domain: spi phys

text:
Anna A Kostek

Felix Lößle

Robin Wickersheim

Manuel Keßler

Ronan Boisard

Gabriel Reboul

Antonio Visingardi

Mattia Barbarino

Anthony D Gardner

EXPERIMENTAL INVESTIGATION OF UAV ROTOR AEROACOUSTICS AND AERODYNAMICS WITH COMPUTATIONAL CROSS-VALIDATION

Keywords:

The study provided a base of comparison of known computational techniques with different fidelity levels for performance and noise prediction of a single, fixed-pitch UAV rotor operating with varying flight parameters. The range of aerodynamic tools included blade element theory, potential flow methods (UPM, RAMSYS), liftingline method (PUMA) and Navier-Stokes solver (FLOWer). Obtained loading distributions served as input for aeroacoustic codes delivering noise estimation for the blade passing frequency on a plane below the rotor. The resulting forces and noise levels showed satisfactory agreement with experimental data, however differences in accuracy could be noticed depending on the computational method applied. The wake influence on the results was estimated based on vortex trajectories from simulations and those visible in Background Oriented Schlieren (BOS) pictures. The analysis of scattering effects showed that influence of ground and rotor platform on aeroacoustic results was observable even for low frequencies.

Introduction

Unmanned aerial vehicles, like quadrocopters, have gained popularity due to their vertical take-off and landing (VTOL) and hover capabilities allowing operation in urban areas. Nevertheless, depending on the mission profile, the operation time of small UAVs may be mostly spent on forward flight [START_REF] Theys | Experimental and Numerical Study of Micro-Aerial-Vehicle Propeller Performance in Oblique Flow[END_REF][START_REF] Yang | Aerodynamic and Aeroacoustic Performance of an Isolated Multicopter Rotor During Forward Flight[END_REF]. Therefore, op-timisation of aerodynamic rotor design in regard to flight in edgewise flow could help to meet an ongoing challenge of increasing flight duration for electric UAVs. On the other hand, the developing UAV market is severely constrained by the public acceptance of the generated noise. While nowadays most multicopters are powered by electrical motors, it is the rotor that represents UAV's main noise source [START_REF] Gur | Design of a Quiet Propeller for an Electric Mini Unmanned Vehicle[END_REF]. Although extensive studies have been done considering propellers operating under axial-flow conditions [START_REF] Ning | An Experimental Study on the Aerodynamic and Aeroacoustic Performances of a Bio-Inspired UAV Propeller[END_REF][START_REF] Ning | An Experimental Study on the Aerodynamics and Aeroacoustic Characteristics of Small Propellers[END_REF][START_REF] Deters | Static Testing of Propulsion Elements for Small Multirotor Unmanned Aerial Vehicles[END_REF][START_REF] Weitsman | Parametric Study of eV-TOL Rotor Acoustic Design Trades[END_REF][START_REF] Gur | Comparison Between Blade-element models of Propellers[END_REF], their results are not applicable for forward flight with higher advance ratios. At the same time, the mechanisms acting on a small propeller in such conditions are not yet fully understood and cannot be directly derived from the full-size helicopter rotor. The main difference comes from the blade planform shape, as multicopters are typically driven by rigid blades with non-linear twist distribution and strong chord variation along the span [START_REF] Deters | Static Testing of Propulsion Elements for Small Multirotor Unmanned Aerial Vehicles[END_REF]. As advancing and retreating side effects are not compensated, like in the case of hinged helicopter rotors, a fixed-pitch propeller in forward flight experiences high thrust fluctuations throughout the rotation, which also results in an asymetry of the produced wake [START_REF] Krebs | Transient Thrust Analysis of Rigid Rotors in Forward Flight[END_REF]. Additional complexity arises when small-size propellers operate at low Reynolds num- bers, which has impact on both performance [START_REF] Deters | Reynolds Number Effects on the Performance of Small-Scale Propellers[END_REF][START_REF] Gur | Propeller Performance at Low Advance Ratio[END_REF][START_REF] Mccrink | Blade Element Momentum Modelling of Low-Re Small UAS Electric Propulsion Systems[END_REF] and noise generation [START_REF] Grande | Aeroacoustic Investigation of a Propeller Operating at Low Reynolds Numbers[END_REF]. As a result, accurate aerodynamic and aeroacoustic prediction tools, capable of handling specifics of small rotors in forward flight are necessary. From aerodynamic methods described in the literature, models based on blade element theory (BET) are the most simplified and time-efficient, yet for many cases they show accuracy comparable with higher-fidelity solvers [START_REF] Gur | Comparison Between Blade-element models of Propellers[END_REF][START_REF] Bergmann | Comparison and evaluation of blade element methods against RANS simulations and test data[END_REF][START_REF] Cerny | Systematic Investigation of a Fixed-pitch Small-scale Propeller under Non-axial Inflow Conditions[END_REF]. For this reason, they are commonly used as an initial loading estimation during the design process [START_REF] Gur | Design of a Quiet Propeller for an Electric Mini Unmanned Vehicle[END_REF][START_REF] Weitsman | Parametric Study of eV-TOL Rotor Acoustic Design Trades[END_REF]. BET methods require external estimation of inflow velocities, which can be derived from momentum theory for cases like hover or axial climb, however forward flight calculations typically involve more complicated models [START_REF] Niemiec | Effects of Inflow Model on Stimulated Aeromechanics of a Quadrotor Helicopter[END_REF]. Methods based on potential flow represent a complexity between BET models and RANS solvers. Their great advantage is the ability to simulate unsteady conditions, while ensuring timeefficiency [START_REF] Krebs | Transient Thrust Analysis of Rigid Rotors in Forward Flight[END_REF]. Potential methods are usually coupled with a free-wake method, as described in [START_REF] Leishman | Principles of Helicopter Aerodynamics[END_REF] but can also include extensions for viscous particle wake [START_REF] Tan | Simulating unsteady aerodynamics of helicopter rotor with panel/viscous vortex particle method[END_REF] or post-processing viscous and compressible corrections. In recent years a few studies have been dedicated to the experimental research of small propeller's performance in edgewise flight, like [START_REF] Theys | Wind Tunnel Testing of a VTOL MAV Pro-peller in Tilted Operating Mode[END_REF][START_REF] Kolaei | Experimental Analysis of Small-Scale Rotor at Various Inflow Angles[END_REF], also including aeroacoustic measurements [START_REF] Yang | Aerodynamic and Aeroacoustic Performance of an Isolated Multicopter Rotor During Forward Flight[END_REF][START_REF] Lößle | Experimental measurement of a UAV rotor's acoustic emission[END_REF]. Studies described in [START_REF] Krebs | Transient Thrust Analysis of Rigid Rotors in Forward Flight[END_REF] showed the application of potential flow method for such conditions. Other studies [START_REF] Theys | Experimental and Numerical Study of Micro-Aerial-Vehicle Propeller Performance in Oblique Flow[END_REF][START_REF] Cerny | Systematic Investigation of a Fixed-pitch Small-scale Propeller under Non-axial Inflow Conditions[END_REF] juxtaposed results from various aerodynamic tools together with experimental data. This study, prepared within the GARTEUR Action Group 25, compares solvers with different fidelity levels including BET, potential flow methods (UPM, RAM-SYS), lifting-line method (PUMA) and Navier-Stokes solver (FLOWer) regarding load-prediction, but also examines their applicability as a base for noise estimation.

