Caroline Martin
email: caroline.martin@univ-rennes2.fr

Pierre Touzard

Nicolas Horvais

Pierre Puchaud

Richard Kulpa

Benoit Bideau

Anthony Sorel

Influence of shoe torsional stiffness on foot and ankle biomechanics during tennis forehand strokes

Keywords: Performance, injury & prevention, 3D analysis

Tennis shoe characteristics need to minimize the risk of athletes suffering ankle injuries and improve players' feet performance. This study aims to evaluate the influence of shoe torsional stiffness on running velocity, stance duration, ground reaction forces and ankle biomechanics during two different tennis forehand runs and strokes. Ten right-handed advanced male tennis players performed two specific tennis forehand runs and strokes at maximal effort (a shuttle run with a defensive open stance forehand -SRDF and a lateral jab run with an offensive open stance forehand -JROF) with four different pairs of tennis shoes with different torsional stiffness. A force platform measured ground reaction forces (GRF). A motion capture system recorded the 3D trajectories of markers located on players' anatomical landmarks. The minimum, maximum angle value, and range of motion were computed using inverse kinematics for each rotation axis of the right ankle. Normalized maximal ankle torques were also computed using inverse dynamics. Shoe torsional stiffness had no effect on running velocity, on stance duration and maximal values of GRF. Shoe torsional stiffness influenced forefoot inversion which was significantly higher for the most flexible shoes. For SRDF, the maximal ankle inversion angle was significantly and largely increased for the stiffest shoe. The stiffest shoe may put the ankle at a higher risk of lateral sprains during SRDF while it was not the case during JROF.

Highlights

• Shoe torsional stiffness has no effect on performance parameters (running velocity of the center of mass, ground reaction forces, and stance duration) during tennis forehand strokes.

• Decreased shoe torsional stiffness increased the maximal forefoot inversion angle and the range of motion of forefoot inversion-eversion during tennis forehand strokes and movements.

• Increased footwear torsional stiffness causes higher maximal ankle inversion angle which may increase the risk for ankle sprains in SRDF.

Introduction

Tennis is a sport that involves quick, intense, and repeated start-stop movements, during which players perform sudden changes of direction while running and striking the ball at high speeds [START_REF] Kovacs | Applied physiology of tennis performance[END_REF]. During the all these runs, changes of direction and strokes, the player's feet and ankles are always the foundation for tennis performance [START_REF] Avagnina | The foot and ankle at risk of injury in tennis players[END_REF] because they interact with the ground to generate ground reaction forces (GRF) that influence stroke performance. For example, it has been reported that lateral, antero-posterior, and vertical GRF positively influenced ball speed during tennis forehands [START_REF] Shimokawa | Does ground-reaction force influence postimpact ball speed in the tennis forehand groundstroke?[END_REF].

The interaction between the feet and the ground induces also high plantar pressures and loadings [START_REF] Girard | Effects of the playing surface on plantar pressures and potential injuries in tennis[END_REF] that can be responsible for foot and ankle injuries that are very common in tennis players [START_REF] Hjelm | Injury profile in junior tennis players: A prospective two year study[END_REF]. Indeed, injury statistics from the ATP World Tour show foot and ankle injuries comprise 12% of all injuries evaluated by physiotherapists during the 2014 and 2015 seasons [START_REF] Sniteman | Acute management of common foot and ankle injuries[END_REF]. Other results show ankle injuries represent 21% of all injuries reported by the National Collegiate Athletic Association Injury Surveillance Program for men's and women's tennis during the 2009/2010-2014/2015 academic years [START_REF] Lynall | Epidemiology of National Collegiate Athletic Association men's and women's tennis injuries, 2009/2010-2014/2015[END_REF]. Among all injuries, ankle sprains are very common in the lower extremity in tennis players [START_REF] Sniteman | Acute management of common foot and ankle injuries[END_REF] (B. M. [START_REF] Pluim | Epidemiology of tennis injuries[END_REF].

Many different variables such as ground-surface, fatigue, poor physical condition and tennis shoe characteristics influence the risks of ankle injuries (B. [START_REF] Pluim | Tennis injuries: Occurence, aetiology and prevention[END_REF] [START_REF] Beynnon | Predictive Factors for Lateral Ankle Sprains: A Literature Review[END_REF]. Tennis shoe characteristics need to minimize the risk of athletes suffering ankle injuries Among all tennis shoe characteristics, the shoe's lateral stability and torsional stiffness are important for ankle injury prevention (B. [START_REF] Pluim | Tennis injuries: Occurence, aetiology and prevention[END_REF]. Torsional shoe stiffness quantifies the resistance of a shoe to twisting about its long axis between the heel and the toe [START_REF] Zifchock | Quantification of torsional stiffness in running footwear: Proposed methodology[END_REF]. Results about the effect of shoe torsional stiffness on ankle injury risks in sports are contradictory in the literature. On the one hand, [START_REF] Graf | The effect of footwear torsional stiffness on lower extremity and kinetics during lateral cutting movements[END_REF] have evaluated the effect of footwear torsional stiffness on knee and ankle kinematics and kinetics during lateral cutting movements often used in basketball, handball or soccer [START_REF] Graf | The effect of footwear torsional stiffness on lower extremity and kinetics during lateral cutting movements[END_REF]. Their results showed that increased footwear torsional stiffness causes higher ankle eversion torque, increasing the risk for ankle injuries. On the other hand, [START_REF] Luethi | Influence of shoe construction on lower extremity kinematics and load during lateral movements in tennis[END_REF] have evaluated the effect of two different shoes (a soft and flexible one vs. a harder and stiffer one) on ankle biomechanics during side-ways shuffle runs in tennis players. They reported lower lateral ground reaction force, lower ankle inversion angle and lower internal resistive force with the stiffer shoe [START_REF] Luethi | Influence of shoe construction on lower extremity kinematics and load during lateral movements in tennis[END_REF]. According to [START_REF] Luethi | Influence of shoe construction on lower extremity kinematics and load during lateral movements in tennis[END_REF], too much or too little shoe torsional stiffness can induce too much or too little inversion movement at the ankle, disturb the equilibrium of force absorption and cause ankle injuries.

