This paper proposes a model and preliminary results to evaluate the efficiency of anticipating the connection of power plants with shorter construction duration than the time needed to obtain the right to upgrade the network and finally to do this reinforcement. This evaluation is made in presence of a cost of anticipation related to the study of the project of network investment and to the administrative procedures needed to obtain the building agreement. This model compares a proactive TSO that anticipates the connection of new generators and then the required network reinforcement, with a reactive one that does not make any anticipation but that may then face greater congestion while the network is being reinforced. The efficiency of these behaviors is measured in terms of social cost. We find out that there exists a limit of probability for the connection of generators beyond which a proactive TSO is more efficient than a reactive one. Evaluated on a realistic case of connection, this limit of probability is found quite low, which indicates that the proactive behavior for a TSO shall generally be the optimal one.

I. INTRODUCTION

OWER generation and transmission are complementary activities that need to be coordinated, to the short-run and to the long term to ensure an optimal use and development of the transmission network.

The coordination between generation and transmission is more difficult in a liberalised power system, not only because these activities are unbundled but also because of the investors' choice for generation technology. The power reform has prompted the generation investors to build mainly power plants that can be built quickly, such as Combined Cycle Gas Turbines or wind farms [START_REF] Glachant | Generation technology mix in competitive electricity markets[END_REF] [START_REF] Etso | European Wind Integration Study (EWIS). Towards a Successful Integration of Wind Power into European Electricity Grids[END_REF]. At the same time, the right of way of powerlines faces increasing oppositions [START_REF] Etso | An Overview of Current Cross-border Congestion Management Methods in Europe[END_REF]. These movements increase the time needed to build transmission lines.

These differences in construction duration create uncertainty for the network planning. Indeed, these differences in construction time are all the more detrimental that the generation capacities of these new plants are Manuscript received April 19, 2008. Vincent Rious gratefully acknowledges the financial and scientific support he received from the French TSO RTE for this work while he was a Ph. D student under the supervision of Prof. Jean-Michel Glachant at both the GRJM Team at the Research Center ADIS -University Paris XI, and at the Energy department at Supélec.

V. Rious and P. Dessante are with Supelec, Gif-sur-Yvette, 91190 France (corresponding author: V. Rious; phone: +33 (0)169 851 531; fax: +33 (0)169 851 539; e-mail: vincent.rious@supelec.fr).

J.-M. Glachant is with University Paris-Sud XI, Fontenay-aux-Roses, 92260 France. significant compared to the transmission lines capacities. The connection of these power plants can thus create congestion.

A solution to this problem could be that the Transmission and System Operator (TSO) anticipates the connection of these new generation plants and the congestions that they may create. By anticipating the connection of generation plants, the TSO can adapt the network planning. To implement this process, the TSO must anticipate the administrative procedures required before the network upgrading. But if the network is not eventually upgraded, this anticipation is costly because of these administrative procedures. The efficiency of anticipating the generation connection and of the required transmission investment thus depends on this cost, on the uncertainty on the effective generation connection and on the required transmission investment.

This paper evaluates the efficiency of the strategy of anticipating the connection of power plants for the TSO in terms of the minimization of the network cost. The question is then to know if it is efficient for such a TSO to plan the development of its network in advance of the request of connection so that there is sufficient planned transmission capacity to accommodate these new generation investments. This problem has been poorly addressed [START_REF] Sauma | Proactive planning and valuation of transmission investments in restructured electricity markets[END_REF].

A model is built in this paper in order to measure the efficiency of anticipating the connection of generation. In this model, the connection of a generator is a probabilistic event and the TSO can choose to anticipate the connections or not, despite this anticipation may be costly if the anticipated event does not eventually occur.

The paper is then organized as follow. In section II, we show that the need to coordinate generation and transmission varies with the considered generation technology. In section III, we present our model to evaluate the efficiency of anticipating the generation connection and the required transmission investment depending on the cost of this anticipation, on the probability of the power plants to connect and on the difference in construction duration between the transmission and generation investments. In section IV, we made a preliminary measure of efficiency of anticipating connection on a realistic example.

II. A NEED TO COORDINATE TRANSMISSION AND GENERATION THAT VARIES WITH THE GENERATION TECHNOLOGY

In a liberalized power system where generation and transmission are generally unbundled, the need to coordinate

Anticipation for Efficient Electricity Transmission Network Investments

Vincent Rious, Philippe Dessante, Jean-Michel Glachant P these activities varies with the generation technology. Indeed, the time needed to build powerlines can be longer than the time needed to build some generation technologies. It takes at least five years to build a powerline and on average seven to ten years in Europe [START_REF] Etso | An Overview of Current Cross-border Congestion Management Methods in Europe[END_REF]. There are two steps to build a powerline. Firstly, the TSO must fulfil the administrative procedures to have the right to build the line. This step to obtain the administrative agreements lasts at least three years. But in practice, it can last five years on average. The second step consists in building the line. This step is quite short, about two years only, and faces few uncertainties. The step to obtain the administrative agreements is then the crucial step for the time between the investment decision and the completion of the project. The uncertainty on building the powerline comes from this period because of the local oppositions to the right of way of the transmission lines, which can result in postponing the line project.

The generation technology induces an important variation of the difference in investment time between transmission and generation. Besides, some generation technologies have an important notional size while they can be quickly built. The connection of the power plants can then create congestion while the TSO has not yet upgraded the network to evacuate this power. This can make the accommodation of these generators more difficult. This difficulty is evaluated in table 1 by the third column that gives the notional size of an installation divided by the time to build it. The investment dynamics of the nuclear and coal technologies are similar to the investment dynamics of network investments. The TSO can then deal with their connection when required. To the contrary, the CCGT and the wind farms can be built and connected faster than the network can be modified to accommodate them. Therefore, these new generation units can create important congestion before the TSO can upgrade the network.

This phenomenon becomes very important because these technologies, CCGT and wind farms, are the fastest to be built and are actually the preferred ones in Europe and in the USA (see [START_REF] Glachant | Generation technology mix in competitive electricity markets[END_REF] for CCGT and [START_REF] Etso | European Wind Integration Study (EWIS). Towards a Successful Integration of Wind Power into European Electricity Grids[END_REF] for wind power).

The time to build CCGT is quite short since it is only about two to three years [START_REF]The cost of generating electricity[END_REF] [6] The notional size of CCGT is 800 MW. It cannot be neglected compared to the transmission capacity of powerlines, between 1000 and 2500 MW for the voltage level where they connect (400 kV or 225 kV).

The massive connection of wind power to the transmission network is also problematic for two reasons. Firstly, compared to the time to upgrade the network, the time to build wind farms is quite short, since it is about two to three years. Secondly, the network must adapt to the massive connection of intermittent power plants. Besides, their massive connection can then require upgrading the transmission network to evacuate the generated power.

Therefore, the problem is the following one: some generation technologies can require important network upgrading whose time to build is quite longer than the time to build these power plants. There may then be congestion between the moment when these generators connect to the network and the moment when the TSO upgrades the facilities.

The TSO can anticipate the connection of these plants and consequently plan the network investment to avoid these congestions. Then it can better deal with the uncertainty coming from the difference in time to build power plants and time to upgrade the network. But this work of anticipation is costly. As a consequence, it is necessary to evaluate the efficiency of anticipating the network investment to accommodate new generators.

III. A MODEL TO MEASURE THE EFFICIENCY OF ANTICIPATING NETWORK INVESTMENTS

In order not to limit and even in order to facilitate the development of the types of generators with the shortest time to build, it can be efficient to anticipate their connections. The network can then have sufficient capacity to accommodate them. The TSO can anticipate the connection of these generators and can so study in advance the opportunity of upgrading the network.

Such anticipation does not compel the TSO to invest if it eventually happens unnecessary. Because, once the TSO has obtained the administrative agreements required before building the power line, the TSO can decide to upgrade the network effectively only after the relevant assumptions of the investment project has come true or extremely certain. To the contrary, a TSO whose objective is to maximise the social welfare can decide to cancel a planned investment if the relevant conditions does not eventually happen. The administrative steps needed before the building of the transmission line have then an appreciable option value if the TSO can implement various planning strategies to invest [START_REF] Boyle | Real options and transmission investment: the New Zealand Grid Investment Test[END_REF].

The TSO can implement two strategies to anticipate transmission reinforcements. 1° The TSO can be proactive and anticipates the change in the generation mix and location. 2° The TSO can be reactive and upgrades the network only once he knows where and when the power plants connect. In the reference [START_REF] Sauma | Proactive planning and valuation of transmission investments in restructured electricity markets[END_REF], Sauma and Oren show that, from the point of view of the minimization of the expected social cost, the proactive TSO is always more efficient than the reactive one in an uncertain environment. But they implicitly assume that anticipation has no cost while it is costly in reality. And it could be quite expensive [START_REF] Christiner | VERBUND-Austrian Power Grid. Austria -Completing the 380kV-Ring. Authorization Procedures and Major Problems[END_REF].

The essential parameters to evaluate the efficiency of the anticipating the generation and transmission investment are then the three following ones: 1° the cost of anticipating investments, 2° the difference between the time to build power plants and the time to upgrade the network, and 3° the probability of connection of generators. Our model will allow measuring the influence of these different elements on the opportunity for the TSO to be proactive. We describe this model below. Next, we will illustrate our results on a representative case of connection.

A. A necessary condition for anticipation to be optimal

We present here a simplified model where the congestion cost is assumed given and sufficient to require a transmission investment. The problem of calculating the congestion cost is dealt with further detail in section IV of this paper in the realistic case of connection of a power plant. In our modelling, we search for the conditions when it is efficient, from the point of view of the minimization of the expected social cost, to anticipate the connection of power plants whose time to build is shorter that the time to upgrade the network.