Experimental setup

The experiment involved aerodynamic and aeroacoustic measurements and was conducted in the Rotor Test Facility Göttingen (RTG) of the German Aerospace Center (DLR) with a setup presented in Figure 1. The aeroacoustic array was positioned 1.35 m below the rotor plane and consisted of 512 MEMS (micro-electrical-mechanical systems) microphones (Fig. 2). Presented noise levels were corrected based on the measurements with loudspeaker emitting white noise to compensate for the effects connected with room acoustics. Thrust and torque were measured with a strain-gauge and piezoelectric balance, respectively. The measurements included variations in flight velocity, rotor RPM and tilt angle. However, special focus was put on a case presenting the effect of a change in rotor inclination between -30°and 30°(Fig. 3) with fixed flight velocity and rotational speed (advance ratio 0.146). Vortex trajectories were detected by the Background Oriented Schlieren (BOS) method using a high-speed camera, reflecting mirror and dotted background mounted above the propeller. A detailed description of the experimental setup can be found in [START_REF] Lößle | Aerodynamics of Small Rotors in Hover and Forward Flight. 48th European Rotorcraft Forum[END_REF].

Figure 3: Tilt angle sign convention

Geometry

A 2-bladed, fixed-pitch KDE 12.5x4.3" rotor with 0.318 m diameter and solidity 0.075 was used. Computational models were prepared based on a 3Dscanned blade, divided into series of spanwise cuts (Fig. 4). Figure 5 presents the obtained twist and chord distributions. Due to inaccuracies of a scanned surface, 4-digit NACA profiles were identified to approximate a hydraulically smooth airfoil shape at the measured cross sections [START_REF] Abbott | Summary of Airfoil Data[END_REF]. The shape of the trailing edge could be adjusted depending on the computational method applied (Fig. 6).

BET and FW-H code

The blade element theory (BET) represents the most simplified and the least computationally expensive of the applied methods. In BET, steady lift and drag values are calculated for spanwise blade sections at different azimuthal positions and then integrated for the whole rotation. A value of the inflow angle and the corresponding angle of attack can be determined iteratively from a loop with an inflow model. A dedicated Python code used in this study included a linear inflow model developed by Pitt and Peters [START_REF] Chen | A Survey of Non-uniform Inflow Models for Rotorcraft Flight Dynamics and Control Applications[END_REF] (Fig. 7). Aerodynamic characteristics for airfoils identified for each spanwise cut were prepared using XFOIL and considered variation of Reynolds and Mach numbers. Lift and drag coefficients were then extrapolated for high angles of attack with the post-stall Viterna model [START_REF] Mahmuddin | Airfoil Lift and Drag Extrapolation with Viterna and Montgomerie Methods[END_REF] (Fig. 8). The BET code did not include wake model. Two ways of including tip-loss effects were investigated, either by adding Prandtl's function to the solution or by estimating a tip-loss factor B as a constant value (as described in [START_REF] Leishman | Principles of Helicopter Aerodynamics[END_REF] typically between 0.95 and 0.98). The Prandtl's function approach lead to strong underestimation of thrust values for a rotor operating in strong upwash (positive tilt angles), therefore in the presented results a B factor was simply approximated as 0.97 and mean thrust values were reduced by a factor B 3 for forward flight cases [START_REF]Helicopter Theory[END_REF].

As the final step, the resulting loading distribution served as an input for a coupled aeroacoustic prediction code based on the Ffowcs Williams-Hawkings (FW-H) equation with the Farassat 1A formulation, as described in [START_REF] Gur | Design of a Quiet Propeller for an Electric Mini Unmanned Vehicle[END_REF]. Only loading noise was taken into account in the acoustic calculation.

UPM and APSIM

UPM is an unsteady free-wake panel method developed at DLR allowing the simulation of flows with arbitrary body shape and motion [START_REF] Ahmed | Unsteady Panel Method Calculation of Pressure Distribution on BO 105 Model Rotor Blades[END_REF][START_REF] Yin | Helicopter Main-Rotor/Tail-Rotor Interaction[END_REF]. The code solves potential flow, although viscosity and compressibility effects can be included in post-processing. A viscous correction, applied to improve the estimation of torque values, estimates the contribution of profile torque using equation (1) [START_REF]Helicopter Theory[END_REF], where section zero-lift drag coefficient C d0 has a default value of 0.0075, σ and µ stand for rotor solidity and advance ratio, respectively.

