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Summary Objective This pragmatic, multicenter, open-label, randomized controlled trial (RCT) aimed to compare the effectiveness, safety, and cost–utility of a custom-made knee brace versus usual care over 1 year in medial knee osteoarthritis (OA). Design 120 patients with medial knee OA (VAS pain at rest >40/100), classified as Kellgren–Lawrence grade II-IV, were randomized into two groups: ODRA plus usual care (ODRA group) and usual care alone (UCA group). The primary effectiveness outcome was the change in VAS pain between M0 and M12. Secondary outcomes included changes over 1 year in KOOS (function) and OAKHQOL (quality of life) scores. Drug consumption, compliance, safety of the knee brace, and cost–utility over 1 year were also assessed. Results The ODRA group was associated with a higher improvement in: VAS pain (adjusted mean difference of −11.8; 95% CI: −21.1 to −2.5); all KOOS subscales (pain: +8.8; 95% CI: 1.4–16.2); other symptoms (+10.4; 95% CI: 2.7–18); function in activities of daily living (+9.2; 95% CI: 1.1–17.2); function in sports and leisure (+12.3; 95% CI: 4.3–20.3); quality of life (+9.9; 95% CI: 0.9–15.9), OAKHQOL subscales (pain: +14.8; 95% CI: 5.0–24.6); and physical activities (+8.2; 95% CI: 0.6–15.8), and with a significant decrease in analgesics consumption at M12 compared with the UCA group. Despite localized side-effects, observance was good at M12 (median: 5.3 h/day). The ODRA group had a more than 85% chance of being cost-effective for a willingness-to-pay threshold of €45 000 per QALY. Conclusions The ERGONOMIE RCT demonstrated significant clinical benefits of an unloader custom-made knee brace in terms of improvements in pain, function, and some aspects of quality of life over 1 year in medial knee OA, as well as its potential cost–utility from a societal perspective.

Background While its importance in daily living, the anaerobic metabolism is not taken into account in clinical practice. The lack of validated functional performance tests for patients with chronic disabilities may explain this defect. In this context, the Short and Fast Step Test (SFST) was recently developed and validated in healthy volunteers. Aim The purpose of this study was to investigate the safety, feasibility and reliability of the SFST, a functional test exploring anaerobic metabolism in coronary patients during cardiac rehabilitation. Design This study was a monocentric prospective study. Settings This study took place in the rehabilitation center of the University Hospital Center of Dijon, France. Population 44 coronary patients, addressed for a first cardiac rehabilitation, were included in this protocol. Methods All participants performed three SFST: T1 and T2 (including respiratory gas exchange) the first day of the program and T3 after 3 to 7 days. SFST consists of walking up and down a 17.5cm-high step as many times as possible in 1 minute. Safety was assessed by the percentage of patients who performed the SFST without reporting a fall, or muscular or cardiovascular events. Feasibility was evaluated by the percentage of patients who succeeded in doing the SFST. Reliability was assessed with the number of raised steps in same condition (T1-T3) and different conditions (T1-T2) using a 2-way intraclass correlation coefficient (ICC). Values were given with their 90% confidence interval [90%CI]. Results The safety was 95.2% [85.8;99.2] for T1, 88.1% [76.6;95.2] for T2 and 90.4% [79.5;96.7] for T3. 100% [93,1;100] of participants completed T1 and T2, 92.9% [82.6;98] T3. An ICC of 0.74 [0.60;0.84] was observed between T1 and T3 and of 0.87 [0.79;0.92] between T1 and T2. Conclusions This study demonstrates the good safety, feasibility and reliability of the SFST to assess anaerobic metabolism in coronary patients in a rehabilitation program. Clinical rehabilitation impact These results show that the SFST seems suitable for the evaluation of brief submaximal functional capacity in daily activities. It offers a real possibility to assess such capacity during the cardiac rehabilitation routine.

