M Rodriguez Pascual

F Ravelet

R Delfos

J J Derksen

G J Witkamp

Large Eddy Simulations and stereoscopic particle image velocimetry measurements in a scraped heat exchanger crystallizer

Keywords: Fluid Mechanics, Crystallisation, Scaling, Heat transfer, Lattice Boltzmann Method, Scraped Heat Exchanger Crystallizers

The transport phenomena in scraped heat exchanger crystallizers are critical for the process performance. Fluid flow and turbulence close to the heat exchanger (HE) surface as generated by stirring elements and scraper blades are crucial in this respect as they aim at avoiding an insulating scale layer on the HE surface. For this reason we performed largeeddy simulations of the turbulent flow (at a Reynolds number of 5⋅ 10 4 ) in a typical cooling crystallizer geometry with a focus on the bottom region where the heat exchanging surface was located. The simulations were validated with stereoscopic PIV experiments performed higher up in the crystallizer. For reasons of optical accessibility being hindered by the scrapers, the experiments could not be done near the heat exchanging surface. The flow structures as revealed by the large-eddy simulations could explain the local occurrence of scaling on an evenly cooled heat exchanger surface, and its irreproducibility caused by instantaneous cold spots.

Introduction

In several types of cooling crystallization processes, solutions or melts are brought by the action of heat exchangers into supersaturated regions where crystals will form. In industrial continuous processes, where solution is constantly fed into the crystallizer, control and stability of the bulk solution temperature is mandatory. For this reason a degree of turbulence inside the crystallizer is necessary to achieve good mixing of the whole solution, and with this aim stirrers are commonly used. Several computational and experimental studies of fluid flow in stirred tanks have been done in the past with a view to optimizing mixing processes motivated by their general importance in the chemical process industries [START_REF] Yianneskis | An experimental study of the steady and unsteady flow characteristics of stirred reactors[END_REF] ; [START_REF] Schäfer | Trailing vortices around a 45 o Pitched blade impeller[END_REF]; Derksen et al., (1999) ; [START_REF] Derksen | Large Eddy Simulations on the Flow Driven by a Rushton Turbine[END_REF]]. In cooling crystallization this turbulent mixing determines the heat transfer rates that are directly responsible for the production rates, while the residence time in the crystallizer determines size and quality of the crystals. Particle flow interactions relate to solid separation, attrition and agglomeration processes. Studies on the influence of the flow on the heat and mass transfer and particle-flow interactions are of major interest but not an easy task to perform due to the complexities related to turbulence and the wide range of length and time-scales involved.

To bring the solution to the desired supersaturation heat exchangers (HE's) are typically in direct contact with the solution. The thermal boundary layer near the HE surface depends on the crystallizer flow characteristics. Because of the higher supersaturation at the HE surface the nucleation and growth rates of the crystals are faster than in the bulk of the solution. This situation is responsible for the formation of a scale layer of crystals on the HE surface in several cases of cooling crystallisation from a solution and (in particular) from a melt, including ice crystallisation from aqueous solutions. This scale layer reduces heat transfer, thus affecting the stability and efficiency of the crystallization process. To avoid this scale layer formation, it is common to use mechanical actions such as scraping. Depending on the composition of the solution and the characteristics of the mechanical scraping action (velocity, scraper shape and applied force), a maximum temperature difference between the solution and the heat exchanger surface can be maintained without the occurrence of scaling. In any case, to prevent scaling the heat exchanger surface temperature also has to be as uniform as possible, avoiding cold spots where scaling will start.

A laboratory scale scraped heat exchanger crystallizer was specifically designed to study the ice scaling behaviour of aqueous electrolyte solutions (Figure1). Further details of the setup and operation of this crystalliser can be found in [START_REF] Rodriguez Pascual | Measurement of flow field and temperature distribution in a scraped heat exchanger crystallizer[END_REF]Vassen et al.(2002); [START_REF] Pronk | Maximum Temperature difference without ice scaling in a scraped heat exchanger crystalliser[END_REF]].

Figure 1 The location where the scaling starts as well as the lack of reproducibility and spread in experimental results encountered in previous studies prompted us to investigate the local temperature and heat transfer distribution across the heat exchanger (HE) surface. These HE surface temperatures were measured by using a thermo chromatic liquid crystal sheet (TLC) placed directly upon the HE-surface (Figure 2). Further details of the experimental procedure are explained in Rodriguez [START_REF] Rodriguez Pascual | Measurement of flow field and temperature distribution in a scraped heat exchanger crystallizer[END_REF].

Figure 2 The result shows that, even though the process as such is stationary, the HE surface temperature is far from uniform. Near the shaft and close to the wall the heat transfer between HE and solution, reflected by the calculated heat transfer coefficient h C (r), is lower by a factor of at least five than halfway the radius. So the question why h C (r) varies so much over the scraped HE plate had to be answered.

Since the heating of the HE plate did not show local variations, the differences in local heat transfer could only be caused by the flow field. The accessible part of the flow field above the scrapers and below the stirrer was therefore investigated using Stereoscopic Particle Image Velocimetry, (3C-PIV); further details can be found in [START_REF] Rodriguez Pascual | Measurement of flow field and temperature distribution in a scraped heat exchanger crystallizer[END_REF]]. The axial, radial and tangential velocities of the flow field in this middle section of the crystalliser were derived from these PIV images.

It was, however, not feasible to measure the velocities in the lower scraper region just above the HE surface where the actual scaling occurs because the revolving scrapers hindered the optical accessibility required for PIV. For a more detailed analysis of the flow field in this region we were obliged to rely on information obtained by modelling the flow field.

To model the flow large eddy simulation (LES) in a lattice-Boltzmann scheme for discretizing the Navier-Stokes equations was used. The major reasons for employing a lattice Boltzmann discretization scheme are its almost full locality of operations, its computational efficiency (in terms of floating-point operations per lattice site and time step), and its ability to simulate flows in complex geometries. An interface model to represent the revolving parts of the geometry was avoided by modelling of the moving geometry with an adaptive force field technique [START_REF] Derksen | Large Eddy Simulations on the Flow Driven by a Rushton Turbine[END_REF]].

The LES methodology has proven to be a powerful tool to study and visualize stirred tank flows, because it accounts for the unsteady and periodic behaviour of these flows, and it can effectively be employed to explicitly resolve phenomena directly related to the unsteady boundaries. Results of the single-phase Lattice-Boltzmann LES code applied to stirred tank flow have been extensively compared to phase-averaged and phase-resolved experimental data [START_REF] Derksen | Large Eddy Simulations on the Flow Driven by a Rushton Turbine[END_REF]; [START_REF] Derksen | Assessment of Large Eddy Simulations for Agitated Flows[END_REF]].

The computational results of the flow field for the scraped heat exchanger crystalliser geometry used in this study are presented in this paper. To validate the correctness of the calculated flow field characteristics the results for the middle section of the crystalliser were compared with the previous experimental results from the 3C-PIV measurements.

Simulation setup

The Navier-Stokes equations governing the flow in the stirred tank were discretized according to the lattice-Boltzmann method. This is an inherently parallel and efficient numerical scheme for computational transport physics (see e.g. [START_REF] Succi | The lattice Boltzmann equation for fluid dynamics and beyond[END_REF] for an overview). The strong turbulence generated by the impeller and scrapers prohibits direct numerical simulation: the computational effort for resolving all length and time-scales would be too large.

In large-eddy simulations only the large-scales are resolved explicitly -the rationale behind it is that the small scales behave more universally and are therefore more prone to modelling than the large scales [START_REF] Lesieur | New trends in large-eddy simulations of turbulence[END_REF]). Modelling instead of resolving the small scales alleviates the computational burden. For modelling of the small scales the standard Smagorinsky subgrid scale model was applied. A value of c S =0.12 was adopted as the Smagorinsky constant, which is within the range of values commonly used in shear-driven turbulence.

The stirred-scraped crystallizer configuration consists of a cylindrical, flatbottomed, tank with diameter of 240 mm and a height of 300 mm. The flat bottom area of the crystallizer that acts as the heat-exchanging surface is scraped by a set of four rotating scraper blades with a diameter of 198 mm that is driven by a vertical shaft. Halfway the shaft a 45 o pitch blade turbine with a diameter of 100 mm is installed to keep the slurry homogeneously mixed. The geometry is defined in figure 3a. The geometry of the scraper in the simulations closely mimics the experimental geometry (Figure 3b and3c).