We consider the two proactive and reactive behaviors of the TSO that we described just above. To anticipate the connection of new power plants, a proactive TSO does in advance the study of the transmission investment project and the administrative procedures that are required to have the agreements to build the powerline.

A reactive TSO does not study the project nor does he make the administrative procedures in advance. He does these steps only once the generators have effectively asked to connect to the network.

We assume that in a step before the application of our modelling, an expert has highlighted the nodes or areas where generators are more likely to connect and the lines that may experience congestion. It is similar to the approach used in the National Electric Transmission Congestion Study of the U.S. Department of Energy [9]. This phase consists in determining where it will be needed to upgrade the network taking into account the primary energy sources and the areas where the generators will be able to locate. The goal of our modelling is then not to find where to upgrade the network. Our modelling finds the lines whose forecasted constraints are such that it is efficient to anticipate its upgrading and especially to anticipate the long administrative procedures. Anticipating can result in accommodating the considered generation technologies more efficiently and more quickly.

B. Definitions and assumptions

For each year y, we define two types of congestion cost that we note CU y and CW y respectively with and without network reinforcement. Then, whatever the year y, the congestion cost without reinforcement is greater than the congestion cost with reinforcement, other saying CW y ≥ CU y . For a year y, the congestion cost CW y or CU y depends only on reinforcing the network, and not on the moment when the network is upgraded. We define two functions of discounted and cumulative congestion cost over several years d with a discount rate a. The first function, CW(d) is the total congestion cost discounted during d years before upgrading the network. The second function, CU(d) is the total congestion cost discounted during ten years after the network being upgraded the year d. The avoided costs thanks to the reinforcement of the network are evaluated only over ten years for two reasons. Firstly it is difficult to know accurately the state of a power system beyond ten years. Secondly discounting considerably decreases the costs beyond this temporal horizon. CW(d) and CU(d) can be expressed as functions of CW y and CU y as follow: We assume that the network must be reinforced as soon as a power plant connects. That is to say that the cost saved by the network upgrading as soon as the generator connects is greater than the related transmission investment cost. Fig. 2 The instant of reference for discounting the cost over time is chosen such that the most conservative condition about the efficiency of a proactive TSO is obtained. This instant is then the moment when the generation investment begins to produce power. This convention degrades the advantage of discounting for the strategy of anticipating compared to the strategy of not anticipating. Indeed, if the beginning of the administrative procedures has been chosen as the instant of reference for discounting, the discounting of cost would have mechanically decreased the cost of network investment. By taking the beginning of production of the power plant as a time reference for discounting, this effect is avoided.

C. Expected cost of the network for a reactive TSO

A reactive TSO does not anticipate the connection of generators. It studies the network upgrading only once the generator has invested. The network investment to evacuate this power is ready to serve only d years after the connection of the generation unit, where d is the difference between the time to build a power plant and the time to upgrade the network. Fig. 3 exemplifies this sequence of the generation and transmission investments.

The generator can connect to the network with a probability p (and so does not connect with a probability of 1-p). This uncertainty is not intrinsically quantifiable. However it is possible to attribute it a subjective value to evaluate the robustness of the study framework. This approach stimulates a dialog with the other stakeholders of the power system and creates a shared anticipation of the evolution of the system [10]. Besides, the sooner the residents are involved in the transmission investment process, the easier the powerline would be built [START_REF] Hughes | Environmental Impact Assessment and Stakeholder Involvement[END_REF] [START_REF] Loring | Wind energy planning in England, Wales and Denmark: factors influencing project success[END_REF].

If the generator connects, the system must successively support:

• CW(d), the total congestion cost discounted for d years, while the TSO is upgrading the network • CU(d), the residual total congestion cost discounted for ten years after upgrading the network, that is to say d years after the connection of the generator, • I/(1+a) d , the discounted cost of this upgrading d years after the beginning of our study (corresponding to the moment when the generator is ready to generate power) . Fig. 3. Sequence of the generation and transmission investment with a reactive TSO. The timeframe of generation is in grey while the timeframe of transmission is in black. While the power plant has already connected and the network has no yet been upgraded, there is congestion for d years.

If the generator does not connect, the network investment cost and the congestion cost to the TSO is null. Table 2 summarises these two cases.

CS(d) + CR(d) + I/(1+a) d 0 + 0 ( ) [ ] ( ) ( ) ( )       + + + = d TSO active a I d CR d CS p p C E 1 re

D. Expected cost of the network for a proactive TSO

A proactive TSO anticipates the connection of the generator. He studies the network upgrading and asks for the administrative agreements to build the powerline (without building it) before the connection of the power station. The network is upgraded only once the power plant is being effectively connected. Fig. 4 illustrates the sequence of the generation and transmission investments.

The generator can connect with a probability p (and so does not connect with a probability 1-p). In case the generator connects to the network, the system must successively support:

• CU(0), the residual total congestion cost discounted for ten years after the power plant connecting and the network upgrading • and I, the upgrading cost. In case of the generator not connecting, the congestion cost is null and the cost to anticipate linked to the non realization of the anticipated event is a share α of the total investment transmission cost. Indeed, the transmission investment is not done but the preliminary steps are however realized. The cost α.I includes not only the cost to anticipate to the TSO but also the cost born by the local authorities involved in the process of administrative agreements. Moreover, the cost α.I takes into account the a posteriori discounting of the cost to anticipate. We assume the cost to anticipate α.I is proportional to the investment cost because a power line faces all the more oppositions that it is longer and goes through a wider area.

Table 3 summarises these cost.

E. Condition for a proactive TSO to be efficient

We are searching for the necessary and sufficient condition for the proactive TSO to be more efficient than the reactive one from the point of view of the minimization of the expected social cost.

This condition links the cost α to anticipate, the probability p to connect a power plant and the difference d in time to build a power plant and a power line such that the equation 3 is respected.

( ) [ ] ( ) [ ] p C E p C E O reactiveTS SO proactiveT ≤ (3)
The equation 4 equivalently expresses this relation.

( ) ( ) ( ) ( ) ( ) [ ] I CW d CU d CW a p d 0 1 1 - + + - + + ≤ - α α (4)
To interpret this formula, we consider the case of equality of the equation 4 and then define the limit of probability or "probability limit" p lim to connect a power plant. If the probability to connect a power plant is greater than p lim , then the proactive TSO is more efficient than the reactive one. To the contrary, if the probability of connection p is less than p lim , then the reactive TSO is more efficient than the proactive TSO. The equivalence between the equations 3 and 4 then shows that the strategy of anticipation is all the more efficient that the probability p lim is small. The interpretation of the equation 4 also consists in evaluating how the probability limit p lim varies with the cost α for anticipating and the difference d in time to build a generation investment and a transmission one. For a given cost α for anticipating, p lim decreases when the difference d between the time to build a power plant and a power line increases. This is because the congestion cost generally increases more quickly than the gain from postponing the network investment and its discounting.

For a given difference d, p lim increases when the cost α to anticipate increases.

IV. ILLUSTRATION OF PROACTIVE AND REACTIVE TSOS

Now we illustrate the equation 4 on the concrete case of connection of a power plant. We can determine the combinations of parameters where the proactive TSO is more efficient than the reactive one in this case.

We apply the criterion of the equation 4 on the simple case of the connection of a power plant on a two node network. The figure 5 is realistic because the connection of a power plant (CCGT or windfarm) raises problems mainly because these power plants are far from the load centres. A new generator wish to connect a 800 MW power plant to the west. To evacuate the power of this new power plant, it is necessary to add a 1000 MW network upgrading that costs 100 million euros. We assume that the situation of Fig. 5 is representative of the 8760 hours of the year. The investments are dashed on this figure .  First of all, we draw p lim the "probability limit" to connect a power plant. When the effective probability is above the probability, the proactive TSO is more efficient for a given cost α to anticipate (equal to 10% of the considered network investment). The "probability limit" can be defined as a function of the difference d between the time of building a power plant and the time of building a powerline. Fig. 6 illustrates this function. Fig. 6. "Probability limit" of connection beyond which the TSO must be proactive depending on the difference of temporal dynamics d between generation and transmission investment Above the curve associating the probability limit with the difference in dynamics of investments, the TSO being proactive is the optimal behavior. Under this curve, the TSO being reactive is the optimal behavior. On Fig. 6, we notice that for the considered case, the probability limit decreases as the difference in dynamics increases. We find again that the TSO has little interest in anticipating the connection if the temporal rhythms of these two complementary investments are near each other. That is to say that the time of building a network investment is short or if the time of building a generation investment is long. For the connection of a CCGT or a windfarm, this difference in time is at best of three to four years (see section II). For such a difference, the probability limit of connection is around 15 to 20%. This weak value is already significant to justify the anticipation of the network reinforcement.

V. CONCLUSION

This paper presents a model to evaluate the efficiency of the strategy of anticipating the connection of power plants to the network for the TSO in terms of the minimization of the network cost. This model has permitted to see on a simple but realistic example that it can be quite efficient for a TSO to anticipate the connection of power plants. He can then plan the reinforcement of the network in advance and reduce congestion on the network. Taking into account the interest of investors for generation technology with short time to build, the proactive behavior of the TSO can facilitate the connection of these types of power plant and increase the market entries.

However, the study proposed in here is only a preliminary one. We assume that the cost of anticipating is know whereas the planner does not know in advance the cost of anticipating the reinforcement, that is to say the cost of the administrative agreements needed to build the reinforcement. It is indeed difficult to rely on historical data for the cost of anticipation, because the powerlines face more and local oppositions. A sensitivity analysis of the probability limit to the cost of anticipating of the investment should then be one of the future researches of this work. Besides, we could duplicate this study for a windfarm with a given generation duration curve. Eventually, regulatory actions should be studied to incentivise the TSO to anticipate investment if it is efficient. This is still an opened question that is still to be answered.