C Q0 = σC d0 8 (1 + 1.5µ 2 -0.37µ 3.7 ) (1)
Lifting bodies in UPM are modelled as a distribution of sources and sinks on the blade surface accounting for the displacement effect and doublet distribution along the chord simulating the lift. The weighting function of doublet strength is prescribed and depends on the profile thickness. An iterative scheme to ensure pressure equality at the trailing edge and satisfy the Kutta condition was applied in the calculations. The panel generation code PANGEN served in this study as a tool to prepare a computational model of meshed blade with finite thickness and sharp trailing edge (Fig. 9). The full span free wake of the blades mostly used a vortex lattice, yet additional calculations were carried out using particle wake method, in which the vortex filaments are replaced by point vortices (Fig. 10). The particle model solves the vorticity transport equation derived from the incompressible Navier-Stokes equations. As there are no connections between the neighbouring particles, this approach enables an improved solution for cases where the wake interferes with solid bodies. Calculations were carried out for approximately 8 rotations with step size reduced from 5°to 2°after 5 rotations. A coupled code APSIM (Aeroacoustic Prediction System based on Integral Methods) [START_REF] Wilke | Prediction of Acoustic Far Field with DLR's Acoustic Code APSIM+[END_REF] takes into account linear sound propagation and includes two in-tegral formulations of FW-H equation for an permeable and impermeable surface. The latter approach was used in this study based on pressure distribution on the blade surface from the last rotation calculated in UPM.

PUMA and KIM

PUMA (potential unsteady methods for aerodynamics) is an unsteady lifting line / free-wake solver developed at ONERA since 2013. It includes a coupling between an aerodynamic module and a kinematic module. The aerodynamic module uses the lifting line method with a free-wake model based on Mudry theory [START_REF] Mudry | La théorie des nappes tourbillonnaires et ses applications à l'aérodynamique instationnaire[END_REF], which describes the unsteady evolution of a wake modelled by a potential discontinuity surface. The lifting line method is based on twodimensional (2D) airfoil characteristics through lookup tables. It can handle some 3D corrections for blade sweep and 2D unsteady nonlinear aerodynamics effects through dynamic stall models. Moreover, different time discretizations are available in order to balance between accuracy, numerical stability and computational time. The kinematic module employs a rigid multi-body system approach using a tree-like structure with links and articulations. It enables any arbitrary motion between the different elements. PUMA is usually used for any aerodynamic study of fixed wings and rotating wings configurations which require low computational cost or a large amount of parametric investigations like pre-design studies. It has also been successfully applied for helicopter rotors wake in interactions with obstacles [START_REF] Gallas | Experimental and numerical investigation of the aerodynamic interactions between a hovering helicopter and surrounding obstacles, 43nd European rotorcraft Forum[END_REF][START_REF] Boisard | Aerodynamic investigation of a helicopter rotor hovering in the vicinity of a building. 74th AHS forum[END_REF] and for rotor / rotor interactions [START_REF] Boisard | Numerical Analysis of Rotor / Propeller aerodynamic interactions on a high speed compound helicopter[END_REF]. In this study, the 2D airfoil characteristics are the same as the ones used in the BET method. The lifting line is divided into 45 radial stations for wake emission using a square root distribution. A time step of 5°was used for the unsteady computation over 8 rotor revolutions. The unsteady spanwise distribution of loads obtained using PUMA are empirically distributed in terms of pressure on the entire blade surface and are then used by the KIM code [START_REF] Prieur | Comparison of the Ffowcs Williams-Hawkings and Kirchhoff rotor noise calculations[END_REF][START_REF] Rahier | An efficient Kirchhoff integration method for rotor noise prediction starting indifferently from subsonically or supersonically rotating meshes[END_REF] to determine the noise emission. KIM is based on a Ffowcs-Williams and Hawkings formulation implemented in an advanced time approach.

FLOWer and ACCO

For high fidelity simulation the numerical process chain used at the IAG was applied. CFD results are generated with the structured code FLOWer, originally developed by DLR [START_REF] Kroll | The Navier-Stokes code FLOWer[END_REF] and further developed at the Institute of Aerodynamics and Gas Dynamics at the University of Stuttgart [START_REF] Kowarsch | Computation of Helicopter Phenomena Using a Higher Order Method[END_REF]. Acoustic coupling was provided by IAG's FW-H solver ACCO [START_REF] Keßler | Source-Time Dominant Aeroacoustics[END_REF] with usage of the data output of FLOWer. A second order dual time stepping for temporal evolution was used with a time step of 1°to resolve the acoustic waves. Furthermore, the Menter-SST turbulence model was applied to close the URANS equations. For spatial discretization the surface of the propeller was meshed with 0.1% of the chord length in streamwise direction. To recognize tip effects mesh refinement up to 1% of the radius in spanwise direction was set. Using the Chimera technique a separate background mesh was created utilizing hanging grid nodes to reduce the numerical expense. Furthermore, in all background volume cells the WENO scheme of 6 th order is carried out for numerical stability and reduced dissipation. In the surface region the dimensionless wall distance is kept low at y + < 1. The λ 2 -criterion for vortex visualization and numerical setup are shown in Figure 11 The acoustic code ACCO uses an acoustic integration surface, within which sound is generated by the fluid. The integration is accomplished on a cylindrical permeable surface (red in Fig. 13) to enclose all sound sources. The selection of the spatial discretization in the background mesh was based on the resolution of the first harmonic wave length, with 20 cells discretizing the wave length of the blade passing frequency (BPF). To avoid excessive dissipation the integration surface is placed in the finest grid area without cell size changes. The scattering effects described in Section 6.1 were computed using the Boundary Element Method (BEM) tool ScatMan [START_REF] Dürrwächter | Numerical Assessment of Open-Rotor Noise Shielding with a Coupled Approach[END_REF] developed at the Institute of Aerodynamics and Gasdynamics [START_REF] Dürrwächter | Simulation of Installation Effects on Open-Rotor Acoustics with a Coupled Numerical Tool Chain[END_REF]. Within the ScatMan tool, the sound propagation in the frequency domain is described by the Helmholtz equation, expanded with Green's second theorem resulting in the Helmholtz-Kirchoff equation [START_REF] Dürrwächter | Simulation of Installation Effects on Open-Rotor Acoustics with a Coupled Numerical Tool Chain[END_REF]. To include ScatMan in the numeric tool chain consisting of FLOWer and ACCO, the shielding had to be discretized in triangle elements. ACCO in the first step calculates the incident sound pressure at the discrete points on the surface of the shielding as well as in a small distance above each surface point. Afterwards, the ambient conditions are added resulting in the complete solution consisting of acoustic and scattering field.