The uniform, cubic grid inherent to most of the lattice-Boltzmann formulations comprised 1.8•10 7 nodes. In terms of spatial resolution: the linear size of a cubic lattice cell amounted to approximately 1 mm. The time step in the LES was such that one impeller revolution took 4200 time steps.

The Reynolds number that fully determines this single-phase flow is defined as Re=ND 2 /ν with N the impeller speed in rps, D the diameter of the scraper (being 198 mm) and ν the kinematic viscosity of the working fluid. The continuous phase was water with a density = 10 3 Kg/m 3 and ν = 10 -6 m 2 /s. The scraper and impeller were set to rotate at a speed of 77 rpm corresponding with Re=5⋅ 10 4 .

The LES is started from a zero velocity field. In the start-up phase of the flow we monitor the total kinetic energy in the tank. Once this has stabilized we start collecting flow data for later statistical analysis such as average velocity and turbulent kinetic energy fields. . This unwanted behaviour of the flow prevents proper mixing of the rotating solution with the bulk, and causes low heat transfer at the bottom of this region. When moving radially inward or outward, the flow tends to conserve its angular momentum; in a frictionless flow this may lead to a vortex. As a simplified physical model of the flow, we fitted the measured tangential velocity profile with the Oseen vortex solution [START_REF] Batchelor | An to Fluid Dynamics[END_REF]], which gradually transits from a solid-body rotation in the inner region to a free vortex flow in the outer the region. The transition takes place at approximately r=40mm, as shown in Figure 5. The measured tangential flow matches qualitatively with the vortex flow in the Oseen model.

Figure 5 Although we now can roughly explain the temperature profile at the HE surface, for a more detailed explanation the flow pattern between the scrapers just above the surface has to be studied. Due to the problematic measuring access created by the presence of the rotating scrapers we have for this purpose to rely on CFD simulations. Figure 6a shows the axial and radial time averaged velocities for the whole tank as obtained from LES computational simulations, under steady-state total kinetic energy condition, plotted as vectors with normalized lengths. To validate the computational results we compare the simulated flow velocities with the velocities calculated from the 3C-PIV measurements in the same middle region of the crystalliser. This region is indicated in Figure 6a The tangential and axial velocities at the three heights are plotted against those calculated from the stereoscopic PIV experiments. The results match quite well, although the tangential and axial velocities from the PIV experiments are slightly smaller than the LES values. Also the tangential velocities decrease when approaching the outside wall, while the LES values increase slightly before decreasing at the wall. The agreement is however in general very satisfactory, and the observed differences can be explained by the unavoidable inaccuracies in the experimental results and by the idealised computational approach.

A qualitative comparison between the PIV and LES snapshots of the same portion of the flow (Figures 8 and9, drawn with the same scale for the velocity vector length) shows interesting resemblance. Clearly turbulence is much stronger close to the outer tank wall. Furthermore the sizes of the turbulent structures observed in PIV and LES agree quite well.

Figures 8 &9 3.2. Flow field at the bottom part between the scrapers. Now that we have confidence in the simulated flow data through their agreement with the PIV results, the non accessible area just above the scraped heat exchanger surface can be analysed from the LES simulations.

By considering time averaged flow fields resolved for the angular position of the scraper in the LES more information about the flow patterns near the bottom can be gained. In Figure 10 we show the average flow one in a vertical cross section through the scrapers (Figure 10a) and one in between the scraper blades (Figure 10b).

Figure 10

The cross-section through the scrapers (Figure 10a) shows that the solution at the tip of the scraper is forced outwards to the wall and subsequently upwards.

Another important observation is that in the middle region the downward flow above the scraper is carried radially towards the centre of the crystalliser instead of being carried outwards as happens in between scrapers (Figure10b).

To be able to explain the radial variation in local heat transfer, a more detailed analysis of the region between the scrapers is needed. Figure 11 zooms in on the time averaged flow in this area half-way between the scrapers, in the region from the shaft to the wall on the horizontal axis and from the 3C-PIV measured area down to the scraped HE surface on the vertical axis. observe that this is the area where the axial velocity is positive removing the liquid from the heat exchanger surface upwards. Here we actually have to differentiate between two levels: the fluid trajectories starting between r=15 mm and 40 mm from the shaft (represented by the top streamline in Figure 11) and the fluid trajectories starting between r=40 mm and 60 mm (bottom curve in Figure11). As we can see, the top trajectory brings the liquid higher up after which it is carried into the main secondary flow that transports the fluid to the top of the crystalliser. In the bottom fluid trajectory the axial velocity is lower. This keeps the liquid close to the heat exchanger surface while approaching the outside tank wall. This makes that the fluid in the bottom trajectory is being cooled further on its way along the trajectory. This limits the local heat transfer coefficient. This could explain why from r=40 mm on the TLC measurements showed that the local heat transfer coefficient starts to decrease [START_REF] Rodriguez Pascual | Measurement of flow field and temperature distribution in a scraped heat exchanger crystallizer[END_REF]]. Also note that fluid can get trapped by the vortex formed at the scraper tip at the HE surface from r=100 mm until the outside wall. This eddy retains the liquid in this region rotating without much mixing with the rest of the liquid causing even lower local heat transfer close to the wall. Also very close to the bottom a small inward radial flow is present in between the scrapers (Figure 11); in Figure 10a a small radial flow is pushed outwards by the action of the scraper. The net effect is quite important as it explains the shape of the region of high heat transfer between two scraper passages as shown in the TLC measurements [START_REF] Rodriguez Pascual | Measurement of flow field and temperature distribution in a scraped heat exchanger crystallizer[END_REF]]. This region becomes less wide when the next scraper approaches. The fluid descending from the bulk to the HE surface by the scraper action is thus pushed outwards to the wall. Some of this fluid is captured by the lower eddy close to the wall, and redirected to the shaft, until the next passing scraper sends it back again to the wall. This redirected fluid is colder and narrows the area of higher heat transfer.

Figure 12 For a better understanding, we should not forget that the three directional components of the flow are together responsible of the complete flow field and its influence in the local heat transfer. Figure 12 shows the time-averaged tangential, radial and axial velocities at heights of z=5, 15 and 30 mm from the bottom in the scraper region. Here we can see how the tangential velocity is dominating throughout all radial positions and that the liquid is largely undergoing solid body rotation. It is remarkable that the area where the heat transfer is relatively high (between r=15 and 62 mm) axial and radial velocities are quite low, and we would have missed the effect if we had not looked at the vertical cross sections. We can however, still appreciate from figure 12 how the radial component increases from the bottom and decreases again when approaching the top of the scraper. So far we only considered time-averaged velocities and related flow structures in relation to heat transfer. This is a valid approach given the relatively long response times of the HE surface temperature. However, eventually instantaneous turbulent flow is responsible for the local, time-dependent heat transfer. This implies that time dependent cold spots could be formed where nucleation starts. We therefore now turn to instantaneous realizations of the flow field as qualitative indicators for heat transfer.

To do that we first image a horizontal cross section of the crystalliser flow at a level halfway the height of the scrapers (Figure 13). This cross section is in the frame of reference of the rotating scraper. It reveals that the scraper tip creates a turbulent flow near the wall behind its blade that dissipates its energy quite rapidly (over roughly half the distance between two scraper blades). The liquid near the tank's outer wall does not mix very well with the rest; it largely flows along the wall until the next scraper blade comes by. The instantaneous differences in local turbulence could however, provoke instantaneous cold spots. At these spots nucleation can start, which is a statistical and instantaneous event followed by fast lateral growth. This would explain the lack of reproducibility and spread in scaling experiments. Near the shaft the flow is less erratic and no instantaneous cold spots are expected there.

