Christophe Jacquet

Firat Gulagaci

Axel Schmidt

Aniruddha Pendse

Sebastien Parratte

Jean-Noël Argenson

Matthieu Ollivier
email: matthieu.ollivier@ap-hm.fr

• Firat Gulagaci

Jean-Noel Argenson

Opening wedge high tibial osteotomy allows better outcomes than unicompartmental knee arthroplasty in patients expecting to return to impact sports

Keywords: Opening wedge high tibial osteotomy, Unicompartmental knee arthroplasty, Impact sport, Patient reported outcomes

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Treatment of knee osteoarthritis (OA) has become more challenging as surgeons are facing younger patients with higher expectation post-surgery 2. In this group of patients, relief from pain is no longer the sole criteria for success but return to pre-disease level of activity is also important [START_REF] Kurtz | Future young patient demand for primary and revision joint replacement: national projections from 2010 to 2030[END_REF][START_REF] Losina | The dramatic increase in total knee replacement utilization rates in the United States cannot be fully explained by growth in population size and the obesity epidemic[END_REF]. For tricompartmental disease the decision making is reasonably straightforward with total knee arthroplasty (TKA) being the obvious choice with predictable outcome [START_REF] Lyons | Unicompartmental versus total knee arthroplasty database analysis: is there a winner?[END_REF][START_REF] Scuderi | The new knee society knee scoring system[END_REF][START_REF] Dahl | Surgery for knee osteoarthritis in younger patients[END_REF].

However, previous studies have demonstrated low proportion of patients are able to return to high impact activities [START_REF] Schmalzried | The John Charnley Award Wear is a function of use, not time[END_REF][START_REF] Witjes | Return to sports and physical activity after total and unicondylar knee arthroplasty: a systematic review and meta-analysis[END_REF]. Unicompartmental knee arthroplasty (UKA) might provide a better alternative in case of varus deformity with isolated medial compartment cartilage wear [START_REF] Berend | Consensus statement on indications and contraindications for medial unicompartmental knee arthroplasty[END_REF]. It is a less invasive procedure for a better range of motion (ROM), preservation of bone stock, maintenance of native biomechanics and quicker recovery time [START_REF] Kleeblad | Larger range of motion and increased return to activity, but higher revision rates following unicompartmental versus total knee arthroplasty in patients under 65: a systematic review[END_REF][START_REF] Naal | Return to sports and recreational activity after unicompartmental knee arthroplasty[END_REF].

High Tibial Osteotomy (HTO) represents an another alternative to UKA in case of extra-articular deformities leading to abnormal knee loading behavior and resultant intra-articular cartilage wear [START_REF] Brinkman | Osteotomies around the knee[END_REF].

An essential advantage of both methods is that the anterior cruciate ligament remains intact and the proprioception is better than in the TKA [START_REF] Bragonzoni | How proprioception changes before and after total knee arthroplasty: a systematic review[END_REF][START_REF] Wautier | Changes in anteroposterior stability and proprioception after different types of knee arthroplasty[END_REF].

Unicompartmental knee arthroplasty (UKA) and high tibial osteotomy (HTO) are established treatment methods for moderate medial compartment OA, although choosing the appropriate surgical treatment for unicompartmental OA for patients with high expectation including return to impact sport remains somewhat controversial. [START_REF] Cao | Unicompartmental knee arthroplasty vs high tibial osteotomy for knee osteoarthritis: a systematic review and meta-analysis[END_REF][START_REF] Kim | Unicompartmental knee arthroplasty is superior to high tibial osteotomy in postoperative recovery and participation in recreational and sports activities[END_REF][START_REF] Mancuso | Clinical outcome after UKA and HTO in ACL deficiency: a systematic review[END_REF].

Although the return to sport after HTO or UKA has already been analyzed [START_REF] Kim | Unicompartmental knee arthroplasty is superior to high tibial osteotomy in postoperative recovery and participation in recreational and sports activities[END_REF][START_REF] Hoorntje | High rates of return to sports activities and work after osteotomies around the knee: a systematic review and meta-analysis[END_REF][START_REF] Waldstein | Sport and physical activity following unicompartmental knee arthroplasty: a systematic review[END_REF], to date, no study of the literature have compared these two techniques in a specific population of patient practicing an impact sport before the onset of osteoarthritis symptoms.

The purpose of this study was to compare functional outcomes and ability to return to impact sport of active patients defined with a pre-arthritis University of California and Los Angeles activity score (UCLA) > 8, after UKA or HTO procedures. We hypothesized that there is no difference between HTO and UKA with regard to recovery to sports and rate of patients returning to impact activities.

Methods

A retrospective comparative study identified 291 patients that underwent Medial UKA and 134 open-wedge HTO in our department between January 2014 and September 2017.

Indication for HTO included (HTO group): isolated medial knee osteoarthritis Ahlbäck grade < 3 [START_REF] Ahlbäck | Osteoarthrosis of the knee. A radiographic investigation[END_REF] with a preserved status of the patellofemoral and lateral tibio-femoral joints assessed using clinical and radiological (X-rays and MRI-scan) examination, a significant metaphyseal tibial vara (Medial plateau tibial angle (MPTA) < 84°), a stable knee in sagittal and coronal plane and the failure of all medical treatments.

Indication for UKA included (UKA group): isolated medial knee OA (Ahlbäck, any grade, see below) with a preserved status of the patellofemoral and lateral tibio-femoral joints assessed using clinical and radiological (X-rays and MRI-scan) examination, a stable knee in sagittal and coronal plane with range of knee movement from 0° to at least 100°, a passively correctible varus on stress radiographs) and the failure of all medical treatments.

When both indications were possible the choice was left to the patient after clear information on the advantages and disadvantages of both techniques.

Exclusion criteria for both groups were: previous ipsilateral knee surgery (excluding knee arthroscopy for meniscal surgery), rheumatological disease process, as well as any contralateral and general co-morbidities restraining the overall mobility (e.g. neurological or neuromuscular conditions) and a follow-up of less than 2 years.

In order, to create comparable group of patients, patients with grade 1 of OA in the HTO group (7 patients) and grade 4 of OA in the UKA group (37 patients) were excluded. Finally, only grade 2 and 3 of OA in both groups were included in the study (Fig. 1).

After the analysis of the routine pre-operative questionnaire, only patients practicing an impact sport activity, as alpine ski, tennis/squash, jogging, soccer/football and martial arts, before the onset of arthritic symptoms (pre-arthritis UCLA score > 8) were included (92 patients in HTO group and 119 patients in the UKA group).

A matching process based on age (± 3 years) and gender allowed to finally include 50 patients in each group for comparative analysis.

Three different periods were compared. The pre-arthritis period corresponding to the period before arthrosis symptoms reported by patients. The preoperative period defined by status right before surgery. The postoperative period described the condition at the last follow-up (consultation or questionnaire if data were missing).

