposed that by choosing the mandibular base bone and the mandibular symphysis as the registration areas, reliable mandible superimposition can be obtained with the voxel-based superimposition method.

Recently, some researchers have used different software to implement the voxel-based superimposition method to register the mandible and obtain a stable three-dimensional mandible superimposition.^{[29],[30],[31]} However, there have been few studies further measuring the movement of mandibular teeth after mandible superimposition.

This study intends to use the voxel-based superimposition method to register the mandible during treatment in adult orthodontic patients, to study the expression rate at the two levels of the crown and the root and to analyze the influencing factors of mandibular molar distalization to provide a reference for the design of the clinical plan.

Materials and Methods

Research object

This retrospective study protocol was approved by the Ethics Committee of Stomatology Hospital, School of Medicine, Zhejiang University, China (No. 2020-08-081). The study was performed on 32 patients admitted to the School of Medicine during September 2018 to September 2020 who were treated with CAs. All of these patients met the inclusion and exclusion criteria and possessed complete imaging data and medical records. The average age in the experimental group (9 males and 23 females) was 24.83 ± 2.48 years (range 18–31 years).

Inclusion criteria

Permanent dentition, 4 s molars had fully erupted and established.
Unilateral or bilateral mandibular molar distalization was designed in the treatment plan.
The patient's compliance was good, the daily appliance wear time was more than 20 h, or each appliance was worn for more than 7 days.
Good oral hygiene, good periodontal condition, no obvious absorption of alveolar bone.
No temporomandibular joint disease or serious systemic diseases.
If the patient has mandibular third molars before the treatment, the mandibular third molars must have been extracted when wearing the CAs.
The retromolar space can ensure 100% completion of the design plan.
Class III elastic or temporary skeletal anchorage devices were designed in the treatment plan as anchorage systems.

Exclusion criteria

The patient's compliance was poor, the daily appliance wear time was <20 h, or each appliance was worn for <7 days.
The observation tooth was adjusted in a large area during the treatment process.
The position and shape of the chin or ramus of the mandible were changed due to trauma or other reasons during the treatment process.
History of systemic diseases or radiation therapy at the head and neck.
History of taking medications that affect bone metabolism, such as a history of taking bisphosphonates, and the long-term use of nonsteroidal anti-inflammatory drugs.

Data collection

The data of all patients at the first visit (T₀ stage) and the end of mandibular molar distalization (T₁ stage) were collected as follows:

Cone-beam computed tomography

All patients underwent CBCT by a uniformly trained physician in the Department of Radiology, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, taking the sitting position, fixing the head (without using the fixation device that affects the occlusion), biting the posterior segment, breathing smoothly, and not swallowing. The data were stored in Digital Imaging and Communications in Medicine.

Panoramic radiography and lateral cephalometrics

All patients underwent panoramic radiography and lateral cephalometrics by a uniformly trained physician in the Department of Radiology, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, taking the standing position, maintaining the natural head position, closing the upper and lower lips naturally, relaxing the tongue and perioral muscles, biting the posterior segment, breathing smoothly, and not swallowing. The data were stored in Bitmap-File (BMP).

Expected movement

ClinCheck software [Figure 1] or iOrtho software [Figure 2] was used to read the expected distalization movement of the target tooth, taking distal movement as positive. The data were stored in a Microsoft Office Excel database.

Figure 1: Tooth movement scale in ClinCheck.

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Figure 2: Tooth movement scale in iOrtho.

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Mandible superimposition for T₀ and T₁ cone-beam computed tomography data

Mandible orientation at the T₀ stage

The T₀ CBCT data were imported into Dolphin Imaging software using the “Orientation” function to reposition the mandible. In the lateral view, the horizontal line was adjusted to tangent to Menton, and the coronal line was adjusted to tangent to Pogonion. In the bottom view, the median sagittal line was adjusted to bisect the median union of the mandible. In the frontal view, the median sagittal line was adjusted to pass the anterior nasal ridge and piriform foramen [Figure 3].

Figure 3: Mandible orientation at T0 stage (a. Left view; b. Right view; c. Front view; d. Bottom view).

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Mandible registration

The “Superimposition” function was used to superimpose the CBCT data of stages T₀ and T₁ based on the lower jaw, as follows:

The most concave points of the bilateral sigmoid notch, the most convex points of the bilateral mandibular angle, and the Pogonion were selected as the marking points to perform preliminary alignment of the mandible [Figure 4].
The mandibular symphysis and mandibular body bone, which were more than 5 mm away from the mandibular tooth roots, were selected as the registration area to register the mandible using the “Volume Auto Superimposition” function. The registration was repeated three times to complete the mandible superimposition [Figure 5].
The “export orientation to 2^nd” function was used to transfer the mandibular position from T₀ to T₁.

