Transmalar Kirshner Wire Fixation Under Ultrasound Scanning is Useful for Unstable Zygomatic Arch Fracture Combined With Zygomatic Body Fracture.

Plate fixation to zygomatic arch fractures carries the risk of facial nerve palsy and scarring of the cheek; however, without plate fixation, bone deviation or displacement may reoccur after surgery. Furthermore, zygomatic arch fractures combined with zygomatic body fractures are more postoperatively unstable than single zygomatic arch fractures. Few reports have focused on this combined fracture type, and no consensus has been reached regarding treatment. Because plate fixation for slight deviation of the zygomatic body has little advantage for stabilization, the authors, usually opt for transmalar pinning alone instead of plate fixation at the hospital. This study is a retrospective case series of 7 patients, among 100 zygomatic fractures excluding isolated zygomatic arch fractures, treated using transmalar pinning under ultrasound scanning. The reduction was performed through the oral and temporal incision as a surgical procedure. Under ultrasound observation, a Kirshner wire was inserted into the zygomatic body from the unaffected side while maintaining the reduced position. The wire was removed at an outpatient visit 2 to 3 months following surgery. In all cases, the zygomatic body was of the laterally rotated type, and postoperative morphologic evaluation showed improvement without postoperative complications. Scores were higher in middle-aged and older than in young people. Correction of zygomatic rotation also scored higher than zygomatic arch morphology. Transmalar Kirshner wire fixation under ultrasound observation is a simple and minimally invasive method for zygomatic arch fractures, which avoids the possible complications related to plate fixation.

Therapeutic Potential of Adipose-Derived Stem Cell-Conditioned Medium and Extracellular Vesicles in an In Vitro Radiation-Induced Skin Injury Model.

Radiotherapy (RT) is one of three major treatments for malignant tumors, and one of its most common side effects is skin and soft tissue injury. However, the treatment of these remains challenging. Several studies have shown that mesenchymal stem cell (MSC) treatment enhances skin wound healing. In this study, we extracted human dermal fibroblasts (HDFs) and adipose-derived stem cells (ADSCs) from patients and generated an in vitro radiation-induced skin injury model with HDFs to verify the effect of conditioned medium derived from adipose-derived stem cells (ADSC-CM) and extracellular vesicles derived from adipose-derived stem cells (ADSC-EVs) on the healing of radiation-induced skin injury. The results showed that collagen synthesis was significantly increased in wounds treated with ADSC-CM or ADSC-EVs compared with the control group, which promoted the expression of collagen-related genes and suppressed the expression of inflammation-related genes. These findings indicated that treatment with ADSC-CM or ADSC-EVs suppressed inflammation and promoted extracellular matrix deposition; treatment with ADSC-EVs also promoted fibroblast proliferation. In conclusion, these results demonstrate the effectiveness of ADSC-CM and ADSC-EVs in the healing of radiation-induced skin injury.

Feasibility and usefulness of recommended screenings at long-term follow-up clinics for hematopoietic cell transplant survivors.

PURPOSE: Advances in allogeneic hematopoietic cell transplantation (allo-HCT) have resulted in a growing number of transplant survivors; however, long-term survivors are at risk of developing late complications, and published guidelines recommend screening of this population. We conducted a single-center prospective study to evaluate the adherence to and usefulness of recommended screenings at a long-term follow-up (LTFU) clinic. METHODS: We included consecutive patients who received allo-HCT at our center from 2014, as well as post-HCT patients visiting our outpatient clinic. Visits and screenings were planned at 3 months, 6 months, and 1 year after allo-HCT, and annually thereafter. Outcomes were reported by physicians including the incidence of findings at each screening that led to interventions. RESULTS: Among the 216 participants, 95% visited the LTFU clinic, and 94% completed planned screenings. However, the rate of secondary cancer screenings targeting high-risk subjects was lower (38% to 68%). The overall percentage of screening results leading to interventions was 4.5%, with higher percentages (> 10%) for bone density testing, ophthalmological examinations, dental assessment, upper gastrointestinal endoscopy, and colonoscopy, with two patients diagnosed with secondary cancers. CONCLUSIONS: Although the overall screening rate was high, it should be possible to improve the detection rate of late complications by decreasing screening failures, especially the screening for secondary cancers limited for high-risk survivors. A nationwide effort to educate HCT survivors and health practitioners using standardized nationwide LTFU tools may be effective, along with the development of institutional, local, and nationwide networks to maintain effective follow-up systems.