Figure 13

The high heat transfer in the middle area of the HE surface is still difficult to interpret from Figure 13. For this purpose vertical cross section of the flow was made perpendicular to the scraper blade at r=60 mm from the shaft, see Figure 14. Figure 14 This cross section shows how in the middle of a scraper blade the liquid from the bulk is carried down to the HE surface in near the wake of the scraper. From figure 11 we now know that this flow at the back of the scraper is pushed outwards to the outside wall and that later on (in between the two scrapers) it is moved upwards away from the HE surface in the region from around 15mm until 40 mm.

Therefore the contact time of the liquid with the heat exchanger surface in the middle region of a scraper blade is lower than in the other areas, and because the liquid comes directly from the bulk, the temperature difference compared with the cooling liquid underneath the HE surface is higher. This down flow also reduces the thickness of the thermal boundary layer, which enhances the heat transfer. At the front of the scraper the liquid is pushed upwards, and most of it is moved outwards and merges with the main secondary flow that runs to the top of the crystalliser.

Realizing that the main cause responsible for the inhomogeneous distribution of local heat transfer on the HE surface is the axial velocity component we now consider the instantaneous axial velocity at three horizontal cross sections at heights of 5, 15, and 30 mm (Figure 15).

Figure 15

As we can see from Figure 15 the fluid is brought down to the heat exchanger in the wake of the scraper blades. This downward axial velocity behind the scraper is zero near the centre of the tank and increases (negatively) in the radial direction until close to the tip of the scraper where it turns positive as approaching the outside wall. As the height increases from 5 to 30 mm the downward velocity gets stronger. This figure also shows how the down flow coming from the bulk (as we already saw in Figure 14) is pushed up again by the front of the next scraper, and as we know from Figure 11 also outwards to the outside wall. This means that the scraper blade's middle region is continuously refreshed with every scraper passage by the bulk liquid, what explains the higher local heat transfer coefficient in the middle area of the HE surface compared to the centre and outside areas.

Conclusions

Cooling crystallization often suffers from scaling that starts at specific areas on a heat exchanger surface even if the HE surface is evenly cooled. In a previous paper this behaviour was investigated by measuring the local temperature distribution across a flat scraped HE surface located at the bottom of a stirred crystallizer.

These measurements showed that the temperature was not uniformly distributed with differences larger than 4 o C. Such differences are sufficiently large to explain local variations in scaling tendency. After excluding all other possible reasons for this inhomogeneous distribution the fluid flow in the crystalliser seemed to be the only responsible cause. Stereoscopic PIV measurements of the flow in the region above the scrapers and below the stirrer were carried out, which showed that the flow pattern in this crystallizer geometry could roughly explain the observed inhomogeneities in heat transfer. For more detailed information on the flow pattern between the scrapers and thus more closely to the HE surface we had to rely on computational flow simulations, because this region was not accessible for PIV measurements.

The flow of the total scraped HE crystalliser was therefore computationally resolved by Large Eddy Simulations using a Lattice Boltzmann scheme. The simulations were validated by comparison with the PIV measurements performed previously. This provided sufficient confidence to focus on the flow pattern in the bottom region.

Analysing the results from the LES we could explain the radial local heat transfer coefficient distribution along the HE surface. The local heat transfer is higher in the middle region of the HE surface between the shaft and the outer wall (from r= 15 till r= 60 mm) because the fluid comes directly from the bulk and its residence time near the HE surface is low. The lower local heat transfer coefficient in the tank's centre is because the fluid is largely in solid body rotation and although (when the scraper passes) liquid is carried up in front and down behind the scraper, it is not mixing in the radial direction with the rest of the liquid. Beyond r=60 mm until around r=100 mm, the local heat transfer coefficient is lower because the residence time of the liquid close to the HE surface is higher. In between r=100 mm and the outside wall, a worse situation for heat transfer is provoked by a static vortex that The formation of an ice layer begins in the colder areas around the centre and near the outside wall of the HE surface, and spreads along the HE surface. In a clear fluid, scale formation starts by primary heterogeneous nucleation at the HE surface followed by a fast lateral growth rate. This nucleation is a statistical event, where local time-dependent cooling conditions play a role. Because the subsequent lateral growth is very fast, irreproducibility can be expected. Under crystallizing conditions crystals may also land on the HE surface. These crystals may firmly attach to the surface by growth, before they are removed by the scraper and contribute to the scale formation. This process also depends upon accidental events that make altogether the appearance of the ice scaling layer time dependent and difficult to predict.

The importance of the flow field for controlling the scale layer formation on the HE surface during crystallisation has been demonstrated. In the context of fluid flow, unexpected results found previously [START_REF] Vaessen | Scale formation of ice from electrolyte solutions on a scraped surface heat exchanger plate[END_REF]]; [START_REF] Pronk | Maximum Temperature difference without ice scaling in a scraped heat exchanger crystalliser[END_REF] where for example lower stirring/scraping velocities show less scaling formation may be understandable. Further computational analysis in this sense including solving of the local heat transfer and liquid temperature then has to be done.

Large eddy simulations using a lattice Boltzmann scheme have proven to be a powerful tool to investigate the flow in future complicated crystallizer designs with various scraper geometries, since inhomogeneities in heat transfer impose strong limitations on the performance of the process.

Outlook

The simulations presented here are those of the fluid dynamics of a clear liquid.

Under crystallising conditions however, even without the occurrence of scaling, crystals that are developed in the bulk of the fluid may come close to or even land on the heat exchanger surface. These crystals are transported back into the bulk liquid by the flow induced by the revolving scrapers. In addition, under scaling conditions mostly small particles are scraped off the scale layer and lifted by the flow. The scraper design has a remarkable importance here and should be such that the particles are transported away from the HE surface by the flow; they should not directly return to the surface by e.g. a trailing vortex. The particles are subjected to collisions with the hardware such as the scrapers and the wall, and to particleparticle collisions. They may even agglomerate into lumps of separate or inter-grown particles. To properly simulate a flow which contains particles, first the particleparticle interactions have to be included. As a second more complicated step a coupled particle-flow interaction has to be implemented, because in areas of high particle densities these particles will affect the flow behaviour.

In a forthcoming paper a first step in this direction has been made by implementing the particle-particle interactions. Direct Numerical Simulations based on a Lattice Boltzmann scheme were carried out, and the results will be compared with an experimental visualisation of particles that are added to the fluid and that are transported by the scraper actions.

  Figure3

Figure 4 In

 4 Figure 4

  by a black rectangle at the right hand side of the picture.

Figure 6

 6 Figure 6

Figure 7

 7 Figure 7

Figure 11 In

 11 Figure 11

  brings the fluid into a segregated area. These fluid flow results explain the mechanisms that provoke the local heat transfer distribution measured by the TLC experiments. Instantaneous fluctuations in the flow are too fast to have any impact on the temperature profile at the HE surface that depends on the different residence times of the fluid in the different areas.

Figure

  Figure 3a). Side view of the crystalliser. b). Top view of the crystalliser. c). Sideway

Figure 4 .

 4 Figure 4. Time averaged radial and axial velocities measured by 3C-PIV depicted as

Figure 5 .

 5 Figure 5. Measured time-axial averaged tangential velocity of the PIV area, the

Figure 6

 6 Figure 6. a) Time averaged velocity vectors of the flow field inside the scraped heat

Figure 7 .

 7 Figure 7. Tangential and axial velocities calculated from 3C-PIV experiments and

Figure 8

 8 Figure 8 a). Instantaneous capture of the flow from the 3C-PIV measurements.

Figure 11 .

 11 Figure 11. Axial-radial vector flow field area from the shaft to the wall and from the

Figure 12 .

 12 Figure 12. Time averaged tangential, radial and axial velocities calculated from LES

Figure 13 .

 13 Figure 13. Instantaneous vertical view of the flow field in the frame of reference of

Figure 14 .

 14 Figure 14. Instantaneous flow velocities of the vertical cut of the scraper region at

Figure 15 .

 15 Figure 15. 3D surfaces of the instantaneous axial velocity at 5, 15 and 30 mm from

Acknowledgment

The authors would like to thank Prof. G. M. Van Rosmalen for in-depth discussions.


