Zhuoran Liu
email: z.liu@cs.ru.nl

Zhengyu Zhao
email: z.zhao@cs.ru.nl

Martha Larson
email: m.larson@cs.ru.nl

Laurent Amsaleg
email: laurent.amsaleg@irisa.fr

Exploring Quality Camouflage for Social Images

Social images can be misused in ways not anticipated or intended by the people who share them online. In particular, high-quality images can be driven to unwanted prominence by search engines or used to train unscrupulous AI. The risk of misuse can be reduced if photos can evade quality filtering, which is commonly carried out by automatic Blind Image Quality Assessment (BIQA) algorithms. The Pixel Privacy Task benchmarks privacy-protective approaches that shield images against unethical computer vision algorithms. In the 2020 task, participants are asked to develop quality camouflage methods that can effectively decrease the BIQA score of high-quality images while maintaining image appeal. The camouflage should not damage the image from the point of view of the user: it needs to be either imperceptible, or else to enhance the image visibly, to the human eye.

INTRODUCTION

Social images shared online can be misused, causing distress and harm to the people who share them. As computer vision algorithms continue to improve, their potential for misuse grows as well. There is a need for technology that can counter the ability of malicious or heedless actors to easily abuse the power of computer vision.

The Pixel Privacy Task at the MediaEval Multimedia Evaluation Benchmark aims to address this need. The objective of the task is to support the development of approaches that can help protect users' multimedia content. The first two years of the Pixel Privacy Task [START_REF] Larson | Pixel Privacy: Increasing image appeal while blocking automatic inference of sensitive scene information[END_REF][START_REF] Liu | Pixel Privacy 2019: Protecting sensitive scene information in images[END_REF] focused on privacy sensitive information depicted in social images of scenes. Task participants were asked to develop image transformation approaches that could mislead scene recognition algorithms, preventing them from predicting the scene classes for images depicting privacy sensitive scenes.

However, semantic class is not the only aspect of images associated with the threat of computer vision algorithms. This year, the Pixel Privacy Task moves beyond semantics to look at hiding the quality of images. We call this task quality camouflage. Specifically the 2020 Pixel Privacy Task asks task participants to create algorithms that cause a Blind Image Quality Assessment (BIQA) algorithm to predict that an image has a lower quality than it actually has. Participants are provided with high-quality images, and must transform them so that they are classified by BIQA to be low-quality images. At the same time, the images must maintain their appeal to the human eye, so that users would still want to share them. The task encourages participants to go beyond maintaining the appeal to actually increasing it by enhancing the image.

Copyright 2020 for this paper by its authors. Use permitted under Creative Commons License Attribution 4.0 International (CC BY 4.0). MediaEval'20, December 14-15 2020, Online In Fig. 1 we see examples of high-quality and low-quality images as judged by an BIQA algorithm. The images are drawn from the development set of the task, described further in Section 2. Note that the quality of an image is defined as independent of its aesthetic qualities or artistic merit. For example, the picture on the left of the bottom row could be considered beautiful, but would not be considered a high-quality image because of lack of contrast and sharpness. The importance of this difference for the task will be discussed further in Section 4.

Our choice of investigating image quality is motivated by the large part that quality plays in determining the fate of an image within a social media platform or an AI system. Computer vision algorithms that classify image quality are ethically problematic when the quality information they infer is used inconsistently with the intent of the users who originally shared the images. This issue is illustrated by two key examples. First, high-quality images can be recommended to users in image sharing social media [START_REF] Gundotra | New Google+: Stream, Hangouts, and Photos[END_REF], or they can also be ranked at the top by the search engine [START_REF] Shum | A behind the scenes look at how bing is improving image search quality[END_REF]. However, users who generated these images may not intend their contents to be spread widely in the general public. Quality camouflage can reduce the chance that an image would be shared widely beyond their family, friends or colleagues. Second, because the performance of computer vision algorithms can be degraded when the image quality is low [START_REF] Dodge | Understanding how image quality affects deep neural networks[END_REF], image quality classifiers are commonly applied as a pre-processing step to filter out low-quality images in the training or testing [START_REF] Chernov | Image quality assessment for video stream recognition systems[END_REF] phase. However, users may not have anticipated or agreed to having their images used to train certain types of ethically questionable classifiers. Quality camouflage can reduce the chance that their images would be used for training.

Adversary Model

Quality camouflage is designed to protect images. However, technically, it is considered an adversary, and defined according to an adversary model. We follow the stand dimensions of the adversary model, set out by [START_REF] Salter | Toward a secure system engineering methodology[END_REF]. First, in the resources/access dimension, we assume that we (i.e., the adversary) have general knowledge of the target. We know that we are protecting against a state-of-the-art quality classifier and also the images we are trying to protect will be subject to some minimal pre-processing intended to counter adversarial examples. Second, in the risk tolerance dimension, we assume that we are not worried whether it is possible to infer that we have protected our images (with human eyes or a classifier). Third, in the objectives dimension, we assume that we are interested in lowering the quality score of high-quality images, thereby raising the probability that the images are passed over. We are not looking for a mathematical guarantee, since our target is open ended.

We are interested in lowering the barrier in task participation, for this initial exploratory investigation of quality camouflage. For this reason, we use a white-box variant of the adversary model, providing participants with the knowledge of the exactly quality classifier (i.e., the BIQA) that is used and the type of pre-processing to expect (90% JPEG compression, which has a negligible effect on the BIQA score). Note that this formulation can also be considered a gray-box, since the exact compression algorithm is not specified.

Relation to Computer Vision Research

The task is related to directions in which research on adversarial examples are currently expanding. In this section, we sketch this connection. A direct way to achieve quality camouflage is by adding small, imperceptible adversarial perturbations to the image. Such imperceptibility has been addressed conventionally by 𝐿 𝑝 distance [START_REF] Carlini | Towards evaluating the robustness of neural networks[END_REF][START_REF] Chen | EAD: Elastic-net attacks to deep neural networks via adversarial examples[END_REF][START_REF] Goodfellow | Explaining and harnessing adversarial examples[END_REF][START_REF] Kurakin | Adversarial examples in the physical world[END_REF][START_REF] Papernot | The limitations of deep learning in adversarial settings[END_REF], and recently by more visual-perceptionaligned measurements [START_REF] Croce | Sparse and imperceivable adversarial attacks[END_REF][START_REF] Luo | Towards imperceptible and robust adversarial example attacks against neural networks[END_REF][START_REF] Wong | Wasserstein adversarial examples via projected Sinkhorn iterations[END_REF][START_REF] Xiao | Spatially transformed adversarial examples[END_REF][START_REF] Zhang | Smooth adversarial examples[END_REF][START_REF] Zhao | Towards large yet imperceptible adversarial image perturbations with perceptual color distance[END_REF].

However, in real-world scenarios, such small, imperceptible perturbations may not actually impact the target model in the end, since their effect can be erased by practical image pre-processing operations. In addition, it has been recently pointed out that such small, imperceptible perturbations were just introduced as an abstract, toy example to facilitate evaluation [START_REF] Gilmer | Motivating the rules of the game for adversarial example research[END_REF] and have no truly compelling real-world use scenario. For these reasons, researchers have started to explore unrestricted adversarial images [START_REF] Bhattad | Unrestricted adversarial examples via semantic manipulation[END_REF][START_REF] Brown | Unrestricted adversarial examples[END_REF][START_REF] Engstrom | Exploring the landscape of spatial robustness[END_REF][START_REF] Qiu | SemanticAdv: Generating adversarial examples via attribute-conditional image editing[END_REF][START_REF] Zhao | Adversarial robustness against image color transformation within parametric filter space[END_REF], which accommodate larger perturbations that are still unsuspicious because they transform groups of pixels along dimensions consistent with human interpretation of images. Participants in past years of the Pixel Privacy Task have also carried out preliminary exploration in such a direction [START_REF] Brugman | Media-Eval 2018 Pixel Privacy Task: Views on image enhancement[END_REF][START_REF] Liu | First steps in Pixel Privacy: Exploring deep learning-based image enhancement against large-scale image inference[END_REF].

The task encourages participants to investigate approaches simultaneously fool BIQA and maintain/enhance appeal. We are interested in creating images that people will want to share on social media, in order to inspire them to protect their privacy. For this reason, image appeal is a key consideration. Our position is that as work on unrestricted adversarial examples moves forward it should be guided by adversary spaces that are well aligned with humaninterpretable image editing processes, i.e., what users themselves do to enhance their images and ensure that they are appealing.

TASK DEFINITION AND DATA

The objective of the Pixel Privacy Quality Camouflage Task is to fool a BIQA algorithm while maintaining or enhancing the appeal of an image to the human eye. Blind image quality assessment is a long-standing research topic in computer vision and image processing [START_REF] Wang | Image quality assessment: From error visibility to structural similarity[END_REF]. It aims to predict the mean opinion score (MOS) of an image among a sufficiently large sample of human emulators, which is also interpreted as the perceived quality of stimulus [START_REF] Moorthy | Blind image quality assessment: From natural scene statistics to perceptual quality[END_REF]. Previously, BIQA algorithms are trained on images with synthetically generated distortions or small scale annotated data. The BIQA we employ here is trained on the KonIQ-10k [START_REF] Hosu | KonIQ-10k: An ecologically valid database for deep learning of blind image quality assessment[END_REF] data set that is the first in-the-wild database with 1.2 million reliable quality ratings from a group of users. We train the model using the same data split of the original paper and achieve PLCC 0.927 on the test set, which is on par with the originally reported results. We release the training code and the pre-trained BIQA model 1,2 . The BIQA model uses an Inception-ResNet-v2 model and predicts a score ranging from 0 to 100. Images with a score of more than 50 are classified as high-quality. We also provide a development set (MEPP20dev) containing all the 1000 images from the official validation set of the KonIQ-10k data set. The test set (MEPP20test) is composed of 550 high-quality (i.e, BIQA score >= 50) images, and it is a subset of the Pixel Privacy 2019 test set [START_REF] Liu | Pixel Privacy 2019: Protecting sensitive scene information in images[END_REF], in turn a subset of the Places-365 Standard data set [START_REF] Zhou | Places: A 10 million image database for scene recognition[END_REF].