La négligence spatiale unilatérale (NSU) est un trouble de la cognition spatiale fréquent et invalidant à la suite d’une lésion cérébrale. Les épreuves papier-crayon classiquement utilisées pour l’évaluer sont néanmoins critiquées pour leur manque de sensibilité. De récents travaux suggèrent que l’oculométrie pourrait pallier ces limites. Toutefois, sa complexité et son coût en restreignent l’utilisation en pratique clinique. Un protocole simplifié basé sur un matériel d’oculométrie destiné à l’usage individuel avec exploration visuelle libre d’une image a été proposé à dix patients cérébrolésés droits. Un index spatial illustrant un biais attentionnel a été calculé selon la répartition des points de fixation. Les résultats ont montré une bonne faisabilité auprès de patients hétérogènes et une forte concordance entre cette procédure et les épreuves classiques de détection de la NSU. Ces données renforcent l'intérêt de l’utilisation d’un protocole d’oculométrie simplifié basé sur un matériel abordable dans l’évaluation de la NSU en pratique courante.

Six to eight months after total hip arthroplasty, patients only attain 80% of the functional level of control groups. Understanding which functional tasks are most affected could help reduce this deficit by guiding rehabilitation towards them. The timed up-and-go test bundles multiple tasks together in one test and is a good indicator of a patient’s overall level of function. Previously, biomechanical analysis of its phases was used to identify specific functional deficits in pathological populations. To the best of our knowledge, this analysis has never been performed in patients who have undergone total hip arthroplasty. Seventy-one total hip arthroplasty patients performed an instrumented timed up-and-go test in a gait laboratory before and six months after surgery; fifty-two controls performed it only once. Biomechanical features were selected to analyse the test’s four phases (sit-to-stand, walking, turning, turn-to-sit) and mean differences between groups were evaluated for each phase. On average, six months after surgery, patients’ overall test time rose to 80% of the mean of the control group. The walking phase was revealed as the main deficiency before and after surgery (-41 ± 47% and -22 ± 32% slower, respectively). High standard deviations indicated that variability between patients was high. On average, patients showed improved results in every phase of the timed up-and-go test six months after surgery, but residual deficits in function differed between those phases. This simple test could be appropriate for quantifying patient-specific deficits in function and hence guiding and monitoring post-operative rehabilitation in clinical settings.

Locomotion assistive devices equipped with a microprocessor can potentially automatically adapt their behavior when the user is transitioning from one locomotion mode to another. Many developments in the field have come from machine learning driven controllers on locomotion assistive devices that recognize/predict the current locomotion mode or the upcoming one. This review synthesizes the machine learning algorithms designed to recognize or to predict a locomotion mode in order to automatically adapt the behavior of a locomotion assistive device. A systematic review was conducted on the Web of Science and MEDLINE databases (as well as in the retrieved papers) to identify articles published between 1 January 2000 to 31 July 2020. This systematic review is reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and is registered on Prospero (CRD42020149352). Study characteristics, sensors and algorithms used, accuracy and robustness were also summarized. In total, 1343 records were identified and 58 studies were included in this review. The experimental condition which was most often investigated was level ground walking along with stair and ramp ascent/descent activities. The machine learning algorithms implemented in the included studies reached global mean accuracies of around 90%. However, the robustness of those algorithms seems to be more broadly evaluated, notably, in everyday life. We also propose some guidelines for homogenizing future reports.

International audience; Theorists have long postulated that facial properties such as emotion and sex are potent social stimuli that influence how individuals act. Yet extant scientific findings were mainly derived from investigations on the prompt motor response upon the presentation of affective stimuli, which were mostly delivered by means of pictures, videos, or text. A theoretical question remains unaddressed concerning how the perception of emotion and sex would modulate the dynamics of a continuous coordinated behaviour. Conceived in the framework of dynamical approach to interpersonal motor coordination, the present study aimed to address this question by adopting the coupled‐oscillators paradigm. Twenty‐one participants performed in‐phase and anti‐phase coordination with two avatars (male and female) displaying three emotional expressions (neutral, happy, and angry) at different frequencies (100% and 150% of the participant's preferred frequency) by executing horizontal rhythmic left‐right oscillatory movements. Time to initiate movement (TIM), mean relative phase error (MnRP), and standard deviation of relative phase (SDRP) were calculated as indices of reaction time, deviation from the intended pattern of coordination, and coordination stability, respectively. Results showed that in anti‐phase condition at 150% frequency, MnRP was lower with the angry and the female avatar. In addition, coordination was found to be more stable with the male avatar than the female one when both displaying neutral emotion. But the happy female avatar was found to elicit more stable coordination than the neutral female avatar. These results implied that individuals are more relaxed to coordinate with the female than the male, and the sensorimotor system becomes more flexible to coordinate with an angry person. It is also suggested social roles influence how people coordinate, and individuals attend more to interact with a happy female. In sum, the present study evidenced that social perception is embodied in the interactive behaviour during social interaction.