Quantitative Evaluation and Midterm Progress of Reconstructed Toe Thickness in Lateral Ray Polydactyly of the Foot.

In lateral ray polydactyly, the reconstructed toe often tends to become thicker, but no standard evaluation criteria for this thickness are available. 57 patients (68 toes) with Hirai-Togashi classification type II, III, or IV whom we were able to follow-up for more than 6 months after the operation were underwent measurement of the "Reconstructed toe width to Third toe width ratio." In addition, 16 patients who could be followed up for 3 years through the mid-term course were evaluated for mid-term progress. At 6 months after surgery, the mean R/T ratio was 1.246. In patients who could be followed up for 3 years after surgery, the mean R/T ratios at 6 months after surgery and at 3 years were significantly decreased. This result suggests that the thickness of the reconstructed toe may become relatively thin in the long term.

Free-flap reconstruction for full-thickness oral defects involving the oral commissure combined with oral modiolus reconstruction using a fascial sling.

BACKGROUND: Oral modiolus reconstruction is important in unilateral oral commissure removal including the modiolus. However, the proper procedure is not yet established. We performed free-flap reconstruction for full-thickness oral defects involving the oral commissure combined with oral modiolus reconstruction using a fascial sling. PATIENTS AND METHODS: From 2008 to 2018, six oral carcinoma patients, aged 65 to 86 years, underwent free-flap modiolus reconstruction after tumor resection. The resulting lip defects of 10% to 80% were labial (two patients), buccal (two patients), and mixed (two patients). RESULTS: Five anterolateral thigh flaps including one perforator and one radial forearm flap were performed. The oral defects were covered with folded flaps (size, 11 × 6-18 × 7.5 cm2 ). The orbicularis oris stumps were connected to the masseter with a fascia lata or palmaris longus tendon (length, 15-20 cm), arranged in a Y-shape in four patients and a V-shape in two patients. All the flaps survived without complications. Almost all the patients achieved good oral static effects (lip deviation and drooping) and dynamic effects (mouth opening, oral commissure narrowing, and diet) in the 6 to 65 months' follow-up. CONCLUSION: Free-flap reconstruction combined with oral modiolus reconstruction using a fascial sling achieves good oral static and dynamic effects for full-thickness oral reconstruction involving the oral commissure.

End-to-Side Venous Anastomosis to a Ligated Vein Stump for Free Flap Transfer in Head and Neck Reconstruction.

INTRODUCTION: In head and neck reconstruction, use of a free flap paired with end-to-side anastomosis to a preserved vein is generally performed. However, it is frequently difficult to select the recipient vein after a neck dissection in which there is only a ligated internal jugular vein/external jugular vein (IJV/EJV). Here, a new anastomosis technique using a ligated IJV/EJV stump is described. PATIENTS AND METHODS: End-to-side anastomoses to ligated vein stump surgeries for free flap transfer in head and neck reconstruction were performed at the Department of Plastic and Reconstructive Surgery, University of Tsukuba, from 2009 to 2016. RESULTS: The subject pool comprised 6 patients. All patients received a free flap transfer after head and neck tumor excision. The free flaps used were 1 free radial forearm flap, 1 free tensor fascia lata muscle perforator flap, and 4 free rectus abdominis musculocutaneous flaps. The cervical vessels used were 3 IJVs and 3 EJVs. All veins of the free flaps could be anastomosed end-to-side to ligated vein stumps without vein grafting. All flaps survived completely without complications. CONCLUSIONS: The end-to-side venous anastomosis to a ligated vein stump procedures were easy to perform and not dependent on the vessel diameters of the free flaps. No complications were observed in any patient owing to differences in vessel diameter, ease of anastomosis, and safety. Results suggest that this new technique is a simple and very useful option in head and neck reconstruction where the IJV/EJV cannot be preserved.

Efficacy and toxicity of transarterial chemoembolization therapy using cisplatin and gelatin sponge in patients with liver metastases from uveal melanoma in an Asian population.