RAMSYS and ACO suite

The CIRA aerodynamic simulations were carried out by using the medium-fidelity code RAMSYS [START_REF] Visingardi | Validation of CIRA's rotorcraft aerodynamic modelling system with DNW experimental data[END_REF], which is an unsteady, inviscid and incompressible free-wake vortex lattice boundary element methodology (BEM) solver for multi-rotor, multi-body configurations developed at CIRA. It is based on Morino's boundary integral formulation [START_REF] Morino | A General Theory of Unsteady Compressible Potential Aerodynamics[END_REF] for the solution of Laplace's equation for the velocity potential φ. The surface pressure distributions are evaluated by applying the unsteady version of Bernoulli equation, which is then integrated to provide the forces and moments on the configuration and the surrounding obstacles. A computational acceleration is obtained by applying the module for symmetrical flows and geometries implemented in the solver and the parallel execution via the OpenMP API. The aeroacoustic simulations were carried out by using the ACOustic suite developed at CIRA and consisting of several tools for the evaluation of noise generation and propagation. The ACO-FWH solver is used for computing the acoustic free-field generated by the rotor blades. It is based on the FW-H formulation [START_REF] Williams | Sound generation by turbulence and surfaces in arbitrary motion[END_REF] described in [START_REF] Casalino | An advanced time approach for acoustic analogy predictions[END_REF][START_REF] Casalino | Simulation of helicopter community noise in complex urban geometry[END_REF]. The advancedtime formulation of Farassat 1A is employed, and the linear terms (the so-called thickness and loading noise contributions) are computed through integrals both on the moving blades surface (impermeable/rigid surface formulation). Moreover, the space derivatives of the linear terms are also evaluated through a numerical integration for coupling the free-field solution computed with FW-H with scattering solvers [START_REF] Barbarino | A high-fidelity aeroacoustic simulation of a VTOL aircraft in an urban air mobility scenario[END_REF]. The quadrupole contribution due to the nonlinear terms distributed in the perturbed field around the blade is neglected. The computational acceleration is obtained by a parallel execution via the MPI API. The simulation of the aeroacoustic free-field was carried out by using the aerodynamic database evaluated by RAM-SYS, and consisting of the rotor blade pressure distributions. The ACO-FAM solver was used for the simulation of the acoustic scattering field. It is based on the numerical solution of the convected Helmholtz equation which can be handled with an integral boundary element formulation [START_REF] Barbarino | A bem-fmm approach applied to the combined convected Helmholtz integral formulation for the solution of aeroacoustic problems[END_REF]. ACO-FAM implements the aforementioned integral boundary element formulation for the solution of interior and exterior acoustic problems (radiation and scattering) and solves the inverse problem through a collocation with the BEM. The ACO-ENV solver implements the acoustic propagation of a generic noise source through a ray approximation as described in [START_REF] Petrosino | Aeroacoustics assessment of an hybrid aircraft configuration with rearmounted boundary layer ingested engine[END_REF]. This solver allows for the computation of several noise metrics starting from the definition of the flight trajectory and the noise source database encompassing the flight envelope. Moreover, it is able also to account for single reflections and attenuation by barriers or buildings. Single reflections are managed through an analytical mirroring of the source whereas the attenuation is managed through semi-analytical formulations [START_REF] Maekawa | Noise reduction by screens[END_REF][START_REF] Kurze | Noise reduction by barriers[END_REF].