Both groups were comparable for demographic parameters and preoperative KOOS scores (Table 1). The mean time between onset of symptoms and knee surgery was 15 ± 8 [START_REF] Naal | Return to sports and recreational activity after unicompartmental knee arthroplasty[END_REF][START_REF] Brinkman | Osteotomies around the knee[END_REF][START_REF] Bragonzoni | How proprioception changes before and after total knee arthroplasty: a systematic review[END_REF][START_REF] Wautier | Changes in anteroposterior stability and proprioception after different types of knee arthroplasty[END_REF][START_REF] Cao | Unicompartmental knee arthroplasty vs high tibial osteotomy for knee osteoarthritis: a systematic review and meta-analysis[END_REF][START_REF] Kim | Unicompartmental knee arthroplasty is superior to high tibial osteotomy in postoperative recovery and participation in recreational and sports activities[END_REF][START_REF] Mancuso | Clinical outcome after UKA and HTO in ACL deficiency: a systematic review[END_REF][START_REF] Hoorntje | High rates of return to sports activities and work after osteotomies around the knee: a systematic review and meta-analysis[END_REF][START_REF] Waldstein | Sport and physical activity following unicompartmental knee arthroplasty: a systematic review[END_REF][START_REF] Ahlbäck | Osteoarthrosis of the knee. A radiographic investigation[END_REF][START_REF] Argenson | Unicompartmental knee arthroplasty: technique through a miniincision[END_REF][START_REF] Elson | High reliability in digital planning of medial opening wedge high tibial osteotomy, using Miniaci's method[END_REF][START_REF] Munier | Can three-dimensional patient-specific cutting guides be used to achieve optimal correction for high tibial osteotomy? Pilot study[END_REF][START_REF] Faschingbauer | Return to work and sporting activities after high tibial osteotomy[END_REF][START_REF] Takeuchi | Fractures around the lateral cortical hinge after a medial opening-wedge high tibial osteotomy: a new classification of lateral hinge fracture[END_REF][START_REF] Ornetti | Cross-cultural adaptation and validation of the French version of the Knee injury and Osteoarthritis Outcome Score (KOOS) in knee osteoarthritis patients[END_REF][START_REF] Zahiri | Assessing activity in joint replacement patients[END_REF][START_REF] Roos | The Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis[END_REF][START_REF] Borus | Unicompartmental knee arthroplasty[END_REF] (HTO) and 19 ± 9 [START_REF] Kleeblad | Larger range of motion and increased return to activity, but higher revision rates following unicompartmental versus total knee arthroplasty in patients under 65: a systematic review[END_REF][START_REF] Naal | Return to sports and recreational activity after unicompartmental knee arthroplasty[END_REF][START_REF] Brinkman | Osteotomies around the knee[END_REF][START_REF] Bragonzoni | How proprioception changes before and after total knee arthroplasty: a systematic review[END_REF][START_REF] Wautier | Changes in anteroposterior stability and proprioception after different types of knee arthroplasty[END_REF][START_REF] Cao | Unicompartmental knee arthroplasty vs high tibial osteotomy for knee osteoarthritis: a systematic review and meta-analysis[END_REF][START_REF] Kim | Unicompartmental knee arthroplasty is superior to high tibial osteotomy in postoperative recovery and participation in recreational and sports activities[END_REF][START_REF] Mancuso | Clinical outcome after UKA and HTO in ACL deficiency: a systematic review[END_REF][START_REF] Hoorntje | High rates of return to sports activities and work after osteotomies around the knee: a systematic review and meta-analysis[END_REF][START_REF] Waldstein | Sport and physical activity following unicompartmental knee arthroplasty: a systematic review[END_REF][START_REF] Ahlbäck | Osteoarthrosis of the knee. A radiographic investigation[END_REF][START_REF] Argenson | Unicompartmental knee arthroplasty: technique through a miniincision[END_REF][START_REF] Elson | High reliability in digital planning of medial opening wedge high tibial osteotomy, using Miniaci's method[END_REF][START_REF] Munier | Can three-dimensional patient-specific cutting guides be used to achieve optimal correction for high tibial osteotomy? Pilot study[END_REF][START_REF] Faschingbauer | Return to work and sporting activities after high tibial osteotomy[END_REF][START_REF] Takeuchi | Fractures around the lateral cortical hinge after a medial opening-wedge high tibial osteotomy: a new classification of lateral hinge fracture[END_REF][START_REF] Ornetti | Cross-cultural adaptation and validation of the French version of the Knee injury and Osteoarthritis Outcome Score (KOOS) in knee osteoarthritis patients[END_REF][START_REF] Zahiri | Assessing activity in joint replacement patients[END_REF][START_REF] Roos | The Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis[END_REF] months (UKA) (p = 0.1). Mean age was 49.3 ± 3.9 [44-54] and 50.8 ± 4.4 [47-57] for HTO and UKA groups, respectively. Mean follow-up period was 3.7 ± 1.6 [2-5.5] years (HTO) and 3.9 ± 1.8 [2-5.7] years (UKA). 11 HTO and 9 UKA (p = 0.5) patients had a pre-operative UCLA score > 8. Only preoperative difference between groups was hip-knee-ankle angle (HKA), since the indication for HTO is significant varus malalignment when UKA doesn't have the goal to interfere with HKA (Table 1). Patients' labor load was similar between the groups (Table 2).

Surgical procedure

In the UKA group, a cemented medial UKA (ZUK LIMA-Corporate Undine) was implanted [START_REF] Argenson | Unicompartmental knee arthroplasty: technique through a miniincision[END_REF].

In the HTO group, the planned correction was calculated by the surgeon using conventional radiographs (weight bearing long-leg, A/P and lateral views) following Miniaci's Method [START_REF] Elson | High reliability in digital planning of medial opening wedge high tibial osteotomy, using Miniaci's method[END_REF]. Subsequently all patients underwent a CT-scan and a Patient Specific Cutting Guide was designed to achieve the osteotomy following a previously published surgeon guided step-by-step procedure [START_REF] Munier | Can three-dimensional patient-specific cutting guides be used to achieve optimal correction for high tibial osteotomy? Pilot study[END_REF]. The bone defect was filled with femoral head wedge allograft in every patient. All the osteotomies were stabilized with the same implant (locking screw plate: New-clip Technics, Haute-Goulaine, France). All procedures were performed by two senior surgeons of our institution using the same previously described technique [START_REF] Faschingbauer | Return to work and sporting activities after high tibial osteotomy[END_REF].

The same peri-operative protocol and postoperative regimen was used in both the groups, including full weight bearing as tolerated and heparin thromboprophylaxis for 30 days. There was no restriction on the patients to go back to impact activities postoperatively either after UKA or HTO. Concerning lateral hinge fractures for the HTO group:

For Takeuchi [START_REF] Takeuchi | Fractures around the lateral cortical hinge after a medial opening-wedge high tibial osteotomy: a new classification of lateral hinge fracture[END_REF] Type 1 and 2 diagnosed intraoperatively; toe touch weight bearing for 6 weeks aided with the use of crutches was recommended. Full weight-bearing was allowed after 6 weeks.

For Takeuchi 3 diagnosed intraoperatively: the fracture was treated intraoperatively by two additional compression screw and no weight bearing during 6 weeks followed by toe touch weight bearing for 6 weeks aided with the use of crutches was recommended. Full weight-bearing was allowed after 12 weeks.

If hinge fractures was diagnosed at 6 weeks' follow-up, for the type I and 2, full weight bearing was extended. For the type III a toe touch weight bearing for 6 weeks was recommended before full weight bearing.

Clinical follow-up

Patients were evaluated at 4 weeks, 3 months, 6 months, 12 months and subsequently at every 12 months. Evaluation included radiographic imaging (AP and lateral views) and assessing complications, if any. Patient reported outcome scores were evaluated at every clinical visit, which included Knee Osteoarthritis Outcomes Score (KOOS), UCLA Activity Score (UCLA), Knee Society Score (KSS) and time to return to sport or previous professional activities [START_REF] Scuderi | The new knee society knee scoring system[END_REF][START_REF] Ornetti | Cross-cultural adaptation and validation of the French version of the Knee injury and Osteoarthritis Outcome Score (KOOS) in knee osteoarthritis patients[END_REF][START_REF] Zahiri | Assessing activity in joint replacement patients[END_REF]. If data were missing, a questionnaire was sent by post (n = 17; 6 for the HTO group and 11 for the UKA group) and any subsequent telephone recalls (n = 7; 4 for HTO group and 3 for the UKA group) were performed in cases of nonreturn of the postal questionnaire. One patient in the HTO group and two patients in the UKA group were considered finally lost to follow-up because of missing data (Fig. 1).

Local Ethical Committee approval was obtained prior to study's initiation (Comité Informatique et Liberté (CIL)/ Assistance Publique des Hopitaux de Marseille (AP-HM)/ Registration Number 2019-17-03)).

Statistical analysis

Prior to initiation of the study, a power calculation was done to estimate the sample size in both the groups to have the pB at 0.8. It was established, 50 patients in each group were needed to distinguish any difference, superior to the published minimal clinically important difference of the KOOS score [START_REF] Roos | The Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis[END_REF]. The study was powered to 80% to detect a difference > 10 points on the KSS or KOOS with a p < 0.05 level. Data were represented as mean values with standard deviations and [ranges]. Normal (Gaussian) distributions was verified to determine adequate statistical testing method (Student t tests vs Wilcoxon-Mann-Whitney tests) to estimate difference between groups in an univariate analysis. Multiple linear regression models were developed to establish the determinants for each of the variables. For each model, variables with a p value less than 0.1 were kept in the final model.

Statistical analyses were performed with use of SSPS software (IBM; Armonk, NY).

Results

Mean time to return to sport activities (whatever sporting level) and previous professional activities were significantly lower for the HTO group than for UKA group [respectively, 4.9 ± 2.2 [2-9] months for HTO group vs 5.8 ± 4.2 [START_REF] Losina | The dramatic increase in total knee replacement utilization rates in the United States cannot be fully explained by growth in population size and the obesity epidemic[END_REF][START_REF] Lyons | Unicompartmental versus total knee arthroplasty database analysis: is there a winner?[END_REF][START_REF] Scuderi | The new knee society knee scoring system[END_REF][START_REF] Dahl | Surgery for knee osteoarthritis in younger patients[END_REF][START_REF] Schmalzried | The John Charnley Award Wear is a function of use, not time[END_REF][START_REF] Witjes | Return to sports and physical activity after total and unicondylar knee arthroplasty: a systematic review and meta-analysis[END_REF][START_REF] Berend | Consensus statement on indications and contraindications for medial unicompartmental knee arthroplasty[END_REF][START_REF] Kleeblad | Larger range of motion and increased return to activity, but higher revision rates following unicompartmental versus total knee arthroplasty in patients under 65: a systematic review[END_REF][START_REF] Naal | Return to sports and recreational activity after unicompartmental knee arthroplasty[END_REF][START_REF] Brinkman | Osteotomies around the knee[END_REF][START_REF] Bragonzoni | How proprioception changes before and after total knee arthroplasty: a systematic review[END_REF][START_REF] Wautier | Changes in anteroposterior stability and proprioception after different types of knee arthroplasty[END_REF] months for UKA group (p = 0.006) and 3.0 ± 3.0 [START_REF] Losina | The dramatic increase in total knee replacement utilization rates in the United States cannot be fully explained by growth in population size and the obesity epidemic[END_REF][START_REF] Lyons | Unicompartmental versus total knee arthroplasty database analysis: is there a winner?[END_REF][START_REF] Scuderi | The new knee society knee scoring system[END_REF][START_REF] Dahl | Surgery for knee osteoarthritis in younger patients[END_REF][START_REF] Schmalzried | The John Charnley Award Wear is a function of use, not time[END_REF][START_REF] Witjes | Return to sports and physical activity after total and unicondylar knee arthroplasty: a systematic review and meta-analysis[END_REF] months for HTO group vs 4.0 ± 3.0 [2-13] months for UKA group (p = 0.006)].