Tennis shoe characteristics also need to improve players' comfort and performance. The studies concerning the effect of shoe torsional stiffness on performance are very limited and controversial [START_REF] Kulessa | The influence of football shoe characteristics on athletic performance and injury risk-A review[END_REF]. While [START_REF] Llana-Belloch | Supination control increases performance in sideward cutting movements in tennis[END_REF] reported that shoes limiting supination (i.e. shoes with more torsional stiffness) allowed tennis players to perform faster sideward cutting movements [START_REF] Llana-Belloch | Supination control increases performance in sideward cutting movements in tennis[END_REF], [START_REF] Graf | The effect of footwear torsional stiffness on lower extremity and kinetics during lateral cutting movements[END_REF] observed no effect of the shoe torsional stiffness on two performance parameters (stance duration and ground reaction impulses) during cutting movements. Moreover, the optimal torsional stiffness of tennis shoes for increasing tennis performance and reducing ankle and foot injury risks is unknown.

Consequently, this study aims to evaluate, during two different tennis forehand runs and strokes, the influence of shoe torsional stiffness on ground reaction forces and stance time, which are related to sports performance, and ankle biomechanics which have been related to ankle sprain injury mechanisms. It is hypothesized that shoes with a high torsional stiffness have no effect on ground reaction forces, stance time and running velocity but decrease maximal ankle inversion angle, angular velocity and torque.

Materials and Methods

Ten right-handed advanced male tennis players (age: 26.8 ± 10.9 years; height: 1.77 ± 0.03 m; weight: 65.3 ± 4.3 kg), with an International Tennis Number of 4 or better, participated voluntarily in this study. Before experiments, participants were fully informed of the experimental procedures. At the testing time, all the players were considered healthy, with no pain or injuries. Each player signed a written consent. The local Ethical Committee approved the study which was conducted under the 1975 Declaration of Helsinki.

Before the start of the movement protocol, participants viewed a demonstration of the experimental procedure and the two specific tennis movements and forehands performed by a professional coach. Such movements and forehand strokes occur frequently in tennis [START_REF] Roetert | Biomechanics of the tennis groundstrokes: Implications for strength training[END_REF]. For both movements, the players were asked to move as quickly as possible until a force plate (0.60 x 1.20 x 0.06 m, AMTI, Watertown, MA, USA) and hit a foam tennis ball as hard as possible they could. A foam tennis ball was fixed and attached to a scaffold with a rope (Figure 1). The first movement was a lateral jab run (JR) during which players performed an offensive open stance forehand (OF). Firstly, the players ran forward along a 45° lane on the left side of the force plate. Once the force plate reached, they stepped onto the plate with the right foot, hit a foam ball with an open stance, and left the plate at a 45° angle towards the left until the finishing point (Figure 1a). The players ran a total distance of 6.40m. The height of the foam ball was adjusted to the right shoulder's height of each player to simulate attacking forehand conditions. The other movement was a side-ways shuttle run (SR), during which players performed a defensive open stance forehand (Figure 1b) (DF). For the SRDF, players performed a split step and then laterally ran towards the force plate (Figure 1b). The distance between the starting point and the middle of the force plate was 4.8m. Then, they ran back to the starting point. Consequently, the players ran a 9.6m distance. The height of the foam ball was adjusted to the right pocket's height of each player to simulate a defensive forehand. The players had all the time they needed to familiarize themselves with the testing environment and the landmarks set and, test the two specific tennis movements (SRDF, JROF). After a warm-up of ten minutes, the participants performed eight repetitions of SRDF and JROF at maximal effort with four different pairs of tennis shoes with different torsional stiffness (32 repetitions in total). The order of the tennis shoes and movements was randomly assigned. A professional tennis coach confirmed the ability of the players to properly perform each forehand stroke movement.

Three tennis shoes were chosen for the study covered high-quality levels and prices:

Wilson "Kaos 3.0", Babolat "Propulse Fury", Asics "Solution Speed". The fourth tennis shoe was a new prototype developed by Wilson. This prototype has the same characteristics than the "Rush Pro 3.0" model, excepted a decreased torsional stiffness. The heel-toe drop (9 mm) was similar between the four tennis shoes. The stiffness of the shoes was determined using a testing device that measures the amount of torque necessary to twist the forefoot part of the shoe to 30 degrees of inversion and eversion, respectively (ISO norm 17707:2005). An average torque was computed based on 3 consecutive trials. The test was validated since the difference between the 3 trials was less than 2%. The four types of shoes had different internal and external torsional stiffness. The internal torsion torque was 2.2 Nm for shoe 1, 2.9 Nm for shoe 2, 3.7 Nm for shoe 3 and 4.2 Nm for shoe 4. The external torsion torque was 2.9 Nm for S1, 4.2 Nm for S2, 4.2 Nm for S3 and 5.3 Nm for S4. S3 and S4 are considered as stiffer shoes while S1 and S2 are more flexible shoes. For the purpose of this study, shoe 1 will be referred to as "high flexible", shoe 2 to "flexible", shoe 3 to "stiff" and shoe 4 to "high stiff". [START_REF] Leardini | Validation of a functional method for the estimation of hip joint centre location[END_REF] [START_REF] Reed | Methods for measuring and representing automobile occupant posture. Technical Paper 990959[END_REF] [START_REF] Zatsiorsky | Contemporary problems of biomechanics[END_REF]. On the feet, landmarks were placed according to the Oxford foot model [START_REF] Stebbins | Repeatability of a model for measuring multi-segment foot kinematics in children[END_REF]. A Vicon motion capture system (Oxford Metrics Inc., Oxford, UK) recorded the 3D trajectories of retro-reflective markers located on anatomical landmarks with a residual error less than 1 mm. The system was composed of 20 high-resolution cameras (4 megapixels) operating at a nominal framerate of 200 Hz. Players were shirtless and wore only tight shorts to limit unwanted markers' movements. After motion capture, the 3D coordinates of the landmarks were reconstructed with Blade software (Blade; Vicon, Oxford, UK) with a residual error of less than 1 mm. The force platform (operating at 2000 Hz) measured vertical, horizontal and lateral ground reaction forces (GRF) on the dominant step (right side) and stance time during forehand strokes. GRF were normalized by the mass of the subjects. All the kinetic and kinematic data was processed with CusToM in Matlab software (Mathworks, Natick, Massachusetts, USA). CusToM is a Customizable Toolbox for Musculoskeletal simulation which solves inverse kinematics and inverse dynamics from motion capture data [START_REF] Muller | CusToM: A Matlab toolbox for musculoskeletal simulation[END_REF]. For both tennis specific movements (SRDJ and JROF), the inversion/eversion rotation of the forefoot with respect to the rearfoot (minimum, maximum and range of motion) was determined about the long axis of the foot. Moreover, the minimum, maximum angle value, and range of motion were computed for each rotation axis of the right ankle during the right foot support on the force plate. Maximal ankle torques (plantar flexion/dorsiflexion, external rotation/internal rotation, and inversion/eversion) were computed and normalized by the mass of the subjects. Absolute approach running velocity of the center of mass at the instant of the first contact between the right foot and the force plate was also computed. This approach running velocity also called the "entry speed" [START_REF] Giles | Applying the brakes in tennis: How entry speed affects the movement and hitting kinematics of professional tennis players[END_REF] corresponds to the velocity at which the player's body arrives to hit the forehand stroke.