Results

Aerodynamic loading prediction

A comparison of time-averaged thrust and torque values presented in Figures 141516indicates that general tendencies captured in the measurements are reproducible using all computational tools, however some differences can be noticed in terms of accuracy. It is worth mentioning that for moderate flight velocities BET solution offers good loading estimation, even with simplified assumptions considering tip-loss factor. As the same 2D airfoil characteristics were used as an input for BET and PUMA, the loading calculated with these both methods is similar in Figures 1415and for low tilt angles in Figure 16. The accuracy of these solvers becomes worse for low advance ratios (Fig. 15), which can be explained by the limitations of XFOIL for calculating cases with very small Reynolds numbers and omission of rotational effects in the airfoil data. For most of the analysed points underprediction of torque values is expected from potential flow solvers, like UPM or RAMSYS caused by neglection of viscosity effects. A post-processing correction in UPM estimating the contribution of profile drag considerably improved the agreement between calculated and measured torque values. The assumption of inviscid flow lead to the underestimation of torque by at least 10% for most of presented cases. With the rotor tilted backwards, the interaction with vortices becomes dominant and the lines from BET and PUMA diverge, as the BET code did not include a wake model in the solution (Fig. 16(b)). The increase in interactional effects between positive and negative rotor inclinations can be observed in Figure 18 presenting wake visualizations and from unsteady loads depicted in Figure 17. For negative tilt angles, like in Figure 18(a), the horizontal component of the velocity induced by the propeller is in the direction of the free stream velocity and the vertical component pushes the wake downward away from the propeller. This combination of velocities causes a rapid convection of the wake downstream. As a consequence, there is little interaction between the wake and the propeller, the unsteadiness is moderate and so are the effects on the loads acting on the propeller disk (Fig. 17(a)). Figure 18(b) shows the wake developed at a positive tilt angle. In this case, the horizontal component of the velocity induced by the propeller is opposite to the free stream velocity. This not only reduces the convection process downstream but also causes the wake to be fully ingested by the propeller disk with the resulting generation of high interactional effects giving rise to unsteady loads (Fig. 17 igure 18: Propeller wake system development for different tilt angles simulated in RAMSYS Additionally, Fig. 17 presents a comparison of unsteady loading for chosen tilt angles calculated in UPM with vortex lattice and vortex particles. Although the discrepancy between time-averaged thrust values calculated with these both methods was negligible, an apparent difference can be noticed in thrust fluctuations for positive angles of attack (here 20°), for which the particle method offers a more stable solution. This can be explained by the distortion of the vortex lattice wake when straight line filaments cross blades and singularity problems appearing when wake panels are too close to each other. The loading calculated using BET differs in phase compared with results from other methods. According to the BET code the maximum thrust is reached around azimuth 90°, which is where the calculated relative velocity coming from the rotational motion of the blade and flight velocity reaches the highest value. For all other results the thrust peak appears around 40°l ater, more to the front of of the rotor disc. This tendency is due to unsteady effects, which are not covered by a simplified inflow model and originate mostly from the wake presence, as shown in Figure 19. The phase delay can be partially corrected by means of Theodorsen's theory, that accounts for unsteady development of lift, as described in [START_REF] Leishman | Principles of Helicopter Aerodynamics[END_REF]. In Figure 19 phase shift resulted from Theodorsen's function was averaged throughout the disc for each blade section and used to correct the initial result. The applied correction helped to include a case-dependent time delay in the BET solution, however it did not ensure com-plete compatibility with other solvers. A comparison between BET and the UPM result without a wake, shows that the time delay can be modelled using the free wake, which is missing in the BET code. In this study, Theodorsen's function served only as a quick estimation, as the main objective was to investigate the possible applications of basic BET assumptions.

Noise prediction

Aerodynamic results indicate that the effect of tilt change with the other parameters kept fixed had the largest effect on the rotor loading (compare Fig. 14, 15 and 16). For this reason, the aeroacoustic study was focused on cases with constant velocity 12.9 m/s and rotational speed of 5400 RPM with a range of rotor inclinations, as analysed in Figure 16. Noise carpets were prepared based on the calculated loadings using several acoustic solvers described in Section 4. The focus of the analysis was put on the blade passing frequency as it had a dominant influence on noise levels. The noise directivity pattern for cases with forward tilt of the rotor (see Fig. 20) is similar for all of the computational methods. However, the accuracy of results depended on fidelity levels of applied tools with the ACCO solution closest to the experimental data. The noise carpet calculated with BET+FW-H shows agreement with other methods, what indicates that the wake had no great influence in these range of tilt angles and that the main noise contribution came from the loading noise. Interestingly, the phase discrepancy observed for unsteady loading calculated with BET did not considerably influence the quality of the result. As expected, for higher tilt angles the loading increases and so do noise levels on all calculated carpets. However, the difference in directivity between the outcome of BET and other methods can be noticed (Fig. 21). This tendency no longer occurred for the highest backward inclination of the rotor as presented in Figure 22. An explanation of this phenomenon can igure 24: Vortex trajectories detected in BOS pictures and UPM wake visualizations be found in vortex trajectories detected in (BOS) pictures and also visible in UPM visualizations (Fig. 24). The marked positions of tip vortices for moderate positive tilt angles were always located in the proximity of the blades, strongly affecting rotor loading (Fig. 24(d), 24(e)). For 30°the vortices tend to move away from the rotor plane, therefore, the result of BET neglecting wake influence again agreed with the measurement. This observation could also explain why the highest noise levels were measured for a tilt angle of 20°even though the highest loading can be observed for 30°inclination.

With the propeller tilted backwards, more differences in calculated noise levels between analysed methods can be observed, which is connected to increased unsteadiness in the flow and decrease of stability of numerical solutions. For these cases also a discrepancy between the aeroacoustic results based on loading prepared with vortex lattice and vortex particles in UPM can be observed (compare Figures 21(b) and 22(b) with 23), as high time derivatives of thrust did not appear in the latter (Fig. 17).

Scattering effects

Although the calculated noise carpets showed satisfactory agreement with experimental data in the vicinity of the rotor, none of completely captured measurement results with the highest deviations observed further behind the rotor. Reasons for this can be found by evaluating the influence of scattering effects at the aerodynamic shielding, rotatable rotor base and ground.

Influence of the shielding

An acoustic study was carried out to observe the influence of the scattered field caused by the aerodynamic shielding placed beneath the rotor during the measurements (Fig. 25). For 5400 RPM and velocity 12.9 m/s a case with tilt angle of -10°was chosen for the investigation as in these conditions propeller wake is expected to interfere the most with the shielding. Calculations were conducted using ScatMan tool described in Section 4.4 with an assumption of a hard shielding surface (v n = 0). Figure 26 shows that acoustic wave reflection caused an increase of up to 2 dB for the BPF on the upstream side of the shielding surface, as well as decrease of around the same value on the downstream side. However, as the dimensions of the shielding are much smaller than the wavelength of the blade passing frequency (3.8 m) sound waves reflected by the shielding caused a negligible deviation in the noise field, which can be observed comparing Figure 27 with the baseline numerical approach in Figure 20(d). Additionally, as the presence of the shielding did not cause a change of more than 3% in the thrust values computed for chosen cases in UPM, the baseline approach to neglect its aerodynamic and aerodynamic influence in the calculations is justifiable.