EVALUATION

Task submissions are evaluated in three steps. First, in the preprocessing step, all submitted images are processed by JPEG compression (ratio = 90%). Then, compressed images are classified by the BIQA model as high-quality or low-quality, and the reduction in the accuracy of the predictions is calculated. Finally, approaches that achieve at least 50% reduction of accuracy (i.e., the percentage of low-quality images is more than 50%) are ranked in terms of their appeal by a jury of computer science students. The twenty test images with the highest variance of BIQA scores among all runs will be judged. For each image, the jury receives a set of camouflaged images, and picks the three "most appealing" and two "least appealing" based on their perception of appeal. This year, we have seven annotators in the jury of computer science students. They are provided with a hint, "Appealing could mean that you would like to share the image with your friends on social media". All submitted runs will be ranked by the frequency of "most appealing".

DISCUSSION AND OUTLOOK

The 2020 Pixel Privacy Quality Camouflage task explores adversarial images that fool a BIQA model and at the same time remain appealing enough to share. As noted before, image quality does not reduce to aesthetics or artistic merit. The relative independence of quality and appeal makes it sensible to approach the task in two steps. However, if we want users to use quality camouflage images in practice, it is important to systematically explore the whole space of appealing images and understand which parts of this space are best adversarial to image quality classifiers. Moving forward, we would like to better understand, image appeal, quality camouflage coutermeasures, and also the possibility that quality camouflage may transfer to protect against semantic classifiers.

Figure 1 :

 1 Figure 1: Examples of training images in MediaEval Pixel Privacy task 2020. Images are selected from high-quality class (top row) and low-quality class (bottom row). BIQA score for each image is on the top right corner.

https://github.com/ZhengyuZhao/koniq-PyTorch

This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative.


Elisa Le Roux

Nathan De Jong

Stéphane Blanc

MD Chantal Simon

MD Daniel H Bessesen

Audrey Bergouignan
email: audrey.bergouignan@iphc.cnrs.fr

Physiology of physical inactivity, sedentary behaviors and non-exercise activity: Insights from space bedrest model

Keywords: Physical inactivity, moderate to vigorous physical activity, light physical activity, bedrest, exercise, non-exercise activity, metabolism

Physical inactivity, i.e., not reaching the recommended level of physical activity (PA) and sedentary behaviors (SB), i.e., sitting time have been associated with increased risk for common metabolic diseases. Recent epidemiological data suggest that high volumes of SB are detrimental for metabolic health, even in the presence of regular exercise, i.e., moderate/vigorous (MVPA). This suggests that the health effects of SB are independent from those of exercise. However, experimentally testing this hypothesis is complicated because of the difficulty in disassociating SB from PA. Bedrest studies, a traditional space science model, can offer new insights. In some bedrest studies, an exercise training protocol has been used to counteract the harmful effects of inactivity. While bedrest induces an inactive and sedentary state, exercise with bedrest represents a unique model of sedentary yet physically active people. Here, we review bedrest studies with and without exercise training.

Although exercise training prevents the loss of muscle mass and function, even large volumes of exercise are not sufficient to fully counteract the negative metabolic adaptations triggered by inactivity. This observation supports the existence of independent adverse health effects of SB, but also the potential benefits of non-exercise activity, i.e., daily living light-intensity activities (LPA). We gathered available data to examine the complex relationships between exercise, non-exercise activity, SB and health outcomes. Given the large amount of SB in modern societies, the sole promotion of exercise, i.e., MVPA may be insufficient, and promotion of LPA may be a complimentary approach to improve health.

members from the two institutions to address the role of sedentary behaviors in the onset and progression of metabolic diseases.

Running title: Independent metabolic health effects of sedentary behaviors

Introduction

Insufficient physical activity (PA) is a public health concern and a major risk factor for early mortality and common chronic diseases including obesity, metabolic syndrome, insulin resistance, type 2 diabetes (T2D), certain type of cancers, mental health disorders and others [START_REF] Lee | Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy[END_REF].

Through research efforts to develop strategies to combat physical inactivity, scientists have identified another health risk behavior: sedentary behaviors (SB). SB are distinct from physical inactivity.

Although physical inactivity is defined as engaging in less PA necessary to meet the current guidelines (<150 min/week moderate or <75min/week vigorous physical activity -MVPA, with energy expenditure above 3.0 metabolic equivalent or METs), SB correspond to "any waking behavior characterized by an energy expenditure <1.5 METs, while in a sitting or reclining posture" [START_REF] Tremblay | Sedentary Behavior Research Network (SBRN) -Terminology Consensus Project process and outcome[END_REF]. Although the recommendations encourage reducing periods of SB, no specific strategy has been proposed to combat the effects of sedentary lifestyles [START_REF] Bull | World Health Organization 2020 guidelines on physical activity and sedentary behaviour[END_REF]. SB are found in every domain of modern daily life: transportation, occupational (e.g., desk bound work) and leisure time activities (e.g., video gaming and internet). Adults in Westernized societies spend between 7.7 and 9.7 h/d sitting, which corresponds up to 60% of adult wake time [START_REF] Ekelund | Dose-response associations between accelerometry measured physical activity and sedentary time and all cause mortality: systematic review and harmonised meta-analysis[END_REF]. Several epidemiological studies have reported associations between sedentary time and health outcomes including early mortality, risk of T2D, metabolic syndrome and cardiovascular disease [START_REF] Dunstan | Too much sitting--a health hazard[END_REF]. These associations were observed in both sexes, all ages, ethnicities and independent of adiposity. They were also found in individuals who reach the recommended levels of MVPA, which suggests that SB is a stand-alone factor in the relationship between PA and health. In other words, spending too much time sitting may have different health effects than not exercising enough. While a plethora of epidemiological data is published, experimental evidence supporting the adverse health effects of SB independent of time spent physically active is lacking. This is mainly due to challenges in isolating the effects of SB from those of PA.

The bedrest model can provide unique insights on the independent health effects of SB. Bedrest studies have traditionally been used by the International Space Agencies to understand the physiological effects of microgravity. During these studies, physically active healthy participants free from any predisposition for chronic diseases stay in bed 24h/7d. They are both physically inactive and highly sedentary (figure 1). In some bedrest studies, the efficacy of exercise training protocols to protect the body against the harmful effects of microgravity have also been tested. Participants in these studies perform exercise training (figure 1) while in bedrest. Participants in these studies are both sedentary and physically active, and represent an extreme but unique model of "sedentary exercisers". Another distinctive characteristic of these bedrest exercisers is that they have very low levels of non-exercise activities of daily living, which correspond to light-intensity physical activities (LPA) with an energy expenditure between 1.6 and 2.9 METs (e.g. walking, taking the stairs, standing, etc.) (figure 1).

The objective of this review is to present experimental evidence from bedrest studies with or without concomitant exercise training to provide new information on the metabolic health effects of SB independent from those of MVPA/exercise. To better understand the complex relationship between SB, LPA, MVPA and metabolic health outcomes, we will also review briefly the health benefits of LPA.

The physiology of physical inactivity: insights from strict bedrest investigations

To understand the respective effects of SB and PA, it is important to first briefly summarize the physiological effects of combined sedentariness and physical inactivity induced by strict bedrest (figure 2). Bedrest induces hypokinesia (loss of body movements) and hypodynamia (loss of strength and power), which leads to modifications in all physiological systems [START_REF] Bergouignan | Physical inactivity as the culprit of metabolic inflexibility: evidence from bed-rest studies[END_REF].