Fig. 1

 1 Fig. 1 exemplifies the two sums CW(d) and CU(d). For illustrative reasons, we assume that the terms CW y / (1 + a) y and CU y / (1 + a) y increase linearly with time.CW(d) corresponds to the grey trapezoid and CU(d) corresponds to the black trapezoid.

Fig. 1 .

 1 Fig. 1. Definition of CW(d) and CU(d).

Fig. 2 .

 2 Fig. 2. Cost saved by upgrading the network as a function of CW(10) and CU(0). The greyed area stands for this saved cost.

Fig. 4

 4 Fig. 4 Sequence of the generation and transmission investment with a proactive TSO. The use of the new transmission line and of the new power plant begins at the same time because the TSO has anticipated the network upgrading.

Fig. 5

 5 Fig. 5 System to test the strategy to anticipate the connection of a power plant. The load and most of generation are to the east. These power stations to the east are quite expensive, 40 €/MWh for the first 3000 MW and

Generation technology Time needed to build (year) Notional size (MW) Size divided by time to build (MW/year)

			TABLE I
	TIME NEEDED TO BUILD DIFFERENT GENERATION TECHNOLOGIES
	[6] [7](RAE2004, DGEMP2003)
	Combustion turbine	1	40	40
	Coal	4-5	150 to 1600*	30 to 400*
	CCG	2	800	400
	Nuclear	5-7	1600	200 to 300
	Hydro	-	-	-
	Wind onshore	2	25	12.5
	offshore	2	100	50
	*Depending on technologies

TABLE II THE COSTS FACED BY A REACTIVE TSO Generator TSO invests Probability p does not invest Probability 1-p Expected social cost

 II

	waits for the
	connection of
	the	power
	plant before
	studying and
	upgrading the
	network

TABLE III THE COSTS FACED BY A PROACTIVE TSO Generator TSO Invests Probability p Does not invest Probability 1-p Expected social cost

 III

	Studies beforehand the installation of the power plant and invests at the	I + CR(0)	α.I + 0	E =	[ C [ proactive CR TSO I p +	( ) ] ( ) p ] ( ) p α -+ 1 0
	same time as the
	generator


Barbara Hrdlickova

Chris J Mulder

MD Georgia Malamut
email: georgia.malamut@aphp.fr

Bertrand Meresse

Mathieu Platteel

Yoichiro Kamatani

Isis Ricano-Ponce

Roy L J Van Wanrooij

Maria M Zorro

Marc Jan Bonder

MD Christophe Cellier
email: christophe.cellier@aphp.fr

A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease

Keywords: Refractory celiac disease, phenotype of intraepithelial lymphocytes, cytokine

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

Key Points

• Refractory celiac disease (RCD) refers to two distinct entities according to the normal (RCDI) or abnormal (RCDII) phenotype of intestinal intraepithelial lymphocytes (IEL).

• Diagnosis requires specialized small bowel investigations (enteroscopy, small bowel imaging) and techniques (immunohistochemistry, molecular analysis, flow cytometry)

• Prognosis of RCDII is worse than RCDI one because of more severe malnutrition and an elevated risk of overt lymphoma.

• Therapeutic arsenal is currently mainly based on open capsule budesonide waiting for efficient targeted therapy.

INTRODUCTION

Treatment of celiac disease (CD) relies on a life-long strict gluten-free diet that allows clinical and histological recovery after one year of gluten free diet and prevents long-term complications such as osteopenia [START_REF] Thomason | Fracture experience of patients with coeliac disease: a population based survey[END_REF], onset of other autoimmune disease [START_REF] Cosnes | Incidence of Autoimmune Diseases in Celiac Disease: Protective Effect of the Gluten-Free Diet[END_REF] and malignancies [START_REF] Holmes | Malignancy in coeliac disease--effect of a gluten free diet[END_REF]. Yet, systematic follow-up of biopsies has revealed that histological recovery does not occur in all patients. Notably one recent population-based study led in 7648 celiac patients in Sweden showed persistent villous atrophy in 43% cases with an increased risk in older patients (up to 56% versus 17% in children diagnosed after 2000) [START_REF] Lebwohl | Predictors of persistent villous atrophy in coeliac disease: a population-based study[END_REF].

The similar rates of persistent villous atrophy among celiac patients biopsied 1-2 years and 2-5 years after diagnosis further argued against mucosal healing after 2 years [START_REF] Lebwohl | Predictors of persistent villous atrophy in coeliac disease: a population-based study[END_REF]. Importantly, lack of mucosal healing has been associated with a risk of complications; it is notably a risk factor for fractures [START_REF] Lebwohl | Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study[END_REF] and for the development of lymphomas [START_REF] Lebwohl | Persistent mucosal damage and risk of fracture in celiac disease[END_REF]. Most cases of resistance to gluten free diet (GFD) and persistence of villous atrophy are due to bad observance [START_REF] Vahedi | Reliability of antitransglutaminase antibodies as predictors of gluten-free diet compliance in adult celiac disease[END_REF].

Nevertheless, a small subgroup of CD patients may be primarily or secondary resistant to a GFD due to an authentic RCD with persistent symptoms of malabsorption and intestinal villous atrophy despite a strict GFD. Diagnosis of this condition is made after exclusion of other intestinal diseases with villous atrophy such as autoimmune enteropathy, tropical sprue, common variable immunodefiency or drug induced enteropathy [START_REF] Akram | Adult autoimmune enteropathy: Mayo Clinic Rochester experience[END_REF][START_REF] Khokhar | Tropical sprue: revisited[END_REF][START_REF] Malamut | The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease[END_REF][START_REF] Scialom | Gastrointestinal Disorder Associated with Olmesartan Mimics Autoimmune Enteropathy[END_REF].

Frequency of RCD remains unknown. A North American referral centre suggests a cumulative incidence of 1.5% for both RCDI and RCDII among CD patients diagnosed in this centre [START_REF] Roshan | The incidence and clinical spectrum of refractory celiac disease in a north american referral center[END_REF]. In the Derby cohort, J. West and G. Holmes report around 0.7% of RCD patients with ulcerative jejunitis in series of 713 celiac patients [START_REF] West | Celiac disease and its complications: a time traveller's perspective[END_REF]. Respective proportion of both types of RCD is also undefined with apparently a higher frequency of RCDI than RCDII in US [START_REF] Rubio-Tapia | Clinical staging and survival in refractory celiac disease: a single center experience[END_REF] in contrast with European studies [START_REF] Al-Toma | Survival in Refractory Coeliac Disease and Enteropathy associated T cell Lymphoma: Retrospective evaluation of single centre experience[END_REF][START_REF] Daum | Refractory coeliac disease[END_REF][START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF][START_REF] Malamut | Is refractory celiac disease more severe in old Europe?[END_REF].

DIAGNOSIS

Diagnosis of RCD relies on persisting malabsorption and villous atrophy after one to two years of strict GFD. Compliance of gluten free diet can be ascertained by a dietician and dosage of serum celiac antibodies IgA and IgG anti-transglutaminase and IgA/IgG antideamidated gliadin peptides, positivity of the latest having a good correlation with gluten exposure [START_REF] De Chaisemartin | Application of Deamidated Gliadin Antibodies in the Follow-Up of Treated Celiac Disease[END_REF]. Detection of gluten immunogenic peptides (GIP) in stool and urine enlarges the possibilities of control GFD [START_REF] Comino | Fecal Gluten Peptides Reveal Limitations of Serological Tests and Food Questionnaires for Monitoring Gluten-Free Diet in Celiac Disease Patients[END_REF][START_REF] Moreno | Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing[END_REF].

Upper gastrointestinal endoscopy with duodenal biopsies is necessary to confirm RCD and define its type (Figure 1). Double balloon enteroscopy may be usefull, guided by capsule endoscopy in suspicion of RCDII for a better assessment of ulcers particularly for evidence of ulcerative jejunitis found in roughly 70% of patients [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF][START_REF] Barret | Diagnostic yield of capsule endoscopy in refractory celiac disease[END_REF]. Thus, the risk of retention of capsule endoscopy, imposes preliminary radiological imaging of the small bowel in order to rule out strictures. Definitive diagnosis relies on histology. In RCDI, histology is similar to that found in active CD with villous atrophy and increased normal IEL. Molecular analysis showed polyclonal repertoire. Not other diagnostic criteria have been yet defined for RCDI.

In contrast, the hallmark abnormal population, detected by 3 combined techniques, makes the diagnosis of RCDII more specific: over 25% of the CD103+ or CD45+ IEL lacking surface CD3-T cell receptor complexes on flow cytometry (Figure 2) or more than 50% IEL expressing intracellular CD3 but no CD8 in formalin fixed sections and/or the presence of a detectable clonal rearrangement of the gamma chain of the TCR in duodenal biopsies (Figure 2) [START_REF] Cellier | Abnormal intestinal intraepithelial lymphocytes in refractory sprue[END_REF][START_REF] Cellier | Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group[END_REF]. Similar features allow detecting lymphocytic gastritis and colitis containing the same abnormal population in around 50% and 30% of RCDII patients, respectively [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF].

NKP46 staining represents a promising diagnostic tool for distinguish clonal RCDII from RCDI or celiac disease [START_REF] Cheminant | NKP46 is a useful diagnostic biomarker in gastrointestinal T-cell lymphoproliferative diseases. A CELAC network study[END_REF].