David Rei
email: david.rei@limsi.fr

Céline Clavel
email: celine.clavel@limsi.fr

Jean-Claude Martin
email: jean-claude.martin@limsi.fr

Brian Ravenet
email: brian.ravenet@limsi.fr

PADMEH: Personality-based Adaptive moDel for Mobile E-Health

Keywords: Human-centered computing → HCI theory, concepts Health -Well-being, Personalization, Sports/Exercise, Adaptive interactions

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

INTRODUCTION

Being physically active prevents from chronic diseases and we need to motivate people for physical activity [START_REF] Myers | Exercise and Cardiovascular Health[END_REF]. Current persuasive technologies are often limited to the mere selection and display of tailored text messages [START_REF] Beck | The role of message tailoring in the development of persuasive health communication messages[END_REF]. There is a need for a more global adaptation of motivational interactions to each user's personality and motivation.

Several frameworks have been proposed for exploring adaptation in HCI. ISATINE [START_REF] López-Jaquero | Towards an Extended Model of User Interface Adaptation: The Isatine Framework[END_REF] expresses the adaptation of user interfaces as a coordination between the user and the system. It uses Norman's interaction model [START_REF] Donald A Norman | Cognitive engineering[END_REF] to build a progressive adaptation whose result is perceived, interpreted and evaluated in turn by the user and the system. The PDA-LPA (Perception Decision Action -Learning Prediction Adaptation) design space [START_REF] Bouzit | The PDA-LPA Design Space for User Interface Adaptation[END_REF] regards the user and the system as two entities being able to perceive, to decide and to act. The user goes through a PDA loop to complete her objective through interactions with the system. This vision of interaction is broadened with the LPA loop: the user learns from the actions of the system. The system does the same, to predict what the user expects from the next interaction. Adaptation is seen in PDA-LPA as a continuous exchange of actions and predictions between the user and the system.

Adaptation in HCI usually includes two components: adaptability and adaptivity [START_REF] Thevenin | Plasticity of User Interfaces: Framework and Research Agenda[END_REF]. Adaptability is user's ability to change the behaviour of the system. Adaptivity is the system's own ability to automatically adapt to the user. Machado et al. [START_REF] Machado | A Conceptual framework for Adaptive User Interfaces for older adults[END_REF] propose a framework focusing on adaptivity. It involves user profiles to drive the adaptation process in Ehealth applications. A user profile is composed of four components: preferences, personal data, visual health and cognitive health. Sensors collect physiological measures to fill visual and cognitive health components. Such information is collected automatically and continuously to allow for real-time adaptation to a given user.

Unfortunately, the different design frameworks about adaptation in HCI mentioned above do not consider personality theories from Psychology to tailor interactions. The Five Factors Model (FFM) is one of the main theories of personality used in HCI. It enables to describe user's personality through five factors [START_REF] Robert R Mccrae | A five-factor theory of personality[END_REF]. Yet, it is a descriptive approach and it does not aim at explaining user's behaviours (which we need if we want to motivate the users for healthy behaviours). In our work, we rely on two other theories: Self-Determination motivational Theory (SDT) and Regulatory Focus personality Theory (RFT).

Self-Determination Theory (SDT) [START_REF] Deci | Self-Determination Theory: A Macrotheory of Human Motivation, Development, and Health[END_REF] is a theory about motivation which identifies three basic needs any individual must meet to achieve motivation and well-being: autonomy, competence and relatedness. Autonomy consists in acting in line with one's own goals and values with strength and will. Competence describes the feeling of being able to accomplish something and being efficient in doing so. Finally, relatedness describes the feeling of being part of a group and connected to other people. The METUX Model (Motivation, Engagement, and Thriving in the User Experience) is a framework for designing well-being application based on SDT and can be used as a blueprint for designing motivational technologies [START_REF] Peters | Designing for Motivation, Engagement and Wellbeing in Digital Experience[END_REF]. METUX considers six spheres of experience staring when a user learns about a brand new technology and ending with the possible impact of this technology on society.

Regulatory Focus Theory (RFT) [START_REF] Crowe | Regulatory Focus and Strategic Inclinations: Promotion and Prevention in Decision-Making[END_REF] describes people's decision-making strategic leanings according to their goal and how they intend to reach their goal. Promotion focus individuals aim at progress and achievement. Instead, Prevention focus individual look for security and avoid situations which pull them away from their aimed end-state. Two individuals with opposite regulatory focuses can aim for the same goal using different approaches to reach it.

Cesario et al. [START_REF] Cesario | Regulatory Fit and Persuasion: Transfer From "Feeling Right[END_REF] link the sensation of "feeling right" with persuasion: they propose to use a regulatory fit to persuade a person to follow or change behaviour. According to these authors, a person presented with a persuasive message framed according to her own focus (e.g. there is thus a fit between the regulatory focus of the user and the regulatory fit expressed by the message and its framing context) should feel right and should be more influenced by the message than when there is not fit. They conclude that experiencing such a fit increases persuasion. Emotions have nevertheless a strong impact on the persuasion process. Feeling right for positive thoughts tends to increase persuasion, while the contrary tends to decrease it. Similar conclusions are drawn by Lee and Aaker [START_REF] Lee | Bringing the Frame Into Focus: The Influence of Regulatory Fit on Processing Fluency and Persuasion[END_REF]. They explore the relationship between regulatory focus, perceived risk and framed-message effects on persuasion, especially within a gain and loss context. They conclude that promotion-focused messages presented within a perceived low-risk context are more persuasive, and accordingly, prevention-focused messages presented within a perceived high-risk context are more persuasive too. Moreover, experiencing fit eases message understanding, thus improving persuasion.

Martin and Clavel [START_REF] Martin | Tailored, multimodal and opportune interactions on a wearable sport coach: The we-nner framework[END_REF] propose the WE-nner framework for tailored and multimodal interactions. Motivational messages that are in fit with user's regulatory focus (collected via a validated questionnaire) are either displayed on a smartwatch in order to motivate users to achieve their recommended 10000 steps per day, or spoken by an expressive virtual character while the user is standing on a stepper [START_REF] Clavel | WEnner: A Theoretically Motivated Approach for Tailored Coaching about Physical Activity[END_REF] .

Researchers in HCI propose several models for adaptive interactions, with the ability to adapt to each step of an interaction between a user and a system. Psychology is able to describe precisely user's personality, strategic inclinations and motivations, through accepted theories. Some researchers have made cross field works, especially linking regulatory fit with persuasive technologies, and by using self determination theory for adaptive interactions. There is still a void on describing user's personality and motivation for adaptive human-computer interactions. Through this paper, we propose such a model, applied to physical activity practice.

In the next section, we introduce PADMEH, a novel model of adaptation, based on users' personality. Section 3 provides two illustrative scenarios.

PADMEH: A PERSONALITY-BASED ADAPTIVE

MODEL PADMEH (Personality-based moDel for Mobile E-Health) is a model for supporting adaptive human-computer interaction (Figure1). Day-to-day interaction aims to improve motivation for physical activity through personalised coaching. Based on user's initial profile and her performance on current physical activity exercise, the model selects next relevant physical exercises, displays tailored motivational multi-modal messages including graphical reports on user's previous activities.

PADMEH has a representation of the intervention proposed to the user [START_REF] Martin | Development and Preliminary Psychometrics of the Exercise Therapy Burden Questionnaire for Patients With Chronic Conditions[END_REF]. A PADMEH intervention is composed of several sessions, each being a collection of physical exercises spanning a few tens of minutes. An exercise usually lasts for a few minutes.

The system refers to the combination of all procedures and elements created to improve user's motivation for physical activity. To reach this goal, it uses adaptivity. At the start of the intervention, the user fills in questionnaires, the output of which is included in her initial profile. Triggering elements are measured continuously to activate the adaptation process appropriately. The adaptation process alters adapted elements, which define the new behaviour of the system, thus completing an adaptive interaction cycle. User profile. In PADMEH, the user profile has three dimensions: motivation, regulatory focus (personality) and physical activity level. There are different ways to measure these dimensions and PADMEH is independent from them. For instance, motivation can be assessed using the global motivation scale [START_REF] Guay | On the Hierarchical Structure of Self-Determined Motivation: A Test of Top-Down, Bottom-Up, Reciprocal, and Horizontal Effects[END_REF] which provides three possible values for motivation: autonomous motivation, controlled motivation or a lack of motivation (amotivation) as defined by the SDT theory [START_REF] Deci | Self-Determination Theory: A Macrotheory of Human Motivation, Development, and Health[END_REF]. Regulatory focus can be evaluated using the Regulatory Focus Questionnaire (RFQ) [START_REF] Higgins | Achievement orientations from subjective histories of success: promotion pride versus prevention pride[END_REF]. Finally, there are multiple scales for measuring physical activity level [START_REF] Ghanvatkar | User Models for Personalized Physical Activity Interventions: Scoping Review[END_REF]. The user profile is initialised when the user launches the application for the first time using answers to such scales. It is then updated according to ongoing interactions, user's behaviour and performed exercises.