Mean and SD values were computed for all parameters. For SRDF and JROF, one-way analyses of variance (ANOVAs) with repeated measures were used to analyze differences in maximal GRF, forefoot and ankle kinematics, and ankle torques between the four shoe conditions. Partial eta squared (η 2 p), defined as small (.10-.24), moderate (.25-.39), or large (≥.40) were also calculated to determine effect sizes. Significant main effects were decomposed using the post hoc Holm-Sidak correction method to determine the source of difference. Where data were not normally distributed, significance was determined using a Friedman analysis of variance with repeated measures on ranks and a post hoc Durbin-Conover test. Kendall's W, defined as small (.10-.29), moderate (0.30-0.49) and large (≥0.50) were also calculated to determine effect sizes for ANOVA with repeated measures on ranks. The level of significance was established at P < 0.05 (Jamovi, version 1.6.23).

Results

Stance time and GRF peaks

As revealed in table 1, the absolute running velocity of the center of mass at the instant of the first contact between the right foot and the force plate, the stance duration and the peaks of GRF are not significantly influenced by the shoe torsional stiffness in both tennis forehands (SRDF and JROF). There was a trivial or small effect sizes among the four shoe conditions for absolute running velocity of the center of mass, stance duration and maximal GRF (Table 1)

Ankle and forefoot angles and ranges of motion

For the SRDF, the shoe torsional stiffness significantly and largely affected the maximal angle of ankle inversion (F(3,27) = 7.57; P < 0.001; h 2 p = 0.486) that was significantly higher in "high stiff" shoes compared with "stiff" shoes (P <0.001), "flexible" shoes (P <0.05) and "high flexible" shoes (P <0.01) (Table 2). The results showed significant and large main effects of the shoe torsional stiffness on the maximal angle of forefoot inversion (c 2 (3) = 20.76, P < 0.001, W = 0.692) and on the range of motion of forefoot inversion -eversion (F(3,27) = 15.5, P < 0.001, h 2 p = 0.632). The maximal angle of forefoot inversion was significantly higher in "flexible" than in "stiff" (P <0.001), "high stiff" (P <0.01) and "high flexible" shoes (P <0.05).

The maximal angle of forefoot inversion was significantly higher in "high flexible" shoes than in "stiff" and "high stiff" shoes (P <0.05). The range of motion of forefoot inversion -eversion was significantly higher in "flexible" than in "stiff" (P <0.001) and "high stiff" shoes (P <0.05) and in "high flexible" than in "stiff" shoes (P <0.001).

For the JROF, the shoe torsional stiffness significantly and moderately affected the maximal angle of forefoot inversion (F(3,27) = 4.49; P = 0.011; h 2 p = 0.333) and the range of motion of forefoot inversion -eversion (F(3,27) = 5.34, P < 0.005, h 2 p = 0.372) (Table 2). The maximal angle of forefoot inversion was significantly higher in "flexible" than in "stiff" and "high stiff" shoes (P <0.05). The range of motion of forefoot inversion -eversion was significantly lower in "stiff" than in "high flexible" (P <0.05) and "flexible" (P <0.05).

Maximal ankle inversion angular velocity

For JROF, the shoe torsional stiffness has no effect on the maximal velocity of ankle inversion. For the SRDF, the shoe torsional stiffness significantly and moderately affected the maximal velocity of ankle inversion (F(3,27) = 3.69; P = 0.037; h 2 p = 0.292). However, posthoc test reveals no significant difference between the four shoes (Table 2)

Ankle and forefoot torques

For the SRDF, the shoe torsional stiffness significantly and largely affected the maximal torque of ankle plantar flexion (F(3,27) = 12.02; P < 0.001; h 2 p = 0.600) that was significantly higher in "high flexible" compared with "high stiff" (P <0.001) and "stiff" shoes (P <0.01) (Table 2) and in "flexible" compared with "high stiff" shoes (P <0.001) (Table 3). The results showed a significant and large main effect of the shoe torsional stiffness on the maximal torque of ankle dorsiflexion (c 2 (3) = 17.93, P < 0.001, W = 0.598). Post hoc results demonstrated that the maximal torque of ankle dorsiflexion was significantly lower in "high flexible" than in "high stiff", "stiff" (P < 0.001) and "flexible" (P < 0.01) and also significantly reduced in "flexible" (P < 0.001) and "stiff" than in "high stiff" shoes (P < 0.01).

For the JROF, a significant and moderate main effect of the shoe torsional stiffness was observed on the maximal torque of ankle plantar flexion (c 2 (3) = 12.60, P = 0.006, W = 0.413).

Post hoc results demonstrate that the maximal torque of ankle plantar flexion was significantly lower in "high flexible" than in "high stiff" and "stiff shoes" (P < 0.

Discussion

This study aimed to evaluate, during two tennis forehand runs and strokes, the influence of shoe torsional stiffness on absolute running velocity of the center of mass at the instant of the first contact between the right foot and the force plate, ground reaction forces and stance duration, which are considered as performance indicators, and on ankle kinematic and kinetic variables which have been related to ankle sprain mechanisms.