Figure 25: Propeller included in CFD simulation and shielding element implemented in the Scatman tool

Installation and ground proximity effects

Further effects were evaluated using ACO-FAM solver as described in Section 4.5. The computational setup included the part of ground and the platform on which the propeller was mounted (Fig. 28).

The integration surface used for FW-H and BEM calculation is presented on Fig. 29. Calculations were conducted for tilt angles -10°and 20°, 5400 RPM and flight velocity 12.9 m/s. As the dimensions of the analysed objects are in the order of the acoustic wavelength, their influence can be observed in the noise carpets of the blade passing frequency. The acoustic fields including scattering effects (Fig. 30) show a visible difference in both noise directivity and noise levels in comparison with base results from Figure 20(f) and Figure 21(f). Depending on the case and the analysed location the presence of the ground and rotor platform caused either an increase (Fig. 30(b)) or decrease in the noise levels (Fig. 30(a)). Aeroacoustic and aerodynamic calculations were performed, indicating that measurement results for most cases were reproducible with satisfactory agreement by all computational methods, regardless of their fidelity level. The most basic and time-efficient BET shows compatibility with other tools for moderate flight velocities and propeller tilt angles, when it comes to time-averaged results, yet the code is not a reliable tool for reproducing transient loading. The BET approach loses credibility for cases where a threedimensional wake influence becomes dominant, like flow with backward inclination of the propeller. An accurate result for such conditions can be achieved with methods including wake in the solution, from which codes incorporating viscous effects (like FLOWer, UPM with particle wake) offer more stability. The BET solution regained applicability for the highest analysed tilt angle of 30°, when wake vortices move further downstream from the blades. Airfoil characteristics used in BET and PUMA allow for including the influence of compressibility and viscosity in the solution. However, one needs to be aware of XFOIL limitations when it comes to accuracy for low Reynolds numbers and lack of consideration of rotational effects in this approach. Mid-fidelity solvers based on potential flow (UPM, RAMSYS) ensured high accuracy of thrust values for cases, where blades do not operate at stall conditions. However, the assumption of inviscid flow leads to strong underprediction of torque. A simple postprocessing correction accounting for profile drag significantly improved the quality of results. Except for the BET+FW-H solution for tilt angle 20°, calculated noise carpets of the blade passing frequency agreed with the measurement when it comes to the location of the highest noise level. Deviations in the results were more apparent for positive tilt angles and appeared for the area further downwash behind the rotor hub. Objects like rotor base or ground with dimensions comparable with the wavelength caused reflections affecting acoustic results. Although the noise carpets including analysed scattering effects still do not explain all deviations in the acoustic measurements, they clearly indicate the importance of reflections analysis, even for low frequencies.

Figure 1 :

 1 Figure 1: Experimental setup

Figure 2 :

 2 Figure 2: Microphone positions relative to rotor plane

Figure 4 :Figure 5 :Figure 6 :

 456 Figure 4: Scanned blade with cross-sections

Figure 7 :

 7 Figure 7: Induced velocity distribution with Pitt and Peters model for 5400 RPM, 12.9 m/s, tilt -10°

Figure 8 :

 8 Figure 8: Viterna extrapolation of lift coefficient for higher angles of attack used in the BET code

Figure 9 :Figure 10 :

 910 Figure 9: Distribution of panels on a blade surface from UPM

  and 12, respectively.

Figure 11 :Figure 13 :

 1113 Figure 11: Wake visualized in FLOWer using λ 2criterion

  (b)). The flight regime of a rotor operating in strong upwash transitions towards windmill state, where the blades are driven by the flow, explains the rapid decrease in torque values in Figure16(b). For FLOWer and PUMA this transition appears RPM effect on rotor torque

Figure 14 :

 14 Figure 14: Results for varying rotor RPM with fixed flight velocity of 12.9 m/s and tilt angle -10°5

Figure 15 :Figure 16 :

 1516 Figure 15: Results for varying rotor velocity with fixed 5900 RPM and tilt angle -10°3

Figure 19 :

 19 Figure 19: Time signal of thrust for tilt 20°during one rotation with 5400 RPM and flight velocity 12.9 m/s

Figure 20 :Figure 21 :Figure 22 :igure 23 :

 20212223 Figure 20: Noise carpets of the BPF, 5400 RPM, flight velocity 12.9 m/s, tilt angle -10°. (a) Experiment, (b) UPM+APSIM, (c) BET+FW-H, (d) FLOWer+ACCO, (e) PUMA+KIM, (f) RAMSYS+ACO

Figure 26 :.Figure 27 :igure 30 :

 262730 Figure 26: Acoustic field for the BPF on the shielding surface including incident noise (a),(b) and the sum of incident and scattered noise (c),(d) for 5400 RPM, flight velocity 12.9 m/s, tilt angle -10°1

Acknowledgments

The study was funded by the German Aerospace Center (DLR) as a part of the Urban Rescue project. Cooperation between research facilities was enabled within the group GARTEUR AG-25 "Rotor-rotor wakes Interactions".