International audience; Interpersonal motor coordination is influenced not only by biomechanical factors such as coordination pattern, oscillating frequency, and individual differences, but also by psychosocial factor such as likability and social competences. Based on the social stereotype of “what is beautiful is good”, the present study aimed at investigating whether people coordinate differently with physically attractive people compared to less attractive people. 34 participants were engaged in an interpersonal coordination task with different looking (virtual) agents while performing at the same time a reaction time task. Results showed that participants had more stable motor coordination with the moving attractive than with the less attractive agent, and that the difference in motor coordination could not be interpreted by a specific attention allocation strategy. Our findings provide the evidence that physical attractiveness genuinely affects how people interact with another person, and that the temporal-spatial coordinated movement varies with the partner’s psychosocial characteristics. The study broadens the perspective of exploring the effect of additional psychosocial factors on social motor coordination.

International audience; Humans seem to take social and behavioral advantages of entraining themselves with discrete auditory rhythms (e.g., dancing, communicating). We investigated the benefits of such an entrainment on posture during standing (spontaneous entrainment) and during a whole-body swaying task (intentional synchronization). We first evaluated how body sway was entrained by different auditory metronome frequencies (0.25, 0.5, and 1.0Hz). We then assessed the stabilizing role of auditory rhythms on postural control, characterized in a dynamical systems perspective by informational anchoring of the head (local stabilization) and fewer transitions from in-phase to anti-phase ankle-hip coordination (global stabilization). Our results revealed in both situations an entrainment of postural movements by external rhythms. This entrainment tended to be more effective when the metronome frequency (0.25Hz) was close to the dominant sway frequency. Particularly, we found during intentional synchronization that head movements were less variable when paced by a slower beat (informational anchoring), and that phase transitions between the two stable patterns in postural dynamics were delayed. Our findings demonstrate that human bipedal posture can be actively or spontaneously modulated by an external discrete auditory rhythm, which might be exploited for the purpose of learning and rehabilitation.

We present novel, low-cost and non-invasive potential diagnostic biomarkers of schizophrenia. They are based on the ‘mirror-game’, a coordination task in which two partners are asked to mimic each other’s hand movements. In particular, we use the patient’s solo movement, recorded in the absence of a partner, and motion recorded during interaction with an artificial agent, a computer avatar or a humanoid robot. In order to discriminate between the patients and controls, we employ statistical learning techniques, which we apply to nonverbal synchrony and neuromotor features derived from the participants’ movement data. The proposed classifier has 93% accuracy and 100% specificity. Our results provide evidence that statistical learning techniques, nonverbal movement coordination and neuromotor characteristics could form the foundation of decision support tools aiding clinicians in cases of diagnostic uncertainty., Mirror game test could detect schizophrenia A new test of movement and social interaction could detect markers of schizophrenia, and help to diagnose and manage the condition. In an effort to establish reliable indicators of schizophrenia, Piotr Slowinski at the University of Exeter, UK and colleagues developed a test that could detect deficits in movement and social interactions, both characteristics of the disorder. They asked people to perform movements alone, and to mirror the movements of a computer avatar or a humanoid robot. Automated analysis of the movements allowed to distinguish people with schizophrenia from healthy participants with accuracy and specificity slightly better than clinical interviews and comparable to test based on much more expensive neuroimaging methods. The technique could help with diagnosis of schizophrenia and to monitor patients’ responses to treatment, but needs to be tested in clinical trials before being applied in clincal practice.