Figure 4: Preliminary alignment of the mandible (white is T0 stage, green is T1 stage, the lower left corner is the preliminary registration preview).

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Figure 5: Mandible registration (a. Region selection, the voxel superimposition area is inside the red rectangle; b. Mandible superimposition, white is T0 stage, green is T1 stage).

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Measurement of the distalization movement of mandibular molars

The “2Dline” and “clipping slice” functions were used to measure the distalization movement of the crown and root in the sagittal plane, taking the left mandibular second molar (LL7) as an example. The details are as follows [Figure 6]:

Figure 6: Measurement of the distalization movement of mandibular molars (a. Bottom view; b. Bottom view; C. the sagittal plane; D. the sagittal plane).

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The CBCT slices were adjusted on the sagittal plane to clearly expose the root furcation.
The vertical distances from the proximal and distal points of the crown to the coronal line were measured and recorded as C_p and C_d.
The vertical distances from the root furcation point to the coronal line were recorded and recorded as R_f.
The vertical distances from the proximal and distal apex to the coronal line were measured and recorded as R_p and R_d.
The coordinates of mandibular molars were calculated: (a) The coordinate of crown at T₀(C₀): C₀= (C_p0 + C_d0)/2 and at T₁(C₁): C₁= (C_p1 + C_d1)/2; (2) the coordinate of root at T₀(R₀): R₀= (R_f0 + R_p0 + R_d0)/3 and at T₁(R₁): R₁= (R_f1 + R_p1 + R_d1)/3.

Calculation of the distalization movement of the mandibular molars

The mandibular molar distalization of the crown (ΔC = C₁ − C₀) and root (ΔR = R₁ − R₀) was calculated, and a positive value was found for distal movement.

The same computer was used to measure all of the data. Measurement was performed twice at an interval of 1 week. The intragroup correlation coefficient test of the data measured at different times was performed. If ICC <0.75, the third measurement was performed. In this experiment, the ICC was 0.976 > 0.75 (P < 0.05), the reliability was good, and the average value of the two measurements was taken and entered into the Microsoft Office Excel database.

Correction treatment evaluation

Expression rate = actual movement/expected movement × 100%.

Analysis of the factors influencing expression rate

The influence of gender on expression rate.
The influence of expected movement on expression rate.
The influence of third molar and sagittal skeletal patterns on the expression rate.
Dolphin imaging software was used to view the T₀ panoramic radiography and lateral cephalometrics. The presence or absence of third molars was recorded before the treatment. The ANB values were measured before treatment, and the sagittal skeletal patterns were recorded according to [Table 1].
The influence of the anchorage system on expression rate.

Table 1: Sagittal skeletal patterns classification.

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Statistical analysis

SPSS 26.0 software (IBM Corp., Armonk, NY) was used to perform the Shapiro–Wilk test and Q-Q chart normality test for each measurement value. All measurement data in this study obeyed or approximately obeyed a normal distribution using the mean ± standard deviation statistical description. The inspection level was α = 0.05. A paired t-test was performed on the measured movement of the left and right molars, and there was no significant difference between the left and right sides (P = 0.839, P > 0.05). Therefore, the mandibular molars were divided into the first mandibular molars (L6) and the second molars (L7), whereas the left and right sides were not distinguished.
The paired t-test was performed on the actual and expected movement to analyze whether there was a significant difference.
Patients were divided into two groups according to sex: Group 0 (female) and Group 1 (male). Levene's test was used for variance analysis. If the variance was homogeneous, two independent samples t tests were used; otherwise, the t-test of two independent samples was used to analyze whether the expression rate between the two groups was significantly different. Point-biserial correlation analysis between different genders and corresponding expression rates was used to analyze whether the two are related.
The linear trend between the expected movement and the expression rate was observed through the scatter diagram. Pearson correlation analysis between the expected movement and the expression rate was used to analyze whether the two were related.
Patients were divided into two groups according to the presence or absence of third molars before treatment: Group 0 (without third molars) and Group 1 (with third molars). Levene's test was used for the analysis of variance. If the variance was homogeneous, two independent samples t tests were used; otherwise, the t-test of two independent samples was used to analyze whether the expression rate between the two groups was significantly different. Point-biserial correlation analysis between the presence or absence of third molars before treatment and the corresponding expression rate was used to analyze whether the two were related.
Patients were divided into three groups according to the sagittal skeletal patterns: Group 1 (Type I), Group 2 (Type II), and Group 3 (Type III). Levene's test was used for the analysis of variance. If the variance was homogeneous, one-way analysis of variance was used to judge the differences between groups, and the Tukey–Kramer test method was used to compare the differences between the groups. Otherwise, Welch analysis of variance was used to judge the differences between groups, and the Games-Howell test method was used to compare the differences between groups. Kendall's tau-b correlation analysis was performed between the sagittal skeletal patterns and the corresponding expression rate to analyze whether the two were related.
Patients were divided into two groups according to the anchorage system: Group 0 (Class III elastic) and Group 1 (temporary skeletal anchorage devices). Levene's test was used for analysis of variance. If the variance was homogeneous, two independent samples t-tests were used; otherwise, the t-test of two independent samples was used to analyze whether the expression rate between the two groups was significantly different. Point-biserial correlation analysis between the presence or absence of third molars before treatment and the corresponding expression rate was used to analyze whether the two were related.