Copyright Statement

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PhD Asma Amrani-Midoun

MD, PhD David Adlam

PhD Nabila Bouatia-Naji
email: nabila.bouatia-naji@inserm.fr

Recent advances on the genetics of spontaneous coronary artery dissection

Keywords: acute coronary syndrome, spontaneous coronary artery dissection, genetics, cardiovascular disease in women. Non-standard Abbreviations and Acronyms ADAMTSL4 ADAMTS like 4 gene AMI Acute Myocardial Infarction

Spontaneous coronary artery dissection (SCAD) has been acknowledged as a significant cause of acute myocardial infarction (AMI), predominantly in young to middle-aged women. SCAD often occurs in patients with fewer cardiovascular risk factors than atherosclerotic AMI. Unfortunately, SCAD remains under-diagnosed due to a lack of awareness among health-care providers leading to misdiagnosis. The underlying pathophysiological mechanisms of SCAD are not well understood. SCAD occurring in members of the same family has been described, suggesting a potentially identifiable genetically triggered cause in at least some cases. However, thus far, the search for highly penetrant mutations in candidate pathways has had a low yield, often pointing to genes involved in other clinically undiagnosed hereditary syndromes manifesting as SCAD. Recent exploratory efforts using exome sequencing and genome-wide association studies have provided several interesting leads toward understanding the pathogenesis of SCAD. Here, we review recent publications where rare and common genetic factors were reported to associate with a predisposition to SCAD and indicate suggestions for the future strategies and approaches needed to fully address the genetic basis of this intriguing and atypical cause of AMI.

Introduction

Since the end of the 20 th century, there has been a persistent disparity in the age-standardized risk of death from acute cardiovascular events for men compared to women. Significantly inferior quality of care and outcomes after acute myocardial infarction (AMI) have been reported in young women compared to young men [START_REF] Wilkinson | Sex differences in quality indicator attainment for myocardial infarction: a nationwide cohort study[END_REF][START_REF] Smilowitz | Acute Myocardial Infarction During Pregnancy and the Puerperium in the United States[END_REF][START_REF] Vaccarino | Myocardial Infarction in Young Women[END_REF][START_REF] Arora | Twenty Year Trends and Sex Differences in Young Adults Hospitalized With Acute Myocardial Infarction[END_REF][START_REF] Gabet | Acute coronary syndrome in women: rising hospitalizations in middle-aged French women, 2004-14[END_REF][START_REF] Virani | Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association[END_REF] . This may, in part, be due to a higher incidence of non-atherosclerotic AMI presentations in women.

Spontaneous coronary artery dissection (SCAD) has emerged as an important cause of AMI and may contribute to these sex disparities in AMI outcomes. The etiology of SCAD is not fully understood. Nevertheless, there are several recognized factors associated with SCAD which include female sex, pregnancy-related factors, emotional stress, extreme exercise and hypertension. SCAD also rarely occurs in patients with inherited connective tissue disorders although data from genetic testing studies indicates that only a small minority of patients carry mutations in established causal genes [START_REF] Carss | Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation from Genome Sequencing[END_REF][START_REF] Verstraeten | Enrichment of Rare Variants in Loeys-Dietz Syndrome Genes in Spontaneous Coronary Artery Dissection but Not in Severe Fibromuscular Dysplasia[END_REF] . However, exploration of these rare pathogenic variants in SCAD has considerable potential both to enhance our understanding of the pathophysiological mechanisms underlying this condition and to help clinicians in determining those cases where genetic testing may enhance clinical management and potentially trigger family screening.

One important feature of SCAD is the demonstration in at least half of affected patients have concurrent extra-coronary arteriopathies, mainly fibromuscular dysplasia (FMD). There is also an association with migraine [START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF] , an important neurovascular disorder. Both migraine and FMD are, like SCAD, more prevalent among women. Increasing evidence has demonstrated the role of common genetic loci in determining the risk of SCAD, illustrated by recent genetic association studies identifying common risk variants [START_REF] Adlam | Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection[END_REF][START_REF] Saw | Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction[END_REF][START_REF] Turley | Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection[END_REF] . Interestingly, some of these variants are shared with FMD, migraine and cervical artery dissection [START_REF] Adlam | Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection[END_REF][START_REF] Saw | Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction[END_REF][START_REF] Turley | Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection[END_REF] .

In this review we discuss the nature of the SCAD phenotype, explore the different genetic research strategies employed in the past five years, and summarize the main results obtained from recent studies dedicated to investigating the genetics of SCAD (Table 1). We also discuss the difficulties and limitations of these studies and provide ideas on how to enhance research efforts aimed at increasing genetic knowledge about this atypical and important cause of AMI.

Clinical features and pathophysiology of SCAD

SCAD causes a non-iatrogenic and non-traumatic spontaneous separation of the coronary artery wall within the tunica media [START_REF] Saw | Spontaneous Coronary Artery Dissection: Clinical Outcomes and Risk of Recurrence[END_REF] . The first report describing SCAD was published as early as 1931 for a case of sudden cardiac death in a 42-years old woman [START_REF] Pretty | Dissecting aneurysm of coronary artery in a woman aged 42: rupture[END_REF] . SCAD predominantly affects women, with fewer cardiovascular risk factors compared to an atherosclerotic AMI population. It may represent 1.7 to 4% of all acute coronary syndrome (AMI) presentations [START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF][START_REF] Saw | Spontaneous Coronary Artery Dissection: Clinical Outcomes and Risk of Recurrence[END_REF] . Some studies have suggested that SCAD represents up to 22-35% of AMI cases affecting women aged under 50 years, which indicates its predominance in early middle-aged women [START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF][START_REF] Saw | Spontaneous Coronary Artery Dissection: Clinical Outcomes and Risk of Recurrence[END_REF] . The coronary arterial dissection is thought to arise either from a disruption or 'tear' in the endothelial/intimal layer allowing blood from the true lumen to enter the sub-intimal space, or from spontaneous bleeding of a traversing micro vessel within the media. The resulting accumulation of blood within the medial layer leads to the formation of a tracking false lumen. The intramural hematoma in the false lumen compresses the true lumen leading to coronary insufficiency and AMI [START_REF] Al-Hussaini | Spontaneous coronary artery dissection[END_REF] . The diagnosis of SCAD is generally made at invasive coronary angiography [START_REF] Combaret | National French Registry of Spontaneous Coronary Artery Dissections: Prevalence of Fibromuscular Dysplasia and Genetic Analyses[END_REF] (Figure 1). Delayed or missed diagnoses are common, primarily due to a lower recourse to biomarker testing and coronary angiography in young women presenting with chest pain, due to their lower perceived risk. SCAD is also a rare cause of sudden cardiac death although post mortem diagnosis is also reportedly challenging [START_REF] Margaritis | Vascular histopathology and connective tissue ultrastructure in spontaneous coronary artery dissection: pathophysiological and clinical implications[END_REF] .