BACKGROUND: Although both immune-checkpoint inhibitors and targeted therapies such as MEK inhibitors have been evaluated in metastatic uveal melanoma, the efficacy of these therapies is modest to date. The purpose of this study was to evaluate the efficacy and toxicity of transarterial chemoembolization (TACE) therapy for liver metastasis from uveal melanoma in an Asian population. METHODS: We retrospectively assessed the clinical data of patients with liver metastases from uveal melanoma who received TACE therapy using cisplatin (70 mg/m2) and gelatin sponge between 1997 and 2008. RESULTS: We identified 29 eligible patients. The overall response rate was 21%. The median survival time was 23 months, and the 1-, 2-, and 5-year survival rates were 72.4, 39.4, and 0%, respectively. The favorable prognostic factors were partial response and stable disease, <25% of the tumor volume within the liver at baseline, and normal serum lactate dehydrogenase (LDH) and normal alkaline phosphatase at baseline. Among them, normal LDH at baseline was the only independent prognostic factor in multivariate analysis. The common adverse events (AEs) were liver enzyme elevation (100%), nausea (72.4%), abdominal pain (65.5%), vomiting (55.2%), post-embolization syndrome (34.5% of patients, 9.6% of TACE procedures), and pyrexia (24.1%). Grade ≥3 AEs consisted of aspartate aminotransferase elevation (34.5%), alanine aminotransferase elevation (51.7%), and serum creatinine elevation (3.4%). CONCLUSION: TACE therapy has a certain degree of clinical efficacy with a tolerable toxicity and, therefore, can still be one of the treatment options. However, considering the lack of long-term efficacy of this therapy, further treatment strategies need to be developed.

Long-term results of orbicularis oris muscle reconstruction in primary cleft lip repair using the "basket-weave method".

The basket-weave method is an orbicularis oris muscle reconstruction method used in primary unilateral cleft lip repair. We compared the long-term results of the basket-weave method with those of a conventional method. For primary unilateral cleft lip repair, we compared the long-term results of 7 cases in which the orbicularis oris muscle was reconstructed by use of the basket-weave method, and of 7 cases in which the reconstruction was performed by use of the conventional method. The average postoperative follow-up period was 12 years and 7 months for the basket-weave method, and 11 years and 9 months for the conventional method. Using photographs of the front and elevation angle views, we evaluated the results as good if the philtrum ridge was formed on the fissure side and was almost symmetrical in height; as fair if the philtrum ridge was lower than the normal side; and as poor if the philtrum ridge had disappeared. For the basket-weave method, the results were good in 6 cases (85.7%), fair in 1 case (14.3%), and poor in 0 cases. For the conventional method, the results were good in 2 cases (28.6%), fair in 4 cases (57.1%), and poor in 1 case (14.3%). A significant difference was found between the 2 groups (Mann-Whitney U test, P = 0.0417). The philtrum ridge shape could be reconstructed by use of the basket-weave method, which gave better results in the long-term than did the conventional method for orbicularis oris muscle reconstruction in primary unilateral cleft lip repair.

Outer retinal tubulation in inherited retinal degenerative disease.

PURPOSE: To investigate the prevalence and characteristics of outer retinal tubulation (ORT) seen in inherited retinal degenerative diseases. METHODS: A total of 354 eyes of 177 patients were examined with spectral domain optical coherence tomography. One hundred and twelve patients had retinitis pigmentosa, 58 patients had cone dystrophy, and 7 patients had the Bietti crystalline dystrophy. The images obtained by horizontal and vertical scans were analyzed to explore the possible presence of ORT, estimate their prevalence, morphologic character, and their location in the retinal layers. RESULTS: With spectral domain optical coherence tomography, ORT was identified in 0 of 112 patients with retinitis pigmentosa, unilaterally in 3 of 58 patients with cone dystrophy, and bilaterally in 5 of 7 patients with the Bietti crystalline dystrophy. Outer retinal tubulation was detected under the fovea, and in the outer nuclear layer, ORT was detected in the Bietti crystalline dystrophy with a significantly higher frequency than in cone dystrophy (P < 0.001). CONCLUSION: There was a higher rate of ORT in the Bietti crystalline dystrophy among inherited retinal degenerative diseases.

Combining a Bilateral Bipedicle Flap and Artificial Dermis for Extensive Coverage in Meningomyelocele Surgery.