Results

Comparison of the actual and expected amounts of distalization

Crown level

The actual movement directions of L6 and L7 were both distal. The actual movement amount was slightly smaller than expected. The difference was statistically significant [Table 2].

Table 2: The actual and the expected amounts of distalization.

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Root level

The actual movement directions of L6 and L7 were mostly consistent with the expected directions, but some actual movement directions were opposite to the expected directions. The actual movement amount was different from the expected amount. The difference was statistically significant [Table 2].

Expression rate of mandibular molar distalization

The expression rate of the L6 crown was 67.19% ± 20.13%, and that of the L7 crown was 58.47% ± 21.07%. The expression rate of L6 roots was 37.87% ± 33.72%, and that of L7 roots was 57.03% ± 48.48%.

Analysis of factors influencing expression rate

Correlation between gender and expression rate

There was no significant difference between the two gender groups in terms of the expression rate, and there was no significant correlation between gender and the mobile expression rate [Table 3] and [Table 4].

Table 3: Comparison of expression rate of different gender.

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Table 4: Correlation analysis of gender and expression rate.

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Correlation between expected movement and expression rate

There was a moderately negative correlation between expected movement and the expression rate at the crown level of L6 and L7 [Table 5].

Table 5: Correlation analysis of expected movement and expression rate.

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Correlation between third molars and expression rate

There was no significant difference in the expression rate with or without third molars before treatment, and there was no significant correlation with the expression rate [Table 6] and [Table 7].

Table 6: Comparison of expression rate of with or without third molars.

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Table 7: Correlation analysis of third molars and expression rate.

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Correlation between sagittal skeletal patterns and expression rate

There was no significant difference in the expression rate between different sagittal skeletal patterns, and there was no significant correlation with the expression rate [Table 8] and [Table 9].

Table 8: Comparison of expression rate of different sagittal skeletal patterns.

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Table 9: Correlation analysis of sagittal skeletal patterns and expression rate.

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Correlation between anchorage system and expression rate

There was no significant difference in the expression rate between different anchorage systems, and there was no significant correlation with the expression rate [Table 10] and [Table 11].

Table 10: Comparison of expression rate of anchorage system.

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Table 11: Correlation analysis of anchorage system and expression rate.

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Discussion

Settings and design

This study was a retrospective study. Adult patients were selected as the research objects. This can prevent the development at the peak of growth from affecting the mandible superimposition and avoid the interference of the strong bone remodeling ability on the effect of tooth movement. In addition, this study excluded cases in which the CA was worn for <20 h per day or 7 days per pair and cases in which the appliance did not fit well before the mandibular molars had finished movement. Thus, the influence of poor compliance on the treatment effect was excluded.

From the design perspective, adequate retromolar space is an essential prerequisite for mandibular molar distalization. With the development of CBCT, scholars^[32],[33] have proposed that the limit of mandibular molar distalization should be considered on two levels. At the level of crowns, 4–6 mm proximal to the front margin of the mandibular ascending ramus is the limit of mandibular molar distalization. At the level of roots, the lingual cortex of the mandibular molar at the apical area is the limit. When the root of the tooth is in contact with the cortex, the movement of the tooth slows down, and the risk of root resorption increases significantly. Therefore, it is necessary to use CBCT to clarify the relationship between the lingual cortex and the roots of the mandibular molars. It is crucial to accurately determine the amount of distal movement of the molars to prevent undesirable consequences.

Combined with the expected movement, this study individually analyzed the patients' CBCT at the crown and root levels to ensure that there was enough retromolar space in the included cases.

CBCT can accurately present the three-dimensional images of the craniomaxillofacial region. Gribel^[34] proposed that the average error is 0.1 mm for a line distance measurement between CBCT and direct observation. The voxel superimposition method built with Dolphin Imaging software was used to perform the three-dimensional superimposition of the mandible with strong reliability. Using multidimensional graphs to measure the movement of the tooth from the crown and the root level, the researcher's measurement was highly reliable.

