Article Text

Strategic combination of cultivated oral mucosal epithelial transplantation and postoperative limbal-rigid contact lens-wear for end-stage ocular surface disease: a retrospective cohort study
  1. Yulia Aziza1,2,
  2. Kojiro Imai1,
  3. Motohiro Itoi1,
  4. Hokoru Yoshioka1,
  5. Seitaro Komai1,
  6. Koji Kitazawa1,
  7. Ratna Sitompul2,
  8. Mayumi Ueta1,
  9. Hideki Fukuoka1,
  10. Tsutomu Inatomi1,3,
  11. Shigeru Kinoshita1,4,
  12. Chie Sotozono1
  1. 1Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
  2. 2Department of Ophthalmology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
  3. 3Department of Ophthalmology, National Center for Geriatrics and Gerontology, Aichi, Japan
  4. 4Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
  1. Correspondence to Professor Chie Sotozono, Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto 602-0841, Japan; csotozon{at}


Purpose To provide the long-term outcome of patients with end-stage severe ocular surface disease (OSD) consecutively treated with cultivated oral mucosal epithelial transplantation (COMET) followed by limbal-rigid contact lens (CL)-wear therapy.

Design Retrospective cohort.

Methods In 23 eyes of 18 patients with severe OSD who underwent COMET surgery between 2002 and 2019 and who were followed with limbal-rigid CL-wear therapy for at least 1 year postoperative, patient demographics, best-corrected visual acuity (BCVA, logMAR), Ocular Surface Grading Scores (OSGS), surgical indication and adverse events were reviewed. Primary and secondary outcomes were BCVA and OSGS changes at baseline and final examination, respectively.

Results This study involved 16 patients with Stevens-Johnson syndrome and 2 patients with mucous membrane pemphigoid (mean age: 59±15 years). The indications for COMET were as follows: corneal reconstruction for vision improvement (10 eyes (43.5%)), corneal reconstruction for persistent epithelial defect (4 eyes (17.4%)) and conjunctival (fornix) reconstruction for symblepharon release (9 eyes (39.1%)). The mean duration of CL-wear postsurgery was 6.4±3.9 years (range: 1.4 to 13.3 years). The mean BCVA at baseline and at final follow-up was logMAR 1.9±0.5 and 1.3±0.7, respectively (p<0.05). Compared with those at baseline, the OSGSs for symblepharon and upper and lower fornix shortening showed significant improvement at each follow-up time point post treatment initiation. No serious intraoperative or postoperative adverse events were observed.

Conclusion In patients afflicted with severe OSD, COMET combined with limbal-rigid CL-wear therapy postsurgery was found effective for vision improvement and ocular surface stabilisation.

  • contact lens
  • ocular surface
  • rehabilitation
  • treatment surgery
  • cornea

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

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  • Limited treatment options are available for end-stage ocular surface disease (OSD), including keratoprosthesis, which has numerous risks of complications such as glaucoma and retroprosthetic membrane. The long-term ocular stability of the treatment still needs to be proven. Cultivated oral mucosal epithelial transplantation (COMET) was introduced as surgical option in end-stage OSD.


  • We reported a long-term outcome of limbal-rigid contact lens following COMET in end-stage OSD through visual acuity and Ocular Surface Grading Score changes.


  • Long-term combination of surgical and non-surgical approaches for end-stage OSD has not yet been reported in a previous study. This strategic combination might be considered as treatment option for ocular stability and vision improvement in end-stage OSD.


Cultivated oral mucosal epithelial transplantation (COMET) is a novel surgical method that is now gaining worldwide acceptance for the treatment of severe ocular surface disease (OSD).1 2 Chronic severe OSDs, although mostly at the end stage of the disease, are reportedly the preferred indication for COMET,3 4 as it has been shown that it improves visual acuity (VA) at 24 weeks postoperative in OSD cases with end-stage total limbal stem cell deficiency (LSCD).5 It has also been reported that COMET is effective for treating persistent epithelial defects (PEDs), that it results in symblepharon improvement, and that it restores vision in eyes afflicted with ocular surface damage.6–8 The findings in a recent prospective interventional case series study by Venugopal et al revealed that in patients afflicted with chronic Stevens-Johnson syndrome (SJS) ocular sequelae, COMET resulted in restoration and stabilisation of the ocular surface, as well as an improvement in VA.9 Moreover, the findings in recent studies conducted by our group on the long-term outcome of COMET revealed diverse results depending on the underlying diseases and the condition of the ocular surface prior to surgery.6 10