24 months after surgery, 31 patients (62%) were practicing impact sport in the HTO group vs 14 (28%) in the UKA group (odd-ratio 4.2 CI 95% (1.8-9.7) p < 0.001).

The mean UCLA score improvement from pre-operative to postoperative (at 24 months) period was significantly superior in the HTO group than in UKA group (1.5 ± 1.9 vs 0.3 ± 2.1 p < 0.001).

The mean UCLA score deterioration from pre-arthritis to postoperative period (24 months) was significantly lower in the HTO group than in UKA group (-0.3 ± 2.1 vs -3.0 ± 2.0 p < 0.001).

At 2-year follow-up, mean UCLA score, KOOS Sports Sub-score and KSS activity score were significantly higher for HTO group (Δ: 2 CI 95% (1.3-2.5 points) p < 0.001, (Δ: 10.9 CI 95% (2.9-18.9 points) p = 0.04 and Δ: 7.8 CI 95% (2.4-13.4 points) p = 0.006, respectively).

Patient reported outcome scores are summarized in Tables 3 and4.

Multivariate analysis demonstrated that patients age significantly influenced the improvement of KOOS sports score (p = 0.01). Postoperative UCLA score was found to be influenced by the pre-arthritis value (p = 0.04).

Concerning complications, for the HTO group 16.7% patients were found to have lateral hinge fractures (83.3% type 1, 8.3% type 2 and 8.3% type 3). One nonunion was seen at 9 months after HTO, union was achieved 5 months after a revision procedure.

No infection was observed in both groups (UKA and HTO).

No patients had a UKA revision or HTO conversion to UKA/TKA during follow-up, 11 (22%) patients from the HTO group underwent hardware removal at a mean followup of 18.1 ± 4.4 [START_REF] Naal | Return to sports and recreational activity after unicompartmental knee arthroplasty[END_REF][START_REF] Brinkman | Osteotomies around the knee[END_REF][START_REF] Bragonzoni | How proprioception changes before and after total knee arthroplasty: a systematic review[END_REF][START_REF] Wautier | Changes in anteroposterior stability and proprioception after different types of knee arthroplasty[END_REF][START_REF] Cao | Unicompartmental knee arthroplasty vs high tibial osteotomy for knee osteoarthritis: a systematic review and meta-analysis[END_REF][START_REF] Kim | Unicompartmental knee arthroplasty is superior to high tibial osteotomy in postoperative recovery and participation in recreational and sports activities[END_REF][START_REF] Mancuso | Clinical outcome after UKA and HTO in ACL deficiency: a systematic review[END_REF][START_REF] Hoorntje | High rates of return to sports activities and work after osteotomies around the knee: a systematic review and meta-analysis[END_REF][START_REF] Waldstein | Sport and physical activity following unicompartmental knee arthroplasty: a systematic review[END_REF][START_REF] Ahlbäck | Osteoarthrosis of the knee. A radiographic investigation[END_REF][START_REF] Argenson | Unicompartmental knee arthroplasty: technique through a miniincision[END_REF][START_REF] Elson | High reliability in digital planning of medial opening wedge high tibial osteotomy, using Miniaci's method[END_REF][START_REF] Munier | Can three-dimensional patient-specific cutting guides be used to achieve optimal correction for high tibial osteotomy? Pilot study[END_REF][START_REF] Faschingbauer | Return to work and sporting activities after high tibial osteotomy[END_REF][START_REF] Takeuchi | Fractures around the lateral cortical hinge after a medial opening-wedge high tibial osteotomy: a new classification of lateral hinge fracture[END_REF][START_REF] Ornetti | Cross-cultural adaptation and validation of the French version of the Knee injury and Osteoarthritis Outcome Score (KOOS) in knee osteoarthritis patients[END_REF][START_REF] Zahiri | Assessing activity in joint replacement patients[END_REF][START_REF] Roos | The Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis[END_REF][START_REF] Borus | Unicompartmental knee arthroplasty[END_REF][START_REF] Zuiderbaan | Modern indications, results, and global trends in the use of unicompartmental knee arthroplasty and high tibial osteotomy in the treatment of isolated medial compartment osteoarthritis[END_REF] months.

Discussion

The most important finding of the present study was that HTO offers statistically significant quicker return to sport activities and previous professional activities with a higher rate of patients able to practice impact activity (62% for HTO vs 28% for UKA) and better sports related functional scores at two years after surgery compared to UKA in a population of active patients defined with a pre-arthritis University of California and Los Angeles activity score (UCLA) > 8. The hypothesis that both procedures were similar for returning to impact sports was not verified in this study.

While both procedures are often realized in a very similar population (in terms of demographic parameters), their aims are deeply different: HTO intends to correct extra-articular deformities leading to abnormal knee loading and resultant intra-articular cartilage wear [START_REF] Brinkman | Osteotomies around the knee[END_REF], while UKA aims solely to resurface a worn tibiofemoral compartment leaving lower-limb mechanical axis in its preoperative configuration. Traditionally, UKA was indicated for patients aged over 60 years old with unicompartimental OA without a high activity level [START_REF] Borus | Unicompartmental knee arthroplasty[END_REF] while HTO was indicated for younger patients (< 60 years old) with varus malalignment and moderate unicompartimental arthrosis [START_REF] Zuiderbaan | Modern indications, results, and global trends in the use of unicompartmental knee arthroplasty and high tibial osteotomy in the treatment of isolated medial compartment osteoarthritis[END_REF]. The surgical indications for UKA have expanded because of improved surgical techniques and modern implant designs, along with increased experience with the procedure [START_REF] Pennington | Unicompartmental knee arthroplasty in patients sixty years of age or younger[END_REF] allowing to use UKA for younger active people. Some of the indications for HTO and UKA may currently be similar in some cases [START_REF] Cao | Unicompartmental knee arthroplasty vs high tibial osteotomy for knee osteoarthritis: a systematic review and meta-analysis[END_REF], but choosing the appropriate surgical treatment for unicompartmental OA for patients with sports expectations remains somewhat controversial [START_REF] Cao | Unicompartmental knee arthroplasty vs high tibial osteotomy for knee osteoarthritis: a systematic review and meta-analysis[END_REF][START_REF] Kim | Unicompartmental knee arthroplasty is superior to high tibial osteotomy in postoperative recovery and participation in recreational and sports activities[END_REF][START_REF] Mancuso | Clinical outcome after UKA and HTO in ACL deficiency: a systematic review[END_REF].

Several studies and meta-analysis are available in the literature comparing clinical outcomes of HTO and UKA, some of them including results about sports activities (Table 5) [START_REF] Kim | Unicompartmental knee arthroplasty is superior to high tibial osteotomy in postoperative recovery and participation in recreational and sports activities[END_REF][START_REF] Faschingbauer | Return to work and sporting activities after high tibial osteotomy[END_REF][START_REF] Bastard | Return to sports and quality of life after high tibial osteotomy in patients under 60 years of age[END_REF][START_REF] Bonnin | Can patients really participate in sport after high tibial osteotomy?[END_REF][START_REF] Yim | Comparison of high tibial osteotomy and unicompartmental knee arthroplasty at a minimum follow-up of 3 years[END_REF]. But the difference in population between the different studies, in particular on the age and level of sport activity, but also the differences in score used, complicated the comparison between the studies. Kim et al. [START_REF] Kim | Unicompartmental knee arthroplasty is superior to high tibial osteotomy in postoperative recovery and participation in recreational and sports activities[END_REF] reported a higher (75.0% vs 94.1%) and quicker (8.4 vs 3.8 months) rate of return to sports activity in favor of UKA patients compared to HTO. The authors attributed this better outcome in the UKA group due to the ability of the procedure to remove the nociceptive stimulus from the medial compartment which was not possible in the joint preserving procedure of the HTO. The reason for the difference in the findings compared to this study lies probably in a less active population of patient in Kim et al., study. Indeed, nearly 20% of the patients in the study by Kim et al. [15] did not participate in any sporting activity in the pre-arthritis period and the mean pre-operative UCLA score for the HTO group was approximately 4 (6.9 in the present study) and 3 (6.8 in the present study) for the UKA group. Also, authors in the study of Kim et al., stated that most patients followed their recommendations to avoid high-impact sports activities after the operation, which could negatively impact their results.

The findings in the present study are in accordance with the paper of Bastard et al. [START_REF] Bastard | Return to sports and quality of life after high tibial osteotomy in patients under 60 years of age[END_REF] who observed that all of their 30 patients treated with HTO returned to sports at 1 year with 7 (23.3%) of them returning at a higher level than before the procedure. A systematic review by Ekhtiari et al. [START_REF] Ekhtiari | Return to work and sport following high tibial osteotomy[END_REF] reported similar findings regarding HTO procedure that 85% of the 216 patients returning to a level of sport similar or better than pre-operatively.