Among other changes, bedrest reduces muscle function and mass as demonstrated by muscle atrophy and a shift from slow oxidative to fast glycolytic muscle fibers (Trappe et al., 2007a;[START_REF] Salanova | Molecular biomarkers monitoring human skeletal muscle fibres and microvasculature following long-term bed rest with and without countermeasures[END_REF][START_REF] Trappe | Human soleus single muscle fiber function with exercise or nutrition countermeasures during 60 days of bed rest[END_REF], reduced mitochondrial volume and oxidative capacity [START_REF] Kenny | Bed rest and resistive vibration exercise unveil novel links between skeletal muscle mitochondrial function and insulin resistance[END_REF], and an impaired expression of genes involved in mitochondrial function (Alibegovic et al., 2010b). Bedrest also rapidly decreases insulin sensitivity in muscle [START_REF] Alibegovic | Impact of 9 days of bed rest on hepatic and peripheral insulin action, insulin secretion, and whole-body lipolysis in healthy young male offspring of patients with type 2 diabetes[END_REF] in association with lower content and activity of key proteins involved in glucose transport, phosphorylation and storage [START_REF] Biensø | GLUT4 and glycogen synthase are key players in bed rest-induced insulin resistance[END_REF]. This results in hyperinsulinemia to maintain normal glucose disposal. This development of glucose intolerance seems to be preceded by a metabolically inflexible state, i.e. an inability of the body to adjust substrate use to changes in substrate availability [START_REF] Rudwill | Metabolic Inflexibility Is an Early Marker of Bed-Rest-Induced Glucose Intolerance Even When Fat Mass Is Stable[END_REF]. Gene expression and activity of enzymes coupled with oxidative metabolism are decreased [START_REF] Bergouignan | Physical inactivity differentially alters dietary oleate and palmitate trafficking[END_REF]Alibegovic et al., 2010b;[START_REF] Fernandez-Gonzalo | Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures[END_REF] in association with a reduction in lipid oxidation in favor of carbohydrate oxidation [START_REF] Bergouignan | Effect of physical inactivity on the oxidation of saturated and monounsaturated dietary Fatty acids: results of a randomized trial[END_REF][START_REF] Bergouignan | Physical inactivity differentially alters dietary oleate and palmitate trafficking[END_REF]. These changes are particularly relevant following meal ingestion since they lead to decreased clearance of dietary lipids, which contributes to hyperlipidemia. Despite reduced adipose tissue lipolysis [START_REF] Alibegovic | Impact of 9 days of bed rest on hepatic and peripheral insulin action, insulin secretion, and whole-body lipolysis in healthy young male offspring of patients with type 2 diabetes[END_REF]Alibegovic et al., 2010a), excess of plasma lipids enhances fat accumulation in the visceral adipose depot [START_REF] Belavý | Preferential deposition of visceral adipose tissue occurs due to physical inactivity[END_REF] and ectopic fat storage in muscle, liver and bone [START_REF] Bergouignan | Physical inactivity differentially alters dietary oleate and palmitate trafficking[END_REF][START_REF] Trudel | Bone marrow fat accumulation after 60 days of bed rest persisted 1 year after activities were resumed along with hemopoietic stimulation: the Women International Space Simulation for Exploration study[END_REF][START_REF] Trudel | Resistive exercises, with or without whole body vibration, prevent vertebral marrow fat accumulation during 60 days of head-down tilt bed rest in men[END_REF][START_REF] Rudwill | Effect of enforced physical inactivity induced by 60-day of bed rest on hepatic markers of NAFLD in healthy normal-weight women[END_REF]. This in turn exacerbates the development of insulin resistance. Fat accumulation in liver likely stimulates de novo lipogenesis and an increased synthesis of atherogenic lipid particles (VLDL), as suggested by a recent study in freeliving individuals who reduced their PA levels [START_REF] Damiot | A nutrient cocktail prevents lipid metabolism alterations induced by 20 days of daily steps reduction and fructose overfeeding: result from a randomized study[END_REF]. This increased secretion of VLDL further facilitates hyperlipidemia and ectopic fat storage. A decrease in high-density lipoprotein (HDL) cholesterol, known to be associated with a reduction in cardiometabolic risk, has also been observed [START_REF] Alibegovic | Impact of 9 days of bed rest on hepatic and peripheral insulin action, insulin secretion, and whole-body lipolysis in healthy young male offspring of patients with type 2 diabetes[END_REF]. Concomitantly, the liver is less able to suppress hepatic glucose production, which results in increased gluconeogenesis, thus worsening hyperinsulinemia. These changes are finally associated with the development of low-grade inflammation as indicated by an increase in plasma pro-inflammatory markers [START_REF] Rudwill | Effects of different levels of physical inactivity on plasma visfatin in healthy normal-weight men[END_REF][START_REF] Mutin-Carnino | Effect of muscle unloading, reloading and exercise on inflammation during a head-down bed rest[END_REF].

All these metabolic features are commonly observed in individuals with obesity, T2D or metabolic syndrome. These observations therefore support a key role of physical inactivity in the onset and progression of metabolic diseases. Although the health enhancing effects of exercise (or MVPA) on these metabolic outcomes are well established, it is unclear whether they are sufficient to reverse the adverse health effects of sedentariness.

Can MVPA reverse the adverse health effects of physical inactivity and SB?: Insights from bedrest studies with concomitant exercise training

To the best of our knowledge, 10 bedrest studies have tested the protective effects of an exercise training program against the metabolic alterations induced by bedrest. These studies span from 20 to 90 days and the exercise prescriptions varied in the type (resistance or aerobic exercise), duration, frequency and intensity (Table 1). Some training protocols were below the current recommendations for PA while others were above. Results have been reported in 26 published articles and are summarized in figure 2.

Effect of resistance exercise alone: Resistance exercise has been shown to mitigate the decrease in cardiorespiratory fitness [START_REF] Guinet | MNX (Medium Duration Nutrition and Resistance-Vibration Exercise) Bed-Rest: Effect of Resistance Vibration Exercise Alone or Combined With Whey Protein Supplementation on Cardiovascular System in 21-Day Head-Down Bed Rest[END_REF][START_REF] Kenny | Effectiveness of Resistive Vibration Exercise and Whey Protein Supplementation Plus Alkaline Salt on the Skeletal Muscle Proteome Following 21 Days of Bed Rest in Healthy Males[END_REF] and prevent the loss of muscle function and mass including the reduction in fiber diameter during bedrest [START_REF] Trappe | Human single muscle fibre function with 84 day bed-rest and resistance exercise[END_REF][START_REF] Moriggi | Long term bed rest with and without vibration exercise countermeasures: effects on human muscle protein dysregulation[END_REF]. However, the mechanisms underlying the protective effects of resistance exercise against unloading-muscle atrophy are not fully clear. Resistance exercise was shown to prevent the bedrest-induced decrease in muscle protein synthesis [START_REF] Ferrando | Resistance exercise maintains skeletal muscle protein synthesis during bed rest[END_REF] and downregulate the gene expression of myostatin [START_REF] Irimia | Metabolic adaptations in skeletal muscle after 84 days of bed rest with and without concurrent flywheel resistance exercise[END_REF], a myokine known to contribute to muscle wasting. The effect of resistance exercise on muscle protein balance, i.e. muscle protein synthesis and breakdown, during bedrest is however still unknown. Despite these positive effects on skeletal muscle, resistance exercise only partially prevents the whole-body metabolic alterations induced by bedrest. It protects against the rise in visfatin [START_REF] Rudwill | Effects of different levels of physical inactivity on plasma visfatin in healthy normal-weight men[END_REF], an adipocytokine that mimics the effects of insulin, but does not prevent the increase in IL-6 and C-reactive protein, two pro-inflammatory markers, or the decrease in adiponectin [START_REF] Brooks | Influence of Exercise on the Metabolic Profile Caused by 28 days of Bed Rest with Energy Deficit and Amino Acid Supplementation in Healthy Men[END_REF], a change associated with inflammation, lipid abnormalities, and insulin resistance. Even when performed at high intensity, resistance exercise does not mitigate the decrease in HDL [START_REF] Brooks | Influence of Exercise on the Metabolic Profile Caused by 28 days of Bed Rest with Energy Deficit and Amino Acid Supplementation in Healthy Men[END_REF][START_REF] Guinet | MNX (Medium Duration Nutrition and Resistance-Vibration Exercise) Bed-Rest: Effect of Resistance Vibration Exercise Alone or Combined With Whey Protein Supplementation on Cardiovascular System in 21-Day Head-Down Bed Rest[END_REF], the development of insulin resistance, hyperlipidemia, or the shift towards the use of carbohydrate as fuel [START_REF] Bergouignan | Effect of physical inactivity on the oxidation of saturated and monounsaturated dietary Fatty acids: results of a randomized trial[END_REF]. This later observation is surprising knowing that resistance exercise prevents against the shift of muscle fibers from oxidative to glycolytic types [START_REF] Trappe | Human single muscle fibre function with 84 day bed-rest and resistance exercise[END_REF], offsets the transcriptomic alterations in muscle related to aerobic energy metabolism (e.g. electron transport chain, fatty acid beta-oxidation and tricarboxylic cycle pathways) [START_REF] Fernandez-Gonzalo | Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures[END_REF], and partially maintains the activity and gene expression of enzymes controlling oxidative metabolism (e.g. citrate synthase, succinate dehydrogenase) at the mitochondrial level [START_REF] Irimia | Metabolic adaptations in skeletal muscle after 84 days of bed rest with and without concurrent flywheel resistance exercise[END_REF]. Although resistance exercise alone does not restore the levels of fatty acid oxidation to baseline values [START_REF] Bergouignan | Effect of physical inactivity on the oxidation of saturated and monounsaturated dietary Fatty acids: results of a randomized trial[END_REF], no accumulation of fat in bone [START_REF] Trudel | Resistive exercises, with or without whole body vibration, prevent vertebral marrow fat accumulation during 60 days of head-down tilt bed rest in men[END_REF] or visceral depots [START_REF] Belavý | Preferential deposition of visceral adipose tissue occurs due to physical inactivity[END_REF] was reported. Furthermore, no data exists on the effects of resistance exercise on ectopic fat storage in liver or muscle during bedrest. In all these studies, the resistance exercise session was performed as a single continuous bout; however novel data suggest that spreading activity throughout the day as multiple short active bouts may have more potent health-enhancing effects [START_REF] Loh | Effects of Interrupting Prolonged Sitting with Physical Activity Breaks on Blood Glucose, Insulin and Triacylglycerol Measures: A Systematic Review and Meta-analysis[END_REF]. Nevertheless, when exercise was performed as intermittent, frequent jumping squats spread throughout the day muscle mass loss was prevented, but not the reduction in whole-body and peripheral insulin sensitivity [START_REF] Ward | Fetuin-A as a Potential Biomarker of Metabolic Variability Following 60 Days of Bed Rest[END_REF].