Our results showed that shoe torsional stiffness had no significant influence on foot performance since absolute running velocity of the center of mass at the instant of the first contact between the right foot and the force plate, stance duration, and maximal values of GRF are similar for the four shoe conditions for both SRDF and JROF. These findings confirm the results of [START_REF] Graf | The effect of footwear torsional stiffness on lower extremity and kinetics during lateral cutting movements[END_REF] who reported no effect of shoe torsional stiffness on performance for lateral cutting movements in team sports [START_REF] Graf | The effect of footwear torsional stiffness on lower extremity and kinetics during lateral cutting movements[END_REF]. However, our results did not confirm that shoes with more torsional stiffness limiting supination allowed tennis players to perform faster sideward cutting movements [START_REF] Llana-Belloch | Supination control increases performance in sideward cutting movements in tennis[END_REF]. In the study of [START_REF] Llana-Belloch | Supination control increases performance in sideward cutting movements in tennis[END_REF], the range of footwear models studied (n = 10 shoes, longitudinal flexibility from 8 to 21°, different quality levels and prices) was more important than in the current protocol (n = 4 shoes, shoe internal torsional stiffness from to 2.2 to 4.2 Nm, high-quality levels and prices). The lower range of footwear may explain the contradictory results between our study and those of [START_REF] Llana-Belloch | Supination control increases performance in sideward cutting movements in tennis[END_REF].

The typical lateral ankle ligamentous sprain mechanism corresponds to a combined motion with ankle inversion, internal rotation and plantar flexion [START_REF] Garrick | The frequency of injury, mechanism of injury, and epidemiology of ankle sprain[END_REF] [START_REF] Fong | Kinematics analysis of ankle inversion ligamentous sprain injuries in sports: Five cases from televised tennis competitions[END_REF] [START_REF] Purevsuren | Influence of ankle joint plantarflexion and dorsiflexion on lateral ankle sprain: A computational study[END_REF]. [START_REF] Lysdal | What we learnt from quantitaive case reports of acute lateral ankle sprains injuries and episodes of "giving-away" of the ankle joint, and what shall we further investigate[END_REF] published a quantitative review of published case reports documenting the kinematics of acute lateral ankle sprains aiming to provide a comprehensive and hierarchical description of the ankle sprains mechanisms. They reported that excessive ankle inversion angle and angular velocity were the most pronounced kinematic pattern observed across all included cases. Other studies considered that excessive ankle inversion angle and velocity appear to be the primary factors of the lateral ankle sprain mechanism [START_REF] Purevsuren | Influence of ankle joint plantarflexion and dorsiflexion on lateral ankle sprain: A computational study[END_REF] [START_REF] Fong | Kinematics analysis of ankle inversion ligamentous sprain injuries in sports: Five cases from televised tennis competitions[END_REF] [START_REF] Mok | Kinematics Analysis of Ankle Inversion Ligamentous Sprain Injuries in Sports: 2 cases during the 2008 Beijing Olympics[END_REF] [START_REF] Delahunt | Risk factors for lateral ankle sprains and chronic ankle instability[END_REF].

In our study, the maximum ankle inversion angle and angular velocity showed no differences between the shoes for JROF. However, for SRDF, the maximal ankle inversion angle was significantly and largely influenced by shoe torsional stiffness. Moreover, for SRDF, the shoe torsional stiffness has a small significant effect on the maximal ankle inversion angular velocity, even if the post-hoc test reveals no significant difference between the four shoes. The lack of statistical power caused by the small sample size (n = 10) of our study can explain the non-significant post-hoc test result. Indeed, when pairwise comparison tests are not statistically powerful, it is less likely to detect significant differences. One may argue that the differences in results observed between JROF and SRDF are linked to the nature of these tennis movements. The JROF is a forward and slightly lateral movement while the SRDF is a strong lateral movement that may solicit more of the ankle in the frontal plane (action of inversion/eversion). In SRDF, the "high stiff" shoes had the disadvantage of largely increasing the maximal angle of ankle inversion (+3 to 5°) and slightly increasing the maximal angular velocity of ankle inversion (+ 48.9 to 75.2 °/s) compared to other shoes. A quantitative synthesis of published case reports documenting the kinematics of acute lateral ankle sprains and episodes of 'giving-way' of the ankle joint reported that excessive ankle inversion was the most pronounced kinematic pattern observed across all included cases, with great variation for peak inversion angle (range 2.0 to 142°) and angular velocity (range 468 to 1752°/s) [START_REF] Lysdal | What we learnt from quantitaive case reports of acute lateral ankle sprains injuries and episodes of "giving-away" of the ankle joint, and what shall we further investigate[END_REF]. A study presenting five cases of ankle sprains from televised tennis competitions reported great variations in the peak inversion angle and angular velocity in the five cases, which cases ranged from 48 to 126° and from 509 to 1488°/s, respectively [START_REF] Fong | Kinematics analysis of ankle inversion ligamentous sprain injuries in sports: Five cases from televised tennis competitions[END_REF].

Our results show that it is for the "high stiff" shoe that the ankle inversion values (peak angle: 42.9° and peak angular velocity: 477.2°/s) are the closest of those previously published from ankle sprain case-studies. Consequently, the "high stiff" shoe seems more conducive to induce lateral ankle sprains in tennis players during SRDF.

Moreover, the literature supports that the higher the ankle eversion torque, the higher the risk of injury. Our results showed a small but not significant effect of the shoe torsional stiffness on maximal ankle eversion torque in SRDF. The maximal ankle eversion torques in "high stiff" and "stiff" shoes were 3 to 12% higher than in "flexible" and "high flexible" shoes.

These results are partially in line with the findings of [START_REF] Graf | The effect of footwear torsional stiffness on lower extremity and kinetics during lateral cutting movements[END_REF] who reported a significant increased ankle eversion torque of 20% for the stiff shoes in comparison with flexible shoes in typical cutting movements for team sports. Behind ankle inversion, internal rotation is considered the second factor of lateral ankle sprain [START_REF] Lysdal | What we learnt from quantitaive case reports of acute lateral ankle sprains injuries and episodes of "giving-away" of the ankle joint, and what shall we further investigate[END_REF]. In our study, the maximal angles and torques of ankle internal rotation were not significantly influenced by the shoe torsional stiffness in SRDF and JROF.