A recent study [START_REF] Hoorntje | Prognostic factors for return to sport after high tibial osteotomy: a directed acyclic graph approach[END_REF] indicated that sustained sports participation in the year before surgery is one of the most important prognostic factors for returning to sports after HTO. This was the case in this study as all patients returned to sports whatever the level of impact in both groups. However, at 2 years of follow up 62% of HTO patients and only 28% in the UKA group were still involved in impact activities. Studies have observed this shift from high to low impact activity level after UKA or HTO [START_REF] Hoorntje | High rates of return to sports activities and work after osteotomies around the knee: a systematic review and meta-analysis[END_REF][START_REF] Waldstein | Sport and physical activity following unicompartmental knee arthroplasty: a systematic review[END_REF][START_REF] Faschingbauer | Return to work and sporting activities after high tibial osteotomy[END_REF], potentially influenced by a variety of factors like physical and mental conditioning, patient motivation, pain or surgeon's advice.

Comparing the UCLA scores, the HTO group improved their scores to almost the pre-arthritis levels (pre-arthritis 9.2 ± 0.1 to postoperative 8.4 ± 0.2), whereas there was a drop in the UCLA scores compared to pre-arthritis values for the UKA group (9.4 ± 0.1 to 6.5 ± 0.2).

These results suggest that in addition to the lower rate of patient practicing an impact sport after UKA compared to those after HTO, the level of sport intensity is also lower after UKA than after HTO. This also suggests that operating the impact sport patients at an earlier stage of osteoarthritis with HTO gives them a better chance to recover a sport level similar or close to the one they had before the onset of arthritis. KOOS sports score improvement was significantly better for the HTO group and age at the time of surgery was found to be an important factor influencing the improvement in all patients. The KSS score was significantly better for the HTO group at 2 years, different from the findings of Cho et al. [START_REF] Cho | Mobile-bearing unicompartmental knee arthroplasty in old-aged patients demonstrates superior short-term clinical outcomes to open-wedge high tibial osteotomy in middle-aged patients with advanced isolated medial osteoarthritis[END_REF] who reported better outcomes for the UKA group or those of Takeuchi et al. [START_REF] Takeuchi | A mid term comparison of open wedge high tibial osteotomy vs unicompartmental knee arthroplasty for medial compartment osteoarthritis of the knee[END_REF] who found no difference between HTO and UKA groups. This difference can be explained by an older population of patient (mean age 67 years old for the HTO group and 77 years old for the UKA group) and the absence of inclusion criteria related to the level of sports activity.

There are several limitations in the present study that must be appreciated when interpreting these findings. Firstly, data collection was done in a retrospective manner, but despite this, matched groups for both treatment modalities were created. The groups were carefully matched for demographic parameters (age and gender). Due to the matching process for age, a substantial number of younger patients who underwent an HTO were excluded to avoid bias outcome against the UKA group.

Secondly, despite the small size sample, in both groups the power calculation was based on the pB set at 0.8 to minimize the type II error. The follow up was set at 2 years as the purpose of the study was only to evaluate the ability to return to impact sports after UKA or HTO surgery.

Thirdly, this is a two surgeons series and there might be an element of bias due to the post-operative regimen and advice. However, the post-operative protocols were similar between the surgeons and there was no restriction on the patients to go back to impact activities postoperatively either after UKA or HTO.

Fourth, these results cannot be generalized for all cases of sports patients with unicompartmental OA. HTO does not solve the problem of severe cartilage diseases (Ahlbäck grade > 3) and in this situation the use of a UKA represents the only surgical therapeutic solution. To build comparable groups in term of preoperative degenerative changes, patients suffering from early and end stages of arthritis were excluded from the final analyses, having those patients included would have created important recruitment bias with more affected joints in the UKA than in HTO group.

Finally, while the most common reason for knee surgery in osteoarthritic patients was improved functioning [START_REF] Wiering | Meeting patient expectations: patient expectations and recovery after hip or knee surgery[END_REF], this study did not evaluate specifically patient's expectation concerning the return to the same level of sport. But this is the only study in the literature that focuses on an active population of patients practicing an impact sport before the onset of osteoarthritis symptoms. The relatively short time between surgery and the onset of symptoms (15 ± 8 [10-28] months for HTO and 19 ± 9 [START_REF] Kleeblad | Larger range of motion and increased return to activity, but higher revision rates following unicompartmental versus total knee arthroplasty in patients under 65: a systematic review[END_REF][START_REF] Naal | Return to sports and recreational activity after unicompartmental knee arthroplasty[END_REF][START_REF] Brinkman | Osteotomies around the knee[END_REF][START_REF] Bragonzoni | How proprioception changes before and after total knee arthroplasty: a systematic review[END_REF][START_REF] Wautier | Changes in anteroposterior stability and proprioception after different types of knee arthroplasty[END_REF][START_REF] Cao | Unicompartmental knee arthroplasty vs high tibial osteotomy for knee osteoarthritis: a systematic review and meta-analysis[END_REF][START_REF] Kim | Unicompartmental knee arthroplasty is superior to high tibial osteotomy in postoperative recovery and participation in recreational and sports activities[END_REF][START_REF] Mancuso | Clinical outcome after UKA and HTO in ACL deficiency: a systematic review[END_REF][START_REF] Hoorntje | High rates of return to sports activities and work after osteotomies around the knee: a systematic review and meta-analysis[END_REF][START_REF] Waldstein | Sport and physical activity following unicompartmental knee arthroplasty: a systematic review[END_REF][START_REF] Ahlbäck | Osteoarthrosis of the knee. A radiographic investigation[END_REF][START_REF] Argenson | Unicompartmental knee arthroplasty: technique through a miniincision[END_REF][START_REF] Elson | High reliability in digital planning of medial opening wedge high tibial osteotomy, using Miniaci's method[END_REF][START_REF] Munier | Can three-dimensional patient-specific cutting guides be used to achieve optimal correction for high tibial osteotomy? Pilot study[END_REF][START_REF] Faschingbauer | Return to work and sporting activities after high tibial osteotomy[END_REF][START_REF] Takeuchi | Fractures around the lateral cortical hinge after a medial opening-wedge high tibial osteotomy: a new classification of lateral hinge fracture[END_REF][START_REF] Ornetti | Cross-cultural adaptation and validation of the French version of the Knee injury and Osteoarthritis Outcome Score (KOOS) in knee osteoarthritis patients[END_REF][START_REF] Zahiri | Assessing activity in joint replacement patients[END_REF][START_REF] Roos | The Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis[END_REF] months for UKA group) suggests that these patients wanted to return to an function. Despite these limits, the results of this study confirm the superior results of HTO compared to UKA in patients practicing impact sports before the onset of arthritic symptoms according to the indications of the two procedures. These results also suggest that operating the high impact sport patients at an earlier stage of osteoarthritis with HTO gives them a better chance to recover a sport level similar or close to the one they had before the onset of arthritis.

Conclusion

HTO offers statistically significant quicker return to sport activities and previous professional activities with a higher rate of patients able to practice impact activity (62% for HTO vs 28% for UKA) and better sports related functional scores at two years after surgery compared to UKA.

Fig. 1

 1 Fig. 1 Patient flow chart. HTO high tibial osteotomy, UKA unicompartmental knee arthroplasty, OA Grade Osteoarthritis Ahlbäck grade

Table 2

 2 Labor load of patients HTO high tibial osteotomy, UKA unicompartmental knee arthroplasty

	Parameters	Sitting	Standing with-	Standing with	Heavy labor	Total (n)	p value
			out labor	some labor
	HTO (n)	14	8	14	14	50	0.2
	UKA (n)	15	11	11	13

Table 3

 3 Patients' postoperative sports and functional outcomes HTO high tibial osteotomy, UKA unicompartmental knee arthroplasty, UCLA University of California Los Angeles, KSS Knee Society Score

	Parameters	HTO ± SD [range] UKA ± SD [range] p value
	Mean time to return to previous professional	3 ± 3.0 [2-7]	4 ± 3.0 [2-13]	0.006*
	occupation (months)
	Mean time to return to sport activities (months)	4.9 ± 2.2 [2-9]	5.8 ± 4.2 [2-13]	0.006*
	Mean postoperative UCLA score	8.4 ± 1.6 [6-10]	6.5 ± 2 [3-10]	< 0.0001*°M
	ean KSS symptom at 24 months	19 ± 5.4 [4-25]	20 ± 6.8 [4-25]	0.3
	Mean KSS satisfaction at 24 months	33 ± 6 [10-40]	30 ± 8 [2-40]	0.04*
	Mean KSS expectation at 24 months	8 ± 1.7 [3-14]	9 ± 2.4 [3-14]	0.3
	Mean KSS activity at 24 months	84 ± 8 [62-100]	75 ± 9 [46-96]	0.006*°M
	ean KSS subtotal at 24 months	61 ± 7 [44-78]	60 ± 9 [40-78]	0.6
	*Statistically significant
	°Reaching minimal clinically important difference