Taken together, the low energy expenditure associated with resistance exercise (Table 1) may be responsible for partial or limited protective effects on metabolic health.

Effect of combined resistance and aerobic exercise: The majority of bedrest studies has combined aerobic exercise with resistance exercise, which likely induced a greater energy expenditure compared to resistance exercise alone. This training approach preserves or at least attenuates cardiorespiratory fitness, muscle structure and function, leg muscle size and power, muscle strength and endurance, muscle fiber composition and diameter and mitochondrial content and oxidative capacity (Trappe et al., 2007a;Trappe et al., 2007b;[START_REF] Salanova | Molecular biomarkers monitoring human skeletal muscle fibres and microvasculature following long-term bed rest with and without countermeasures[END_REF][START_REF] Trappe | Human soleus single muscle fiber function with exercise or nutrition countermeasures during 60 days of bed rest[END_REF][START_REF] Bergouignan | Physical inactivity differentially alters dietary oleate and palmitate trafficking[END_REF][START_REF] Krainski | The effect of rowing ergometry and resistive exercise on skeletal muscle structure and function during bed rest[END_REF][START_REF] Lee | WISE-2005: Countermeasures to prevent muscle deconditioning during bed rest in women[END_REF][START_REF] Ploutz-Snyder | Exercise Training Mitigates Multisystem Deconditioning during Bed Rest[END_REF]. Although muscle alterations were prevented by all the tested resistance and aerobic exercise protocols regardless of the type, duration, intensity and frequency of the training, the protective effects on metabolic outcomes were variable. Combined resistance and aerobic exercise training prevents the development of a pro-inflammatory state [START_REF] Mutin-Carnino | Effect of muscle unloading, reloading and exercise on inflammation during a head-down bed rest[END_REF], insulin resistance and the shift in substrate use from total fat oxidation to carbohydrate oxidation [START_REF] Bergouignan | Physical inactivity differentially alters dietary oleate and palmitate trafficking[END_REF]. However, it does not counteract the increase in fasting triglycerides, the reduced oxidative rate of dietary fatty acids likely due to an impaired transport of fatty acids into the myocyte, and fat accumulation in skeletal muscle [START_REF] Bergouignan | Physical inactivity differentially alters dietary oleate and palmitate trafficking[END_REF] and bone [START_REF] Trudel | Bone marrow fat accumulation after 60 days of bed rest persisted 1 year after activities were resumed along with hemopoietic stimulation: the Women International Space Simulation for Exploration study[END_REF]. Hepatic fat accumulation is however likely offset [START_REF] Rudwill | Effect of enforced physical inactivity induced by 60-day of bed rest on hepatic markers of NAFLD in healthy normal-weight women[END_REF]. Surprisingly, these alterations were observed despite levels of MVPA mostly above recommended levels (Table 1), and total daily energy expenditure maintained to pre-bedrest levels in the exercising participants [START_REF] Bergouignan | Regulation of energy balance during long-term physical inactivity induced by bed rest with and without exercise training[END_REF].

Taken together these studies show that exercise (or MVPA) protects skeletal muscle mass and function, and cardiorespiratory function against large volumes of SB induced by bedrest. However, even if a dose-response relationship exists (Figure 2 and Table 1), very high levels of exercise do not fully prevent the manifestation of metabolic dysfunction, i.e. whole-body insulin resistance, glucose intolerance, alterations of lipid metabolism, and systemic inflammation. These observations support the role of organs other than muscle in the health-enhancing effects of physical activity [START_REF] Thyfault | Exercise and metabolic health: beyond skeletal muscle[END_REF], and the existence of health effects of SB independent of those from MVPA. It further highlights the importance of non-exercise activity (i.e. LPA), which mainly corresponds to daily living activities performed throughout the day.

Health benefits of daily living activities

Evidence from epidemiological studies indicate that LPA has a potential role in reducing the risk of early mortality. In cross-sectional studies, LPA is favorably associated with waist circumference, body mass index (BMI), plasma triglyceride, insulin, HDL-cholesterol concentrations [START_REF] Amagasa | Is objectively measured light-intensity physical activity associated with health outcomes after adjustment for moderate-to-vigorous physical activity in adults? A systematic review[END_REF] and 2h plasma glucose [START_REF] Healy | Objectively measured light-intensity physical activity is independently associated with 2-h plasma glucose[END_REF], independent of MVPA. Iso-temporal substitution modelling suggests that replacing 30 min of SB per day with 30 min of LPA (and not MVPA) is associated with lower waist circumference and BMI [START_REF] Healy | Accelerometer-derived sedentary and physical activity time in overweight/obese adults with type 2 diabetes: crosssectional associations with cardiometabolic biomarkers[END_REF]. A growing number of experimental studies have also examined the effects of LPA prescribed as short bouts spread throughout the day on metabolic health (table 2). As previously reviewed (Dempsey et al., 2016a), LPA bouts (15-40 min) acutely decrease postprandial glycemia and insulinemia. Even brief intermittent bouts (≤5 min) of walking spread throughout the day reduce glucose and insulin concentrations following meal ingestion, with more potent effects observed in adults with overweight to obesity and T2D [START_REF] Chastin | How does light-intensity physical activity associate with adult cardiometabolic health and mortality? Systematic review with meta-analysis of experimental and observational studies[END_REF], and those with lower cardiorespiratory fitness compared to healthy lean individuals [START_REF] Mccarthy | Fitness Moderates Glycemic Responses to Sitting and Light Activity Breaks[END_REF]. Importantly, acute exposure to bouts of LPA elicits similar responses to those observed with short, frequent bouts of MVPA. With regards to standing, although some studies did not show a reduction in postprandial glycemic response [START_REF] Bailey | Breaking up prolonged sitting with light-intensity walking improves postprandial glycemia, but breaking up sitting with standing does not[END_REF][START_REF] Pulsford | Intermittent walking, but not standing, improves postprandial insulin and glucose relative to sustained sitting: A randomised crossover study in inactive middle-aged men[END_REF], others did [START_REF] Benatti | Intermittent Standing but not a Moderate Exercise Bout Reduces Postprandial Glycemia[END_REF]. Benatti and colleagues even reported that intermittent standing, but not a single continuous bout of MVPA, lowers postprandial glycemia in healthy adults. The difference in the observed effects may be explained by the duration of the standing bouts (2 min vs 15 min) and the total active duration (30 min MVPA vs 15 min standing every 30 min for 8.5 hours). Although these acute studies suggest that LPA of higher energy expenditures or longer duration decrease glycemia and insulinemia in a dose-dependent manner, none of these studies controlled for energy expenditure across the interventions. In an elegant series of studies, Duvivier and colleagues compared the metabolic effects of replacing SB with LPA walking and standing to those of 1h/d of MVPA. Both interventions lasted four days and were matched for energy expenditure. Replacing SB with high volumes of LPA without any increase in MVPA, decreased postprandial insulin, fasting triglycerides and non-HDL cholesterol in healthy adults [START_REF] Duvivier | Minimal intensity physical activity (standing and walking) of longer duration improves insulin action and plasma lipids more than shorter periods of moderate to vigorous exercise (cycling) in sedentary subjects when energy expenditure is comparable[END_REF]. In adults with T2D, increasing time spent standing and walking improved glucose control and insulin sensitivity. It further reduced diastolic blood pressure, blood triglycerides and non-HDL cholesterol while increasing HDL cholesterol (Duvivier et al., 2017a;Duvivier et al., 2017b). The MVPA intervention tended to improve these metabolic parameters, but the effects were less pronounced. These studies show that when energy expenditure is matched, replacing SB with high volumes of LPA (i.e. non-exercise activity) is more beneficial than performing MVPA as a single continuous bout (i.e. structured exercise), at least for glucose control, insulin sensitivity and circulating lipids. On the contrary, if frequent LPA bouts (>2 min) improves endothelial function [START_REF] Thosar | Effect of prolonged sitting and breaks in sitting time on endothelial function[END_REF]Dempsey et al., 2016b), a single bout of MVPA may be more beneficial for microvascular function than increasing LPA throughout the day [START_REF] Duvivier | Reducing sitting time versus adding exercise: differential effects on biomarkers of endothelial dysfunction and metabolic risk[END_REF]. These findings suggest that MVPA (i.e., exercise) and LPA (i.e., non-exercise activity) might elicit differential cardiometabolic effects. Future studies will need to further compare the effects of LPA versus MVPA on cardiometabolic health outcomes, including maximal aerobic capacity, muscle strength, substrate metabolism, glucose control, and insulin sensitivity in different populations and investigate the mechanistic underpinnings.

Where do we go from here?