In 2007, our group reported the effectiveness of our new grading system, the Ocular Surface Grading Score (OSGS), for objectively evaluating the chronic ocular manifestations in patients afflicted with SJS.11 We also reported that post COMET, additional surgeries such as penetrating keratoplasty and deep lamellar keratoplasty are sometimes required to improve VA and help maintain the surgical outcome.5 12 In addition, several studies have reported a non-surgical approach for OSD. The use of Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) model, which involves using a large-diameter, gas-permeable scleral contact lens (CL), resulted in favourable visual outcomes on SJS/toxic epidermal necrolysis (TEN) cases.13 14

In 2014, we reported the development of a new 13.0 mm to 14.0 mm diameter limbal-rigid CL with a peripheral zone that covers the limbal region.15 To obtain government approval for the use of our new limbal-rigid CL, we performed an investigator-initiated clinical trial of the lens in patients with SJS and TEN along with ocular sequelae, and our findings revealed that at 3 months after the initiation of limbal-rigid CL therapy, best-corrected visual acuity (BCVA) had increased in all patients and their overall quality of life, as assessed by use of the National Eye Institute Visual Function Questionnaire, was vastly improved.16 The long-term follow-up (mean follow-up period: 4.3±1.1 years) of limbal-rigid CL therapy for SJS showed VA improvement.17 Moreover, the effectiveness of our new limbal-rigid CL when used as a therapeutic modality post COMET for the treatment of severe OSDs was evaluated, and we found that the use of the lens reduced corneal irregularity and improved visual function. In addition, the limbal-rigid CL was found to have good wettability when worn, thus reducing eye pain related to severe dryness of the ocular surface and providing long-term stabilisation of the ocular surface.6

To date, the long-term outcome of combining COMET with limbal-rigid CL-wear therapy postsurgery in patients with severe OSD has yet to be examined. Thus, the purpose of this present study was to retrospectively evaluate the long-term results of limbal-rigid CL-wear therapy post COMET in patients with severe OSD by assessing the VA and OSGS changes following the initiation of treatment.


Collection of patient data

The protocols of this study were approved by the Institutional Review Board of Kyoto Prefectural University of Medicine, Kyoto, Japan. The data of the patients who underwent COMET surgery at our institute were divided into four COMET study-related periods: (1) a retrospective cohort clinical study (study period: 2002–2008), (2) a retrospective cohort clinical study (study period: 2009–2011), (3) a prospective clinical study (study period: 2014–2017) and (4) an investigator-initiated clinical trial (phase III) (study period: 2017–2020). The protocol of the prospective clinical study was approved by the Ministry of Health, Labor and Welfare (UMIN000012819), and the protocol of the investigator-initiated clinical trial (phase III) was approved by the Pharmaceuticals and Medical Devices Agency of the Japanese regulatory authority (UMIN000034335). All studies were conducted in accordance with the tenets set forth in the Declaration of Helsinki, and prior written informed consent was obtained from all patients who participated in the study.

The inclusion criteria were as follows: patients aged 15 years or older who underwent COMET surgery for the treatment of a severe OSD, followed by limbal-rigid CL (Suncon Kyoto-CS; Sun Contact Lens Co, Kyoto, Japan) wear therapy for one or more years postoperative from 2002 to 2020. The medical records of all study participants (ie, patient demographics such as age, sex, eye laterality, disease onset and aetiology, length of the follow-up period, surgical indication; and follow-up evaluation through hospital visit included intraoperative and postoperative adverse events, BCVA (in logMAR) and the OSGS) were collected and reviewed.

In the retrospective cohort studies (ie, the first and second period of the COMET study), the indication for undergoing COMET was divided into the following four categories: (1) corneal reconstruction for vision improvement, (2) corneal reconstruction for the treatment of PED with acute inflammatory activity, (3) conjunctival fornix reconstruction and (4) other reasons.5 In the prospective clinical study, the indication for undergoing COMET was divided into the first three categories described above. In the investigator-initiated clinical trial, the primary endpoint was the release of symblepharon, so the surgical indication in those cases was categorised depending on the specific area of the eye in which the COMET sheet was applied.