Table 4

 4 Patient reported outcome scores at 3, 6, 12 and 24 months

	*Statistically significant
	°Reaching minimal clinically important difference

HTO high tibial osteotomy, UKA unicompartmental knee arthroplasty, KOOS knee injury and osteoarthritis outcome score, QOL quality of life, ADL activity of daily life

Table 5

 5 Literature review of recent studies comparing HTO and UKA sports recovery HTO high tibial osteotomy, UKA unicompartmental knee arthroplasty, KOOS knee injury and osteoarthritis outcome score, UCLA University of California Los Angeles, KSS knee society score, VAS visual analogue scale, WOMAC Western Ontario and McMaster Universities Osteoarthritis Index, SF short form, IKDC international knee documentation committee, M male, F female, Postop postoperative

	Studies	Study group(s) Age	Gender	Follow-up	Return to sports UCLA	Outcome scores
				M:F
	Bonnin et al.	HTO	59.1 ± 8.4	98:41	49.8 ± 10.9 months Rate not given	N/S	WOMAC
	[32]					(56.1%
						achieved
						preoperatively
						expected
						activeness)
						Same Level:		SF-12
						44.6%
						Higher Level:
						20.8%
						Lower Level:
						33%
	Yim et al. [38] HTO vs. UKA 58.3 ± 5.4 vs.	7:51 vs. 2:48	3.6 ± 0.4 vs.	78.0% vs.	N/S	Lysholm
			60.3 ± 4.5		3.7 ± 0.4 years	71.4%		Tegner
	Faschingbauer	HTO	42 ± 11.2	32:11	22 ± 9.3 months	92.3%	N/S	Lysholm
	et al. [21]							Tegner
								Naal Sports and
								Activity
								SF-36
								VAS
	Bastard et al.	HTO	55.6	6:24	1.3 years	100%	N/S	Tegner
	[31]					Same level:
						73.3%
						Higher level:
						23.3%
						Lower level:		Lysholm
						3.4%		SF-36
								IKDC
	Kim et al. [15] HTO vs. UKA 56.1 ± 6.2 vs.	6:43 vs. 7:35	Minimum	75.0% vs.	Mean change	Tegner
			63.6 ± 5.5		24 months	94.1% (Of the patients who participated in sports	from preop-erative condi-tion: postop 24 months:	Lysholm VAS WOMAC
						preoperatively	1.5 vs. 2.1	UCLA
						(81.3%))
	Our study	HTO vs. UKA 49.3 ± 3.9 vs.	28:22 vs. 34:16 3.1 ± 1.6 vs.	Return to	Mean change	UCLA
	(2019)		50.8 ± 4.4		3.3 ± 1.8 years	impact activi-ties 62 vs. 28%	from preop-erative condi-tion: postop	KOOS KSS
							24 months:
							1.5 vs. 0.3

Funding No funding was required for this study.

Compliance with ethical standards

Author contributions CJ and FG have made substantial contributions to acquisition of data, or analysis and interpretation of data. AP, AS, JNA, and SP have been involved in drafting the manuscript or revising it critically. MO has made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data. Every authors have given final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflict of interest

Local ethic committee approved our study protocol prior to investigation. Some of the authors disclosed potential conflict of interest.

Ethical approval


Jerome R Lechien
email: jerome.lechien@umons.ac.be

MD Thomas Radulesco

MD Christian Calvo-Henriquez

MD Carlos M Chiesa-Estomba

MD Stéphane Hans

MD Maria Rosaria Barillari

MD Giovanni Cammaroto

PhD Géraldine Descamps

MD Julien Hsieh

MD Luigi Vaira

MD Jerome R Lechien

MD, FEBOMFS Giacomo De Riu

MD Leigh Sowerby

MD Isabelle Gengler

MD Justin Michel

MD, PhD Sven Saussez

Dr Jay R Lechien

ACE2 & TMPRSS2 Expressions in Head & Neck Tissues: A Systematic Review

Keywords: COVID-19, coronavirus, ACE2, TMPRSS2, receptor, virus, entry, head, neck

des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

The renin angiotensin aldosterone system is one of the most important systems regulating the homeostasis of cardiovascular and pulmonary functions, which involves many molecules as the angiotensin converting enzyme-2 (ACE2). [START_REF] Crackower | Angiotensin-converting enzyme 2 is an essential regulator of heart function[END_REF] ACE2 is also known to be the functional receptor of some coronavirus species as firstly found in 2003 during the epidemic of severe acute respiratory syndrome coronavirus (SARS-CoV). [START_REF] Li | Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus[END_REF] The current pandemic of coronavirus disease 2019 (COVID-19) has brought to light the importance of ACE2 regarding the host contamination, the virus spread and the development of the clinical COVID-19. [START_REF] Li | Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor[END_REF] In the same time, another SARS-CoV2 receptor has been identified: the transmembrane protease serine -2 (TMPRSS2). [START_REF] Shang | Cell entry mechanisms of SARS-CoV-2[END_REF] ACE2 and TMPRSS2 tissue expressions are particularly important to identify the virus entry pathways and to better understand the organ-related clinical expression of the disease. [START_REF] Li | Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor[END_REF][START_REF] Shang | Cell entry mechanisms of SARS-CoV-2[END_REF] According to the recent data reporting otolaryngological clinical pictures of the disease, [START_REF] Vaira | Olfactory and gustatory function impairment in COVID-19 patients: An Italian objective multicenter-study[END_REF][START_REF] Lechien | COVID-19 Task Force of YO-IFOS. Clinical and Epidemiological Characteristics of 1,420 European Patients with mild-to-moderate Coronavirus Disease[END_REF][START_REF] Lechien | Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study[END_REF] the study of ACE2 and TMPRSS2 expressions in ear, nose and throat tissues makes particularly sense.

The aim of this systematic review is to summarize the current data about the ACE2 and TMPRSS2 expressions in head & neck tissues.

Methods

The review was conducted regarding the Preferred Reporting Items for a Systematic Review and Meta-analysis (PRISMA) checklist. [START_REF] Mcinnes | Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement[END_REF] A modified population, intervention, comparison, outcome, timing and setting (PICOTS) framework was used to structure the review process. [START_REF] Thompson | A Framework To Facilitate the Use of Systematic Reviews and Meta-Analyses in the Design of Primary Research Studies[END_REF] Precisely, the PICOTS structure was kept but adapted to experimental/basic research studies on human and animal tisssues.

Studies: Animal and human experimental published studies in English-language peerreviewed journals were considered. Preprint studies were also considered regarding the current pandemic and the need to rapidly get substantial data. Investigators needed to assess ACE2 or TMPRSS2 expressions in head & neck tissues through immunochemistry (IHC), in situ hybridization, Western Blot, RNA sequencing (RNA-seq), or reverse transcription polymerase chain reaction (RT-PCR).

Participants and inclusion criteria:

The papers had to include human, monkey or mouse subjects to analyze ACE2 or TMPRSS2 tissue expressions. The authors extracted substantial information about the sample characteristics (species) and ACE2 and TMPRSS2 identification method.

Outcomes:

The main studied outcome was the tissue expression of ACE2 and TMPRSS2.

The anatomical location; the types of cells that expressed both receptors were studied. A particular attention has been done on the method used to detect ACE2-TMPRSS2 in tissues.

Additional useful information, such as virus impact on the functioning of the tissue/cell that expressed receptor or inter-individual differences, were collected.

Intervention and comparison:

Because the aim of the study was to investigate the tissue ACE2 expression, we did not consider potential intervention on patient or animal models.

Timing:

Timing and Setting: In case of receptor analysis in infected subjects, any timing in the disease process was considered.

Search strategy

The PubMed/MEDLINE, Scopus and Cochrane search was conducted by 4 independent authors (JRL, TR, CCH, GD) to identify papers published between January 1990 and April 2020. The authors screened publications with database abstracts and available full texts referring to the condition. The following keywords were used for the search strategy: 'ACE2'; 'TMPRSS2'; 'COVID-19'; 'coronavirus'; 'Receptor'; 'Head'; 'Neck'; 'Nasal'; 'ear, nose throat (ENT)'; 'Tissue' and 'Cell'. The authors investigated papers for number of samples/individuals, study type & design, inclusion criteria and ACE2/TMPRSS2 detection outcomes.

Results:

The electronic search identified 24 papers, of which 17 met our inclusion criteria (Table 1). 10- 26 A total of 16 studies investigated the expression of ACE2 and TMPRSS2 on human head and neck tissues, while 5 and 2 researches focused on mouse and monkey samples (Table 1).