International audience; Human interaction often relies on socio-motor improvisation. Creating unprepared movements during social interaction is not a random process but relies on rules of synchronization. These situations do not only involve people to be coordinated, but also require the adjustment of their posture in order to maintain balance and support movements. The present study investigated posture in such a context. More precisely, we first evaluated the impact of amplitude and complexity of arm movements on posture in solo situation. Then, we assessed the impact of interpersonal coordination on posture using the mirror game in which dyads performed improvised and synchronized movements (i.e., duo situation). Posture was measured through ankle-hip coordination in medio-lateral and antero-posterior directions (ML and AP respectively). Our results revealed the spontaneous emergence of in-phase pattern in ML direction and antiphase pattern in AP direction for solo and duo situations. These two patterns respectively refer to the simultaneous flexion/extension of the ankles and the hips in the same or opposite direction. It suggests different functional roles of postural coordination patterns in each direction, with in-phase supporting task performance in ML (dynamical stability) and antiphase supporting postural control in AP (mechanical stability). Although amplitude of movement did not influence posture, movement complexity disturbed postural stability in both directions. Conversely, interpersonal coordination promoted postural stability in ML but not in AP direction. These results are discussed in terms of the difference in coupling strength between ankle-hip coordination and interpersonal coordination.

International audience; Socio-motor improvisation is defined as the creative action of two or more people without a script or anticipated preparation. It is evaluated through two main parameters: movement synchronization and movement richness. Experts in art (e.g., dance, theater or music) are known to exhibit higher synchronization and to perform richer movements during interpersonal improvisation, but how these competences evolve over time is largely unknown. In the present study, we investigated whether performing more synchronized and richer movements over time can promote the acquisition of improvisation. Pairs of novice participants were instructed to play an improvisation mirror game in three different sessions. Between sessions, they performed an unintended interpersonal coordination task in which synchronization and richness were manipulated, resulting in four different groups of dyads. Our results demonstrate that synchronization during improvisation improved for all groups whereas movement richness only enhanced for dyads that performed synchronized movements during unintended coordination tasks. Our findings suggest that movement synchrony contributes more than movement richness to the acquisition of socio-motor improvisation in the mirror game.

BACKGROUND CONTEXT Sagittal balance is frequently evaluated in preoperative planning in spinal surgery by using a measure called “sagittal vertical axis” (SVA) during full body bi-planar low dose radiography (EOS). This radiographic measurement has been correlated with various clinical parameters, particularly in vertebral deformations. However, this measure is radiographic, then only established in static position, whereas it would be particularly interesting to quantify it during dynamic tasks. 3D motion analysis would allow this measure by using external cutaneous markers located on body landmarks close to those used during EOS procedure. PURPOSE The aim of this study is to validate the indirect computation of SVA during 3D motion analysis against the gold standard EOS–SVA. STUDY DESIGN/SETTING Mononcentric open-labeled study. PATIENT SAMPLE Patients undergoing lumbar laminectomy and without other neurological or orthopedic deficit were enrolled in this study. OUTCOME MEASURES Radiographic EOS measurement of SVA. 3D postural motion analysis. METHODS A total of 15days before surgery, patients had a full body EOS where the reference SVA was calculated. Then the patient underwent a postural 3D motion analysis recorded using 8 optoelectronics camera at a 100 Hz frequency. Reflective markers were positioned following validated conventional gait model procedure. Patients performed a balance test of 52.6 seconds in the same position as EOS examination and in standard postural position. Two distances were computed: in sagittal plane, the distance between markers on the 7th cervical vertebrae and the middle of posterior superior iliac spines were computed and further called “C7_PSI” and in sagittal plane, the distance between markers on the auditory canals and the middle of posterior superior iliac spines were computed and further called “EAR_PSI.” Multiple linear regressions were performed with EOS–SVA as variable to explain and C7_PSI or EAR_PSI as explicative variables both adjusted on BMI and age. RESULTS A total of 20 patients were included in the study with a mean age of 70.7±7.8years and BMI of 29.4±3.6. The EOS–SVA was 58.4±58.9 mm (range: –18 to 226 mm). Multiple linear regression have shown good significant fit for C7_PSI in both postural positions (R²=0.78 in EOS position and R²=0.7373 in standard position). The significant model included C7_PSI distance, BMI and age during EOS postural position was 1.88*age–2.61*BMI+0.815*C7_PSI. EAR_PSI distance did not show sufficient level of fit to be considered as good. CONCLUSIONS 3D motion analysis seems to be a promising tool to indirectly assess the SVA. Consequently, we propose a model that might be used to quantify SVA during dynamics tasks like reaching, walking and other functional tests. This method might also be used more frequently for the evaluation of patients and potentially to quantify the effect of surgery. Nonetheless, the model proposed need to be confirmed and externally validated in further studies.