Although MVPA produces a myriad of health benefits, it does not reduce time spent sedentary. Indeed, physically active people, even those who exceed the current guidelines, can be as sedentary as their inactive counterparts [START_REF] Rantalainen | Are habitual runners physically inactive?[END_REF]. Increasing MVPA can even trigger spontaneous behavioral compensations in sedentary adults leading to a decrease in non-exercise activities (i.e. LPA) in favor of sedentary time [START_REF] Lefai | Exercise training improves fat metabolism independent of total energy expenditure in sedentary overweight men, but does not restore lean metabolic phenotype[END_REF]. Furthermore, MVPA does not fully offset the adverse health effects of large volumes of SB, as shown by the bedrest studies with concomitant exercise training. The remaining question is how much MVPA is needed to offset the effects of a certain amount of SB. It was shown that independent of physical activity, every hour spent sitting increases the risk of mortality by 5.9%, of T2D by 22% and of obesity by 23% [START_REF] Hu | Television watching and other sedentary behaviors in relation to risk of obesity and type 2 diabetes mellitus in women[END_REF][START_REF] Wilmot | Sedentary time in adults and the association with diabetes, cardiovascular disease and death: systematic review and meta-analysis[END_REF][START_REF] Chau | Daily sitting time and all-cause mortality: a meta-analysis[END_REF]. A meta-analysis including more than 1 million individuals further showed that 60-75 min/d of MVPA are needed to prevent the risk of premature death associated with 9h/d or more of sitting time [START_REF] Ekelund | Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women[END_REF]; 9h/d being close to the average sitting time observed in modern societies. When most of the population does not reach the recommended guidelines (i.e. 30 min/d of MVPA, 5d/wk.), adding 30-45 more minutes per day of MVPA is unrealistic. Therefore, other pragmatic and efficient strategies are needed. Activities of daily living (i.e. LPA) are inversely associated with SB; increases in LPA are associated with reductions in sedentary time [START_REF] Pate | The evolving definition of "sedentary[END_REF]. In addition, large volumes of LPA, here considered as any body movements associated with activities of daily living, have been shown to confer health benefits. Knowing that lack of time is a major barrier to the practice of exercise/MVPA, reintroducing LPA into daily life could be an effective strategy to reduce sedentary time and prevent its effects on metabolic health. In this line, the latest guidelines from the World Health Organization [START_REF] Bull | World Health Organization 2020 guidelines on physical activity and sedentary behaviour[END_REF] promote the practice of physical activity of any intensity to reduce sedentary activities. In other words, moving is better than sitting. Future mechanistic studies will need to establish the physiology of SB and LPA to better understand the respective negative and positive health effects, and thus better define the dose-response relationship between the components of PA behavior and key health outcomes. Experimental research examining these relationships will foster the development of more specific and pragmatic public health guidelines.

FIGURES Abstract figure:

Although the exact physiological mechanisms remain unclear, sedentariness has been shown to negatively affect metabolic health and the main organs involved in its regulation. The 2020 World Health Organization [START_REF] Bull | World Health Organization 2020 guidelines on physical activity and sedentary behaviour[END_REF] guidelines on physical activity recommend practicing a weekly volume of 150-300 min of moderate intensity or 75-150 min of vigorous intensity or an equivalent combination of MVPA to limit the appearance of certain maladaptation. Recently, some large-scale studies have revealed the importance of LPA to prevent the effects of sedentary lifestyles. Since then, limiting periods of sedentary time have become part of the recommendations for the first time, raising the question of how to reduce periods of sedentary living. This review aims to highlight the potential role of LPA in effectively reducing sitting time and preventing its associated harmful health effects. Intervention studies specifically targeting LPA and SB, in addition to MVPA, are necessary to develop specific recommendations and limit the risk of developing metabolic

Estimated energy cost

Resistance exercise [START_REF] Bergouignan | Effect of physical inactivity on the oxidation of saturated and monounsaturated dietary Fatty acids: results of a randomized trial[END_REF][START_REF] Fernandez-Gonzalo | Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures[END_REF]Irimia J. et al. 2017[START_REF] Rudwill | Effects of different levels of physical inactivity on plasma visfatin in healthy normal-weight men[END_REF][START_REF] Trappe | Human single muscle fibre function with 84 day bed-rest and resistance exercise[END_REF]LTBR 2001-2002 90 Only then, brief rests (< 5s) were allowed with the entire foot on the vibration platform in order to recover, and subjects started to raise their heels again (foot plantar flexors).

3. Toe raises: Similar to 2, but toes were raised instead of heels (foot dorsiflexors). 4. "Kicks": With the same loading as in 1-3, knees were extended as quickly and forcefully as possible. The platform was struck with the balls of the feet, and legs rested on the Galileo Space framework in between the kicks. This was done 10 times with 10s of rest inserted.

Figure 1 :

 1 Figure 1: Schematic representation of the components of total energy expenditure during bedrest, conducted with or without exercise training. Based on total energy expenditure, participants enrolled in bedrest protocols can be compared to the general population. Strict bedrest suppresses both components of physical activity energy expenditure: exercise activity energy expenditure and non-exercise activity energy expenditure. Exercise activity energy expenditure refers to the energy spent in MVPA and/or structured exercise. Non-exercise activity energy expenditure corresponds to any activity of daily life, which are essentially LPA. Participants who are subjected to moderate to vigorous exercise training along with bedrest maintain high exercise activity energy expenditure mainly due to MVPA. However, they are sedentary with very low levels of non-exercise activity energy expenditure and are lacking LPA. These individuals represent an extreme but unique model of "sedentary exercisers", i.e. physically active yet sedentary people. Strict bedrest leads to a decrease of both MVPA and LPA while increasing SB. These bedrest individuals represent a model of the modern physically inactive sedentary individuals. SED: sedentary activities; LPA: light-intensity physical activity; MVPA: moderate-to-vigorous physical activity. Adapted from Bergouignan et al 2010.

Figure 2 :

 2 Figure 2: Preventive effect of exercise (resistance exercise or resistance plus aerobic exercise) against the bedrest-induced physiological and metabolic alterations. -: no effect ; + : partially

  13.5h/d, stand 1.4h/d, LIW 0.7 h/d 2) Sit 7.6h/d, stand 4.0h/d, LIW 4.3h/d OGTT insulin AUC: LIW < sitting Insulin sensitivity (Matsuda index): LIW < sitting Fasted lipids: LIW < sitting Fasted lipoproteins: LIW < sitting Diastolic blood pressure: LIW < + 5min LIW every hour Flow-mediated dilation: LIW > sitting Shear rate: LIW > sitting

Table 1 : Summary of the exercise training protocols tested during bedrest studies Publication Study name Duration of BR Sample size Exercise modalities Estimated duration of MVPA

 1

Table 2 : Summary of the acute metabolic health effects of light-intensity physical activity from experimental laboratory-controlled studies Publication Sample size and characteristics Study design Study conditions Primary results Studies investigating light-physical activity compared to sitting

 2

	Krainski F. et al., 2014	35 d HDT-BR	REX: 25-30min 2 d/wk. 2x8-12 of lower body exercises (leg press, plantar	381 min MVPA/wk	49.5 MET.h/wk
		n=27 ♂/♀	flexion, knee flexion, hip flexion, and hip abduction) and 1x8-12 of upper	54.4 min MVPA/d	7.1 MET.h/d
			body EX (shoulder press, elbow flexion and extension, chest press,
			pullovers, and abdominal crunches) were performed in the supine position,
			loads were adjusted weekly to reach muscle fatigue during each set of EX.
			After 5 wk of BR, 2x20 plantar flexion exercises on each leg 2/d (6-8min)
			against an elastic band were added for all remaining subjects in EX group.
			AEX: 6 d/wk. During each week of BR, subjects completed 1 recovery (low
			intensity, typically <70% max HR), 2 base (moderate intensity, between 70-
			80% max HR), 1 MSS (vigorous intensity, 80-90% maximal HR), and 2
			interval sessions (high intensity, 90-95% max HR or above), each lasting a
			total of 30 -46 min and separate warm-up/cool-down phases lasting 5 min
			each. Intervals consisted of 6 cycles of 3 min at 90-95% of max HR, followed
			by 3 min at recovery pace.
	Ploutz-Snyder L. et al. 2018	70 d HDT-BR	REX: 3 d/wk. 3x4 supine lifts (squat, leg press, unilateral leg curl, and heel	314.5	min	40 MET.h/wk
		n=26 ♂	raise); squats and leg press were each performed using a standard shoulder-	MVPA/wk		5.7 MET.h/d
			width stance, single-leg stance, or wide-leg stance on a rotating basis.	45 min MVPA/d
			Training followed a nonlinear periodized model in which load and
			repetitions were varied on a daily basis to optimize adaptations.
			AEX: 6 d/wk. Alternating days of continuous cycle EX for 30 min at 75% of
			VO 2 peak (3 d/w) with interval treadmill sessions of 30s, 2min, or 4min
			intervals (3 d/wk) at nearly max intensity.
	Ward K. et al. 2020 (In press)	RSL	48 sessions including 4 types of training sessions based on varying CMJ and	17.5 min MVPA/wk	2.6 MET.h/wk
		60 d HDT-BR	repetitive hops between 80-90% of BW during 1.5-3min preceded by a	2.5 min MVPA/d	0.4 MET.h/d
		n=23 ♂	warm-up and 3 max CMJ at 80% of BW.
	HDT-BR: 6° head-down tilt bedrest; d: days; wk: week; max: maximal; BW: body weight; CMJ: countermovement jump; EX: exercise; REX: resistive exercise; AEX: aerobic
	exercise

Funding This publication was made possible by funding to ELR from the CNRS GDR Sport & Activité Physique, by funding to NDJ from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institute for Health (NIH) (F31DK125061), by funding to DHB from the Colorado Nutrition Obesity Research Center (NORC P30DK048520), by funding to CS and SB from the French Space Agency, by funding to AB from the French Space Agency (CNES), the NIH/NIDDK (R00DK100465), the NORC (P30DK048520).

Conflict of interest

No conflict of interest to declare.

Authors contribution

E.L.R., N.D.J. and A.B. wrote the first draft of the review, and all authors contributed to revising and editing the paper. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

diseases.

protected ; ++ : fully protected ; ?: no data available ; ± : no consensus.