FACs analysis of freshly isolated IEL is particularly useful to distinguish RCDII from other causes of severe enteropathy with villous atrophy and clonal TCRgamma rearrangement such as Granular lymphocytic Leukemia infiltrating intestine of CD patients [START_REF] Malamut | Large Granular Lymphocytic Leukemia complicating Celiac disease: a rare cause of refractory celiac disease[END_REF] or intestinal small CD4 T cell lymphoma [START_REF] Malamut | Small intestinal CD4+ T-cell lymphoma is a heterogenous entity with common pathology features[END_REF]. Analysis of the delta chain rearrangement may be useful in RCDII patients presenting oligoclonal rearrangement of the gamma chain [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. Interest of detecting of the beta chain of the TCR has also been suggested [START_REF] Perfetti | TCRbeta Clonality Improves Diagnostic Yield of TCRgamma Clonality in Refractory Celiac Disease[END_REF][START_REF] Ritter | T-cell repertoires in refractory coeliac disease[END_REF]. Finally, specificity of the PCR product needs to be attested by formation of homoduplexes [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF] because of prominent clonal peaks possibly found in RCDI or CD patients [START_REF] Hussein | Clonal T cell receptor gene rearrangements in coeliac disease: implications for diagnosing refractory coeliac disease[END_REF].

CLINICAL FEATURES AND OUTCOME

Resistance to a GFD is primary in roughly one third and half patients with RCDI and RCDII, respectively [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. Symptoms are notably less severe in RCDI than RCDII frequently associated to protein losing enteropathy [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. RCDII is associated with poor prognosis with 5-year survival rates of 44% to 58% [START_REF] Rubio-Tapia | Clinical staging and survival in refractory celiac disease: a single center experience[END_REF][START_REF] Al-Toma | Survival in Refractory Coeliac Disease and Enteropathy associated T cell Lymphoma: Retrospective evaluation of single centre experience[END_REF][START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. The more severe malnutrition combined with the higher risk of developing overt lymphoma explains the higher mortality in RCDII than in RCDI [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. Confirming this hypothesis decreased albumin and abnormal IEL phenotype are significantly associated with 5 years mortality in a multivariate model to predict survival in refractory celiac disease [START_REF] Hussein | Clonal T cell receptor gene rearrangements in coeliac disease: implications for diagnosing refractory coeliac disease[END_REF]. Nevertheless, the mortality rate in RCDI appears higher than in uncomplicated CD [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. One explanation is the lack of curative treatment for RCD. Immunosuppressive drugs have only a poor therapeutic effect and may predispose to overt lymphoma [START_REF] Goerres | Azathioprine and prednisone combination therapy in refractory coeliac disease[END_REF]. The second reason is the natural increased risk of developing overt lymphoma (Enteropathy Associated-T cell Lymphoma (EATL)). Indeed, 33% to 52% of RCDII patients develop EATL within the five years after diagnosis [START_REF] Rubio-Tapia | Clinical staging and survival in refractory celiac disease: a single center experience[END_REF][START_REF] Al-Toma | Survival in Refractory Coeliac Disease and Enteropathy associated T cell Lymphoma: Retrospective evaluation of single centre experience[END_REF][START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. Onset of EATL in RCDI is not null even if much lower than in RCDII, with a five-year rate of 14% in the more pessimistic studies [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. In RCDII abnormal IEL may be found in mesenteric lymph nodes, blood, bone marrow, and in different epitheliums such as lung and skin [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. Extra-intestinal dissemination of RCDII IEL explains that EATL do not develop exclusively in the intestine. EATL may notably arise from RCDII cutaneous lesions. Their expression of CD103 and their identical TCR clonality [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF] ascertain their origin from RCDII IEL. RCDII patients require regular clinical follow-up combined with enteroscopy, computed tomography scan (CT-scan) or MRI small bowel follow-through and positron emission tomography (Pet-scan) [START_REF] Hoffmann | 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) for assessment of enteropathy-type T cell lymphoma[END_REF]. Pet-san can further guide realization of radiological guided biopsy or explorative laparoscopy It must however be stressed that EATL can arise in CD patients who do not display any evidence of RCDII. Histological diagnosis is easier than in RCDII with infiltration by medium to large lymphoid expressing CD30 in more than 80% of cases [START_REF] Malamut | Enteropathy associated T cell lymphoma in celiac disease: A large retrospective study[END_REF]. The prognosis of EATL is poor with an overall survival currently estimated at 20% to 25%, 5 years after the diagnosis with a better diagnosis in EATL complicating CD compared to EATL complicating RCDII [START_REF] Malamut | Enteropathy associated T cell lymphoma in celiac disease: A large retrospective study[END_REF][START_REF] Gale | Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment of 31 patients in a single center[END_REF].

PATHOGENESIS

It remains unknown whether RCD patients have a particular genetic background differentiating them from patients with uncomplicated CD. It has been reported that severity of celiac disease was correlated with the number of HLA-DQ2 copies: homozygosity for HLA-DQ2 was observed in 25.5% of RCD I, 44.1% of RCD II, and 53.3% of EATL patients vs 20.7% of uncomplicated CD patients and 2.1% of controls [START_REF] Al-Toma | Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathyassociated T-cell lymphoma[END_REF]. In a recent European study most patients with RCDII were homozygous HLA-DQ2 (>64.4%) [START_REF] Verkarre | Recurrent partial trisomy 1q22-q44 in clonal intraepithelial lymphocytes in refractory celiac sprue[END_REF]. Moreover this study identified the locus 7p14.3 as favoring progression to RCDII [START_REF] Verkarre | Recurrent partial trisomy 1q22-q44 in clonal intraepithelial lymphocytes in refractory celiac sprue[END_REF]. Besides inherited genetic factors, some acquired somatic mutations have been identified. Indeed a recurrent partial trisomy 1q22-q44 has been found in majority of RCDII patients [START_REF] Verkarre | Recurrent partial trisomy 1q22-q44 in clonal intraepithelial lymphocytes in refractory celiac sprue[END_REF]. More recently the JAK1 and STAT3 mutations were identified in abnormal IEL in RCDII patients [START_REF] Ettersperger | Interleukin-15-Dependent T-Celllike Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease[END_REF].

Onset of RCD may be favored by environmental factors such as exposure to gluten. Risk of lymphomatous complications was reported 4 times higher in patients without adherence to a gluten free diet than compliant patients [START_REF] Holmes | Malignancy in coeliac disease--effect of a gluten free diet[END_REF]. The scientific rationale may rely on more intense production of IL-15 under gluten exposure [START_REF] Mention | Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease[END_REF].

Infections and particularly viral infections may constitute another environmental factor favouring emergence of RCD. We observed B or C hepatitis at onset of refractoriness in 20% and 10% of RCDI and RCDII patients, respectively [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. More than a specific virus, it is rather suspected that components of the antiviral responses and notably Type I interferons might promote the onset of chronic inflammatory disorders (reviewed in [START_REF] Foxman | Genome-virome interactions: examining the role of common viral infections in complex disease[END_REF]). Type I interferon may notably stimulate the survival and proliferation of CD8+ T cells and NK cells, either directly or via the induction of IL-15 [START_REF] Foxman | Genome-virome interactions: examining the role of common viral infections in complex disease[END_REF]. We can hypothesis that such mechanism may occur in RCDI helping the immunological reaction initiated by gluten to evolve toward autoimmunity. Accordingly, symptoms improve under immunosuppressive treatments [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF].

However mechanisms of RCDI are largely unknown and remain to be substantiated. More progress has been performed recently in the understanding of the pathogenesis of RCDII.

Contrary to EATL which expressed Ki67, RCDII is characterized by massive accumulation of abnormal IEL without in situ detectable proliferation but with apoptosis defect [START_REF] Mention | Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease[END_REF]. In active CD and RCDII, IL-15 produced in excess exerts potent anti-apoptotic effects that prevent the elimination of activated IELs and promote their massive accumulation by activating a survival signal [START_REF] Mention | Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease[END_REF][START_REF] Foxman | Genome-virome interactions: examining the role of common viral infections in complex disease[END_REF]. Indeed clonal RCDII IEL acquired somatic mutations (JAKI, STAT3) which selectively increase their responsiveness to IL-15. Human anti-IL-15 antibodies inhibit ex vivo the IL-15 driven signalling pathway in intestinal organotypic cultures of RCDII patients. In vivo, treatment, by this antibody of mice overexpressing human IL-15 in small bowel wiped out the IEL hyperplasia observed in these mice [START_REF] Malamut | IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis[END_REF].

TREATMENTS

Steroids improved clinical symptoms in most patients with either type of RCD with various histological response from 30-40% of cases to nearly 90% in a recent study using open capsule budesonide [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF][START_REF] Mukewar | Open-Capsule Budesonide for Refractory Celiac Disease[END_REF]. Because of steroid dependence, immunosuppressors such as azathioprine or anti-TNF-are used and produce transient clinical response but rare mucosal improvement [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. In RCDII immunosuppressive drugs have no impact on the abnormal clonal IEL population and could enhance the risk of overt lymphoma as observed with azathioprine and anti-CD52 by depletive effect [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. In RCDI no scientific rational has been yet establish to treat specifically RCDI patients with targeted therapy. The non proliferative RCDII cells are thus difficult to eradicate by regular chemotherapy and may represent a reservoir of cells susceptible to more aggressive transformation. Purine analogues such pentostatine or cladribine (2 CDA) showed moderate clinical, histological and haematological efficacies [START_REF] Dray | A severe but reversible refractory sprue[END_REF][START_REF] Al-Toma | Cladribine therapy in refractory celiac disease with aberrant T cells[END_REF]. In our experience, 2CDA can induce clinical and histological response in RCDII patients [START_REF] Malamut | Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II[END_REF]. However, explosive onset of overt lymphoma was observed in the 2 treated patients within 3-8 weeks after treatment, precluding further use of these drugs. Another strategy is the use of the autologous haematopoietic stem cells transplantation which induced clinical and histological response but no sustained reduction of abnormal IEL in the 13 treated patients [START_REF] Al-Toma | Autologous hematopoietic stem cell transplantation in refractory celiac disease with aberrant T-cells[END_REF][START_REF] Tack | Auto-SCT in refractory celiac disease type II patients unresponsive to cladribine therapy[END_REF]. The use of chemotherapy before autologous haematopoietic stem cells transplantation may probably increase haematological response.