PADMEH Dimensions.

Triggering elements are mechanisms used to trigger the adaptation process. Three of them are used to initialise the user profile: regulatory focus, motivation and physical activity levels. User's performance during previous physical exercises is also used as a triggering element. The system adapts its behaviour depending on exercise outcome, on duration of previous session and previous exercise, on the number of exercises achieved during a session or during the global intervention. Triggering elements may be considered by PADMEH at different time, for example the time of events occurring before, during or after an exercise. The first event is the initialisation of the application, during which the user profile is created. Table 1 illustrates adapted elements according to time (columns) and triggering elements (rows).

Adapted elements are components, functions and processes of the interactive motivational application that are selected and tailored to fit the profile of the user. They are modified at different points in time, and activated by different triggering elements. For example, a summary report is displayed at the end of a session to sum up what happened during the exercises and how the user performed. These overviews are personalised to fit the profile of the user. For instance, if the user has a promotion regulatory focus, then displayed messages during an exercise are promotion-oriented to get him to challenge himself [START_REF] Ludolph | Does regulatory fit lead to more effective health communication? A systematic review[END_REF].

Adaptation process. This process links together PADMEH dimensions to create the adapted behaviour of the model. Its inputs are triggering elements, which is information about who is the user or what she did during her use of the application. The outputs of this process are the changes made to the application. For instance, a motivational message is composed of a frame (how it is presented), a content (the message itself) and a timing (when it is presented). The frame and the content of the message can differ depending on the regulatory focus. The frame of promotion-focused messages aim to reach a desired end-state (e.g. "be healthy") where as the frame of prevention-focused messages aim to avoid a non-desired end-state (e.g. "do not gain weight") [START_REF] Higgins | How self-regulation creates distinct values: The case of promotion and prevention decision making[END_REF]. Promotion content is framed according to risky or enthusiastic strategies, where as prevention content is more focused on safe and calm strategies [START_REF] Higgins | Beyond pleasure and pain[END_REF]. Another example: reports about the activity of the user, such as exercises or sessions reports, are adapted to their regulatory focus too. For example, promotion-oriented people are more directed to abstract and global data where as prevention-oriented people are more interested by precise and local data [START_REF] Förster | How global versus local perception fits regulatory focus[END_REF].

SCENARIOS

Scenario #1

Let's consider a fictive User X. He has a promotion focus: he is mostly motivated by success, achievement and progress [START_REF] Crowe | Regulatory Focus and Strategic Inclinations: Promotion and Prevention in Decision-Making[END_REF]. His motivation is extrinsic: he needs an external regulation [START_REF] Deci | Self-Determination Theory: A Macrotheory of Human Motivation, Development, and Health[END_REF]. His physical activity level is inactive.

Profile creation. User X launches the application and provides personal data: name, age, gender, height and weight. Then he fills in questionnaires, the output of which is used to initialise the profile of this user with a physical activity level, a regulatory focus and a motivation level. This individual profile is lately used for supporting tailored interactions used to initialise the system and to set it up for its use. A message appears to confirm the user profile has been created. This message is promotion-oriented (like this very user), as it emphasises the successful experience the user is about to have: 'Thank you! Your profile is now created. Your daily experience will be greatly improved thanks to this information. '.

Session #1. The system suggests a first session for today: the user has to walk at least 45 minutes during the day [START_REF]Global recommendations on physical activity for health[END_REF]. This objective is divided into three exercises, each consisting in walking 15 minutes in a row. When the first exercise is launched by the user, a diagram is displayed (Figure 2 -Start), showing a small character, a scale and the number '15' (mn).

It represents the remaining distance to the goal in terms of number of minutes to walk. The scale and the number are coloured in orange, since promotion-oriented people are known to better perceive this colour [START_REF] Dries-Tônnies | Human-Computer-Interaction and Regulatory Focus : using Graphic User-Interfaces[END_REF].

During the exercise, the diagram is updated: the cartoon character gets closer to the '15' mark on the scale (Figure 2 -Mid). If relevant interaction devices are available and compatible with the exercise, tailored motivational actions are used such as the display of a promotion-focused motivational textual message: 'Come on, you are getting closer to your goal!' [START_REF] Clavel | WEnner: A Theoretically Motivated Approach for Tailored Coaching about Physical Activity[END_REF], or an equivalent audio message encouraging the user to complete the exercise.

Let's suppose user X did not complete Session #1. A report nonetheless displays a motivational graph, tailored to his profile. Curves are approximate and global or average values are highlighted in orange with varying hues, as promotionfocused people better perceive these details [START_REF] Dries-Tônnies | Human-Computer-Interaction and Regulatory Focus : using Graphic User-Interfaces[END_REF][START_REF] Förster | How global versus local perception fits regulatory focus[END_REF]. Finally, a question is asked to the user in order to assess his motivation after performing the session.

Session #2. The day after, PADMEH suggests a new session: the user has to walk at least 30 minutes during the day. The new value for walking duration is decided thanks to knowledge about physical activity and user activity history [START_REF] Pirovano | Self-adaptive games for rehabilitation at home[END_REF]. The walking session is still divided into three exercises, but now each exercise consists in walking only 10 minutes in a row. When the first exercise is started, a diagram displays '10' (mn) as the walking duration goal. An additional (promotion-oriented as this user) motivational message is displayed under the diagram: 'You will get there: if you have the desire you will succeed!' [START_REF] Clavel | WEnner: A Theoretically Motivated Approach for Tailored Coaching about Physical Activity[END_REF]. To enhance his feeling of autonomy (one of the three dimensions of SDT) [START_REF] Laguardia | Buts personnels, besoins psychologiques fondamentaux et bien-être : théorie de l'autodétermination et applications[END_REF], the choice is left to the user to follow this new session or to keep the previous objectives of walking 45 minutes during the day. An orange frame surrounds the new session to help him make this decision [START_REF] Dries-Tônnies | Human-Computer-Interaction and Regulatory Focus : using Graphic User-Interfaces[END_REF]. In this scenario, User X is motivated by progress and thus chooses the new session objectives [START_REF] Cesario | Regulatory Fit and Persuasion: Transfer From "Feeling Right[END_REF].

At each completed exercise during the session, the application sends to the user feedback on distance to the goal, such as 'Go for it! You are the best!'. User X gets more motivating feedback, for instance audio messages and diagram updates to encourage him to reach his goal this time. User X completes Session #2. At completion time, a message notifies him of success: 'You did it, well done!'. A summary diagram is then displayed. The same colours and shapes are used [8][9] as at the end of Session #1 to enhance the readability of the graphs. At last, a question is asked to assess user's motivation.

Scenario #2

Let's consider another user. User Y has a prevention focus, which means she is mostly motivated by security, safety and chooses conservative options [START_REF] Crowe | Regulatory Focus and Strategic Inclinations: Promotion and Prevention in Decision-Making[END_REF]. Her motivation is intrinsic, as she is able to motivate herself to achieve her goals, whether they are set by herself or an external entity [START_REF] Deci | Self-Determination Theory: A Macrotheory of Human Motivation, Development, and Health[END_REF]. Her physical activity level is active: she is used to physical activity practice.

Profile creation. This step is the same as in Scenario #1, except the fact that the validating message is prevention-oriented: it emphasises the necessary exercise the user needs to do to keep her healthy: 'Your profile is now created. It will help you prevent you from an unhealthy life. '.