Belavy D. et al 2014[START_REF] Trudel | Resistive exercises, with or without whole body vibration, prevent vertebral marrow fat accumulation during 60 days of head-down tilt bed rest in men[END_REF] BBR2-2 60 d HDT-BR n=24 ♂ 3 d/wk: 1. Bilateral leg press (~75-80% of pre-bed-rest max voluntary contraction); 2. Dingle-leg heel raises (~1.3 times body weight); 3. Double leg heel raises (~1.8 times body weight); 4. back and forefoot raise (performing hip and lumbar spine extension against gravity with ankle dorsiflexion, but with ~1.5 times body weight applied at the shoulders). The RVE group performed the same exercises as the REX group, except that whole body vibration was applied. The corresponding vibration parameters were as follows: 1. frequency 24 Hz, amplitude 3.5-4 mm, and peak acceleration ~8.7 g, where g ~ 9.81 ms -2 ; 2. frequency 26 Hz, amplitude 3.5-4 mm, and peak acceleration ~10.2 g; 3. frequency 26 Hz, amplitude 3.5-4 mm, and peak acceleration ~10.2 g; 4. frequency 16 Hz, amplitude 3.5-4 mm, and acceleration ~3.9 g 15.8 min MVPA/wk 2.3 min MVPA/d 1.6 MET.h/wk 0.2 MET.h/d [START_REF] Bergouignan | Physical inactivity differentially alters dietary oleate and palmitate trafficking[END_REF][START_REF] Bergouignan | Regulation of energy balance during long-term physical inactivity induced by bed rest with and without exercise training[END_REF][START_REF] Lee | WISE-2005: Countermeasures to prevent muscle deconditioning during bed rest in women[END_REF]Mutin-Carnino M. et al.,2013[START_REF] Rudwill | Effect of enforced physical inactivity induced by 60-day of bed rest on hepatic markers of NAFLD in healthy normal-weight women[END_REF][START_REF] Salanova | Molecular biomarkers monitoring human skeletal muscle fibres and microvasculature following long-term bed rest with and without countermeasures[END_REF][START_REF] Trappe | Influence of concurrent exercise or nutrition countermeasures on thigh and calf muscle size and function during 60 days of bed rest in women[END_REF][START_REF] Trappe | Single muscle fiber function with concurrent exercise or nutrition countermeasures during 60 days of bed rest in women[END_REF]Trappe S. et al., 2008 Trudel G. et

Combined resistance and aerobic exercise


MS Johanna Calderon

MD, PhD Damien Bonnet

PhD Charlotte Pinabiaux

Isabelle Jambaqu

PhD Nathalie Angeard

Use of Early Remedial Services in Children with Transposition of the Great Arteries

Objectives To characterize the prevalence of use of early remedial services and its associated demographic, medical, and cognitive factors in children aged 4-6 years with corrected transposition of the great arteries (TGA).

Study design

This was a prospective study of neurocognitive outcomes after TGA. Children underwent formal neu-ropsychological testing including general intelligence and a comprehensive battery of executive functions (EF) includ-ing motor and interference control, short-term memory, and working memory as well as cognitive flexibility. Parental reports on the children's behavior and EF were also evaluated. Demographic factors and preoperative, intraoperative, and postoperative factors as well as cognitive factors were examined according to the current use of remediation.

Results Forty-five patients (67% male) and their parents participated in this study. Twenty-four (53%) patients were receiving remedial services. Male sex, a postnatal diagnosis of TGA, and a longer postoperative intensive care unit stay were significantly associated with use of remediation. Children receiving remediation had lower EF scores, had more severe EF deficits as observed by formal testing, and were rated as having more behavioral daily life difficulties. However, in the group without remediation, 13 children (43%) also displayed EF deficits rated as moderate to severe.

Conclusions Demographic and medical factors could help identify children at higher risk for neurocognitive delays.

Evaluation of executive functioning from an early age may influence referral for remediation. (

(Paris, France), were screened for participation in a single center prospective study of neurocognitive outcomes. Patients meeting inclusion criteria received a diagnosis of TGA with intact ventricular septum or ventricular septal defect and underwent a neonatal arterial switch operation under continuous full-flow cardiopulmonary bypass. Neonates with associated genetic syndromes (including 22q11 deletion), associated extra-cardiac pathologies or cardiovascular anomalies requiring aortic arch reconstruction, and the use of deep hypothermic circulatory arrest or additional open surgical procedures as well as neonates with a birth weight less than 2.5 kg were excluded. Children whose native language was not French and/or who were living outside the Paris area at the time of enrollment were also excluded from participation. Data from a control group of same aged children (n = 45) living in the same geographic area was used as a reference to compare the prevalence of remedial service use.

The institutional ethics committee of Necker Children's Hospital approved the protocol and informed consent. Eligible families were contacted by a letter explaining the aim of the study with telephone follow-up to further explain the protocol. Families who agreed to participate were scheduled for a 2 to 2.5-hour visit at the hospital, and written informed consent was obtained from the parent(s) and the child. A cognitive evaluation was performed on all children by a trained neurodevelopmental psychologist who did not review medical records before conducting the neuropsychological battery.

Cognitive assessment included a nonverbal IQ evaluation using the Columbia Mental Maturity Scale. [START_REF] Burgemeister | Columbia Mental Maturity Scale[END_REF] Motor control was assessed with the knock and tap subtest from the Developmental Neuropsychological Assessment (NEPSY) [START_REF] Korkman | NEPSY: A developmental neuropsychological assessment manual[END_REF] ; interference control and impulse control were measured with the Animal Stroop test, [START_REF] Wright | A new Strooplike measure of inhibitory function development: typical developmental trends[END_REF] a pictorial version of the Stroop task that does not require reading abilities. This test provides an evaluation of interference sensitivity and control of attention expressed by reaction times as well as an evaluation of cognitive impulse control skills expressed by the total number of incorrect responses. Verbal short-term memory and verbal working memory were assessed with the forward and backwards digit span subtests from the Wechsler Intelligence Scale for Children-fourth edition. [START_REF] Wechsler | Manual of Wechsler Intelligence Scale for Children-fourth edition[END_REF] Spatial immediate memory and spatial working memory were assessed with the spatial span task. [START_REF] Berch | The Corsi block-tapping task: methodological and theoretical considerations[END_REF] In this test, analogous to the verbal working memory task, the stimuli are visual (a set of small squares randomly positioned). Children reproduce a sequence of squares locations in the same order as they saw it and then backwards. Finally, cognitive flexibility was evaluated with the Dimensional Card Sorting Test, [START_REF] Zelazo | The Dimensional Change Card Sort (DCCS): a method of assessing executive function in children[END_REF] a well-known neuropsychological test for preschool children. Normative values for all tests were obtained from national standardizations and previous references published. [START_REF] Calderon | Executive function and theory of mind in school-aged children after neonatal corrective cardiac surgery for transposition of the great arteries[END_REF][START_REF] Calderon | Impact of prenatal diagnosis on neurocognitive outcomes in children with transposition of the great arteries[END_REF][START_REF] Wright | A new Strooplike measure of inhibitory function development: typical developmental trends[END_REF] Parental reports on the children's behavior and EF were obtained using the Behavior Rating Inventory of Executive Function-preschool and school-age versions [START_REF] Gioia | Behavior rating inventory of executive function[END_REF] for children between 4 and 6 years 11 months. For this scale we analyzed the global executive composite score, a T score (expected mean = 50; SD = 10) with a higher T score indicating greater impairment (Appendix; available at www.jpeds.com).

Information regarding remedial services use was gathered through parental reports during the visits. A short written survey with a multiple-choice format was used to collect diverse data regarding health status, demographic variables, and developmental information including current remedial service use. Patient's medical records were reviewed for potential risk factors associated with cognitive deficits and remedial service use. Preoperative medical factors included pre-vs postnatal diagnosis of TGA, presence or absence of a ventricular septal defect, birth weight, gestational age, Apgar score at 5 minutes, hemodynamic condition (metabolic acidosis defined with a pH level <7.2), and the need for balloon-atrial septostomy. Age at the arterial switch operation, total bypass time and total cross-clamp time, and postoperative intensive care unit (ICU) stay duration were also examined. Demographic variables including sex, age at evaluation, family socioeconomic status, and parental educational levels were also recorded.

Statistical Analyses

Statistical analyses were performed with Statistica software (v. 9.1; StatSoft Inc, Maisons-Alfort, France). Descriptive results are presented with means (SD) and proportions in each group. Demographic and medical variables were compared between groups by using c 2 tests for categorical variables and ANOVA for numerical variables. Differences in cognitive scores were assessed using ANOVA with posthoc testing (Tukey Honestly Significant Difference Test) for specific comparisons across groups for all continuous variables. Multivariate logistic regression analyses including separate analyses with demographic and medical variables were performed to identify significant predictors of remedial service use. Scores in each EF subtest were compared with normative values and deficits were described according to their severity as "mild" (À1 SD) or "moderate to severe" (À2 SD or below). The total number of mild and moderate to severe deficits were calculated for each individual, each one ranging from 0 = no deficits to 8 = deficits in all EF subtests. Mean numbers of mild and moderate to severe deficits were then calculated for the groups (with and without remediation), and Poisson regression analyses were used for comparisons between the groups. Multiple logistic regression analyses were used to determine significant determinants (medical and demographic) once the severity of EF deficits was adjusted. A P value of .05 was considered significant.