The chart flow of the study is available in Figure 1. One study focused on ACE2 genetic analysis, without anatomical expression report. [START_REF] Cao | Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations[END_REF] Three studies were preprint. [START_REF] Brann | Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia[END_REF][START_REF] Chen | The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in human and mouse brain[END_REF][START_REF] Lee | Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers[END_REF]

Tissue expression in Human

ACE2 expression

ACE2 was studied in 16 studies. [START_REF] Hamming | Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis[END_REF][START_REF] Jia | ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia[END_REF][START_REF] Liu | Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques[END_REF][START_REF] Bilinska | Expression of the SARS-CoV-2 Entry Proteins, ACE2 and TMPRSS2, in Cells of the Olfactory Epithelium: Identification of Cell Types and Trends with Age[END_REF][START_REF] Brann | Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia[END_REF][START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF][START_REF] Cao | Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations[END_REF][START_REF] Chen | The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in human and mouse brain[END_REF][19][START_REF] Lee | Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers[END_REF][START_REF] Li | Expression of the SARS-CoV-2 Cell Receptor Gene ACE2 in a Wide Variety of Human Tissues[END_REF][START_REF] Sungnak | SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes[END_REF][START_REF] Xu | High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa[END_REF][START_REF] Xu | Salivary Glands: Potential Reservoirs for COVID-19 Asymptomatic Infection[END_REF][START_REF] Wu 26 | SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues[END_REF][26] The expression of ACE2 was found in all mucosa of the respiratory upper tract, including trachea, [START_REF] Jia | ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia[END_REF][START_REF] Liu | Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques[END_REF][START_REF] Lee | Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers[END_REF][START_REF] Sungnak | SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes[END_REF][START_REF] Wu 26 | SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues[END_REF] sinus and nasal cavities. [START_REF] Hamming | Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis[END_REF][START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF][START_REF] Lee | Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers[END_REF] Among the respiratory mucosa, ACE2 was expressed in several types of cells, including epithelial, goblet, and endothelial cells. [START_REF] Hamming | Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis[END_REF][START_REF] Jia | ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia[END_REF]26 One study reported that ACE2 was expressed on ciliated epithelial cells and not on non-ciliated (goblet) cells. [START_REF] Lee | Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers[END_REF] Butowt et al. compared the intensity of expression of both ACE2 in human respiratory tract regarding the cell localization (upper versus lower airway). [START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF] They found that nasal epithelial cells had lower levels of ACE2 expression compared with epithelial cells of the lower respiratory tract. [START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF] Among the nasal region, two studies investigated the ACE2 expression in the mucosa of the olfactory region, including olfactory bulb. [START_REF] Brann | Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia[END_REF][START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF] ACE2 receptor was identified in sustentacular/non-neuronal cells of the olfactory tissues. Moreover, ACE2 was found in a low proportion of neuronal stem cells of the olfactory bulb. [START_REF] Brann | Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia[END_REF][START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF] The expression of ACE2 in olfactory neurons (non-stem cells) remains uncertain because Butowt et al. and Brann et al. observed that ACE2 has only nonneuronal expression pattern in olfactory epithelium. [START_REF] Brann | Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia[END_REF][START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF] Five studies investigated ACE2 expression in oral and pharyngeal regions, including oral, hypo-oro-and nasopharyngeal spaces. [START_REF] Hamming | Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis[END_REF]19,[START_REF] Xu | High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa[END_REF][START_REF] Xu | Salivary Glands: Potential Reservoirs for COVID-19 Asymptomatic Infection[END_REF][START_REF] Wu 26 | SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues[END_REF] The study that explored ACE2 expression in human nasopharynx, 19 did not exhibit significant ACE2 immunostaining in nasopharyngeal cells. 19 ACE2 receptor was identified in oral endothelial, [START_REF] Hamming | Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis[END_REF] epithelial, [START_REF] Hamming | Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis[END_REF][START_REF] Xu | High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa[END_REF][START_REF] Wu 26 | SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues[END_REF] and salivary [START_REF] Xu | Salivary Glands: Potential Reservoirs for COVID-19 Asymptomatic Infection[END_REF] cells. Xu et al. found that ACE2 was also expressed in T and B cells as well as fibroblasts of the oral cavity. [START_REF] Xu | High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa[END_REF] Moreover, ACE2 was expressed in major salivary gland tissues [START_REF] Chen | The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in human and mouse brain[END_REF] and thyroid tissue. [START_REF] Li | Expression of the SARS-CoV-2 Cell Receptor Gene ACE2 in a Wide Variety of Human Tissues[END_REF] In many publications, authors reported the type of cells (goblet versus epithelial versus stem cells) that expressed ACE2 or TMPRSS2 (Table 2).

The genetic analysis of Cao et al. reported that there are 15 unique expression quantitative trait loci variants in East Asian population, supporting a gene polymorphism and tissuerelated differences between individuals. 17

TMPRSS2 expression

TMPRSS2 expression was investigated in 5 studies. [START_REF] Vaarala | Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues[END_REF][START_REF] Brann | Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia[END_REF][START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF][START_REF] Sungnak | SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes[END_REF]26 Similarly to ACE2, TMPRSS2 was identified in nasal [START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF][START_REF] Sungnak | SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes[END_REF]26 and respiratory mucosa cells, [START_REF] Sungnak | SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes[END_REF] including both epithelial and goblet cells, with higher expression in lower airway compared with upper airway. [START_REF] Sungnak | SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes[END_REF] Moreover, TMPRSS2 receptor was identified in sustentacular and neuronal olfactory cells [START_REF] Brann | Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia[END_REF][START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF] but not in olfactory neurons. [START_REF] Brann | Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia[END_REF] TMPRSS2 was also identified in salivary major gland tissue. 10

ACE2 & TMPRSS2 tissue expression in Mouse and Monkey

Six studies used animal models to assess ACE2 or TMPRSS2 expressions in head and neck tissues. [START_REF] Vaarala | Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues[END_REF][START_REF] Liu | Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques[END_REF][START_REF] Bilinska | Expression of the SARS-CoV-2 Entry Proteins, ACE2 and TMPRSS2, in Cells of the Olfactory Epithelium: Identification of Cell Types and Trends with Age[END_REF][START_REF] Brann | Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia[END_REF][START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF]26 The mouse studies of Butwot et al. and Bilinska et al. revealed that that elderly mouses had higher expression of both ACE2 and TMPRSS2 in nasal mucosa compared with young specimen. [START_REF] Bilinska | Expression of the SARS-CoV-2 Entry Proteins, ACE2 and TMPRSS2, in Cells of the Olfactory Epithelium: Identification of Cell Types and Trends with Age[END_REF][START_REF] Brann | Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia[END_REF] In olfactory tissue, ACE2 was identified in sustentacular/non-neuronal and neural stem cells of mouses. [START_REF] Bilinska | Expression of the SARS-CoV-2 Entry Proteins, ACE2 and TMPRSS2, in Cells of the Olfactory Epithelium: Identification of Cell Types and Trends with Age[END_REF][START_REF] Brann | Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia[END_REF][START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF] Liu et al. analyzed ACE2 expression in monkey, [START_REF] Liu | Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques[END_REF] reporting a higher ACE2 expression in tracheal, naso-, oro-and hypopharyngeal tissues as well as in the salivary ducts of the pharyngeal gland, and, therefore, in saliva. In this study, the cell expression was mainly localized in lamina propria. In the same vein, Vaarala et al. reported TMPRSS2 expression in mouse salivary tissues. [START_REF] Vaarala | Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues[END_REF]

Cell Detection methods

The following methods have been used for detecting ACE2 and TMPRSS2 in cells of human and animal tissues: RNAseq (N=12); IHC (N=5); RT-PCR (N=1); in situ hybridization (N=1) and WB (N=1). Different detection approaches were used in 2 studies. [START_REF] Jia | ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia[END_REF][START_REF] Bilinska | Expression of the SARS-CoV-2 Entry Proteins, ACE2 and TMPRSS2, in Cells of the Olfactory Epithelium: Identification of Cell Types and Trends with Age[END_REF] One study reported specific genetic analyzes. 17 There were significant differences about XX, XX, and XX regarding the following methods: XX, XX, XX.(Geraldine part)

Discussion:

The COVID-19 infection may present several clinical forms from 'benign' isolated anosmia to severe multiple organ failure. The mechanisms underlying the COVID-19 polymorphism are still unknown. To infect tissues, SARS-CoV2 needs to entry into the cells, which is allowed through ACE2 and TMPRSS2 receptors. [START_REF] Shang | Cell entry mechanisms of SARS-CoV-2[END_REF] The identification of virus receptor expression in the tissues makes particularly sense to better understand the clinical expression of the disease. This systematic review sheds light many points.