Targeted strategy appears necessary to complete the therapeutic armoury to treat RCDII.

Blocking IL-15 signaling appears the treatment of choice in RCDII [START_REF] Malamut | IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis[END_REF]. The preliminary results of phase II clinical trial using the the humanized anti-IL-15 antibody are encouraging [START_REF] Cellier | doubleblind, placebo-controlled study evaluating AMG714 in adult patients with RCDII/pre-EATL[END_REF]. Treatment of RCDII will probably combine, in the next future, conventional chemotherapy agents and targeted therapy blocking IL-15 signaling (reviewed in [START_REF] Celiac | [END_REF]).

CONCLUSION

In conclusion, RCD refers to two distinct entities, RCDI the benign form and the malignant form RCDII characterized by clonal expansion of small aberrant IEL. Small bowel investigations (enteroscopy, videocapsule endoscopy) and specialized techniques of IEL analyses (immunohistochemistry, molecular biology, flow cytometry) are necessary for diagnosis of both forms of RCD. Prognosis of RCDII is severe due to malnutrition and high risk of overt lymphoma. Recent advances in dissecting the lymphomagenesis associated to CD intend to hope next efficient treatments.

ACKNOWLEDGMENTS

We thank Nadine Cerf-Bensussan (Inserm UMR1163, Institut Imagine) for FACs analysis of normal and abnormal IEL, Nicole Brousse (Anatomopathology Necker, Université Paris Descartes) for immunohistochemistry and Elisabeth Macintyre (Biological Hematology, Hôpital Necker Enfants Malades, Paris) for providing example of Multiplex PCR.

Legends


X Dubernard
email: xdubernard@chu-reims.fr

J-C Kleiber

M Makeieff

A Bazin

A Chays

Drilling and control of the internal auditory canal by fixed endoscope

Keywords: schwannoma, fixed endoscopy, internal auditory canal, hearing preservation

Preservation of vestibular structures, particularly the posterior semicircular canal, is essential to ensure hearing preservation in addition to complete tumour resection during retrosigmoid surgical resection of a vestibular schwannoma. Drilling of the internal auditory canal (IAC) is a delicate step, during which these structures can be accidentally perforated. The orientation of the IAC results in the formation of poorly visible zones that can predispose to perforation of these structures when drilling is performed with a microscope. Hand-held endoscopy exposes all of the operative field, but immobilizes one of the surgeon's hands, making this surgery even more delicate. Fixed endoscopy is a solution that gives the surgeon greater freedom of movement, while ensuring precise control of the surgical procedure. It allows identification and avoidance of vestibular structures, while allowing resection as close as possible to the tumour. The schwannoma can be entirely cleaved when the fundus of the IAC is correctly controlled, while sparing the facial and cochlear nerves.

INTRODUCTION

The therapeutic objective of vestibular schwannoma surgery is to ensure complete resection of the tumour, from the fundus of the internal auditory canal to the cerebellopontine angle. Improvement of surgical techniques with the advent of microsurgery over the last fifty years has improved the postoperative outcome of these patients. Limitation of functional sequelae, particularly preservation of facial nerve function, is now a primary objective for all surgical teams. Preservation of hearing function is also a newly defined objective in some patients and requires preservation of the cochlear nerve during dissection and preservation of the vestibule during drilling of the internal auditory canal (IAC). The use of a fixed endoscope appears to constitute a major technical improvement in order to preserve these structures and improve dissection of the tumour in the canal, while freeing the surgeon's two hands.

OPERATIVE TECHNIQUE

The technique described below concerns patients with vestibular schwannoma with no extension to the cochlear fossa, with preserved hearing and in whom preoperative axial CT scan centered on the lateral semicircular canal shows the presence of a triangle excluding the patient's vestibule. The limits of this triangle are the posterior surface of the temporal bone and the IAC, the origin of the perpendicular line.

Surgical management of vestibular schwannoma can only be considered in an otoneurosurgical setting by a team experienced in cerebellopontine angle surgery, assisted by specially trained anaesthetists to ensure optimal surgical safety based on modulation of intracranial pressure by titration of anaesthetic drugs, while limiting venous pressure and venous return. Control of these parameters facilitates retrosigmoid opening of the cerebellopontine angle, ensuring wide access to this space after aspiration of CSF from the cerebellopontine cisternae. An endoscope can then be introduced to explore this space right from the beginning of surgery in order to identify the position of the various nerves in relation to the tumour, or after having performed debulking of the portion of the tumour protruding into the angle. Two types of endoscope can be used: a STORZ 30° endoscope (diameter: 4 millimetres, length: 18 centimetres) and a STORZ Endocameleon ® endoscope (diameter: 4 millimetres, length: 18 centimetres), allowing variable angulation during surgery without moving the endoscope. The endoscope, protected by a sterile drape, is fixed to an HD camera head and a cold light source, connected to a video tower placed in front of the surgeon and the assistant. No sheath is attached to the endoscope in order to allow the largest possible surgical space to facilitate the procedure. Absence of a sheath avoids aspiration of nerves or brain tissue during introduction of the endoscope, but does not prevent overheating of cerebellar tissue and the self-irrigating system does not provide any advantages, as irrigation is not directed towards the zone of interest. The force of the irrigation stream can also damage nerves around the operative site. The endoscope fixation system consists of a STORZ articulated arm composed of two 16 cm articulated elements and a 30 cm initial segment, 16 mm in diameter. Installation of this system requires the addition of a cramp on the operating table before sterile draping. The sterile arm is installed at the last moment by attaching the shaft through the cramp underneath the drapes. The camera head attached to the endoscope is held by a specific toothed clamp, and the endoscope is then placed directly in the cerebellopontine angle (Figure 1). Once the endoscope has been correctly positioned, it is firmly fixed in the position desired by the surgeon by means of a screw. The microscope, not required during this phase of the operation, remains sterile and at hand if required, for example to control bleeding. Endoscopic drilling of the IAC is performed after placing cottonoids designed to prevent dissemination of bone powder in the angle. The Neuropatch ® used to protect the cerebellum in the retrosigmoid approach is left in place underneath the endoscope. The surgeon's hands are placed on either side of the endoscope, one hand holding the suction tube and the other holding the motor connected to the drill. The assistant places the irrigation syringe on top of the endoscope by guiding it towards the drilling zone, while cooling the endoscope and moistening adjacent structures, which considerably decreases the risk of thermal burns. Angulation of the endoscope provides complete exposure without no blind drilling zones in contrast with the operating microscope. The IAC is opened progressively by creating a halfarch using a 6 mm faceted drill and is limited superiorly by the superior petrosal sinus and inferiorly by the superior bulb of the jugular vein, as exposure of these structures is rarely necessary. Drilling is continued with a 3 mm diamond drill, avoiding injury to the dura mater of the IAC enveloping the intrameatal portion of the schwannoma (Figures 2 and3). The fundus of the IAC is exposed, as confirmed by palpation of the falciform crest by the operator. Tumour resection is performed after opening the dura mater anteroposteriorly, by reclining the mass towards the cerebellopontine angle, while controlling the position of the facial nerve and cochlear nerve. All of the lesion is removed under endoscopic control as close as possible to nerve structures [START_REF] Miller | An anatomic and radiologic evaluation of access to the lateral internal auditory canal via the retrosigmoid approach and description of an internal labyrinthectomy[END_REF]. Preservation of vestibular structures, particularly the posterior semicircular canal (PSCC), is mandatory when hearing preservation is considered. There is no reliable anatomical landmark to identify the PSCC, as the surrounding bone is white, compact with no air cells. The endoscope can identify the position of the PSCC by revealing a bluish line, indicating the presence of labyrinthine fluid. The endoscope is used to perform skeletonization of the canal by precise drilling, while preserving the PSCC without fistula by adapting the position or the angle of the endoscope, if necessary. The semicircular canal is not systematically identified if it is not discovered during the procedure. After completion of tumour resection, the microscope is used to check haemostasis and fill the IAC drilling zone with pieces of fascia to avoid CSF leak due to possible perforation of mastoid air cells. A hand-held endoscope may be useful to detect and fill any CSF leaks. Fixation of the endoscope avoids repeated changes of the endoscope and surgical instruments in the angle, which decreases the risk of cerebellar, vascular or nerve injuries. Direct control of drilling spares the vestibule and allows the possibility of hearing preservation.

DISCUSSION

The primary objective of surgical management of vestibular schwannoma is to ensure complete resection of the tumour. Regardless of the surgical approach used, particular attention must be paid to exposure and inspection of the fundus of the IAC, the main site of residual tumour.

When a retrosigmoid approach is used, exposure of the fundus of the IAC is never a problem unless the anatomical structures of the inner ear (vestibule, PSCC) need to be preserved. Drilling is performed with an operating microscope, allowing enlargement of the IAC, as required, as far as the fundus of the canal, the only limits being the large veins (superior petrosal sinus and superior bulb of the jugular vein). Resection is then performed under visual control in an anteroposterior direction as far as the porus.

When the objective of treatment also includes hearing preservation, the anatomical structures of the inner ear must be preserved. The angulation of the IAC requires large and deep drilling with the operating microscope to access the fundus. "Blind zones" during drilling make it difficult to ensure control of the PSCC, the main structure at risk during this phase of the operation.