International audience; Introduction L’utilisation de stimuli auditifs discrets générés par un métronome pour la synchronisation de mouvements rythmiques est connue pour améliorer la stabilité locale (diminution de la variabilité du mouvement appelée ancrage) et la stabilité globale des coordinations (retard de la transition de patrons). Néanmoins, les travaux portant sur la synchronisation posturale avec une information extérieure se sont principalement cantonnés à une stimulation continue, illustrant alors les caractéristiques dynamiques du système postural. L’objectif de cette étude était de montrer l’intérêt d’une synchronisation posturale avec un environnement auditif discret et les bénéfices qui l’accompagnent. Matériel et méthode Vingt adultes se tenaient debout dans une position confortable, équipés d’un casque audio. Premièrement, ils étaient exposés à l’écoute d’un métronome à différentes fréquences : silence ; 0,25 Hz ; 0,50 Hz ; 1 Hz (synchronisation non-intentionnelle). Deuxièmement, ils devaient synchroniser leurs mouvements posturaux dans le plan antéro-postérieur pour chaque « bip » du métronome (synchronisation intentionnelle). Résultats Nos résultats montrent qu’un environnement auditif discret est propice à une synchronisation du système postural. Les effets étaient majorés lorsque la fréquence de stimulation était proche de celle des oscillations posturales naturelles du sujet. Par ailleurs, un phénomène d’ancrage (augmentation de la régularité du mouvement) ainsi qu’un retard de transition de patrons de coordination (phase vers antiphase) étaient observés dans la condition intentionnelle aux fréquences les plus basses. Discussion–conclusion Notre étude suggère ainsi que l’utilisation de stimuli auditifs discrets permet d’augmenter la stabilité dynamique de la posture.

Introduction In psychiatry, behavioral therapies do not focus on motor behaviors embedded in social interaction. Yet, it is well known that nonverbal motor behaviors play a fundamental role in the success of our interactions [1] . Several studies have previously shown that our motor behaviors of imitation (i.e. behavioural matching : BM) and of synchronization (i.e. temporal matching : TM) improve social competences such as affiliation between interactants or pro-social behaviors. However, no study has investigated theirs effects of the acquisition of motor competences. At both fundamental and clinical levels, it seems crucial to understand the mechanisms that underlie the acquisition and the improvement of socio-motor competences. We hypothesized a beneficial effect of theses “matching” on the acquisition of social and motor competences. Methods 48 dyads of healthy subjects were split in a two-by-two experimental design. They were asked to perform three sessions of a mirror game task. Between each session, participants performed an interpersonal motor coordination task in which BM and TM have been manipulated (BM: Similar or Dissimilar amplitude; TM: Easy or Difficult movements). Motor competences were evaluated by the accuracy and by the variety of movements performed in the mirror game tasks; and social competences by the affiliation score between participants evaluated before and after the experiment. Results The results showed that Similar groups and Easy groups improved their motor and social competences whereas Dissimilar groups and Difficult groups only improved their social competences. These results suggest that socio-motor competences could be improved and that BM and TM promote this acquisition. Consequently, the manipulation of motor behaviors of imitation and of synchronization seems relevant to foster the acquisition of theses competences. A complementary study, including patients suffering from schizophrenia, confirms our results showing the beneficial effect of this paradigm in social pathologies. This study has been funded by the European project AlterEgo (Grant #600610).

Schizophrenia, autism, or social phobia are typically accompanied by social interaction deficits. The objective of the AlterEgo European project is the creation of an interactive cognitive architecture, implementable in various artificial agents, allowing a continuous interaction with patients suffering from social disorders by virtue of changes in behavioral (robot-based) as well as morphological (avatar-based) properties of that agent. Here we present the scientific foundations of the project and its four main experimental steps. The results of the first similarity experiments are reported, which show that healthy participants functionally adapt their social motor interaction when they interact with agents (real or artificial) morphologically and behaviorally similar to, or different from, them. These results obtained with healthy participants have consequences for the rehabilitation of socially deficient patients.