The ankle plantar flexion angle and torque are considered minor factors of injury because it might not play a crucial role in the lateral ankle sprain mechanism [START_REF] Purevsuren | Influence of ankle joint plantarflexion and dorsiflexion on lateral ankle sprain: A computational study[END_REF] [START_REF] Lysdal | What we learnt from quantitaive case reports of acute lateral ankle sprains injuries and episodes of "giving-away" of the ankle joint, and what shall we further investigate[END_REF]. Indeed, high plantar flexion is not always required for an ankle sprain to occur [START_REF] Mok | Kinematics Analysis of Ankle Inversion Ligamentous Sprain Injuries in Sports: 2 cases during the 2008 Beijing Olympics[END_REF] [START_REF] Kristianslund | Kinematics and kinetics of an accidental lateral ankle sprain[END_REF] [START_REF] Panagiotakis | Biomechanical analysis of ankle ligamentous sprain injury cases from televised basketball games: Undrestanding when, how and why ligament failure occurs[END_REF].

Whereas ankle plantar flexion and dorsiflexion angles were not significantly influenced by shoe torsional stiffness in SRDF and JROF (only small or trivial effects), our results surprisingly showed large and significant effects of shoe torsional stiffness on ankle plantarflexion torques in SRDF and dorsiflexion torques in SRDF and JROF. The reason for these results remains unclear. While it has been reported that a muscular deficit in plantar flexion torque characterized unstable ankles [START_REF] Fox | Eccentric plantar-flexor torque deficits in participants with functional ankle instability[END_REF], the literature lacks clear and consensual data about the potential effects of ankle plantar flexion and dorsiflexion torques on ankle injury risks and mechanisms [START_REF] Lysdal | What we learnt from quantitaive case reports of acute lateral ankle sprains injuries and episodes of "giving-away" of the ankle joint, and what shall we further investigate[END_REF]. Further studies are necessary to understand them and to enlighten our current results.

The maximal angle of forefoot inversion and the range of motion of forefoot inversion -eversion were significantly affected by the shoe torsional stiffness for both forehand strokes and movements. The effect of the shoe torsional stiffness on these kinematic parameters was large for the SRDF and moderate for the JROF. For the SRDF, the "stiff" and the "high stiff" shoes demonstrated smaller maximal angle of forefoot inversion and range of motion of forefoot inversion -eversion. All these results are in line with the findings of [START_REF] Graf | The effect of footwear torsional stiffness on lower extremity and kinetics during lateral cutting movements[END_REF]. In stiff shoes, the forefoot and the rearfoot were more rigidly coupled. This mechanism reduces the maximal angle of forefoot inversion but increases the ankle inversion angle to provide an effective angle between forefoot and shank in stiff shoes [START_REF] Graf | The effect of footwear torsional stiffness on lower extremity and kinetics during lateral cutting movements[END_REF]. On the contrary, in "flexible" and "high flexible" shoes, the forefoot and the rearfoot acted and moved in a more free or independent way than in stiffer shoes. The difference between shoe conditions was small (1 to 6 °) and it is assumed that the observed increase in forefoot movement does not increase the risk of injury in the flexible shoes [START_REF] Graf | The effect of footwear torsional stiffness on lower extremity and kinetics during lateral cutting movements[END_REF]. The difference in forefoot inversion angle could explain the higher feeling of comfort associated with flexible shoes in tennis players [START_REF] Herbaut | Determination of optimal shoe fitting for children tennis players: Effects of inner-shoe volume and upper stiffness[END_REF] [START_REF] Llana | A study of the discomfort associated with tennis shoes[END_REF]. According to [START_REF] Avagnina | The foot and ankle at risk of injury in tennis players[END_REF], the relationship between the rearfoot and forefoot is fundamental for the comfort, the speed, the fluidity and the transfer of rotation from the foot to the lower limb during tennis motions. In running, different studies showed that the stiffer the shoe, the more the natural barefoot motion of the foot was modified [START_REF] Stacoff | The torsion of the foot in running[END_REF]) [START_REF] Stacoff | The effect of shoes on the torsion and rearfoot motion in running[END_REF]. As a consequence, by "freeing" the foot and inducing more forefoot torsion, one may hypothesize that flexible shoes could help tennis players to perform more natural foot actions during tennis forehands and strokes. Further studies comparing barefoot and different conditions of shoes' stiffness during tennis motions are necessary to confirm this hypothesis.

Our study had several limitations. First, the comfort of the shoes was not assessed, this is a limitation of the present work. Moreover, the sample size was small because we only included male advanced tennis players able to properly perform both specific forehand stroke movements (SRDF and JROF) and their participation was voluntary. The small sample size of this exploratory study also increased the chance of type II errors and decreased statistical power.

Another limitation of the current study was that the measure of foot and ankle motions was based on markers placed on the shoes' upper and on the skin of the players. This could slightly increase errors in the kinematic and kinetic calculations despite efforts to minimize them, such as by placing markers on bony prominences with the least amount of skin motion. A recent study compared ankle kinematic measures during running trials with an optoelectronic markerbased system and biplanar videoradiography [START_REF] Kessler | A Direct Comparison of Biplanar Videoradiography and Optical Motion Capture for Foot and Ankle Kinematics[END_REF]. Results showed a good agreement of ankle plantarflexion/dorsiflexion angles between the two systems but moderate agreements for the ankle inversion/eversion and internal/external rotation angles. As a consequence, the interpretation of ankle inversion/eversion and internal/external rotation angles in the current study should be treated with caution. Moreover, the movement of the foot inside the shoe could not be quantified with the motion capture system. One may suppose that the torsion angle of the foot in the shoe was larger than the torsion angle of the shoe [START_REF] Graf | The effect of footwear torsional stiffness on lower extremity and kinetics during lateral cutting movements[END_REF]. One may hypothesize that the difference between the torsion angle of the foot in the shoe and the torsion angle of the shoe may be more important in the most flexible shoes that less constrain and less modify the natural motion of the foot [START_REF] Stacoff | The torsion of the foot in running[END_REF]) [START_REF] Stacoff | The effect of shoes on the torsion and rearfoot motion in running[END_REF]. Finally, we evaluated ankle loadings using the inverse dynamics method but we did not use musculoskeletal modeling and computer simulations to predict the ankle muscle and ligament forces during the forehand strokes. The insight into how leg and foot muscles interact to produce the motion may be of importance for a better understanding of possible ankle injury mechanisms.