Myelomeningoceles with soft tissue defects are often difficult to close primarily and require reconstructive surgery. Furthermore, cases with large skin defects or cases with kyphosis of the spine require a large area to be covered, making reconstruction even more difficult. We performed closure of soft tissue defects using a bilateral bipedicle flap and application of artificial dermis to the flap donor area in three cases in which surgery was difficult. The bilateral bipedicle flap was able to easily and reliably close the soft tissue defect even in highly difficult emergency myelomeningocele surgery. We believe that applying artificial dermis to the flap donor area is a useful method that avoids autologous skin grafting and facilitates wound management. There have been no cases of major donor wound contracture. The healing period of the flap donor area may be predicted to some extent by the width immediately after surgery.

Accessory columellas: A case series on surgical method and short-term postoperative course.

PURPOSE: Accessory columellas are rare congenital anomalies characterized by skin appendage in the columella of the nostril. Case reports are scattered, but there are few descriptions about the clinical features and surgical course. METHOD: In this study, 3 patients with 4 lesions were identified (2013-2020). They were morphologically classified, and the accompanying nose deformity, surgical procedure, and postoperative course were examined. RESULTS: According to the morphologic classification, 1 lesion was of the sessile-lobed type, 2 lesions were of the sessile-nodular type, and 1 lesion was of the pedunculated-ovoid type. In terms of accompanying nose deformities, 1 lesion had a wide nasal columella, and 1 lesion had an enlarged left nostril due to a depression at the base of the lesion. Simple ablations were performed in 2 of the lesions, and plastic procedures were performed in the 2 lesions with an accompanying nose deformity. CONCLUSION: As in our cases, accessory columellas may have a variety of appearances and accompanying deformities. The surgical procedure must be considered according to the case. In addition, any changes due to growth must be observed and taken into consideration when they are reoperated.

Combination of Three Different Negative Pressure Wound Therapy Applications and Free Flap for Open Elbow Joint Injury With Extensive Burns.

Negative pressure wound therapy (NPWT) for treating burns has a variety of therapeutic applications. Here, we present a case of a 53-year-old woman with self-inflicted burn injuries in whom NPWT was applied for three different purposes. The injured sites were the anterior neck, bilateral arms from the wrists upwards to the chest, and back. The left arm was deeply injured, and the elbow joint cavity was opened during treatment. First, NPWT was used for bridge to skin grafting on the entire upper left limb. Second, NPWT was used as a bolster dressing for the autograft after skin grafting was performed on the left arm except the open part of the joint. Third, NPWT over flap was used on the subsequent flap surgical site to address prolonged exudate from the flap margin. The exudate resolved after about a week. Good results were obtained using NPWT during the perioperative period of free flap transplantation for extensive open elbow joint burns. The use of NPWT is an effective option in the treatment of burns.

Therapeutic Potential of Adipose Stem Cell-Derived Conditioned Medium on Scar Contraction Model.

Scars are composed of stiff collagen fibers, which contract strongly owing to the action of myofibroblasts. To explore the substances that modulate scar contracture, the fibroblast-populated collagen lattice (FPCL) model has been used. However, the molecular signature of the patient-derived FPCL model has not been verified. Here, we examined whether the patient-derived keloid FPCL model reflects scar contraction, analyzing detailed gene expression changes using comprehensive RNA sequencing and histological morphology, and revealed that these models are consistent with the changes during human scar contracture. Moreover, we examined whether conditioned media derived from adipose stem cells (ASC-CM) suppress the scar contracture of the collagen disc. Detailed time-series measurements of changes in disc area showed that the addition of ASC-CM significantly inhibited the shrinkage of collagen discs. In addition, a deep sequencing data analysis revealed that ASC-CM suppressed inflammation-related gene expression in the early phase of contraction; in the later phase, this suppression was gradually replaced by extracellular matrix (ECM)-related gene expression. These lines of data suggested the effectiveness of ASC-CM in suppressing scar contractures. Therefore, the molecular analysis of the ASC-CM actions found in this study will contribute to solving medical problems regarding pathological scarring in wound prognosis.

Nasal molding prevents relapse of nasal deformity after primary rhinoplasty in patients with unilateral complete cleft lip: An outcomes-based comparative study of palatal plate alone versus nasoalveolar molding.