Session #1. The system presents the same exercise as for User X in Session #1. A diagram is displayed (Figure 2 -Start), showing a small character, a scale and the number '15' (mn). Prevention-oriented people tend to be more sensitive to red colour, hence the hues of the scale and the number [START_REF] Dries-Tônnies | Human-Computer-Interaction and Regulatory Focus : using Graphic User-Interfaces[END_REF]. During the exercise, updates to the diagram are displayed: the small character gets closer to the red '15' end mark on the scale (Figure 2 -Mid). After each completed exercise, personalised actions are used such as a prevention-focused text message enhancing competence (a dimension of SDT): 'Come on! You need to complete one more exercise only!'. User Y is successful at the end of Session #1. Displayed graphs are personalised in a prevention-focus way: curves are sharp, minimal values are highlighted in red, and the local minima are accentuated by a grey colour [START_REF] Dries-Tônnies | Human-Computer-Interaction and Regulatory Focus : using Graphic User-Interfaces[END_REF][START_REF] Förster | How global versus local perception fits regulatory focus[END_REF]. Finally, a question is asked to User Y to evaluate her motivation after completing the session.

Session #2. The day after, the system proposes more difficult objectives for Session #2. User Y has to walk at least 60 minutes during the day, divided into three 20-minutes spans. These new values for walking durations are decided following a similar process as in Scenario #1 [START_REF] Pirovano | Self-adaptive games for rehabilitation at home[END_REF]. An updated diagram appears, featuring the number '20' at the end of the scale. The goal of the previous session and the new goal for session #2 are displayed, to leave her the choice for her session objectives [START_REF] Deci | Self-Determination Theory: A Macrotheory of Human Motivation, Development, and Health[END_REF]. A red frame highlights the previous session objectives, advised by the system. User Y chooses again the previous session objectives, as she prefers to have control over a known environment before moving forward [START_REF] Cesario | Regulatory Fit and Persuasion: Transfer From "Feeling Right[END_REF].

Only after the first completed exercise User Y receives an update of the diagram and a prevention-oriented message: 'You will do what is necessary to avoid failing!'. User Y completes Session #2. A prevention-oriented message is displayed: 'Congratulations! By continuing like this, you will preserve your health!'. A final report is displayed, featuring the same graphs as previously, and colours selected according to the regulatory focus of User Y. Another measure of motivation is being collected to drive the selection of the next session.

CONCLUSION AND FUTURE DIRECTIONS

In this article we introduced the PADMEH model of adaptive human-computer interactions, based on user's personality. Our approach inspires from two theories of psychology to design an interactive motivational application. In the future, we plan to implement this model through a user-centred approach. Semi-directed interviews with target users will allow us to gather knowledge useful for the design of the decision engine, which will be based on decision tree techniques. Ethical principles of persuasive technology design [START_REF] Berdichevsky | Toward an Ethics of Persuasive Technology[END_REF] will be considered during the proper implementation of the motivational application.

Figure 1 :

 1 Figure 1: PADMEH considers a set of Triggering Elements to tune and combine a set of Adapted Elements for motivational interactions.

Figure 2 :

 2 Figure 2: Graphical display of distance to the current goal (exercise during 15 mn) adapted to the current performance (location of the simple cartoon character) and the regulatory fit of the user (Above: promotion display in orange ; below: prevention display in red).

Table 1 :

 1 Adapted elements according to time (columns) and triggering elements (rows)

	Triggering elements	Time and events	Profile creation	Intervention or session beginning	During session	End of session	End of intervention
	Physical activity level	User profile	Proposed exercises
	Motivation	User profile	Intensity and objectives of exercises
	Personality	User profile	Objectives reminder	Motivational messages	Report display
	Exercise performance		Intensity and objectives of exercises	Badges, audio and text messages, vibrations	Report display, badges	Physical activity level update, motivation update


Joelle Sobngwi-Tambekou

Dirk Taljaard

Pascale Lissouba

Kevin Zarca

Adrian Puren

Emmanuel Lagarde

Bertran Auvert

Ô Progressus

H Pital

Ambroise Par

Effect of HSV-2 serostatus on acquisition of HIV by young men: results of a longitudinal study in Orange Farm, South Africa

Keywords: Adolescent, Antibodies, Viral, blood, Circumcision, Male, HIV Infections, epidemiology, etiology, prevention & control, HIV-1, Herpes Genitalis, complications, epidemiology, immunology, Herpesvirus 2, Human, immunology, Humans, Incidence, Longitudinal Studies, Male, Risk Factors, South Africa, epidemiology, Young Adult

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

Introduction

Genital herpes is a major public health problem worldwide . Genital herpes is most frequently caused by the Herpes Simplex Virus [START_REF] Corey | Genital herpes and public health: addressing a global problem[END_REF] type 2 (HSV-2). Clinical, biological and epidemiological studies support the hypothesis that HSV-2 increases the risk of HIV-1 acquisition 2-to 4-fold and increases the risk of HIV-1 transmission , . A recent meta analysis found that genital ulcer disease 4.9 ) .

-] [START_REF] Johnson | The Effect of Genital Tract Infections on HIV-1 Shedding in the Genital Tract: A Systematic Review and Meta-Analysis[END_REF] HIV, in turn, increases the risk of HSV-2 transmission . There is a direct relationship between CD4 cell count and the rate of HSV-2 reactivation. Outbreaks of HSV-2 are more severe, extensive, persistent, and invasive for those with advanced HIV disease , [START_REF] Schacker | Frequency of symptomatic and asymptomatic herpes simplex virus type 2 reactivations among human immunodeficiency virus-infected men[END_REF] . Persistent HSV-2 infection was one of the original opportunistic infections that resulted in the identification of AIDS . 16 ] [START_REF] Siegal | Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions[END_REF] Three randomized controlled trials have demonstrated that male circumcision reduces the female-to-male sexual transmission of HIV by about 60

. A meta-analysis of observational data showed that male circumcision reduces the risk of HSV-2 infection with a % [18 -20 ] borderline statistical significance (summary RR, 0.88 95 CI, 0.77 1.01 ) .

[ % -] [START_REF] Weiss | Male circumcision and risk of syphilis, chancroid, and genital herpes: a systematic review and meta-analysis[END_REF] The main objectives of this study were to estimate a) the effect of HSV-2 status on HIV incidence among young males b) the population fraction of HIV infections attributable to HSV-2 infection and c) the effect of HSV-2 status on the protective effect of male circumcision on HIV acquisition by men. The secondary objective was to study the risk factors of HSV-2 incidence, especially the effect of male circumcision.

For these analyses, we used data collected during a male circumcision randomized controlled trial conducted in Orange Farm (South Africa), which demonstrated a reducing effect of male circumcision on the acquisition of HIV .

[18 ]

Methods

Collection of data

The technical details of the trial (ANRS-1265), description of the participants and HIV testing methods having been published elsewhere , only a summary will be presented in this article. Between February 2002 and July 2004, 3274 uncircumcised males, aged [START_REF] Auvert | Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial[END_REF] 18 to 24, were recruited, randomized into two groups and followed-up. Recruitment was conducted independently of HIV and HSV-2 status. Male circumcision was offered to the intervention group immediately after randomization and to control group participants after the end of the follow-up period. During each follow-up visits at 3 (M3), 12 (M12) and 21 (M21) months, circumcision status was ascertained by a nurse by genital examination and a blood sample was obtained. In addition, information about sexual behavior was collected, including number of sexual partners as a function of time and history of condom use with each sexual partner.

The dataset used in this study included 590 additional 21-month follow-up visits (20.0 of the total number of 21-month visits) which

%

were not included when the analysis of the effect of male circumcision on HIV was published because corresponding biological data were not available at that time.

Laboratory methods

Plasma specimens were extracted from each blood sample immediately after collection, frozen at 20 C and kept frozen until -°processing.

They were tested using an HSV type 2 specific IgG assay to detect HSV-2 antibodies with an index cutoff value of 1.1 (Kalon HSV-2 gG2 assay; Kalon Biologicals Ltd., Aldershot, UK), according to the manufacturer s recommendations.