To limit this risk, some authors measure the distances between anatomical landmarks on the preoperative axial CT scan [START_REF] Savardekar | Preservation of labyrinthine structures while drilling the posterior wall of the internal auditory canal in surgery of vestibular schwannomas via the retrosigmoid suboccipital approach[END_REF][START_REF] Scerrati | Exposing the fundus of the internal acoustic meatus without entering the labyrinth using a retrosigmoid approach. Is it possible?[END_REF]. Patients are then classified according to the risk of perforation of the inner ear. Some teams also use sterile phantoms or templates applied to the temporal bone during surgery, especially to limit the maximum depth of drilling in order to predict the position of and preserve the PSCC. These techniques appear somewhat complicated and of limited practical value, as the patient's operative position does not correspond to that during acquisition of the CT scan. These CT measurements can be falsely reassuring, as the risk of perforation of the inner ear varies considerably according to the level at which these measurements were performed. CT also only provides a two-dimensional volume, which differs from 3D surgical anatomy.

Other teams use a intraoperative neuronavigation system integrated directly in the drill or a Digipointeur ® neuronavigator [START_REF] Pillai | Image-guided, endoscopic-assisted drilling and exposure of the whole length of the internal auditory canal and its fundus with preservation of the integrity of the labyrinth using a retrosigmoid approach: a laboratory investigation[END_REF]. Fusion of anatomical and CT data by the surgeon helps to guide the procedure. However, the resolution of these devices is about one millimetre [START_REF] Komune | The accuracy of an electromagnetic navigation system in lateral skull base approaches[END_REF], which can be insufficient when the IAC must be opened as close as possible to the PSCC and the risk of perforation persists when the drilling zone remains invisible to the microscope. This problem can be resolved by using an endoscope, allowing exposure of all of the drilling zone when it is placed as close as possible to the IAC [START_REF] Chovanec | Impact of videoendoscopy on the results of retrosigmoid-transmeatal microsurgery of vestibular schwannoma: prospective study[END_REF]. The use of endoscopy in the cerebellopontine angle was proposed and popularized by J. Magnan and A. Chays in the context of minimally invasive retrosigmoid approaches for the treatment of schwannomas and neurovascular compression [START_REF] Magnan | Contribution of endoscopy of the cerebellopontine angle by retrosigmoid approach. Neuroma and vasculo-nervous compression[END_REF]. However, it is not always easy to perform when the endoscope is hand-held by the operator, as, in order to ensure a stable image, one of the operator's hands must hold the endoscope, making it impossible to simultaneously use suction during drilling. The surgical assistant can replace the surgeon by holding and immobilizing the endoscope, but even for skilled operators, accidental mobilizations of the camera can damage adjacent structures and may not provide direct vision of drilling. Depth landmarks are often lost during this procedure, associated with a high risk of perforation of the PSCC despite the improved exposure.

These limitations are largely resolved by using a fixed endoscope. The good exposure is preserved, the surgeon's hands are freed and the stable image allows more accurate assessment of depth. The mobility of the articulated arm allows the endoscope to be turned in in all directions and the use of the Endocameleon ® also facilitates exposure. Skeletonization of the PSCC is performed under visual control, limiting the risk of perforation. The number of endoscope and drilling instrument changes in the cerebellopontine angle is decreased, thereby reducing the risk of accidents (nerve, vessel, cerebellar injuries). Use of an endoscope, particularly a fixed endoscope, is associated with a risk of thermal burns of the nerves, blood vessels or cerebellum, which can be prevented by ensuring that the endoscope remains at a minimum distance from vital structures, while protecting the cerebellum from the endoscope by a piece of artificial dura mater. The light intensity must be limited to 40% maximum power. Continuous irrigation with normal saline, directed by the surgical assistant, is essential to limit any local temperature rise, which is then not more dangerous than the heat released by the operating microscope.

Fixed endoscopy is also indicated in the retrolabyrinthine approach, which constitutes a real otoneurosurgical alternative to the retrosigmoid approach. The choice between the two techniques simply depends on the surgeon's usual practice. With the same advantages and disadvantages, the endoscope allows visual control of the fundus of the IAC either during tumour resection or to verify the absence of residual tumour. The endoscope is less useful for preservation of vestibular structures and the superior bulb of the jugular vein, which are identified during bone drilling.

CONCLUSION

The use of a fixed endoscope helps to improve the surgical management of patients operated for vestibular schwannoma, particularly when the preoperative objective includes hearing preservation. However, preservation of the anatomical structures of the inner ear alone cannot guarantee maintenance of the patient's hearing thresholds, as release of the cochlear nerve from the tumour always remains a delicate procedure. This technical refinement can therefore be added to existing techniques and should be considered in the appropriate indications.

Figure 1 :

 1 Figure 1: Retrosigmoid endoscope fixation and orientation system during drilling of the IAC.

Figure 2 :

 2 Figure 2: Fixed endoscopic half-arched drilling of the IAC revealing the dura mater.

Figure 3 :

 3 Figure 3: Appearance of the IAC after drilling and tumour resection. Preservation of the facial and cochlear nerves.

Conflict of interest: none

Acknowledgments: To all of the medical and surgical team for their active participation.


Michel Hosny

R Abou

Jacques Bou Khalil

Anthony Fontanini

Emeline Baptiste

Nicholas Armstrong

MD Bernard La Scola
email: bernard.la-scola@univ-amu.fr

Rita Abou Abdallah

Clostridium pacaense: a new species within the genus Clostridium

Keywords: Culturomics, taxono-genomics, Clostridium pacaense Culturomics, taxono-genomics, Clostridium pacaense

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

Introduction

Human intestinal flora is incorporated mainly in the terminal part of small intestine and colon. It consists of about 100,000 billion bacteria, grouped into 500 species including 90% of anaerobic bacteria [START_REF] Eckburg | Diversity of the human intestinal microbial flora[END_REF][START_REF] Palmer | Development of the human infant intestinal microbiota[END_REF]. Oxygen-tolerant species such as lactobacilli, thus aerobic organisms such as E. coli and enterococci represent minorities within intestinal microbiota [START_REF] Palmer | Development of the human infant intestinal microbiota[END_REF]. It appears that each adult own a signature of microbial community, and increasingly influenced on human health [START_REF] Hosny | Updating on gut microbiota and its relationship with the occurrence of necrotizing enterocolitis[END_REF][START_REF] Cassir | Gut microbiota and the pathogenesis of necrotizing enterocolitis in preterm neonates[END_REF][START_REF] Lagier | Human gut microbiota: repertoire and variations[END_REF]. Clostridiaceae is a family of Clostridia and has traditionally been described by anaerobic growth and spore formation [START_REF] Hosny | Updating on gut microbiota and its relationship with the occurrence of necrotizing enterocolitis[END_REF][START_REF] Hosny | Description of Clostridium phoceensis sp. nov., a new species within the genus Clostridium[END_REF]. Clostridia included major composition of mammalian gastrointestinal tract microbiomes [START_REF] Lagier | The rebirth of culture in microbiology through the example of culturomics to study human gut microbiota[END_REF]. For that purpose, culturomics combined with taxonogenomics revealed main tools for the isolation and characterization of new bacterial species. These techniques allowed the accessibility to study their phenotypes like antibiotics resistance and biochemical features, thus genomics characteristics and the potential impact on human health [START_REF] Abdallah | The impact of culturomics on taxonomy in clinical microbiology. Antonie van Leeuwenhoek[END_REF][START_REF] Fournier | Anaerobes in the microbiome From culturomics to taxonomogenomics: A need to change the taxonomy of prokaryotes in clinical microbiology[END_REF]. In the present work, we propose Clostridium pacaense sp. nov. strain Marseille-P3100 T (CSUR P3100) as a new species within the Clostridium genus. This strain was isolated from a 3.3-months-old Senegalese girl, with clinical aspects of marasmus [START_REF] Pham | Urmitella timonensis' gen. nov., sp. nov., 'Blautia marasmi' sp. nov., 'Lachnoclostridium pacaense' sp. nov., 'Bacillus marasmi' sp. nov. and 'Anaerotruncus rubiinfantis' sp. nov., isolated from stool samples of undernourished African children[END_REF].

2.

Materials and Methods

Phenotypic, biochemical and antibiotics susceptibility

Gram staining, motility, catalase and oxidase were determined as described by Lagier et al. [START_REF] Lagier | Current and past strategies for bacterial culture in clinical microbiology[END_REF]. Sporulation was tested using a thermal shock on bacterial colonies (diluted in phosphate buffered saline) for 20 minutes at 80°C. For electronic microscopy, a colony was collected from agar and immersed into a 2.5 % glutaraldehyde fixative solution. The slide was gently washed in water; air dried and examined with approximately 60 centimeters in height and 33 cm in width to evaluate bacteria structure on TM4000 microscope. Mass spectrum was obtained from C. pacaense colonies using MALDI-TOF (Figure 1). Biochemical characteristics were tested using API 50CH, API ZYM and API 20A strips (bioMérieux, Marcy l'Etoile, France). Antibiotic susceptibility referred to European Committee on Antimicrobial Susceptibility Testing 2018 recommendations.

Fatty acid methyl ester analysis

Cellular fatty acid methyl ester (FAME) analysis was performed by GC/MS. Two samples were prepared with approximately 35 mg of bacterial biomass per tube harvested from several culture plates. Fatty acid methyl esters were prepared as described previously [START_REF] Sasser | Bacterial Identification by Gas Chromatographic Analysis of Fatty Acids Methyl Esters[END_REF].

GC/MS analyses were carried out as described before [START_REF] Dione | Genome sequence and description of Anaerosalibacter massiliensis sp[END_REF]. Briefly, fatty acid methyl esters were separated using an Elite 5-MS column and monitored by mass spectrometry (Clarus 500 -SQ 8 S, Perkin Elmer, Courtaboeuf, France). Spectral database search was performed using MS Search 2.0 operated with the Standard Reference Database 1A (NIST, Gaithersburg, USA) and the FAMEs mass spectral database (Wiley, Chichester, UK).