OBJECTIVES: In recent years, many studies have reported that the presurgical nasoalveolar molding method improves the nose morphology; however, the reason for its effectiveness after surgery has never been understood. We evaluated the effect of nasoalveolar molding by comparing it with a passive orthopedic method without a nasal stent and focusing on the nostril morphology after primary cheiloplasty using various measurement methods. We then analyzed the essential factors. MATERIALS AND METHODS: The patients involved were 31 infants with unilateral complete cleft lip and palate treated with primary cheiloplasty at the University of Tsukuba Hospital from 2004 to 2011. Of the 31 infants, 16 received nasoalveolar molding treatment and 15 received passive orthopedic treatment as controls. Photographic facial measurements were performed for all patients immediately and 7 months after primary cheiloplasty. The esthetics of the nostrils were assessed according to the left-right nostril symmetry, as measured by the Hausdorff distance, area ratio, perimeter ratio, and aspect a/u (the aspect ratio of the affected side)/(the aspect ratio of the unaffected side) ratio. In addition, the inclination of the nasal ridge was assessed using anthropometric measurements (Grc-Grn∠midline and midline∠columellar axis). RESULTS: The area ratio, perimeter ratio, and Grc-Grn∠midline were significantly greater in the nasoalveolar molding group immediately after surgery (p = 0.00062, 0.016, and 0.048, respectively) than in the control group. However, the Hausdorff distance and aspect a/u ratio were more favorable (p = 0.0018 and 0.0039, respectively) in the nasoalveolar molding group after 7 months. CONCLUSIONS: The results of our study suggested that using nasoalveolar molding as a presurgical orthopedic treatment could improve the shape of the nasal cartilage with surgeon's corrections.

[Cost-effectiveness of ranibizumab, photodynamic therapy and pegaptanib sodium in the treatment of neovascular age-related macular degeneration in Japanese].

PURPOSE: To perform cost-utility analysis of ranibizumab, photodynamic therapy (PDT) and pegaptanib sodium treatment of neovascular age-related macular degeneration (AMD) with subfoveal choroidal neovascularization. MATERIALS AND METHODS: The analyses were performed on a 75-year old man with the starting visual acuity of letter score of 50 on an Early Treatment of Diabetic Retinopathy Study (ETDRS) chart, with the affected eye having better sight than the contralateral eye, for the time horizons of 1 and 11 year (s). Visual acuity data from the large controlled studies for ranibizumab, photodynamic therapy and pegaptanib sodium, were applied. The results were compared with best supportive care (BSC) data. Cost indications included direct medical costs and costs related with social blindness. Utility values were estimated from the time trade off method. This analysis was performed from a societal perspective. RESULTS: In the 1-year model, cost of treatment was dominant in the treatment groups, whereas the cost of blindness was dominant in the BSC. In the 11-year model, influence of cost of blindness resulted in the increasing costs for BSC. Of note, ranibizumab and PDT were less costly and showed an increase in utility compared to the BSC. Pegaptanib sodium was found to be costly. Sensitivity analysis found that the results were robust to changes in various model parameters. CONCLUSION: In the current model, ranibizumab and PDT confer quality-adjusted life years (QALY) gains and are less costly compared to BSC in the lifetime treatment. In contrast, pegaptanib sodium treatment could be considered to be of minimal cost-effectiveness. Ranibizumab and PDT confer excellent value in the models of the lifetime treatment.

Aesthetic reconstruction for syndactyly using the "gradation skin graft" from the plantar instep area.

In syndactyly, the donor site of the skin graft should have the characteristics of both the dorsal and the plantar or palmar skin because the skin defects after the dividing procedure are at the lateral sides of the digits. The plantar instep region has a color and texture border between the dorsal and plantar skin as a gradational boundary belt. We performed "gradation skin grafting" including the belt for syndactyly. We retrospectively analyzed 110 skin graft sites in 56 patients, aged ≤ 2 years, with syndactyly of the hand or foot. The follow-up durations were ≥ 6 months. The skin graft sites were divided into the gradation skin graft (G[+]) and the traditional skin graft (G[-]) groups. They were examined for matching of the skin graft with the circumferential skin, the causes of mismatching, the closing method of the donor site, and the complications. Regarding skin graft matching, the excellent rate of achievement was greater in the G(+) than in the G(-) group (P < 0.01). The causes of mismatching were misalignment of the gradational boundary belt in the G(+) group and postoperative pigmentation in the G(-) group. All the donor sites were closed directly without complications. The gradation skin graft for syndactyly was cosmetically superior to the traditional one from the submalleolar area. The design's hazard is that the gradational boundary belt of the skin graft should match the alignment with the gradational boundary belt around the skin defect of the digits.