For analysis, all VA values in decimal were converted to logarithm of the Minimal Angle of Resolution (logMAR), and the Snellen-chart VA test values of counting fingers, hand movement, light perception and no light perception were converted to 2.1, 2.4, 2.7 and 3.0 logMAR, respectively.18

To prevent information and selection bias, we collected data only from patients who had a minimum 1-year follow-up period after the limbal-rigid CL-wear therapy was initiated, and the study population was clearly defined. By grouping the COMET study-related periods, the chance of having an absence of data was minimised, and the STROBE cohort checklist was used when writing our report.19

Grading system evaluation

The OSGS was used to clinically evaluate the eyelid, conjunctiva and cornea involvement in the chronic OSD cases in this study.11 Based on our previous report on the long-term progression of OSD in cases of SJS and TEN, the following seven OSGS components of the cornea and conjunctiva were included in this present study: cornea (conjunctivalisation, neovascularisation, opacification and keratinisation) and conjunctiva (symblepharon and shortening of the upper and lower conjunctival sac).20 Each component was graded on a scale from 0 to 3 based on the severity of the ocular involvement. The cumulative score of all seven components represented the total OSGS, with a maximum score of 21, and the scoring system was used to evaluate the clinical appearance through the use of slit-lamp photographs taken by the trained doctors. The OSGS was assessed at baseline (ie, at the time of the initial examination before COMET surgery), at 6 months post COMET, at immediately prior to initiating limbal-rigid CL-wear therapy and at the final follow-up examination.

The indication of COMET in the severe OSD cases presented in this study was corneal reconstruction for vision improvement, corneal reconstruction for PED management and conjunctival (fornix) reconstruction for symblepharon release.6

Limbal-rigid CL prescription

After complete re-epithelialisation was obtained post COMET, each patient underwent slit-lamp examination for the fitting of the limbal-rigid CL. In each patient, a specific limbal-rigid CL was prescribed, and the fitting of the lens was evaluated at each follow-up examination. The details of the CL prescription were as described previously.15 16 21 Briefly, the specifications of the trial set of fitted CLs prescribed were as follows: (1) a 7.90 mm base curve, (2) a 14.0 mm diameter, (3) an 8.50 mm optical zone and (4) a flat peripheral edge design. Fluorescein staining was performed, as the staining pattern was needed to evaluate the centration of the lens, the dynamic fit of the lens, and the tear pooling. A 'best-fit' CL was defined as a lens having a curvature that ran parallel with the cornea and with a moderate tear layer in the sclera. After the size of the best-fit lens was determined, a subjective VA examination was performed and the lens was then accordingly prescribed.21

Adverse events

All adverse events, including the incidence and the severity of the event that occurred during the course of the limbal-rigid CL-wear therapy, were collected from the patients' medical records, and then analysed.

Statistical analysis

Statistic analysis was performed using IBM SPSS Statistics software V.26.0 (International Business Machines Corporation, Armonk, New York, USA). On a non-normal data distribution, we used the Wilcoxon signed-rank test to compare the mean BCVA and OSGS findings at baseline (before COMET surgery) and at the final follow-up examination. Dunnett’s test was used to compare the OSGS at each time point. A p value of <0.05 was considered statistically significant.


Demographic data

From a total of 136 eyes that underwent COMET between 2002 and 2019, 23 eyes (18 patients) that underwent limbal-rigid CL-wear therapy postsurgery were included. The patient demographics are shown in table 1. The cause of severe OSD in the cases reviewed in this study was SJS and mucous membrane pemphigoid (MMP). In 9 (38.7%) of the total 23 eyes, additional surgeries were performed post COMET. The aetiology of SJS was the oral ingestion of cold medicine (12 patients (74.8%)), non-steroidal anti-inflammatory drugs (2 patients (12.6%)), an antibiotic (1 patient (6.3%)) and an antiepileptic drug (1 patient (6.3%)).