Genome sequencing, assembly and annotation

Genomic DNA was sequenced on MiSeq sequencer (Illumina, Inc., San Diego, CA) using paired-end strategy as described previously [START_REF] Hosny | Description of Clostridium phoceensis sp. nov., a new species within the genus Clostridium[END_REF]. Spades software was used for genome assembly [START_REF] Bankevich | SPAdes: A New Genome Assembly Algorithm and Its Applications to Single-Cell Sequencing[END_REF]. Contaminations were eliminated after performing BLASTn. Open reading frames (ORFs) were predicted and annotated using Prokka software [START_REF] Seemann | Prokka: Rapid prokaryotic genome annotation[END_REF]. C. pacaense genome was for protein functions against the Clusters of Orthologous Groups (COG) database using BLASTP (E-value of 1e -03 , coverage 0,7 and identity percent 30%). The genome is available on EMBL-EBI scaffolds accession numbers: LS999944-LS999965.

Comparative genomics

Species to be compared were those with higher similarity based on 16s RNA (Figure 2), provided the genome is available. The following bacterial species were used in this analysis and their genomics features are summarized in supplementary Table S1: Clostridium bolteae (GCA_002234575.2), Clostridium lavalense (GCA_003024655.1), Clostridium saccharolyticum (GCA_000144625.1), Clostridium aldenense (GCA_003434055.1),

Lachnoclostridium citroniae (GCA_000233455.1), Clostridium amygdalinum (GCA_900205965.1), Clostridium celerecrescens (GCA_000732605.1). Amino-acids and ORF sequences were predicted using Prodigal software to obtain optimized prediction within all genomes [START_REF] Hyatt | Prodigal: prokaryotic gene recognition and translation initiation site identification[END_REF]. Then, for each couple of genomes, a similarity percentage was computed using the OrthoANI software [START_REF] Lee | OrthoANI: An improved algorithm and software for calculating average nucleotide identity[END_REF].

Results

Phenotypic and biochemical characterization

C. pacaense is a Gram-variable, spore-forming, non-motile, anaerobic bacillus, with no catalase and oxidase activities. Electron microscopy revealed that its length was 3.5 µm and 0.5 µm of diameter (Figure 3). C. pacanese produced α-glucosidase and Napthol-AS-Blphosphohydrolase. General feature and biochemical characteristics are summarized in Table 1. Antibiotic susceptibility testing revealed that C. pacaense was susceptible to amoxicillin, amoxicillin-clavulanic acid, ceftriaxone, ceftazidime, cefepime, ertapenem, metronidazole and vancomycin.

Predominant fatty acids

The major fatty acids were Hexadecanoic acid (59 %), Tetradecanoic acid (20 %) and 9-Hexadecenoic acid (9 %). No branched structures were detected (Table 2). 3). Based on 16s RNA similarity the closest species was C. aldenese (Table 4). This was in agreement with genome data as C. aldenese was also the closest species with OrthoANI value of 89.9744 % (C. aldenese) but below the 95% cut-off defining a species (Figure 4).

Genomes properties and comparison

Description of Clostridium pacaense sp. nov.

Clostridium pacaense (pa.ca.en'se L. masc. adj. pacaense, of PACA, the abbreviation of Provence Alpes Cote d'Azur, the French area where the strain was isolated). In addition to the characteristics in the genus description, cells are Gram-variable with a length of 3.5 µm and a width of 0.5 µm. Produces α-glucosidase and Napthol-AS-Bl-phosphohydrolase. [START_REF] Hall | An important software for molecular biology[END_REF].

Figure 1 :Figure 2 :

 12 Figure 1: Reference mass spectrum (MALDI-TOF) from Clostridium pacaense strain Marseille-P3100

Figure 3 :Figure 4 :

 34 Figure 3: Electron microscopy of Clostridium pacaense

  C. pacaense draft genome consisted of 22 scaffolds, genome length was 2,672,129 bp, with a 50% of GC content. 2,360 proteins were predicted. The draft genome sequence of C. pacaense owned the smallest genome. Its GC content was same as C. aldenense, but smaller than C. lavalense and greater than others. Additionally, C. pacaense owned the smallest number of predicted genes. Carbohydrate transport and metabolism thus secondary metabolites biosynthesis, transport and catabolism were the predominant COG categories identified within C. pacaense (Table

Table 2 : Cellular fatty acids of Clostridium pacaense

 2 The major fatty acids are C 16 H 32 O 2, C 14 H 28 O 2 and C 16 H 30 O 2 . The type strain Marseille-P3100 T has been deposited in the CSUR and CCUG culture collections under numbers CSUR P3100 and CCUG 71489, respectively. The type strain was isolated from stool sample of a Senegalese girl with marasmus. The draft genome of the type strain is 2,672,129 bp long with a DNA G + C content of 50% and is available on EMBL-EBI scaffolds accession

	No
	No
	No

sequences were aligned and similarity matrix were calculated using Bioedit Software

Acknowledgments

We thank the genomics and biobank platforms of the Institut Hospitalo-Universitaire (IHU)-Méditerranée Infection for technical assistance.

Funding

This work was supported by a grant from the French State managed by the National Research Agency under the "Investissements d'avenir (Investments for the Future)" program with the reference ANR-10-IAHU-03 (Méditerranée Infection) and by Région Provence Alpes Côte d'Azur and European funding FEDER PRIMI.

numbers: LS999944-LS999965.

Conflict of interest

The authors have no conflict of interest to declare.

Current classification


Sami Achour
email: sami.achour@fst.rnu.tnwahid.nasri@ensi.rnu.tn

Wahid Nasri

Angelo Luiz

Steffenel

On the use of performance models for adaptive algorithm selection on heterogeneous clusters

Due to the increasing diversity and the continuous evolution of existing parallel systems, solving efficiently a target problem by using a single algorithm or writing efficient and portable programs is becoming a challenging task. In this paper, we present a generic framework that integrates performance models with adaptive techniques in order to design efficient parallel algorithms in heterogeneous computing environments. To illustrate our approach, we study the matrix multiplication problem, where we compare different parallel algorithms. Experiments demonstrate that accurate performance predictions obtained from analytical performance models allow us to select the most appropriate algorithm to use depending on the problem and the platform parameters.

Introduction

The last years have witnessed a proliferation of powerful heterogeneous computing systems and an ever-increasing demand for practice of high performance computing. The inherent heterogeneity in terms of software and hardware components represents a challenge to develop efficient parallel algorithms in such environments. Indeed, it is very difficult to solve efficiently a given problem by using a single algorithm or to write portable programs developing good performances on any computational support.

The adaptive approach represents an interesting solution to these challenges. Depending on the problem and platform parameters, the program will adapt to achieve the best performances. To ensure that these techniques guarantee good performances, accurate performance models are essential to represent the problem in the target platform.

In this work, we propose a generic framework that al-lies adaptive approaches and performance models to solve a given problem. Our objective is to integrate techniques for accurately predicting execution times of the available algorithms and automatically determine the most appropriate one in terms of a set of parameters (problem size, number of available processors, network performances, etc.). The remainder of the paper is organized as follows. We begin in section 2 by discussing some related works. In section 3, we describe the methodology of our adaptive framework and detail its components. Section 4 is devoted to a case study where we apply our approach on the matrix multiplication problem. We present in section 5 practical experiments performed on computing systems made up heterogeneous clusters proving the interest of this work. Finally, section 6 concludes the paper and discusses some perspectives to extend this work.

Related works

Over recent years, several research works have addressed the use of adaptive techniques to minimize the execution time and to ensure portability for both sequential [START_REF] Whaley | Automated empirical optimization of software and the ATLAS project[END_REF][START_REF] Bilmes | Optimizing matrix multiply using PHiPAC: a Portable, High-Performance, ANSI C coding methodology[END_REF][START_REF] Mccracken | Performance modeling for dynamic algorithm selection[END_REF] and parallel algorithms [START_REF] Frigo | The design and implementation of fftw3[END_REF][START_REF] Berman | Adaptive computing on the grid using AppLeS[END_REF][START_REF] Hartmann | Adaptive selection of communication methods to optimize collective mpi operations[END_REF][START_REF] Bhat | Adaptive communication algorithms for distributed heterogeneous systems[END_REF][START_REF] Hong | Adaptive matrix multiplication in heterogeneous environments[END_REF]. However, only few parallel adaptive algorithms were implemented as frameworks. In Yu et al. [START_REF] Yu | An adaptive algorithm selection framework for reduction parallelization[END_REF], a framework for reduction parallelization is presented, consisting on three components: (i) an offline process to characterize parallel reduction algorithms, (ii) an online algorithm selection module and (iii) a small library of parallel reduction algorithms. In Thomas et al. [START_REF] Thomas | A framework for adaptive algorithm selection in STAPL[END_REF], the authors developed a general framework for adaptive algorithm selection for use in the Standard Template Adaptive Parallel Library (STAPL). Their framework uses machine-learning techniques to analyze data collected by STAPL installation benchmarks and to select different algorithms for sorting and matrix multiplication at run-time.

Another methodology is described by Cuenca et al. [START_REF] Cuenca | Automatic optimisation of parallel linear algebra routines in systems with variable load[END_REF], which presents the architecture of an automatically tuned linear algebra library. During the installation process in a system, the linear algebra routines will be tuned to the system conditions. At run-time, the parameters that define the system characteristics are adjusted to the actual load of the platform. The design methodology is analyzed with a block LU factorization. The main difference between the above approaches and the work presented in this paper is that we do not refer to empirical measures or statistical techniques; rather, we use analytical models serving as the basis of the automatic processing in our framework for making a quick decision while obtaining relatively accurate results.