'

Data analysis

HIV status, treated as censored data with time being continuous, was established at each follow-up visit for periods of non-uniform duration. These data were modeled using a piecewise exponential proportional hazards model in which the baseline hazard was considered constant between consecutive follow-up visits. This theoretical model was established to take into account the precise duration between each visit as well as the time-dependent covariates. It was implemented by running a Poisson log-linear model on a dataset with each line corresponding to one of three periods of follow-up: from randomization (M1) to M3, from M3 to M12 and from M12 to M21. During these periods participants remained HIV negative or became HIV positive . HIV incidence rates (IRs) and incidence rate ratios [22 -24 ] (IRRs) were thus estimated for the intervention and control groups (intention-to-treat analysis, ITT) and for circumcised and uncircumcised men (as-treated analysis, AT).

Adjusted IRRs were obtained by including in the analysis covariates that were collected for each period when they were time-dependent. The multivariate model included a) the period number, treated as a categorical variable, with the logarithm of the duration of exposure, in days, reported for each period as an offset, b) the participants sociodemographic factors, c) behavioral time-dependent ' covariates and d) HSV-2 status coded in three categories (stayed HSV-2 negative, became HSV-2 positive during follow-up, was HSV-2 positive at enrollment).

The participants sociodemographic factors were age, religion, ethnic group and alcohol consumption. The reported sexual behavior ' covariates were, for each period of follow-up, sexual risk behavior (defined as having at least one sexual contact unprotected by a condom), having a spousal partner and number of non-spousal sexual partners.

To assess the relative importance of HSV-2 seropositivity on HIV incidence among young men, the proportion of HIV incident cases attributable to HSV-2 seropositivity was computed using the formula given by Bruzzi and colleagues . 95 confidence intervals (95

[25 ] % %
CI) were obtained by bootstrapping.

The effect of HSV-2 status on the protective effect of male circumcision on HIV acquisition by men was assessed by testing the corresponding interaction term.

The piecewise exponential proportional hazards model was repeated to identify the risk factors of HSV-2 incidence.

In order to account for 1) the median time to seroconversion (window period) estimated at 120 days for the assay used and 2) the [START_REF] Morrow | Performance of the focus and Kalon enzyme-linked immunosorbent assays for antibodies to herpes simplex virus type 2 glycoprotein G in culture-documented cases of genital herpes[END_REF] healing period following male circumcision, the effect of male circumcision on HSV-2 was analyzed for the period M12 M21. This period included all those tested for HSV-2 at least 240 days after male circumcision. The other factors were studied for the period M1-M12.

Furthermore, since HIV infection is reduced by male circumcision and associated with HSV-2 infection , , the [18 -20 ] [27 28 ] analyses of the association between HSV-2 and male circumcision were repeated excluding those who HIV seroconvert during follow-up in order to determine whether the effect of male circumcision on HSV-2 was affected by HIV acquisition during follow-up.

Lastly, the association between HSV-2 incidence and health-seeking behavior, defined as at least one visit to a clinic for a genital problem during the 12-month period prior to a visit to the centre, was studied separately, univariately and multivariately, using male circumcision status and the cofactors listed above.

The confidence intervals of the percentages were calculated using Bayesian estimation . Statistical analyses were performed using [START_REF] Newcombe | Two-sided confidence intervals for the single proportion: comparison of seven methods[END_REF] the statistical package SPSS for Windows version 8 (SPSS, Chicago, Illinois, United States) and R (version 2.6.2) for analysis .

[30 ]

Complementary epidemiological data

To estimate HSV-2 prevalence by age and gender among the population of Orange Farm we used the data from a representative sample of 436 men and 476 women aged 15 to 49 from the community. These data were collected during a cross-sectional survey conducted in 2002 . Blood samples were tested for HSV-2 serostatus using the same HSV-2 assay as the one used in the present study.

[31 ]

For men and women, HSV-2 prevalences were 31.7 95 CI, 27.4 36.1 and 67.7 95 CI, 63.3 71.7 , respectively. HSV-2

% [ % %- %] % [ % %- %]
prevalence was 1.8 95 CI, 0.28 5.6 among men aged 15 to 19 and 13.8 95 CI, 7.9 21.7 ) among men aged 20 to 24.

% [ % %-%] % [ % %- % ]
Among circumcised and uncircumcised men, the percentage of HIV infections occurring among HSV-2 negative participants was similar, 64.9 (37/57) and 66.7 (10/15), respectively. The HSV-2 window period had a limited impact on this percentage: In effect, Effect of HSV-2 status on the protective effect of male circumcision on HIV acquisition

The protective effect of MC on HIV acquisition did not differ in terms of HSV-2 status (P .93 for the interaction effect between = randomization group and HSV-2 status). Among HSV-2 positive participants at baseline, the protective effect of male circumcision on HIV acquisition was 0.37 95 CI, 0.09 1.55 ; P .17 (ITT) (0.20 95 CI, 0.04 0.97 ; P .046 (AT)). This effect was 0.38 95 CI, 0.22 HIV positive.

[ % - ] = [ % - ] = [ % 0
presents the number of HSV-2 infections observed during follow-up and the univariate effect of male circumcision on HSV-2 Table 2 incidence as a function of the randomization group and circumcision status. There was a borderline protective effect in the ITT analysis and the effect became stronger and significant in the AT analysis. When both analyses were repeated for the follow-up period M1 M21, the effect was, as expected, diluted, but still significant for the AT analysis: IRR, 0.87 95 CI, 0.61 1.22 ; P .42 and IRR, 0.70 95 CI, presents the ITT and AT multivariate analyses of HSV-2 incidence. In both instances, the value of the protective effect of male Table 3 circumcision and its level of statistical significance were close to the corresponding univariate values ( ). HSV-2 incidence was Table 2 significantly associated with older age, sexual risk behavior and HIV status at enrollment. illustrates the strong association of HIV Table 4 status on HSV-2 acquisition during follow-up.

When those who HIV seroconverted during follow-up were excluded from the analyses, the univariate ITT and AT IRRs of HSV-2 incidence became 0.71 95 CI, 0.41 1.25 ; P . [START_REF] Holford | The analysis of rates and of survivorship using log-linear models[END_REF]

- ] = [ % - ] = Tables 2 3
that the observed effect of male circumcision on HSV-2 acquisition cannot be due to the effect of male circumcision on HIV acquisition.

Attendance at a health clinic for a health problem related to the genitals

The percentage of participants who attended a clinic for a health problem related to the genitals in the past 12 months was 10.8 95 % [ % CI, 9.7 12.0 . Participants who attended a clinic were more likely to have been recently infected with HSV-2 in the univariate analysis

%- %]
(IRR, 4.55 95 CI, 2.94 7.02 ; P < .001) and the multivariate analysis (aIRR, 3.31 95 CI, 2.12 5.18 ; P < .001).

[

% - ] [ % - ]

Discussion

The primary aim of this study was to assess the role of HSV-2 status on HIV acquisition by men, using data collected during a male circumcision trial conducted in Orange Farm (South Africa).

We found a strong association between the incidences of these two viruses. Such association may be due to the fact that the viruses are both sexually transmitted and must share risk factors. It may also be due to the fact that one virus increases the risk of transmission of the other , . [2 11 -14 ] This study was conducted in an area with high HIV and HSV-2 prevalences among adults , . As shown by the data of a [32 33 ] cross-sectional survey, the relatively low HSV-2 prevalence among our sample is likely due to the fact that participants were young men.

The population fraction of HIV incidence among young men due to HSV-2 in this study was around a quarter, value close to the lower bound of the estimates, ranging from 25 to 48 , obtained by modeling studies , . These results suggest an overall substantial % %

[ 34 35 ] effect of the HSV-2 status on the HIV epidemic. They further indicate that treating HSV-2 infection effectively could possibly prevent about a quarter of new HIV infections among males. However, recent research has shown that current acyclovir HSV-2 suppressive therapy is not able to reduce HIV acquisition among HSV-2 positive women . This can be explained by the fact that acyclovir does not

[36 ]
cure HSV-2 infection.

Our results also suggested with a borderline significance level that HIV incidence may be twice as high among those who became HSV-2 positive than among those who were HSV-2 positive at baseline. These results concur with those from a study, conducted among commercial sex workers in South Africa , which suggested that recent HSV-2 seroconversion appeared more important than established [START_REF] Ramjee | The impact of incident and prevalent herpes simplex virus-2 infection on the incidence of HIV-1 infection among commercial sex workers in South Africa[END_REF] HSV-2 infection for the acquisition of HIV. Finally, we found that the protective effect of male circumcision on HIV acquisition was not altered by HSV-2 status or HSV-2 acquisition.