Table 1

Demographic data of the patients who underwent COMET followed by limbal-rigid CL-wear therapy

Intervention time

The mean elapsed period from the onset of the disease to the patient undergoing COMET surgery was 18.5±18.1 years (range: 3 months–53.7 years). Post COMET surgery, the mean duration of the limbal-rigid CL-wear therapy post fitting of the CL was 1.8±2.3 years (range: 4 months–10 years). The clinical research of the limbal-rigid CL-wear therapy was initiated in 2009, and the prospective COMET study was initiated in 2014. In 6 of the 9 cases, the time period selected for initiating limbal-rigid CL-wear therapy post COMET surgery ranged between 3 and 6 months. Moreover, during the COMET retrospective study period (ie, before 2014), we began administering limbal-rigid CL-wear therapy for more than 6 months after COMET. In all patients, the CL was worn during daily activities, with a mean daily duration of use of 15–16 hours. The patients wore the CL for a median duration of 6.4±3.9 years (range: 1.5–13.3 years) (online supplemental table).

Supplemental material

BCVA and OSGS evaluation

The BCVA changes from at baseline to the final follow-up examination are shown in figure 1. The mean BCVA (logMAR) at baseline and at the final follow-up examination was 1.9±0.5 and 1.3±0.5, respectively, thus showing a significant improvement in VA (Wilcoxon signed-rank test, p=0.01). The mean change of BCVA was 0.5 (logMAR). The findings obtained at the final follow-up examination revealed that BCVA had not improved in five eyes (21.7%) due to persistent central corneal opacity (n=4 patients) and inconsistent follow-up (n=1 patient). As is shown in the box plot graph (figure 2), in comparison to that at baseline, BCVA improved post COMET. Moreover, additional improvement in BCVA was found post limbal-rigid CL-wear therapy in all COMET indication group subjects; that is, in 17 eyes (94.4%), BCVA was found to have improved more than 0.2 (logMAR) when compared with that observed at baseline.

Figure 1

Scatter plot graph of BCVA at baseline (precultivated oral mucosal epithelial transplantation surgery) and at final follow-up examination. As is shown in the scatter plot graph, BCVA was found to have increased in more than half of the subjects at the final follow-up examination. BCVA, best-corrected visual acuity.

Figure 2

Box plot graph of BCVA change based on three COMET indications evaluated at the following four time-points: (1) at baseline (ie, before COMET surgery), (2) at 6 months post COMET, (3) at prior to initiating limbal-rigid CL-wear therapy post COMET and (4) at the final follow-up examination. BCVA, best-corrected visual acuity; CL, contact lens; COMET, cultivated oral mucosal epithelial transplantation; PED, persistent epithelial defect.

The data on the BCVA and OSGS change at baseline, at post COMET, at prior to initiating the limbal-rigid CL-wear therapy and at final follow-up examination are shown in the online supplemental table. The mean total OSGS change between at baseline and at the final follow-up examination was 5.7±4.3. During the early COMET study period (ie, 2002–2011), vision improvement was the most common indication for undergoing COMET surgery, as is represented by the cornea being the most common location for the surgical application of the COMET sheet. The mean change in each of the seven OSGS components is shown in figure 3.

Figure 3

The seven OSGS components used for the evaluation of change post-treatment. The initial examination performed before COMET surgery was used as the baseline point. A slight significant reduction of corneal opacification was observed at the final follow-up examination. Significant reduction of symblepharon and fornix shortening (upper and lower fornix) was observed at 6 months post COMET, at prior to the initiation of the limbal-rigid CL-wear therapy, and at the final follow-up examination. p<0.05. CL, contact lens; COMET, cultivated oral mucosal epithelial transplantation; OSGS, Ocular Surface Grading Score.

A case-specific illustration of the timeline of each indication of COMET, that is, corneal reconstruction for vision improvement, corneal reconstruction for PED and conjunctival fornix reconstruction, is shown in figure 4. No serious adverse events, including intraoperative and postoperative complications and infections, occurred during the study period.