In conclusion, shoe torsional stiffness had no effect on performance since absolute running velocity of the center of mass at the instant of the first contact between the right foot and the force plate, stance duration, and maximal values of GRF are similar for the four shoe conditions for both SRDF and JROF. For SRDF and JROF, the shoe torsional stiffness influenced forefoot inversion which was significantly higher for the most flexible shoes. As a consequence, in flexible shoes, the forefoot and the rearfoot acted and moved in a freer way.

For SRDF, the maximal ankle inversion angle was significantly and largely increased for the stiffest shoe. This result showed that the stiffest shoe may put the ankle at a higher risk of lateral sprains during shuttle run defensive forehand stroke (SRDF) while it was not the case during jab run offensive forehand stroke (JROF).

From a practical relevance point of view, adapting shoe torsional stiffness to the population of interest might be beneficial for limiting tennis ankle sprains. This study leads to encouraging defensive or baseliner tennis players, who like to play long rallies with shuttle run defensive strokes behind the baseline, to wear shoes with low torsional stiffness to limit ankle inversion and consequently lateral ankle sprain risks. One may hypothesize that this advice could also be provided to players with chronic ankle instability. Further complementary studies combining biomechanical analyses of the lower limbs during specific tennis motions and prospective epidemiological follow-up of the foot and ankle injuries sustained by the players according to the stiffness of their shoes could help to approximate a threshold value for the maximal shoe torsional stiffness tennis use.

  ********************************** Figure 1 near here ************************** Players were equipped with 52 retroreflective markers placed on anatomical landmarks determined in agreement with previously published data

  . **************************** Table 1 near here ***********************

  . **************************** Table 2 near here ***********************

  001). **************************** Table 3 near here ***********************

Figure captions Figure 1 .

 captions1 Figure captions

Table 1 .

 1 Statistical comparison of absolute running velocity of the center of mass at the instant of the first contact between the right foot and the force plate, stance duration, and maximal ground reaction force values across the 4 shoes for the shuttle run defensive forehand (SRDF) and the jab run offensive forehand (JROF). Values are expressed as mean ± SD.

				SRDF						JROF
		"high	"flexib	"stif	"hi	P	Effe	"high	"flexib	"stif	"hi	P	Effe
		flexibl	le"	f"	gh	val	ct	flexibl	le"	f"	gh	val	ct
		e"			stiff	ue	size	e"			stiff	ue	size
					"						"
	Runni	3.1	3.1	3.1	3.1	0.3	0.11	3.5	3.4	3.5	3.6	0.4	0.06
	ng	± 2.1	± 2.3	±	±	59	1	± 3.0	± 3.0	±	±	72	8
	veloci			2.7	2.3					3.2	3.0
	ty of
	the
	center
	of
	mass
	(m.s -1 )
	Stanc	645	643	648	635	0.7	0.04	314	312	309	301	0.7	0.04
	e	± 84	± 86	± 93	±	57	2	± 93	± 90	± 97	±	24	4
	durati				83						71
	on
	(ms)
	Anteri	5.2	5.6	5.6	5.5	0.1	0.16	14.1	13.6	15.0	14.	0.2	0.13
	or	± 1.4	± 2.0	±	±	69	8	± 5.2	± 4.8	±	7	63	5
	GRF			1.4	1.6					4.6	±
	(N.kg -										5.3
	1 )
	Latera	20.2	20.6	20.6	20.	0.8	0.02	6.2	6.1	6.7	6.3	0.5	0.07
	l GRF	± 2.9	± 2.8	±	3	68	4	± 2.4	± 1.7	±	±	28	8
	(N.kg -			2.7	±					2.0	2.4
	1 )				3.0
	Vertic	30.7	30.3	31.6	30.	0.6	0.05	25.8 ±	25.5 ±	26.1	26.	0.5	0.06
	al	± 7.9	± 6.3	±	7	72	5	8.0	7.1	±	7 ±	89	8
	GRF			6.5	±					6.4	8.1
	(N.kg -				6.0
	1 )

Table 2 .

 2 Maximal ankle and forefoot angles and ranges of motion across the 4 shoes for the shuttle run defensive forehand (SRDF) and the jab run offensive forehand (JROF). Values are mean ± SD.

* P < 0.05; ** P < 0.01; *** P < 0.001; NS: non-significant. HF: high flexible, F: flexible, S: stiff, HS: high stiff.

Funding details

This work was supported by the Wilson Footwear Department, Salomon SAS, 14 Chemin des Croiselets, 74370 Épagny Metz-Tessy, France

Declaration of interest

The authors report there are no competing interests to declare.


Lionel Arnaud

Marie-Thérèse Abi

Giulia Barcia

Julitta De Bellescize

Nicolas Chatron

Marie Faoucher

Anne De Saint

Delphine Héron

Guillaume Jedraszak

Caroline Lacoste

Anne-Sophie Lèbre

Mélanie Jenneson-Lyver

Audrey Labalme

Eric Leguern

Cyril Mignot

Mathieu Milh

Rima Nabbout

Caroline Nava

Eleni Panagiotakaki

Amélie Piton

Elise Schaefer

Julien Thevenon

Laurent Villard

Dorothée Ville

Gaetan Lesca
email: gaetan.lesca@chu-lyon.fr

The EPIGENE network: A French initiative to harmonize and improve the nationwide diagnosis of monogenic epilepsies

Keywords:

Background: The EPIGENE network was created in 2014 by four multidisciplinary teams composed of geneticists, pediatric neurologists and neurologists specialized in epileptology and neurophysiology. The ambition of the network was to harmonize and improve the diagnostic strategy of Mendelian epileptic disorders using nextgeneration sequencing, in France. Over the years, five additional centers have joined EPIGENE and the network has been working in close collaboration, since 2018, with the French reference center for rare epilepsies (CRéER). Results: Since 2014, biannual meetings have led to the design of four successive versions of a monogenic epilepsy gene panel (PAGEM), increasing from 68 to 144 genes. A total of 4035 index cases with epileptic disorders have been analyzed with a diagnostic yield of 31% (n = 1265/4035). The top 10 genes, SCN1A, KCNQ2, STXBP1, SCN2A, SCN8A, PRRT2, PCDH19, KCNT1, SYNGAP1, and GRIN2A, account for one-sixth of patients and half of the diagnoses provided by the PAGEM. Conclusion: These results suggest that a gene-panel approach is an efficient first-tier test for the genetic diagnosis of Mendelian epileptic disorders. In a near future, French patients with "drug-resistant epilepsies with seizureonset in the first two-years of life" can benefit from whole-genome sequencing (WGS), as a second line genetic