Results

A total of 60 eligible children born between 2003 and 2005 were identified in the database. Six families could not be contacted because of a change of address. Fifty-four families were contacted for enrollment in a single-center prospective study of neurocognitive outcomes. Parents of 6 children declined participation in the study, 2 children were excluded due to developmental disorders not previously identified (autism spectrum disorder and severe language disability), and 1 child refused to cooperate with the administration of the tests. Forty-five children participated in the study (mean age = 5 years; SD = 4 months, 30 [67%] males and 15 [33%] females). No significant differences were found between participants and nonparticipants for all medical related variables (all P > .05).

Twenty-four (53%) children with TGA were receiving at least 1 remedial service. Among children using remedial services (n = 24), 15 (62%) were receiving special educational support, 10 (42%) were using speech and language therapy, 9 (37%) psychology/psychiatry therapy, 4 (17%) occupational therapy, and 2 (8%) were followed-up by a pediatric neurologist.

No significant differences between the groups were found regarding children's age (t[43] = 0.04; P = .96), parental socioeconomic status (t[43] = 0.02; P = .98), or parental educational levels (father's [t {43} = 0.63; P = .53); mother's [t {43} = 0.81; P = .42]). The proportion of males and females significantly differed between the groups (c 2 [1] = 3.61; P = .05). A logistic regression analysis model including all demographic variables confirmed sex as the only significant demographic predictor for the use of remedial services (Walds c 2 [dl = 1] = 4.15; P = .04). Results are summarized in Table I. The prevalence of children with TGA using services (53%) was significantly higher than that observed in a reference control group of same-aged children (18%) (c 2 [1] = 12.41; P = .0004) in which the majority were also boys (75%). The results concerning medical related variables are presented in Table II.

In our sample, 29 (64%) children were prenatally diagnosed with TGA against 16 (36%) who were diagnosed after birth. All children with prenatal diagnosis were delivered on site; the median age at admission for those diagnosed postnatally was 16 hours. As shown in Table II, results indicated that the proportion of children prenatally diagnosed was significantly higher in the group without remedial services (c 2 [1] = 4.68; P = .03). Moreover, ICU stay was significantly longer for the group with remedial services (Wald c 2 [1] = 3.48; P = .05). No other significant differences were found. A logistic regression analysis model including all categorical and numerical medical factors revealed that postnatal diagnosis of TGA and ICU stay significantly predicted the use of remedial services in this cohort (Wald c 2 [1] = 5.53; P = .01 and Wald c 2 [1] = 3.88; P = .04).

Formal Testing

ANOVA with post hoc testing (Tukey Honestly Significant Difference Test) for specific comparisons including all cognitive variables showed that children with TGA who were using remedial services had significantly lower scores in motor control (P = .04), short-term spatial memory (P = .03), spatial working memory (P =.01), and cognitive flexibility (P = .04; Table III).

More specifically, according to type of remediation, lower scores on motor control (Wald c 2 [1] = 0.04), interference control (Wald c 2 [1] = 0.009), short-term verbal (Wald c 2 [1] = 0.04), and spatial memory (Wald c 2 [1] = 0.05) were significantly associated with the use of special educational support. No other significant association with other types of remediation (language therapy, psychology/psychiatry therapy, occupational therapy, and neurologic follow-up) was found (P > .05).

As deficits in EF are rarely isolated and their potential accumulation may suggest a higher cognitive risk, we sought to determine if the mean number of executive deficits across the 8 EF components differed between the groups with and without remediation. As shown in Table III, children with TGA who were receiving remedial services did not have more cumulated mild EF deficits than those who had no current remedial service (Walds c 2 [1] = 0.63; P = .42). However, when compared on moderate to severe deficits, children currently using remedial services had significantly more cumulated EF deficits than children who were not using Values are n (%) and means (SD). *P < .05 for comparisons between patients with and without remedial services. Analyses were calculated by using one-way ANOVAs and c 2 tests. †Socioeconomic status was scored according to the index from the French National Demographic Statistical Institute in a scale from 0-3, with a higher score indicating a higher socioeconomic status. zParental educational level was scored according to the French National Education Diploma classification (0 = primary school education; 1 = middle education; 2 = high school diploma; 3 = college undergraduate; 4 = college graduate/masters degree, and 5 = postgraduate/doctoral degree). One-way ANOVA and c 2 were used to determine significant differences between groups with and without remedial services for medical related variables. *P < .05 for comparisons between patients with and without remedial services.

any remediation (Wald c 2 [1] = 10.81; P = .001). Moreover, despite the fact that deficits below À2 SD were less numerous in the group without remediation, analyses revealed than among these 21 children, 13 (43%) had at least 1 moderate to severe EF deficit. Finally, to determine if the factors associated with the remediation use remained significant once the severity of EF deficits was controlled, we conducted a multiple logistic regression analysis with adjustment for the severity of the EF dysfunction (number of deficits below À2 SD). We included in this model all variables that were significantly associated with the use of remediation services (sex, postnatal diagnosis of TGA, and postoperative ICU stay). Analyses revealed that for children with similar severity of EF deficits, those who were diagnosed after birth still had a significantly higher prevalence of remediation use (Wald c 2 [1] = 3.84; P = .04). The significant effects of other factors did not remain once the severity of EF deficits was controlled.

The findings on the Behavior Rating Inventory of Executive Function reported a significantly higher general executive composite score indicating greater impairment for children with TGA currently receiving remedial services (m = 54.75; SD = 11.62) compared with those without current remediation (m = 47.42; SD = 10.49) (F[1,39] = 6.28; P = .01). In addition, the proportion of children in the whole cohort with scores greater than the cut-off for clinical concern (60) was 18%. Among children in the clinical concern range, 4 out of 8 were not currently receiving remediation. Parents of children receiving special educational support and psychology/psychiatric therapy reported significantly more behavior and EF impairments (F[1,39] = 6.41; P = .01; F [1,39] = 25.2; P = .00001).

Discussion

Our results show that 53% of the children in our cohort received at least 1 remedial service. This percentage was significantly higher than that observed in a same-aged control group recruited in the same geographic area (18%). In the Boston Circulatory Arrest Trial, 8 more than one-third of children with TGA aged 4-8 years were evaluated by a speech pathologist, one-sixth by an occupational therapist, and less than 10% by a psychiatrist and by a physical therapist. No information regarding associated patient-related factors to the use of these services was provided. [START_REF] Bellinger | Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: the Boston Circulatory Arrest Trial[END_REF] Our proportion using remediation at a mean age of 5 is higher than the proportion reported in children with various types of CHD aged 8 (23%). [START_REF] Majnemer | Patterns of use of educational and rehabilitation services at school age for children with congenitally malformed hearts[END_REF] In this later study, the majority of developmentally delayed children were not receiving any resource support. In France, systematic general pediatric and developmental examinations of all preschool children before the transition to primary school may help refer children with important delays (eg, language or psychomotor) with or without EF dysfunction. However, mild deficits and specific impairments in attention and EF, when not associated with other disabilities, can easily go undetected.

Our results demonstrate that male sex was significantly associated with remedial service use. Boys with CHD have been reported to be twice as likely to exhibit neurologic abnormalities on examination as well as poorer fine motor skills. They were at significantly greater risk for dependency in functional daily tasks (self care, age-appropriate communication skills, problem solving tasks). [START_REF] Majnemer | Gender differences in the developmental outcomes of children with congenital cardiac defects[END_REF] Evidence of a male disadvantage has been reported in preterm infants [START_REF] Kent | Mortality and adverse neurologic outcomes are greater in preterm male infants[END_REF] and in very low birth weight preterm male neonates who presented worse neurologic outcomes and higher rates of abnormal neurodevelopment compared with female neonates. [START_REF] Rose | Neonatal brain structure on MRI and diffusion tensor imaging, sex and neurodevelopment in very-low-birth weight preterm children[END_REF] However, it is worth noting that the majority of children requiring remediation in the reference group in Paris region are also boys (75%) suggesting that the gender difference in the CHD population may perhaps only reflect the fact that males are generally more likely to require these services.

Data from this study also demonstrate that a postnatal diagnosis of TGA and longer postoperative ICU stay are significantly associated with the use of remediation. These results support previous findings indicating a beneficial impact of prenatal diagnosis of TGA on neurocognitive results. [START_REF] Calderon | Impact of prenatal diagnosis on neurocognitive outcomes in children with transposition of the great arteries[END_REF][START_REF] Bonnet | Detection of transposition of the great arteries in fetuses reduces neonatal morbidity and mortality[END_REF] Delayed diagnosis of the cardiac condition may be a surrogate for vulnerability as children diagnosed after birth display more adverse neonatal risk factors [START_REF] Bonnet | Detection of transposition of the great arteries in fetuses reduces neonatal morbidity and mortality[END_REF] including a higher incidence of preoperative acidosis. [START_REF] Calderon | Impact of prenatal diagnosis on neurocognitive outcomes in children with transposition of the great arteries[END_REF] In our sample, children who were receiving remedial services had significantly worse scores on motor control, spatial short-term, and working memory, as well as on cognitive flexibility. More specifically, motor and interference control, short-term verbal memory, and spatial memory were significantly associated with special educational support use, suggesting a relationship between EF vulnerability and general early learning difficulties. Moreover, parental reports on children's everyday behavioral and EF difficulties were also found to be significantly associated with remediation use. In typical early childhood, difficulty with selfregulation and delay in EF maturation (rather than general intelligence levels) are main causes of lack of school readiness. [START_REF] Blair | Biological processes in prevention and intervention: the promotion of self-regulation as a means of preventing school failure[END_REF] Children with TGA who display EF impairments may encounter difficulties in various aspects of academic and daily life including problem solving, retaining pertinent information, focusing attention, shifting between alternatives, and carrying out step-by-step processes. Our analyses revealed a significant effect of cumulating multiple moderate to severe deficits in EF on receiving developmental remediation. However, not receiving rehabilitation or educational services does not necessarily reflect an absence of dysfunction as 13 children in the group without remediation still presented at least one important EF deficit.