First, ACE2 and TMPRSS2 receptors are overall expressed in epithelial and non-epithelial cells of head and neck tissues. The head and neck expression may support the otolaryngological clinical picture of the disease, which was recently found in European and U.S. COVID-19 patients. [START_REF] Lechien | COVID-19 Task Force of YO-IFOS. Clinical and Epidemiological Characteristics of 1,420 European Patients with mild-to-moderate Coronavirus Disease[END_REF][START_REF] Lechien | Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study[END_REF][START_REF] Kaye | COVID-19 Anosmia Reporting Tool: Initial Findings[END_REF][START_REF] Lechien | Loss of Smell and Taste in 2,013 European Mild-to-Moderation COVID-19 Patients[END_REF] The virus would entry into the epithelial cells of the upper aerodigestive tract mucosa, leading to an inflammatory reaction and the development of the otolaryngological symptoms. The nasal entrance of the virus through high ACE2 expression was supported in the study of Wu et al. who found a higher virus concentration in nasal swabs compared with throat swabs. [START_REF] Wu 26 | SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues[END_REF] The olfactory cleft is a nasal region that drawn attention of many researchers over the past few weeks. Indeed, recent data supported that more than 70% of COVID-19 patients developed olfactory dysfunction, especially when patients suffered from mild-to-moderate forms of the disease. [START_REF] Vaira | Olfactory and gustatory function impairment in COVID-19 patients: An Italian objective multicenter-study[END_REF][START_REF] Lechien | Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study[END_REF][START_REF] Lechien | Loss of Smell and Taste in 2,013 European Mild-to-Moderation COVID-19 Patients[END_REF][START_REF] Vaira | Anosmia and Ageusia: Common Findings in COVID-19 Patients[END_REF] Because ACE2 and TMPRSS2 are both expressed in the nasal mucosa of the olfactory cleft, the entry way of the virus into the olfactory bulb seems obvious. Once in the bulb, according to some human studies, [START_REF] Brann | Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia[END_REF][START_REF] Butowt | SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection[END_REF] the virus could infect cells that express ACE2 or TMPRSS2, namely glial and neuronal stem cells. The raise of glial cells, which are important in the neuron support, could overall impair the functioning of the olfactory way, leading to transient olfactory dysfunction.(Julien: ok ? References?) Because the duration of glial cell recovery is shorter than that of neurons, the duration to clinically recover the smell sense would be shorter. In clinical studies, the recovery time of olfaction ranged from 4 to 14 days in more than 40% of patients, [START_REF] Vaira | Olfactory and gustatory function impairment in COVID-19 patients: An Italian objective multicenter-study[END_REF][START_REF] Lechien | Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study[END_REF][START_REF] Lechien | Loss of Smell and Taste in 2,013 European Mild-to-Moderation COVID-19 Patients[END_REF][START_REF] Spinato | Alterations in Smell or Taste in Mildly Symptomatic Outpatients With SARS-CoV-2 Infection[END_REF] which supports this pathophysiological hypothesis. An additional pathophysiological mechanism that could explain the early recovery of some patients is the anosmia related to edema of the olfactory cleft mucosa. As observed in a recent imaging study, some patients had bilateral olfactory cleft edema, which was associated with olfactory dysfunction. [START_REF] Lechien | Clinical and Radiological Evaluations of COVID-19 Patients with Anosmia: Preliminary Report[END_REF] However, the study also support that the majority of patients did not exhibit such findings over the clinical course of the disease, strengthening the 'neurological' anosmia. Interestingly, in another study, we reported magnetic resonance imaging abnormalities in the olfactory bulb of anosmic COVID-19 patients. [START_REF] Chetrit | Magnetic Resonance Imaging of Olfactory Structures in COVID-19 Patients: Preliminary Report[END_REF] These additional findings also support the neurological hypothesis of olfactory dysfunction.

In this systematic review, we found that three studies reported high ACE2 expression in major or minor salivary gland human tissues. [START_REF] Vaarala | Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues[END_REF][START_REF] Chen | The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in human and mouse brain[END_REF][START_REF] Xu | Salivary Glands: Potential Reservoirs for COVID-19 Asymptomatic Infection[END_REF] These data corroborate the literature findings that reported a salivary pattern of SARS-CoV-2 and related parotitis. [START_REF] Lechien | Parotitis-like Symptoms associated with COVID-19 disease, France[END_REF][START_REF]Acute Parotitis: A Possible Precocious Clinical Manifestation of SARS-CoV-2 Infection?[END_REF] Moreover, the virus spread into the salivary gland tissues allows to better understand the mechanisms underlying the saliva contamination. Interestingly, in 2011, Liu et al. observed that Monkeys infected by SARS-CoV had a salivary virus spread, which was associated with a salivary virion excretion. [START_REF] Liu | Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques[END_REF] These data support the need to conduct future studies investigating the presence of SARS-CoV-2 in the saliva of infected human and to corroborate the saliva findings with the ACE2 salivary gland expression.

The ENT expression of ACE2 and TMPRSS2 and the related ENT clinical pattern seems obvious but could vary across individuals and populations. Furthermore, Lee et al. observed that ACE2 expression is influenced by patient demographics, clinical characteristics, comorbidities and medication. [START_REF] Lee | Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers[END_REF] As reported in the genetic analysis of Cao et al., there would be different susceptibilities or responses to SARS-CoV2 in different populations. [START_REF] Cao | Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations[END_REF] The polymorphism of ACE2 and TMPRSS2 expression could explain the clinical differences between individuals. Indeed, many physicians reported in clinical and epidemaiological studies different clinical presentation of the disease, [START_REF] Lechien | Loss of Smell and Taste in 2,013 European Mild-to-Moderation COVID-19 Patients[END_REF][START_REF] Spinato | Alterations in Smell or Taste in Mildly Symptomatic Outpatients With SARS-CoV-2 Infection[END_REF] which could be associated with virus mutations. [START_REF] Coppee | SARS-CoV-2: virus mutations in specific European populations[END_REF][START_REF] Saha | A virus that has gone viral: amino acid mutation in S protein of Indian isolate of Coronavirus COVID-19 might impact receptor binding, and thus, infectivity[END_REF] The virus mutations and the related impact on receptor binding and infectivity is another point that has to be considered in future studies.

The present study has several limitations. First, the heterogeneity between studies about the detection method may lead to detection bias because some approaches are more sensitive than others.(Geraldine + une ou deux phrases sur la qualité de marquage et les étapes nécessaires pour obtenir un bon marquage? Ont ils été trop vite? Quid de la qualité de leur marquage) Second, the majority of studies that were conducted during the SARS-CoV-2 pandemic did not consider many demographic and clinical factors such as the age of patients from who the tissues were extracted, the use of ACE inhibitor drugs and its potential impact on ACE2 expression, etc. Third, some otolaryngological region remains non-investigated such as vocal folds. The investigation of these remaining regions makes sense regarding recent study reporting some unusual clinical expression of the disease such as severe dysphonia.

37

 37

  are both expressed in head and neck tissues, which may explain the otolaryngological clinical pattern of the disease and the entry of SARS-CoV-2 into the host organism. Future studies considering demographical and clinical characteristics of patients from who the tissues are extracted are needed to better understand the cell entry mechanisms of SARS-CoV-2.

Immunohistochemistry=IHC; RT-PCR=reverse transcription polymerase chain reaction; SARS-CoV-2= severe acute respiratory syndrome coronavirus-2; TMPRSS2: transmembrane protease serine-2; WB=Western Blotting.

Table 2: Summary of Cell Expression of ACE2 and TMPRSS2.

Table 2 footnotes: Abbreviations: ACE2=Angiotensin Converting Enzyme-2; NA=not available; TMPRSS2: transmembrane protease serine-2.


T Radulesco

D Hazbri

M Penicaud

P Dessi

J Michel

Title of the article: Rhinoplasty: French validation of the MiRa scale Titre: Rhinoplastie: Validation française de l'échelle MiRa

Keywords: questionnaire, rhinoplasty, aesthetic analysis, linguistic adaptation, French

Aims

The aim of this study was to translate the MiRa scale into French and validate its use for French-speaking surgeons.

Material and methods

ISPOR and WHO recommendations were used to carry out the translation process from English to French in five steps. The MiRa scale is a validated analysis scale of nasal dysmorphoses. Few tools are available in French for French-speaking surgeons. ISPOR and WHO recommendations were used to complete the translation process from English into French in five steps. To assess the reliability of MiRa scale -French version, we statistically compared intra-observer repeatability (comparison of scores obtained when one observer assessed each patient twice at a one-month interval) and inter-observer repeatability (comparison of scores obtained when 2 observers assessed the same patient) using the Wilcoxon test and the intraclass correlation coefficient (ICC) (α = 5%).

Objectives

Our goal was to obtain a translation of the idea or concept rather than a literal translation with good intra and inter-observer repeatability.

Results

Each step enabled us to make changes to work towards a conceptual translation equivalent to the original version.

Conclusion

The MiRa scale is the only aesthetic analysis scale validated in the literature for nasal dysmorphoses. The combined use of two sets of translation recommendations, with a five-step translation-back-translation process, made it possible to obtain a French version perfectly in line with the original. This version is usable by French-speakers.

TEXT 1. INTRODUCTION

The analysis of nasal dysmorphoses is a key point for practitioners seeking to determine their surgical strategy and analyze the esthetic consequences of the surgical techniques used. The differences in interpretation between surgeon and patient have already been discussed in the literature [START_REF] Radulesco | The MiRa scale, a new standardised scale for evaluating nasal deformities before and after septorhinoplasty: a prospective study comparing patient satisfaction and the surgeon's assessment[END_REF]. The French-speaking surgeons uses few questionnaires due to the lack of translated instruments. Consequently, systematic evaluation by French-speaking practitioners of post-rhinoplasty esthetic results is problematic.

Available translated questionnaires mainly concern functional assessment [START_REF] Leplège | The French SF-36 Health Survey: translation, cultural adaptation and preliminary psychometric evaluation[END_REF][START_REF] Mortuaire | Psychometric evaluation of the SinoNasal Outcome Test-16 for quality of life in chronic rhinosinusitis with nasal polyps[END_REF][START_REF] Marro | French validation of the NOSE and RhinoQOL questionnaires in the management of nasal obstruction[END_REF].

Validated translation processes make it possible to provide a questionnaire for use by French-speakers.