In terms of risk factor for HSV-2, our findings indicated that participants who were HIV positive at enrollment were more likely to acquire HSV-2. There was an independent and protective effect of male circumcision on HSV-2 acquisition by young males, which was significant only in the AT analysis. This effect was diluted and the statistical significance was lower in the ITT analysis, which can be attributed to the cross-over of 8.2 of participants in this study . In the ITT analysis, the size of the protective effect of male % [START_REF] Auvert | Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial[END_REF] circumcision on HSV-2 acquisition observed in this study was consistent with the results of a meta-analysis of observational studies which showed a relative risk of 0.88 95 CI, 0.77 1.01 , and the preliminary results from the Rakai male circumcision trial . However

[ % - ] [21 ] [37 ]
the AT analysis suggested a strong protective effect of MC against HSV-2 acquisition.

There are some limitations to this study: First, the window period of HSV-2 testing may impact the prevalence and incidence of HSV-2. Secondly, the crossover of participants was 8.2 and may explain the discrepancy between results from the ITT and AT analyses.

%

Thirdly, the sample included young men among whom HIV and HSV-2 prevalence is relatively low compared to the general population, so our findings may not be generalized. Finally, the participants were taking part in a randomized controlled trial, so there may have been a

selection bias.

This study provides additional evidence supporting the promotion of male circumcision in Africa: male circumcision has the potential to reduce the female-to-male transmission of HSV-2 and thus the spread of HSV-2, in addition to being a method proven to reduce the female-to-male transmission of HIV. The protective effect of male circumcision on HSV-2 is another argument in favor of rolling-out male circumcision in African countries were most males are uncircumcised .

[38 ]

Because of the complex interplay between HSV-2, HIV and male circumcision, further studies, in particular modeling studies, are needed to better understand their interactions; not only in the short term, as studied by randomized controlled trials, but also in the long term. Such studies should provide a comprehensive investigation of the epidemiological and geographical distribution of HIV and HSV-2 in Africa, taking male circumcision prevalence into account. Part of the effect of male circumcision on HIV may be attributed to its effects on HSV-2, such as the reduction of genital herpetic lesions which are associated with HSV-2 infection and may facilitate HIV transmission. However, this study contends that this effect is limited at population level.

Ackowledgements:

Financial support ANRS grant 1265 (France), NICD (South Africa), Gates Foundation (USA) grant 33759, INSERM (France), SACEMA (South Africa).

The authors would like to thank all those who agreed to take part in this study, answer the questions put to them and provide swab samples.

The authors would like to thank Gaph Sipho Phatedi for his management of the recruitment process and Yvon de La Soudi re for his help in è the management of the data set. The authors would like to thank Dr Bhekuyise Gwala, Dr George Shilaluke and Dr Dumiso Zulu who performed the male circumcisions for the study. The authors would like to thank Goliath Gumede for the clinical investigation and Zodwa

Nkosi for interviewing all the respondents. They would also like to thank Bongiwe Klaas for the data capture as well as Mabel Hunter, the

Footnotes: Potential conflicts of interest

None reported.

Conference

Presented in part: 16th Biennial Meeting of the International Society for Sexually Transmitted Diseases Research, abstract TO-704.

Amsterdam, The Netherlands, July 10 13, 2005.

-

Contributions

JT and BA analyzed the data and wrote the first draft. DT organized the collection of the samples. AP analyzed the samples. All authors contributed to the writing.

Table 1

HIV incident cases among men HIV negative at baseline and effect of HSV-2 on HIV incidence.

HIV infection HIV IRR HIV aIRR

[2 - 10 ][ 2

 102 11 -14 ] associated with HSV-2 significantly increased the odds of HIV-1 detection in genital shedding (OR, 2.4 95 confidence interval CI , 1.2

=

  aIRR adjusted for the circumcision status, age, religion, ethnic group, alcohol consumption, sexual risk behavior, marital status and non-spousal partners (see notes in )= Table3

  Using the proportion of participants among those who became HIV positive who were HSV-2 positive at recruitment or became HSV-2 positive during follow-up, 34.2 (25/73) 95 CI, 24.1 45.4 ) and the corresponding aIRR, 5.3 95 CI, 3.1 8.9 , we estimated that 27.8 95 CI, 17.7 37.2 of HIV incident cases in men were attributable to HSV-2 seropositivity or HSV-2 acquisition.

	%		%
	among the 33 HIV infections occurring during the M1 M12 period, 57.6 (19/33) 95 CI, 41 73 were among participants who -% [ % %-%]
	remained HSV-2 negative during the M1 M21 period.
			%	[ %	%-	%]	[ %	-]
	% [ %	%-	%]

-

  .66 P < .001 (ITT) (0.24 95 CI, 0.13 0.45 ; P < .001 (AT)) among those who were HSV-2 negative. The protective effect of male

	-	]	[ %	-	]
	circumcision on HIV among those who became HSV-2 positive during follow-up was 0.45 95 CI, 0.16 1.27 ; P .13 (ITT) (0.28 95 [ % -] = [ %
	CI, 0.08 0.99 ; P .048 (AT)). -] =
	Risk factors of HSV-2 incidence
		130 HSV-2 infections were diagnosed during follow-up: 102 (78.5 ) 95 CI, 70.9 84.9 among HIV negative participants, 11 % [ % %-%]
	(8.5 ) 95 CI, 4.5 14.1 among HIV positive participants and 17 (13.1 ) 95 CI, 8.0 19.6 among participants who became % [ % %-%] % [ % %-%]

  and 0.63 95 CI, 0.36 1.11 ; P .11. The corresponding aIRRs became 0.73 95

	[ %	-	]	=	[ %	-	]	=	[ %
	CI, 0.39 1.38 ; P .34 and 0.50 95 CI, 0.26 0.95 ; P .035. These values are close to the values reported in	and , indicating

Table 2

 2 HSV-2 seroincidence and univariate effect of male circumcision in the period M12-M21 of follow-up.

	Type of analysis	HSV-2 cases	Follow-up (py)	HSV-2 IR (95 CI; per 100 py) %	HSV-2 IRR (95 CI; P) %
	Intention-to-treat
	Control	35	1003	3.54 (2.54 4.93)
	Intervention	23	995	2.33 (1.55 3.51) -	0.66 (0.39 1.12) P 0.12 -=
	As-treated
	Uncircumcised	37	985	3.81 (2.76 5.26)
	Circumcised	21	1012	2.09 (1.36 3.21) -	0.55 (0.32 0.94) P 0.028 -=
	IR incidence rate

-1 -1 = py person-year = IRR incidence rate ratio =

Ethics

The research protocol was reviewed and approved by the University of Witwatersrand Human Research Ethics Committee (Medical) on February 22, 2002 (protocol

Results

Population characteristics

Among the 3274 participants enrolled in the trial, 5.9 were HSV-2 positive and 4.4 were HIV positive. 2974 participants were

HIV incidence and HIV incidence rate ratio

73 new HIV infections were diagnosed during follow-up.

indicates the effect of HSV-2 status during follow-up on HIV Table 1 incidence: HIV incidence rate ratio was significantly higher among participants who were HSV-2 positive at recruitment and among participants who became HSV-2 positive during follow-up than among participants who stayed HSV-2 negative during follow-up. The HIV incidence rate ratio was about twice as high among those who became HSV-2 positive than among those who were HSV-2 positive at baseline, with a borderline level of significance, IRR, 2.2 95 CI, 0.95 5.1 ; P .067 and aIRR, 2.1 95 CI: 0.87 5.1 ; P .098.

Population attributable fraction

Of the 73 new HIV infections diagnosed during follow-up, 65. among participants who got infected with HSV-2 during follow-up.

Married or living as married 5 Yes 1.60 (0.85 3.00) P 0.14 4 Defined as having at least one sexual contact not protected by condom. 5 At some time in the past 3-month period before M3, and in the past 9-month period before M12 and M21. 6 In the past 3-month period before M3, and in the past 9-month period before M12 and M21.