Figure 4

Images illustrating the treatment course (timeline and indication for COMET surgery) in specific cases. Case 7, a patient with mucous membrane pemphigoid who underwent COMET for vision improvement at nearly 6 years from disease onset and limbal-rigid CL-wear therapy initiated at 1 year post COMET. Case 14, a patient with SJS who underwent COMET surgery for vision improvement at 1 year from disease onset and limbal-rigid CL-wear therapy initiated at 3.25 years post COMET. Case 10 and 11 represent both eyes of a patient with SJS with different indications for undergoing COMET surgery; that is, for symblepharon release in the right eye and for persistent epithelial defect in the left eye. COMET was performed simultaneously at 4 months after disease onset, and limbal-rigid CL-wear therapy was initiated at 5 months post COMET. In all cases, the clinical findings showed clear improvement at 6 months post COMET, and final follow-up examination revealed a stable ocular surface with a slight change of the clinical findings. CL, contact lens; COMET, cultivated oral mucosal epithelial transplantation; SJS, Stevens-Johnson syndrome.


For the treatment of chronic severe OSD, specifically at the end-stage of the disease, there is currently no standard method applied for the improvement of vision.22–24 In patients afflicted with chronic severe OSD, COMET surgery results in successful reconstruction of the ocular surface, and moreover, BCVA following limbal-rigid CL-wear therapy improves.5 15 16 This study revealed that the combination of these two therapeutic approaches is safe without serious adverse effects and has shown favourable results for the improvement of vision. In addition, long-term ocular surface stabilisation was obtained in severe OSD cases (figures 2 and 3).

Furthermore, the other surgical approach for the treatment of end-stage OSD, keratoprosthesis, was reported by several ophthalmology centres.25–27 The long-term evaluation of keratoprosthesis retention and vision improvement within 3–5 years ranged from 30%–87.8% to 32%–52%, respectively.27 The most common complication experienced was sterile melts, glaucoma, retroprosthetic membrane and endophthalmitis.25 28 29

Of interest, other therapeutic interventions have recently been reported for the successful treatment of severe OSD, such as the combination of mucous membrane grafting and PROSE CL-wear, that is, a large-diameter rigid CL that ranged between 17.5 and 24 mm.13 30 31 However, it should be noted that in this present study, the baseline logMAR VA was worse than that reported in one of those two studies (range: 0.5–2.7 (median: 2.1) logMAR and 0.05–1.2 (median: 0.68) logMAR, respectively).30

Limbal-rigid CL-wear therapy initiated early post COMET surgery was found to have no adverse effect on the ocular surface healing process. However, it should be noted that in order to initiate the limbal-rigid CL-wear therapy, complete re-epithelialisation of the ocular surface must first be surgically obtained. In most cases, ocular surface stabilisation developed at 5–6 months post COMET.32 The findings in our recent case-series study revealed that limbal-rigid CL-wear therapy post COMET resulted in a gradual improvement of BCVA.33

In this study, BCVA significantly improved for a minimum of 1 year following the initiation of limbal-rigid CL-wear therapy post COMET, possibly due to tear-exchange being maintained while the CL is worn. The design of the limbal-rigid CL allows for the creation of a reservoir of tears under the lens, which neutralises regular and irregular astigmatism arising from the corneal surface and prevents excessive tear evaporation.16 21 34 Other studies have described the use of a scleral CL (ie, the PROSE system), which has similarities with the limbal-rigid CL in terms of tear accumulation behind the lens. Reportedly, the PROSE CL provides improvement in VA and visual function in patients with SJS with chronic ocular sequelae that did not respond to conventional treatment, however, due to the large diameter of the lens a wider interpalpebral opening is required.13 14 35

Most of the chronic OSD cases in this present study were patients afflicted with SJS (ie, 20 of the total 23 eyes). In 2016, the government of Japan approved SJS as an indication for the initiation of limbal-rigid CL-wear therapy, thus explaining why SJS was the most common aetiology in this study. Following that government approval, we were able to start planning treatments involving the combination of COMET and limbal-rigid CL-wear therapy for cases of end-stage chronic OSD, and that intervention improved the visual prognosis, as is shown in online supplemental table. Moreover, our limbal-rigid CL can now be used for the clinical treatment of other types of chronic OSD, such as MMP and graft-versus-host disease. However, MMP cases, which are usually older age subjects, have difficulties in wearing and taking care of the CL, which is one reason for the low number of MMP cases in this present study.