The MiRa scale is a validated tool enabling practitioners to perform detailed analysis of nasal dysmorphoses in patients before and after cosmetic surgery of the nasal pyramid. The MiRa scale has been rigorously developed to validate its reliability [START_REF] Radulesco | The MiRa scale, a new standardised scale for evaluating nasal deformities before and after septorhinoplasty: a prospective study comparing patient satisfaction and the surgeon's assessment[END_REF].

Our translation seeks to be more conceptual than strictly literal [START_REF]The World Health Organization Quality of Life Assessment (WHO-QOL): development and general psychometric properties[END_REF][START_REF] Guillemin | Cross-cultural adaptation of healthrelated quality of life measures: literature review and proposed guidelines[END_REF][START_REF] Weinberger | Are health-related quality-of-life measures affected by the mode of administration?[END_REF][START_REF] Beaton | Guidelines for the process of cross-cultural adaptation of self-report measures[END_REF]. We have translated this analysis scale in accordance with international translation recommendations [START_REF] Wild | Principles of good practice for the translation and cultural adaptation process for patient-reported outcomes (PRO) measures: report of the ISPOR task force for translation and cultural adaptation[END_REF][START_REF]Process of translation and adaptation of instruments[END_REF].

The purpose of this study was to translate the MiRa scale into French and validate its use for speakers of French.

METHODS

Ethical considerations

All patients who contributed to the development of this study gave their consent before participating. The study was carried out in accordance with the Declaration of Helsinki.

Translation process

The MiRa scale in its English version served as a source document for translation [START_REF] Radulesco | The MiRa scale, a new standardised scale for evaluating nasal deformities before and after septorhinoplasty: a prospective study comparing patient satisfaction and the surgeon's assessment[END_REF].

Patients were allocated an initial sore of 40 points. One or two points were then deducted for each item depending on the esthetic severity of the deformity. Professional photographs were taken from 3 angles (full face, right profile, lower face) and were used to complete the scale. The ISPOR (International Society for Pharmacoeconomics and Outcomes Research) and WHO (World Health Organization) recommendations were implemented throughout the translation process [START_REF] Wild | Principles of good practice for the translation and cultural adaptation process for patient-reported outcomes (PRO) measures: report of the ISPOR task force for translation and cultural adaptation[END_REF][START_REF]Process of translation and adaptation of instruments[END_REF]. We already used this validated translation process [START_REF] Radulesco | French validation of the FACE-Q Rhinoplasty module[END_REF]. An expert panel of 3 French-speaking rhinoplastician surgeons modified the scale after analysis of 40 patient records.

The translation process (Table 1) was performed in 5 steps:

Step 1: Two independent translations were made of the original scale from English into French: one by a surgeon specialized in the management of rhinoplasties and the second by a professional translator. Both were native French-speakers and both spoke English fluently. A consensus between the two translations was established, leading to French version 1.

Step 2: A back-translation was made into English of French version 1 by an English native language professional translator. This version was compared with the original MiRa scale. The items revealing discrepancies were re-translated and modifications were made, leading to French version 2.

Step 3: French version 2 was submitted to a panel of specialist surgeons to determine whether it was understandable and easy to use. Further corrections were made resulting in French version 3.

Step 4: The instructions were added in the French version 3. This version was then tested on 40 photographic records of patients to determine whether the instructions, the method for completing the evaluation grid and the scoring method and the different items were understandable and unambiguous. Based on these findings, we modified the scale and obtained French version 4.

Step 5: French version 4 was examined by a panel of surgeons and validated to produce the final version (Table 2).

2.3.Reliability of MiRa scale -French version

To assess the reliability of MiRa scale -French version, two senior surgeons examined each photographic record twice, at a minimum 4-week interval. We statistically compared intra-observer repeatability (comparison of scores obtained when one observer assessed each patient twice at a one-month interval) and inter-observer repeatability (comparison of scores obtained when two observers assessed each patient once) using the Wilcoxon test and the intraclass correlation coefficient (ICC) (α = 5%) as defined by Fleiss and Shrout [START_REF] Fleiss | Effects of measurement errors on some multivariate procedures[END_REF].

RESULTS

Following the recommendations for translation, we were able to obtain a French version of the MiRa scale usable by French-speaking practitioners and equivalent to the original English version.

Regarding

Step 1, we chose to have two independent translations made by two people from different professional backgrounds with a view to establishing an exchange between them and obtaining a consensus. Some terms chosen by the practitioner (e.g. "cyphose" and "ensellure") were deemed too technical by the translator, who preferred "concavity" and "convexity". Comparison and adjustment of the two translations resulted in French version 1. In the English back-translation of French version 1, we identified no difference except for the above-mentioned items. In Step 2, it was decided to keep some terms in English in the French version, e.g. "pinched nose", "double break" and "supratip", as they are in everyday use among French rhinoplasticians. Also, in French version 3, we integrated more detailed instructions for completing the evaluation. In fact, in the original article, instructions are not presented in the scale itself. Step 3 was fundamental and provided many modifications: eg. "déviation" and "bifidité" were replaced by "déviée" and "bifide" to ensure grammatical coherence. "Portion cartilagineuse" and "Portion osseuse" were also changed to "Nez osseux" and "Nez cartilagineux". The item concerning nostril orientation was also adapted. The test on photographic records was satisfactory with the various practitioners in agreement with the proposed translation. No changes were made during the last step.

Assessment of the reliability of the MiRa scale -French version

Intra-observer repeatability of MiRa scale -French version was 97.9% (p=0.56). Interobserver repeatability was 95.9 % (p=0.21). There were no statistical significative differences between the observations.

DISCUSSION

Other teams have already used the same methodology [START_REF] Poulsen | Danish translation and linguistic validation of the BODY-Q: a description of the process[END_REF]. Our translation process was simplified as the MiRa scale is intended for practitioners and not for patients. Actually, we did not need patient feedback. Moreover, most terms in the scale cannot be mistranslated since an international consensus already exists for anatomical terms.

Possible differences of interpretation due to cultural variations were not an obstacle in our translation procedure [START_REF] Naito | An international comparison of characteristics of the sensation of nasal obstruction between Canadian and Japanese patients[END_REF]. As Lacasse points out, the translation -backtranslation process helps reveal imperfect translations and harmonizes understanding of a document by different populations [START_REF] Lacasse | Health-related quality of life measurement: a readers' guide[END_REF]. This process is more constraining than a straight-forward, one-way translation and ensures that the translated evaluation grid is identical to the initial document. This point is very important methodologically, since we must be certain to measure what we are supposed to.

ISPOR and WHO recommendations were chosen for the translation process, which made it possible to obtain a culturally-adapted version in French of the MiRa scale equivalent to the English version [START_REF] Wild | Principles of good practice for the translation and cultural adaptation process for patient-reported outcomes (PRO) measures: report of the ISPOR task force for translation and cultural adaptation[END_REF][START_REF]Process of translation and adaptation of instruments[END_REF]. Although these two sets of guidelines for translation are not strictly identical, they complement each other, thus allowing us to blend the two. Two translators each submitted a version before agreeing on a joint first French version, backtranslated into English for comparison with the initial scale. The combined use of both methodologies minimizes biases in the translation process.

The use of an expert panel (3 rhinoplasticians) to test the scale is essential and makes it possible to overcome errors due to the non-consensual nature of translation. Finally, it was decided to keep certain English terms such as "pinched nose", "double break" or "supratip" in the final French text as these terms are commonly used in English by French professionals, much more than their French translation.

CONCLUSION

The MiRa scale is the only validated esthetic analysis scale for nasal dysmorphoses in the literature. Using two sets of international translation recommendations, we were able to obtain a French version of this scale identical to the original English version. This version is usable by French-speaking surgeons.

We have no conflicts of interest.

TABLES

2 6

 2 photographic records.

Table 1 .

 1 ISPOR, WHO recommendations and translation process used in our study.

			Points Pré Post			Points Pré	Pos t		Points Pré Post
	Dorsum nasal		Lobule		Angle nasofrontal (choisir 1 réponse)
	Déviatio	Nez osseux	2	Excès de hauteur	1		Creusé	2
	n frontale	Nez cartilagineux	2	Asymétrie des dômes	1		Comblé	2
		Nez osseux	2	Narines		Dorsum nasal (choisir 2 items maximum)
	Déviatio n en "C"	Nez cartilagineux	2	Orientati on (choisir 1 réponse)	Verticale Horizontale	1	Cyphose	Nez osseux	2
	Excès de largeur	Nez osseux	1	Asymétriques	1		Nez cartilagineux	2
	du
	dorsum nasal	Nez cartilagineux	1	Rebord épais	1	Ensellure	Nez osseux	2
	Base nasale		Columelle			Nez cartilagineux	2
	Excès de largeur des narines	1	Déviée	1	Projection de la pointe (choisir 1 réponse)
	Murs latéraux nasaux		Bifide	1	Hyperprojetée	2

Table 2 .

 2 French version of the MiRa scale. In the "points" column, the maximum score that can be subtracted per item (1 or 2 points): 1 point for a slight deformation, 2 points for severe deformation (ANF = Angle nasofrontal).

ACKNOWLEDGEMENT

Thanks to George Morgan for linguistic revision.