Introduction

Identification of genes causing Mendelian epileptic disorders has long been made difficult by several factors, especially the high frequency of de novo variants in epileptic and developmental epileptic encephalopathy and the high prevalence of epilepsy in the general population, resulting in a high proportion of phenocopies. In addition, most of the common epilepsies, named genetic generalized epilepsy or idiopathic generalized epilepsies, do not follow a Mendelian inheritance pattern but result from multifactorial inheritance. A few genes were identified in the late 1990's and were associated with recognizable familial phenotypes, such as autosomal dominant frontal-lobe epilepsy, epilepsy with auditory features, and genetic epilepsies with febrile seizures plus. Over the past decade, the identification of genes involved in Mendelian epileptic disorders has grown exponentially, thanks to technological advances, first in cytogenetics (array-CGH, SNP-array) and then in next-generation sequencing [START_REF] Lesca | Epilepsy genetics: the ongoing revolution[END_REF][START_REF] Bayat | Epilepsy syndromes in the first year of life and usefulness of genetic testing for precision therapy[END_REF].

In the early 2010's, two University Hospital departments were involved in the diagnosis of epileptic disorders in France, each working on a limited number of genes: in Paris Pitié-Salpétrière for fever-related epilepsies (e.g. SCN1A, PCDH19) and in Lyon for Lafora disease (EP-M2A, NHLRC1), Unverricht-Lundborg disease (CSTB), benign familial neonatal/infantile focal epilepsies (KCNQ2, SCN2A), and epilepsyaphasia syndrome (GRIN2A). In 2014, a working group called the EPI-GENE network was created including these two labs and two others: Marseille laboratory, involved in the field of genetic research for earlyonset epileptic encephalopathies and Strasbourg laboratory that had developed the first gene panel for the diagnosis of neurodevelopmental disorders in France (intellectual disability). Each of these four teams was multidisciplinary, including molecular and clinical geneticists, pediatric neurologists and epileptologists. Their objectives were to rationalize and homogenize the genetic strategy using next-generation sequencing for the etiological diagnosis of Mendelian epileptic disorders in France. Over the years, additional multidisciplinary centers joined the EPIGENE network: Reims (2016), Paris Necker and Grenoble (2018), and more recently, Amiens and Rennes (2020). Each of these centers had a multidisciplinary team and most of them have been involved in the identification of genes causing Mendelian epilepsies [START_REF] Ishida | Mutations of DEPDC5 cause autosomal dominant focal epilepsies[END_REF][START_REF] Lesca | GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction[END_REF][START_REF] Barcia | De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy[END_REF][START_REF] Milh | Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2[END_REF]. Upon joining the network, each new center signed the network charter for data sharing and collaboration rules.

In 2018, this initiative was acknowledged by the French Reference Center for Rare Epilepsies (CRéER) dedicated to research, education, and to the care of patients with rare epilepsies. The CRéER includes 7 Reference centers and 20 competence centers in France and is itself part of the DéfiScience rare diseases healthcare network, which brings together resources and expertise in the field of rare neurodevelopmental diseases.

A first version of the list of most wanted genes list was defined by the EPIGENE network in 2014 and was revised annually to add novel genes. Criteria for inclusion of a novel gene in the list are: i) epilepsy is a leader symptom of the disease or is frequently present in patients, ii) the mode of inheritance is Mendelian, iii) the role of the gene in the disease is supported by relevant data from the literature. The resulting gene panel, named PAGEM (PAnel de Gènes pour les Epilepsies Monogeniques, i.e. gene panel for epileptic monogenic epilepsies) was designed as a diagnostic tool for the pediatric neurologist, epileptologist and clinical geneticist following patients with epileptic disorders. We chose not to include the genes causing brain malformations, tuberous sclerosis and most genes for inborn errors of metabolism that were covered by other dedicated gene panels in France. Yet, a limited number of genes causing metabolic disorders, which are frequently associated with seizures and can benefit from specific treatments were included in the PAGEM gene panel: SCL2A1 (GLUT1 deficiency), CAD (CAD deficiency), BTD (biotinidase deficiency), SLC19A3 (thiamine transporter deficiency), TPP1 (CLN2), as well as ALDH7A1 and PNPO (deficiency of vitamin B6 metabolism).

Two centers (Lyon and Paris Pitié-Salpétrière), use the PAGEM as a specific panel whereas the other laboratories included the common gene list in a larger screening tool, including genes for other disease entities, with different library-building technologies, or used it as an insilico panel on exome sequencing. The objectives of the EPIGENE network were: i) to harmonize the practices (clinical questionnaire, core gene list), ii) to improve practices (inter-laboratory quality control, discussion of complex cases on a regular basis) and of cross knowledge between clinicians and geneticists, iii) to provide equal access to genetic testing throughout the country, and iv) to facilitate common research projects.

Results and discussion

From 2014 to 2020, four successive versions of the PAGEM gene panel were designed and included 68 (V1), 71 (V2), 116 (V3) and 144 (V4) genes, respectively. All the gene panels (or exome sequencing) used correspond to type C tests according to the European Society of Human Genetics guidelines [START_REF] Matthijs | Guidelines for diagnostic next-generation sequencing[END_REF], with gene panels covering more than 99% of the target. The regions with no or insufficient coverage are indicated in the report or were available upon request. In parallel, EPIGENE has organized an inter-laboratory quality control, annually since 2018 in order to improve practices, homogenize the interpretation and report of panel analysis nation-wide, from DNA sequencing to clinical report.

Between 2015 and 2020, 4035 index cases with epileptic disorders were analyzed with the PAGEM gene panel in a diagnostic setting, with the following distribution: Lyon: 1377, Paris Pitié Salpétrière: 974, Marseille: 691, Paris Necker: 530, and Strasbourg: 463. Data from centers that recently joined the network, or that used several lines of analyses before the PAGEM, were not included in this survey.