In this study, the OSGS-associated objective findings of the ocular surface revealed that symblepharon and fornix shortening had significantly improved post COMET surgery. The combination of COMET surgery and postoperative limbal-rigid CL-wear therapy stabilised the anatomical structure of the fornices until the final follow-up examination. Moreover, postoperative use of the lens reduced the amount of upper and lower conjunctival tarsal abrasion to the cornea, decreased the amount of ocular discomfort, and prevented contact between the bulbar and tarsal conjunctiva. In our previous study, the subjective tolerance of using the limbal-rigid CL for the reduction of ocular pain after CL-wear was assessed and evaluated via use of the National Eye Institute Visual Function Questionnaire (NEI-VFQ25).16 When a comparison was made between pre-CL fitting and 3 months after the initiation of the limbal-rigid CL-wear therapy, our findings revealed that conjunctival hyperaemia was decreased and that the reduction was maintained until the final follow-up examination performed at 5 years after the therapy was initiated.17 Moreover, the design of the limbal-rigid CL in combination with proper and frequent use of artificial tears allowed each patient to wear the lens for more than 12 hours per day and avoid any pain associated with the extended usage.6 21

Compared with at baseline, only a slight significant improvement in the condition of the OSGS corneal score was found at the final follow-up examination, and for unknown reasons, there was a slight reduction in corneal opacification. Thus, further investigation is needed to elucidate the underlying cause of the change in corneal opacification. It should be noted that similar findings of corneal opacity and neovascularisation regression after PROSE CL treatment were previously reported by Cressey et al and Liao et al.36 37 The proposed mechanisms are that the scleral lens provides an environment to support stromal remodelling, and that back-surface channels of the lens increase oxygen exchange and may reduce physical and sectional forces of the lens on the ocular surface.36 37

It has been reported that a large-diameter CL may present the risk for LSCD worsening due to limbal hypoxia and mechanical trauma, as reported in several studies.38 39 It has also been reported that the Asian population has tighter eyelids with more narrow palpebral apertures, which tend to increase the force of CL movement against a less steep cornea.39 The limbal-rigid CL presented in this study has a smaller diameter than the scleral lens, thus possibly reducing the risk of LSCD worsening as indicated via the score of the OSGS being maintained until the final follow-up.

It should be noted that no VA improvement occurred in five eyes in this study, even after undergoing limbal-rigid CL-wear therapy post COMET. For example, case 20 and case 22 were end-stage OSD eyes with severe stromal opacity and symblepharon. Although COMET was performed to improve vision in those two cases, central stromal opacity remained at the final follow-up visit. Subjectively, the patients reportedly felt that vision had improved in comparison to the VA and overall ocular condition they experienced prior to undergoing COMET. Several factors have an influence on visual improvement, such as the presurgical condition, patient compliance and the progression of the disease itself.20 As reported by Komai et al, the condition pre-COMET and the underlying disease can affect the therapeutic outcome.10

It should be noted that one limitation in this present study was the small number of cases. Thus, we are currently performing a prospective study to more deeply clarify the benefit of the combined treatment of COMET and postoperative limbal-rigid CL-wear therapy in cases afflicted with severe OSD, which has already approved by the government.

In conclusion, the findings in this study show that COMET surgery improves the conjunctival fornix and cornea appearance, and that in combination with limbal-rigid CL-wear therapy postsurgery, results in an advancement in visual rehabilitation and ocular surface stability in cases of end-stage severe OSD.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved by Institutional Review Board of Kyoto Prefectural University of Medicine, Kyoto, Japan: RBMR-C-662-4 for the limbal-rigid and CLERB-C-1581-2 for the follow-up study of post COMET. Participants gave informed consent to participate in the study before taking part.


Supplementary materials

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  • Contributors YA, KI, MI, HY, SeitaroK and KK carried out the data collection. YA wrote the manuscript with support from KK, RS, MU and HF and also analysed the data. TI, MU and RS helped supervise the project. MU, ShigeruK and CS conceived the original idea. CS supervised the project. All authors discussed the results and commented on the manuscript. CS acted as the guarantor of the study.

  • Funding This study was supported by a Grant-in-aid for Scientific Research from the Japanese Ministry of Health, Labor and Welfare (grant number: 23FC1038), a Research Grant from the Japan Agency for Medical Research and Development (grant number: AMED, JP23ek0109572h0003) and a Research Grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology (grant number: 23FC1038).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.