3 Description of the adaptive framework

Methodology

In this section, we describe our framework for integrating performance models with adaptive approaches in a heterogeneous execution environment. An overview of its architecture is sketched in Fig. 1. The processing is separated into three phases: (i) platform discovery, (ii) performance modeling and (iii) adaptive execution. Note that this processing does not generate heavy additional cost compared to the overall execution time, particularly for large matrix sizes. Indeed, on a given dedicated platform, the first phase will be executed only once. The second and third phases are based on analytical formula that can be evaluated with a neglected cost. In the sequel, we give more details on the major components of the framework.

Platform discovery

During this phase, we aim to discover automatically the performances of the target execution platform by collecting available information, such as computing powers of processors, interconnection network performances, etc. These parameters are to be used as input for the phase of adaptive execution.

Network monitoring There exist many tools for network monitoring, such as NWS. These tools permit to determine many useful parameters of the target parallel system like the current network performance, the speeds of the processors, the CPU load, the available memory, etc. Let us note that this step should provide quick and accurate results, since the third phase of the framework is based on these results.

Processing performance The processing performance can be obtained with the execution of benchmarks. In our work, we have chosen the well-known LAPACK benchmark [START_REF] Anderson | Performance of lapack: A portable library of numerical linear algebra routines[END_REF] to determine the performances of the processors of the target parallel platform. These performances will be used for two main purposes: (i) to determine the relative performance of each processor, and (ii) to estimate the time of processing.

Performance modeling

In this second phase, we have to model each available algorithm according to a performance model. The performance modeling of an algorithm depends on two main aspects: the computational cost and the communication cost. In most cases, it is possible to describe an algorithm as the composition of these two aspects, which by instance can be modeled separately according to specific techniques. An analytical model based on the number of operations can be used to determine the computational cost, while communication models such as LogP [START_REF] Culler | LogP -a practical model of parallel computing[END_REF] or pLogP [START_REF] Kielmann | Network performance-aware collective communication for clustered wide area systems[END_REF] can be used to predict the communication costs.

This phase ends by determining a set of analytical formulas to be associated with the platform performances given by the first phase for calculating the performances of the candidate algorithms during the third phase.

Adaptive execution

As mentioned in the previous section, this phase is based on the results determined in the two first phases. Indeed, assuming that a set A = {A 1 , A 2 , . . ., A q } of q algorithms is available, determining the best algorithm on a given platform is based on the matrix of performances constructed by the performance analysis of each candidate algorithm.

Formally, assuming a cost model, we denote by P (A i , C j ) the performance of algorithm A i on cluster C j . Let us precise that A i is qualified to be the best on cluster C j when:

P (A i , C j ) = min{P (A k , C j ), 1 ≤ k ≤ q} (1)
4 Applying the framework: the parallel matrix multiplication problem

The chosen problem to validate our methodology is the dense matrix multiplication problem on heterogeneous platforms, which has raised a considerable interest this decade [START_REF] Beaumont | Matrix multiplication on heterogeneous platforms[END_REF][START_REF] Kalinov | Heterogeneous distribution of computations solving linear algebra problems on networks of heterogeneous computers[END_REF][START_REF] Ohtaki | Parallel implementation of strassen's matrix multiplication algorithm for heterogeneous clusters[END_REF][START_REF] Lastovetsky | On grid-based matrix partitioning for heterogeneous processors[END_REF]. The majority of these works rely on efficiently distribute the data among the processors of the heterogeneous platform.

In this paper, we have implemented three algorithms for the resolution of this problem. Two of these implementations are based on the standard matrix multiplication algorithm and the third one combines both standard and Strassen [START_REF] Strassen | Gaussian elimination is not optimal[END_REF] algorithms. The architecture of the computation of these three algorithms is based on the master/slave architecture. Indeed, the computation of the matrix product is performed in three steps: (i) the distribution of the input matrices A and B from the master node to other nodes, (ii) a local computation on all nodes, and (iii) the gather of the result matrix C. In the sequel, we describe each algorithm.

Std Col Based This algorithm [START_REF] Lastovetsky | On grid-based matrix partitioning for heterogeneous processors[END_REF] is based on the standard method, where all matrices are partitioned identically into slices as follows: the processors are already arranged into a set of processor columns, for each processor we assign a slice of matrix proportionally to the speed of this processor with the constraint that the slices must be arranged in columns (see Fig. 2). Once the blocks of the matrix C are computed, each processor has to send his slice of result matrix to the master node. The analytical model determining the theoretical performance of such an algorithm be described by Equation 2.

T exe(p

i ) = N b Comm(β + Bloc Size × τ ) (2) +2 × N b Comp × Bloc Size 3 × P erf (p i )
Where -T exe(p i ) is the execution time of processor i, -Bloc Size is the size of a square bloc, -N b Comp is the number of blocs computed by processor i, -N b Comm is the number of blocs sent/received by processor i, -P erf (p i ) is the performance of processor i, -β is the network latency and τ is the network bandwidth, Note that β, τ and P erf (p i )are obtained during the phase of platform discovery, while N b Comm and N b Comp are determined for each target problem.

Std Cart Based This algorithm [START_REF] Lastovetsky | On grid-based matrix partitioning for heterogeneous processors[END_REF] is similar to the previous one, however it presents an additional constraint: the slices should be arranged in both columns and rows (see Fig. 2). In this case, the communications are simplified because each processor has only one neighbor from the right and/or from the left, while the analytical model is still described by Equation 2.

Str Cannon This algorithm, inspired on Ohtaki's algorithm [START_REF] Ohtaki | Parallel implementation of strassen's matrix multiplication algorithm for heterogeneous clusters[END_REF], combines two algorithms: the higher level is based on the algorithm of Cannon [START_REF] Cannon | A cellular computer to implement the Kalman filter algorithm[END_REF] (also called BMR algorithm) and the bottom level is based on one recursion of the Strassen's algorithm [START_REF] Strassen | Gaussian elimination is not optimal[END_REF]. In this algorithm, the matrices are partitioned in a grid of blocks.

For each processor, we assign a number of blocks to compute proportionally to its computational speed (see Fig. 3). After being distributed, the matrix multiplication uses the principle of Cannon's algorithm with the specificity that the multiplication of two blocks of matrices A and B is done applying one recursion of the Strassen's algorithm. The analytical model determining the theoretical performance of such an algorithm may be described by Equation 3.

T exe(p

i ) = N b Comm(β + Bloc Size 2 × τ ) (3) +(7/4) × N b Comp × Bloc Size 3 × P erf (p i ))

Validation

To validate our approach, we used two clusters from the Grid'5000 platform 1 , namely Azur and Sol. Azur is composed by 72 IBM eServer 325 nodes (dual Opteron 246 1 Experiments presented in this paper were carried out using the Grid'5000 experimental testbed, an initiative from the French Ministry of Research through the ACI GRID incentive action, INRIA, CNRS and RE-NATER and other contributing partners (see https://www.grid5000.fr). 2.0GHz, 2GB) while Sol is composed by 50 Sun Fire X2200 M2 nodes (dual Opteron 2218 dual-core 2.6GHz, 4GB).

Both clusters run over Gigabit-Ethernet networks, the same technology used in the backbone that interconnects them. Machines from both clusters run Linux with kernel version 2.6.13, and the algorithms were implemented using MPICH2 1.0.7 on square matrices of data with double precision. Disk swapping is disabled to prevent out-of-core computations.

Performance analysis

As stated in the previous sections, our policy of performance evaluation consists on the analysis of the different available algorithms and elements of the platform. With the help of a performance model that represents the target problem and the platform to be used, and the network connectivity data, we are able to predict the performance of the different algorithms and to select the algorithm that should perform faster for a particular context.

In order to validate the accuracy of our models, we have initially compared the measured execution times from the algorithms with the predictions obtained using our approach. For instance, we depict in Fig. 4 a comparison for the case of P=9 processors for both Std Col Based and Str Cannon algorithms (Std Cart Based model being similar to Std Col Based). Diagrams show that our methodology provides accurate results with a reduced overhead, as the prediction error is about 3% (resp. 5%) for Std Col Based (resp. Str Cannon) algorithm for large sizes.

We also depict in Fig. 5 the completion times of Std Col Based, Std Cart Based and Str Cannon algorithms distributed on two clusters from the Grid'5000 platform for different numbers of processors and matrix sizes. We particularly observe that algorithms have different behaviors according to the context (number of processors and matrix size). Let us take for example Str Cannon algorithm which provides the best performance for the case of P=7 processors and the worst one for the other cases. On the other

Conclusions and future works

We have presented in this paper an adaptive framework for dealing with the design of efficient parallel algorithms in heterogeneous computing environments. The methodology we propose integrates performance models with adaptive approaches, proceeding in a self-adapting fashion to determine an execution scheme, minimizing the overall execution time of a given problem on a target heterogeneous platform. To illustrate the interest of this approach, we demonstrate how an important numerical problem, the matrix multiplication, can be adapted over different computational supports. Although simple, the case of the matrix multiplication demonstrates the advantages of associating the accuracy of performance models and the power of adaptive techniques.

As future prospects, we intend to perform experiments on other numerical problems whose performances depend on both the distributions of the processes and their related communications. We also plan to integrate other existing adaptive approaches and performance modeling techniques to our framework and to implement more candidate algorithms. One way to address this later issue is to express it as a combinatorial optimization problem. Finally, extending our methodology to dynamic systems seems worthwhile.

Figure 1 .

 1 Figure 1. Architecture of the adaptive framework.

Figure 2 .

 2 Figure 2. Distribution of the matrices for the standard algorithm.

Figure 3 .

 3 Figure 3. Data distribution for the Str Cannon algorithm.

Figure 4 .

 4 Figure 4. Measured and modeled completion times (sec) of the matrix multiplication on two clusters (P=9) from Grid'5000 platform.

Figure 5 .

 5 Figure 5. Completion times (sec) of the matrix multiplication on two clusters from Grid'5000 platform.