A scientific statement from the American Heart Association categorized children requiring open-heart surgery at high risk for developmental disorders or disabilities and recommended that they should be referred for formal developmental and medical evaluations at key stages where important transitions are made such as school-age and adolescence. [START_REF] Marino | Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management a scientific statement from the American Heart Association[END_REF] Evaluations should ideally also include early identification of specific behavioral and executive impairments that may have a direct impact on the onset of interventions for these patients. Parental reports and formal assessments of these domains before primary school entry have demonstrated to be good indicators of further learning and adaptation disabilities and therefore should be considered when evaluating young children with CHD. It has been demonstrated that training of working memory and executive control through computerized programs can result in significant improvement in these abilities [START_REF] Rueda | Training, maturation, and genetic influences on the development of executive attention[END_REF] and also may have a positive impact on emotional and social development. [START_REF] Diamond | Interventions shown to aid executive function development in children 4 to 12 years old[END_REF] Results from this study should be considered in light of several limitations. TGA constitutes a cardiac defect successfully corrected in the neonatal period, and therefore, our results concerning the prevalence and factors associated with remediation utilization may not be generalized to all children with CHD. However, including a sample with very homogeneous medical characteristics allowed us to control for adverse variables such as chronic hypoxemia, number of operations, or hospitalizations. The predictive value of other potential isolated or associated language or psychomotor delays on the use of services remains to be investigated. Differences in health care accessibility and insurance coverage should be taken into account when interpreting these findings as the prevalence of remediation use may also be highly dependent on resources available to families according to geographic and cultural settings.

Clearly, consequences of neurocognitive morbidities associated with CHD should become a high priority in these patients' follow-up. Particular attention should be drawn to early surveillance, screening, evaluation of specific cognitive and behavioral difficulties including executive functioning. n

Appendix

The Columbia Mental Maturity Scale [START_REF] Burgemeister | Columbia Mental Maturity Scale[END_REF] is an individually administered test designed to assess the general reasoning ability of children from the age of 3-9 years. This test includes 100 pictorial and figural classification items arranged in levels of complexity. It evaluates general nonverbal intellectual abilities. Raw scores are converted to a standard IQ with a mean of 100 and a SD of 15.

The NEPSY is a developmental neuropsychological assessment battery. [START_REF] Korkman | NEPSY: A developmental neuropsychological assessment manual[END_REF] Each subtest assesses a specific neuropsychological domain for children from 3-12 years old. Knock and Tap Subtest, assess the capacity to control motor actions in response to a contradictory visual stimulus. The child learns a pattern of motor and has to inhibit the automatic tendency to imitate the experimenter's contradictory motor actions. Validity studies show that there is a weak correlation between the executive function subtests of the NEPSY and tests of general intelligence. NEPSY is commonly used in clinical populations including children diagnosed with ADHD. Subtests of EF have been described as good predictors of attention and hyperactivity disorders.

Animal Stroop test [START_REF] Wright | A new Strooplike measure of inhibitory function development: typical developmental trends[END_REF] is used to assess cognitive inhibition capacities in young children from 3 years old. It consists of a pictorial version of the Stroop task, and it does not require reading abilities. It was designed to be sensitive to individual and age-related differences in impulse control and visual interference sensitivity. Visual stimuli (4 exemplar images of animals) are congruent in the first condition, neutral in the second condition, and then incongruent in the third condition, where each animal's head is substituted with another animal's head. Interference is elicited from the well documented preferential processing of facial information over body information. Children are required to name the body and inhibit a preferred response based on the identification of the animal's head. Scores are given in terms of reactions times as well as the number of errors committed. Validity studies of populations with frontal lobe epilepsy, traumatic brain injury, or ADHD support this task as a sensitive measure of cognitive inhibition.

Digit span is a subtest from the Wechsler Intelligence Scale for Children-fourth edition [START_REF] Wechsler | Manual of Wechsler Intelligence Scale for Children-fourth edition[END_REF] It measures verbal working memory skills: retaining and manipulating information for a short time. It includes 2 parts: forwards and backwards. The forward part requires the child to repeat numbers as they were stated by the experimenter, whereas the backward part requires the child to repeat in the reverse order as they were stated. If scores in the forward part are within the normal range, digit span backwards is taken as the reference for verbal working memory. In the spatial span task, [START_REF] Rose | Modeling a cascade of effects: the role of speed and executive functioning in preterm/full-term differences in academic achievement[END_REF] analogous to the verbal working memory task, the stimuli are visual (a set of small squares randomly positioned). Children reproduce a sequence of squares locations in the same order as they saw it and then backwards.

Dimensional Card Sorting Test 24 is a widely used measure of cognitive flexibility capacities in young children. Children are required to sort a series of bivalent cards, first according to one dimension (eg, shape), then according to the other (eg, color), and finally a combination of trials with rapid switches between dimensions. Performances progressively increase between 4 and 6 years and are commonly impaired in children with ADHD, prefrontal cortical damage, and autism.

Behavior Rating Inventory of Executive Functionpreschool and school-age versions [START_REF] Gioia | Behavior rating inventory of executive function[END_REF] is a questionnaire for parents of children aged 2 and one-half to 5 years (preschool version) and children aged 5-18 years (school-age version). It assesses executive function behavior in the home and school environments. Validity studies have been conducted on various pediatric populations including children with learning disabilities and attention disorders, traumatic brain injuries, lead exposure and other developmental, neurologic or and medical conditions. The parent forms contain 63 items for the preschool version and 86 items for the school age version, both measuring different aspects of executive functioning: inhibition, shifting, emotional control, working memory, organization and planning skills, organization of materials, and monitoring abilities. Raw scores are converted to a standard score named Global Executive Composite with a mean of 50 and a SD of 10.

Table I .

 I Group characteristics regarding sociodemographic variables

		Remedial	No remedial
		service (n = 24)	service (n = 21)
	Sex, % males	19 (79%)*	11 (52%)
	Age, m (SD)	5.47 (0.93)	5.49 (1.18)
	SES, m (SD) † Father's educational level, m (SD) z Mother's educational level, m (SD) z	1.96 (0.95) 3.3 (1.60) 3.5 (1.61)	1.95 (0.90) 3.0 (1.39) 3.0 (1.72)

SES, socioeconomic status.

Table II .

 II Pre-, intra-, and postoperative factors according to remedial services use

		Remedial	No remedial
		service (n = 24)	service (n = 21)
	Prenatal diagnosis, n (%)	12 (50%)*	17 (81%)
	Birth weight, kg	3.25 (0.49)	3.23 (0.42)
	Gestational age, wk	39.1 (1.89)	38.7 (1.64)
	Apgar score, 5 min	8.5 (1.75)	9.2 (0.85)
	Associated VSD, n (%)	6 (30%)	8 (38%)
	Acidosis, n (%)	2 (10%)	2 (10%)
	Atrial septostomy, n (%)	14 (70%)	13 (62%)
	Age at surgery, d	6.4 (3.39)	8.05 (3.70)
	Bypass time, min	128.65 (23.26)	131.76 (19.63)
	Aortic clamp time, min	84.1 (16.01)	86.3 (11.53)
	ICU stay, d	7.25 (5.68)*	5.76 (2.77)

VSD, ventricular septal defect.

Table III .

 III Cognitive scores and total number of EF deficits according to the use of remedial services BEM-144, battery of memory efficiency 144 blocks; DCST, Dimensional Card Sorting Test; WISC-IV, Wechsler Intelligence Scale for Children-fourth edition. Mean scores with SD in parentheses. *P < .05 for comparisons between patients with and without remedial services.

			Remedial service (n = 24)	No remedial service (n = 21)
	Cognitive domain	Cognitive test	Mean (SD)	Mean (SD)
	IQ	Columbia Mental Maturity Scale	110.3 (7.15)	111.9 (8.89)
	Motor control	NEPSY-Knock/Tap	23 (4.49)*	25 (2.30)
	Interference control	Stroop test (reaction time)	84.1 (32.54)	80.49 (31.20)
	Impulse control	Stroop test (number of errors)	3.54 (3.68)	2.57 (2.01)
	Short-term verbal memory	Digit span forward WISC-IV	5.45 (2.02)	5.47 (1.50)
	Verbal working memory	Digit span backwards WISC-IV	2.50 (2.73)	3.23 (2.18)
	Short-term spatial memory	BEM-144 spatial span forward	4.08 (1.24)*	4.90 (1.33)
	Spatial working memory	BEM-144 spatial span backwards	2.33 (2.03)*	3.90 (1.94)
	Cognitive flexibility	DCST	6.45 (3.18)*	8.2 (2.19)
	Total mean number of EF mild deficits (-1 SD) (0-8)	-	1.8 (1.16)	1.5 (1.03)
	Total mean number of EF moderate to severe deficits	-	2.4 (2.06)*	1.09 (1.44)
	(-2 SD or below) (0-8)

The authors thank all the families who participated in this study.

Submitted for publication Jan 7, 2013; last revision received Mar 28, 2013; accepted Apr 30, 2013.

Supported by the Association pour la