Treatment effect of mandibular molar distalization

This study shows that the actual movement direction of the mandibular molar was the same as expected, but there was a significant difference between the actual movement amount and the expected amount. The expression rate was 58.47%~67.19% at the level of crowns. According to Simon,^[12] the average expression rate of CAs is 59%. It can be said that the expression rate of the CAs for mandibular molar distalization is high.

However, compared with the reported expression rate of maxillary molar distalization,^[12] the expression rate of mandibular molar distalization is lower. The difficulty and slowness of tooth movement may be attributed to the dense bone of the mandible.

The actual movement direction of mandibular molar distalization was roughly the same as that expected at the root level. Most of the roots moved distally. However, in some cases, the actual movement direction is opposite to the expected direction. There was a significant difference between the actual movement amount and the expected amount, and the expression rate of mandibular molar distalization at the root level was low (37.87%~57.03%). This suggests that the CAs distalize the mandibular molars by tipping movement, not bodily movement. This is consistent with the inclination phenomenon of the mandibular molars in the process of distalization. In fact, the CAs act on the center of the crown but not the resistance center of the tooth, which will cause tooth tipping. This is consistent with the report that maxillary molar distalization occurs by tipping movement.^[13] Previously, there have been studies reporting that CAs can move molars bodily.^[14] However, this study was based on lateral cephalograms, whereas factors such as image superimposition might cause large errors when judging the root position.

As mentioned above, it is necessary to evaluate the position of the crown and root carefully before designing mandibular molar distalization, especially the relationship between the root and the surrounding bone cortex. When designing mandibular molar distalization, the amount of distal movement of the root can be appropriately extended to realize bodily movement of the molar. In addition, close attention should be given to the difference between the actual amount of movement and the expected amount during the process, and the anchorage should be strengthened when the molars are found to move obliquely.

At present, intraoral scanners are widely used. For follow-up of patients, in addition to checking regular aligner fitness and attachment inspections, it is recommended to perform oral digital scans to compare with the expected models in the corresponding period. When obvious molar tipping movement is observed in clinical practice, it is recommended to use CBCT to examine the relationship between the tooth root and the surrounding alveolar bone to adjust the treatment plan in time.

Influencing factors of expression rate

This study shows that the larger the expected amount of movement of the mandibular molars designed, the lower the expression rate. This study analyzed the relationship between the root and the surrounding bone cortex. Cases lacking adequate retromolar space were ruled out in advance. However, due to the various degrees of tipping movement during mandibular molar distalization, it is more difficult to realize the expression rate when the expected amount is larger. Therefore, proper overcorrection should be designed. The V pattern design plan for molar distalization can be appropriately optimized. Molar distalization can be designed more than once. The specific treatment plan should be personalized according to the patient's situation.

There was no significant correlation between the third molars or the sagittal skeletal patterns and the expression rate. This is because this study accurately assessed the retromolar space when the cases were included. It was indeed found that the roots of the mandibular second molars were in contact with the lingual cortex during the process of mandibular molar distalization with the CAs, and the lingual cortex was even absorbed by compression when the researchers were selecting the cases [Figure 7]. However, since CBCT was not taken before the treatment in these cases, it was impossible to analyze the relationship between the root contact and the orthodontic treatment. This also suggests that during the process when tipping movement of molars or slow movement is observed, it is necessary to use CBCT to clarify the relationship between molar roots and alveolar bone.

Figure 7: Cone beam computer tomography image during treatment (arrow shows the contact between the root of the mandibular second molar and the lingual cortex).

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Bias analysis

The weakness of this study included selection bias and recall bias intrinsic to retrospective studies, which might decrease the credibility of the experimental results. In addition, the study needs to collect CBCT data before and after treatment. However, it was difficult to obtain consent from the participants, so the sample size of the study was small. With the wide application of in-mouth scanners, the in-mouth model can be made directly by digital scanning, the retention process is simplified, and the accuracy is good. In later research, the sample size can be further expanded to obtain more reliable statistical data. In the future, we will carry out relevant prospective studies and minimize potential bias.

Conclusions

CAs can achieve mandibular molar distalization, and the movement pattern of molars is mainly a tipping movement. To accomplish bodily movement, overcorrection should be fully considered. In addition, it is suggested that close attention should be given to observing root movement during molar distalization.

Financial support and sponsorship

This study was supported by grants from National Natural Science Foundation of China (No. 81400511), Zhejiang Provincial Natural Science Foundation of China (No. LY18H140001).Presentation at a meeting: Nil.

Conflicts of interest

There are no conflicts of interest.

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