International audience; During bilateral coordination, some level of inter-hemispheric remapping (i.e., the congruency between afferent and efferent force signals from both hemispheres) is required. In this case, sensory-motor information is exchanged between the two hemispheres, but it remains unclear whether this information exchange is always equivalent or not, especially in a bilateral isometric force-matching task. We used unilateral fatigue applied to one arm in order to determine whether inter-hemispheric remapping can vary asymmetrically during a bilateral isometric matching task. Because fatigue is considered to bias the sensory-motor system, we hypothesized that if bimanual coordination is modulated solely in function of the state of the sensory-motor system (motor efferences, inter-hemispheric inhibitions, and sensory reafferences), we should not observe any asymmetric effect of fatigue with movement intention (leading vs. matching arm). However, if any other process could participate in the modulation of inter-hemispheric remapping, we should observe an interaction between movement intentions and fatigue on the force produced. We found that, when the leading arm was the non-fatigued arm, participants succeeded in reproducing the force level with their fatigued arm. By contrast, when the leading arm was fatigued, subjects over-estimated the force level produced with their non-fatigued arm. Hence, lateralized fatigue exacerbates an asymmetric behavior that seems modulated by movement intention (leading vs. matching). In other words, when unilateral fatigue is introduced in a bilateral isometric force-matching task, inter-hemispheric remapping is asymmetrical. Intensity levels of motor commands sent to both arms (directly or modulated through inter-hemispheric inhibitions) and sensory reafferences alone cannot explain these observations. Some attentional focus may be not balanced continuously between both arms but may be mainly directed toward the matching arm.

International audience; Parietal cortical areas are involved in sensori-motor transformations for their respective contralateral hemifield/body. When arms of the subjects are crossed while their gaze is fixed straight ahead, vision of the hand is processed by the hemisphere ipsilateral to the arm position and proprioception of the arm by the contralateral hemisphere. It induces interhemispheric transfer and remapping. Our objective was to investigate whether a single pulse TMS applied to the left parietal cortical area would disturb interhemispheric remapping in a similar case, and would increase a simple reaction time (RT) with respect to a control single pulse TMS applied to the frontal cortical area. Two LED were superimposed and located in front of the subjects on the saggital axis. Subjects were asked to carefully fixate on these LED during each trial. The lighting of the red LED was used as a warning signal. Following the green one was illuminated after a variable delay and served as a go-signal. The hand for the response was determined before the start of each trial. TMS was applied to the left parietal, the left frontal cortical areas, or not applied to the subject. Results revealed that: (1) Irrespective of its location, single pulse TMS induced a non-specific effect similar to a startle reflex and reduced RT substantially (15 ms on average) with respect to a control condition without TMS (mean value = 153 ms). (2) Irrespective of TMS, RT were shorter when the right or the left hand was positioned in the right visual hemi-field (i.e. normal and crossed positions respectively). (3) Finally, RT increased when single pulse TMS was applied to the left parietal area and when hands were crossed irrespective of which hand was used. We concluded that interhemispheric sensori-motor remapping was disrupted by a single pulse TMS that was applied to the left parietal cortex. This effect was also combined some visual attention directed towards the hand located on the right visual hemi-field.

Introduction Nowadays, high-technology (utilization of avatars or robots) has been becoming widely used in medical rehabilitation programs. The biggest advantage of the high-tech agents is to help designing individualized rehabilitation plans and saving caregivers’ time. Since previous research in human-human interaction showed that the way individuals interact with others is influenced by the physical attractiveness of the other people (i.e. [1] ), the present study aims to investigate whether interpersonal coordination is influenced by the physical attractiveness of virtual agents. Methods 34 healthy participants coordinated with a physically attractive virtual agent and a less attractive virtual agent on a Wacom tablet. Agents were shown in a static (picture) or in a dynamic (video) form. Participants were instructed to perform in-phase or anti-phase coordination with the agents at the 100 or 150% of their own preferred frequency. At the same time, a reaction time task (on the agent's forehead) was answered simultaneously in order to attract participants’ attention to the physical attractiveness of the agent. Results Results showed that when coordinating at the preferred frequency, participants showed the most stable motor coordination with the moving attractive agent as compared to other static or moving agents. Discussion Our results suggest that it is critical to take into account the physical attractiveness of the agents when using them as a means of medical rehabilitation. Attractive agents can help to foster a more stable coordination, thus motivating patients to adhere more to rehabilitation. Since motivation to perform more physical activity is a major problem causing dropouts from rehabilitation program, it is of vital importance to design physically attractive agent to entrain patients more engaged in the rehabilitation program. Of course, clinical trials are necessary in order to explore whether the finding of the present study could be generalized to patients.