Fig. 1 shows the distribution, for each gene, of the pathogenic or likely pathogenic variants according to the ACMG classification [START_REF] Richards | Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology[END_REF]. The global diagnostic yield was 31.3% (n = 1265/4035). No pathogenic or likely pathogenic variant was found in 34 genes, among which four were present since V1, two were added in V2 and the others had been added in the V4. Pathogenic or likely pathogenic variants were found for 94 genes (65.3%, 94/144) in at least two patients. The top 10 genes (i.e., SCN1A, KC-NQ2, STXBP1, SCN2A, SCN8A, PRRT2, PCDH19, KCNT1, SYNGAP1, and GRIN2A) accounted for about 17% of the patients and more than 50% of the confirmed diagnoses (Fig. 1). These genes cause early-onset epileptic disorders in most of the patients. This top 10 representation has probably been reinforced in our cohort by historical interest in a few genes in each group, especially for genes such as GRIN2A (Lyon, Strasbourg), SCN1A (Paris Pitié-Salpétrière), KC-NT1 (Paris Necker), and KCNQ2 (Marseille, Lyon).

However, this peculiar distribution of genes in epileptic disorders was already observed in previous cohorts and is different from the distribution of genes causing intellectual disability without epilepsy or from diseases which epilepsy is a secondary feature [START_REF] Heyne | Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy[END_REF]. In that latter case, the number of genes involved is far higher, many of them accounting for a small subset of patients. One of the reasons for the recurrent involvement of a subset of genes in epilepsy disorders is related to the role of ion channels that are globally rather intolerant to missense variants and the presence of multiple functional consequences (gain of function, loss of function, dominant negative, or more complex combinations of functional dysfunctions) [START_REF] Heyne | De novo variants in neurodevelopmental disorders with epilepsy[END_REF]. Pathogenic or likely pathogenic variants were found in genes causing treatable inborn errors of metabolisms for 38 patients (3% of patients with a diagnosis), including SLC2A1 (15), ALDH7A1 (11), PNPO (7), BTD (3), and SLC19A3 (2).

Our global results are quite consistent with those from previous studies and suggest that a gene-panel approach is an efficient first step for the genetic diagnosis of Mendelian epileptic disorders. This approach allows a rapid turn-over for very young patients who can benefit from treatment adaptation.

The EPIGENE network capitalized on groups' interests over the past few years and enable deep phenotyping collaborative studies and new epilepsy genes discoveries [START_REF] Kuchenbuch | KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP[END_REF][START_REF] Mignot | IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients[END_REF][START_REF] Denis | Clinical study of 19 patients with SCN8A-related epilepsy: two modes of onset regarding EEG and seizures[END_REF][START_REF] Bar | Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature[END_REF][START_REF] Bar | Adaptive behavior and psychiatric comorbidities in KCNB1 encephalopathy[END_REF]. The EPIGENE network enhances translational collaborations in genetic epilepsies and beyond within the reference center for rare epilepsies frame. A detailed study of the clinical and genetic data of the global EPIGENE series is in preparation.

In 2016, the French government launched a national effort -The Plan France Medecine Genomique 2025 -to ensure that every patient with rare disease can access to new genomic medicine technologies in an equitable manner across the territory, in order to improve the way diseases are diagnosed, prevented and treated. Two first platforms performing whole-genome sequencing in cancer (somatic) and rare diseases (germline) were created in Lyon (AURAGEN) and in Paris (SE-QOIA) and the first sequences were produced in 2020.

The CRéER and the EPIGENE network obtained that patients presenting "drug-resistant epilepsies with seizure-onset in the first two Arnaud et al. European Journal of Medical Genetics xxx (xxxx) 104445 years of life" are eligible for genome sequencing. This category of patients was prioritized because expected to be associated with the higher proportion of Mendelian disorders and the higher diagnostic yield. WGS can be performed in trios (affected patient and the unaffected parents), in quartets (two affected children and the unaffected parents) or any other family combination including several affected individuals. Patients without any pathogenic or likely pathogenic variants identified by the panel can now benefit from WGS in order to look for missed variants in frequent genes, to screen less commonly involved genes, and to identify non-coding pathogenic variants or novel genes causing Mendelian epilepsies.

U N C O R R E C T E D P R O O F L.
The Plan France Medecine Génomique requested to add specific case discussion meetings corresponding to the geographical area of each platform (AURAGEN and SEQOIA), to validate the relevance of genomic testing and the results that require additional expertise (some variants of unknown significance, variants in unusual or novel genes …). This organization, based on our 6yearsexperience as a multidisciplinary network, aims to improve the genetic diagnosis of epileptic disorders and to disseminate our shared knowledge and practices to other French Centers (Fig. 2). The strength of the multidisciplinary video case discussions is to provide comprehensive overview of the patients' phenotype, including the expertise of video-EEG and correct brain MRI interpretation, to improve the accurate interpretation of the molecular data. The molecular geneticists and cytogeneticists of the EPIGENE network will be involved in the analysis of WGS data, including singlenucleotide variants, indels, copy-number variations and structural variants. After the validation step of this organization and of the scale-up of the sequencing workflow of both platforms, other categories of patents with epileptic disorders of yet unknown etiology will also benefit from WGS. A next step will be a national consensus in order to restrict the number of genes on the panel to core recurrent genes that will have to be tested quickly in patients with early-onset epilepsy. The proposal will be to leave for WGS the non-urgent cases and those with a negative gene panel.

This collaboration between expert clinicians and biologists enables the EPIGENE members with CRéER to be ready for the coming challenges of genome analysis, functional analysis based on collaborations at European level mainly ERN-EPICARE, and International level with the acceleration of the open data space.

Fig. 1 .

 1 Fig. 1. Diagnostic yield of the French Mendelian epilepsy gene panel (PAGEM) for 4035 patients analyzed from 2015 to 2020.

Fig. 2 .

 2 Fig. 2. Summary of the EPICARE network expertise and organization.

Authors statement

All the authors contributed to conceptualization, data acquisition and curation, as well as writing and review. GL Drafted and edited the manuscript.