Surgical management and postoperative evaluation based on morphological classification in central polydactyly of the foot.

PURPOSE: Central polydactyly of the foot is rare, with few reports on surgical methods and treatment indications. In this study, based on the experience of central polydactyly in our department, we will consider morphological classification and describe our treatment plan. METHOD: In this retrospective study, 11 patients (11 digits) with central polydactyly were identified among 136 patients of polydactyly of the foot (2009-2018). They were classified according to morphologic characteristics: type I, the duplicated digits are independent of each other; type II, digits of the same size are duplicated; and type III, digits of different sizes are duplicated. RESULTS: In morphologic classification, there were 4 cases of type II and 7 cases of type III, but there was no case of type I. For type II, surgery was performed using the Bilhaut-Cloquet (BC) procedure in 2 patients, bone-removing flap (flap) method in 1 patient, and simple ablation in 1 patient. For type III, surgery was performed using the BC procedure in 1 patient, flap method in 3 patients, simple ablation in 2 patients, and ligation in 1 patient with floating type. CONCLUSION: In order to obtain good cosmetic results in digits of morphologic classifications type II and III, it is necessary to select the surgical approach with careful consideration of every feature.

Salvaging exposed microtia cartilage framework with negative pressure wound therapy.

One of the most severe complications of auricular reconstruction for microtia is exposure of the cartilage framework. Recently, negative pressure wound therapy (NPWT) has become popular for a variety of complex wounds but reports on methods for microtia reconstruction are scarce. Thus, we aimed to detail the use of NPWT for cartilage exposure in microtia reconstruction. We retrospectively analyzed 7 cartilage exposure wounds in 6 patients treated by NPWT after auricular reconstruction for microtia. All wounds appeared from postoperative days 3 to 30 with 3 on the antihelix, 2 on the helix, 1 on the triangular fossa and 1 on the scaphoid fossa. Skin defect sizes ranged from 1 to 24 mm2 and 2 cartilage frames were infected at onset. Our NPWT system was the KCI Negative Pressure Wound Therapy with V.A.C.Ⓡ GranuFoam Black™ or Silver™ and continuous suction was applied in a range of 25-125 mmHg. All wounds healed within 8 to 39 days with NPWT antecedent cases taking longer than surgery ones. All cartilage frames survived but partial cartilage atrophies remained in 4 cases. Although a secondary infection occurred in an NPWT antecedent case it was still useful as a continuous external drainage system to remove dead space exudate and stimulate granulated tissue formation. In addition to vigilance against secondary infection, surgeons should consider an additional surgical intervention if the wound fails to improve within 7 days.

Protocol for a multicentre, prospective, cohort study to investigate patient satisfaction and quality of life after immediate breast reconstruction in Japan: the SAQLA study.

INTRODUCTION: The aim of breast reconstruction (BR) is to improve patients' health-related quality of life (HRQOL). Therefore, measuring patient-reported outcomes (PROs) would clarify the value and impact of BR on a patient's life and thus would provide evidence-based information to help decision-making. The Satisfaction and Quality of Life After Immediate Breast Reconstruction study aimed to investigate satisfaction and HRQOL in Japanese patients with breast cancer who undergo immediate breast reconstruction (IBR). METHODS AND ANALYSIS: This ongoing prospective, observational multicentre study will assess 406 patients who had unilateral breast cancer and underwent mastectomy and IBR, and were recruited from April 2018 to July 2019. All participants were recruited from seven hospitals: Okayama University Hospital, Iwate Medical University Hospital, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Showa University Hospital, University of Tsukuba Hospital, Osaka University Hospital and Yokohama City University Medical Center. The patients will be followed up for 36 months postoperatively. The primary endpoint of this study will be the time-dependent changes in BREAST-Q satisfaction with breast subscale scores for 12 months after reconstructive surgery, which will be collected via an electronic PRO system. ETHICS AND DISSEMINATION: This study will be performed in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects published by Japan's Ministry of Education, Science and Technology and the Ministry of Health, Labour and Welfare, the modified Act on the Protection of Personal Information and the Declaration of Helsinki. This study protocol was approved by the institutional ethics committee at the Okayama University Graduate School of Medicine, Dentistry, on 2 February 2018 (1801-039) and all other participating sites. The findings of this trial will be submitted to an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000032177.