Several potential triggers and precipitants have been described in SCAD. A recent Dutch cohort of patients reported a higher frequency of a precipitating emotional stressor in the 24 hours prior to acute SCAD presentation, compared to an atherosclerotic AMI population [START_REF] Smaardijk | Psychological and clinical characteristics of patients with spontaneous coronary artery dissection: A case-control study[END_REF] . Another reported precipitant is extreme physical effort or stress, such as weight lifting. This occurs more often among men, compared to women [START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF] . Given the female sex predominance, sex hormone fluctuations may have a role in SCAD risk, although the precise mechanism remains unclear and SCAD is also known to occur in men, nulliparous and post-menopausal women. There is a clear association between SCAD and the peri-partum period in some cases. Indeed, this condition was historically reported primarily as a cause of pregnancy-associated AMI, although estimations from more recent series suggest only 2 to 8% of SCAD cases occur during pregnancy or the post-partum period [START_REF] Faden | A nationwide evaluation of spontaneous coronary artery dissection in pregnancy and the puerperium[END_REF][START_REF] Elkayam | Pregnancy-associated acute myocardial infarction: a review of contemporary experience in 150 cases between 2006 and 2011[END_REF] . A causal link with hormonal contraception or hormone replacement therapy remains to be unequivocally demonstrated in a valid comparison with an appropriate control population. SCAD has been consistently associated, in several large observational studies, with extracoronary arteriopathies, mainly FMD [START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF][START_REF] Adlam | European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection[END_REF][START_REF] Tweet | Clinical features, management, and prognosis of spontaneous coronary artery dissection[END_REF][START_REF] Saw | Spontaneous coronary artery dissection in patients with fibromuscular dysplasia: a case series[END_REF][START_REF] Persu | Hypertension and the Kidney" of the European Society of Hypertension and the European Fibromuscular Dysplasia Initiative. Revisiting Fibromuscular Dysplasia: Rationale of the European Fibromuscular Dysplasia Initiative[END_REF][START_REF] Prasad | Prevalence of extracoronary vascular abnormalities and fibromuscular dysplasia in patients with spontaneous coronary artery dissection[END_REF] . FMD is a non-inflammatory, non-atherosclerotic vascular disease that affects medium size arteries (Figure 2). FMD, like SCAD, has a strong female predominance (˃80%) [START_REF] Gornik | First international consensus on the diagnosis and management of fibromuscular dysplasia[END_REF] . FMD is characterized by the pathognomonic radiological 'string-of-beads' appearance, most commonly of renal, cervical, femoral and iliac arteries, although any arterial bed can be affected. It may additionally be associated with arterial stenosis, aneurysm, dissection, occlusion or arterial tortuosity [START_REF] Olin | The United States Registry for Fibromuscular Dysplasia: results in the first 447 patients[END_REF][START_REF] Persu | European consensus on the diagnosis and management of fibromuscular dysplasia[END_REF][START_REF] Maas | Spontaneous coronary artery dissections and fibromuscular dysplasia: Current insights on pathophysiology, sex and gender[END_REF] . Importantly, FMD has been associated with SCAD, with a prevalence of 50 to 75% [START_REF] Saw | Spontaneous coronary artery dissection in patients with fibromuscular dysplasia: a case series[END_REF][START_REF] Henkin | Spontaneous coronary artery dissection and its association with heritable connective tissue disorders[END_REF] . Whist the association between SCAD and extra-coronary arteriopathies has been widely demonstrated, the underlying coronary artery vulnerability in SCAD is less clear. Angiographic and intracoronary imaging appearances reportedly of coronary artery FMD have been reported in SCAD [START_REF] Moulson | Histopathology of Coronary Fibromuscular Dysplasia Causing Spontaneous Coronary Artery Dissection[END_REF] , but such changes do not seem universal and histological appearances of classical medial FMD seem uncommon [START_REF] Margaritis | Vascular histopathology and connective tissue ultrastructure in spontaneous coronary artery dissection: pathophysiological and clinical implications[END_REF] . The association of SCAD and extra-coronary FMD does however suggest these conditions may share pathophysiological elements. SCAD may also share causal aspects with migraine (Figure 2), which is reportedly increased in several series of patients and registries of SCAD and FMD patients [START_REF] Kok | Prevalence and Clinical Factors of Migraine in Patients With Spontaneous Coronary Artery Dissection[END_REF] .

Many important factors remain to be established regarding the underlying pathogenesis of SCAD, including the role of specific genetic risk factors and how these interact with suspected environmental triggers. Nonetheless, recent efforts have enabled important advances to clarify several key elements of the genetic basis of SCAD, including both rare and common genetic factors.

Familial SCAD and panel testing for arteriopathy-associated genes

Initially, SCAD was considered as a rare and largely sporadically occurring disease, with evidence of familial inheritance only reported in a small subset of patients [START_REF] Goel | Familial spontaneous coronary artery dissection: evidence for genetic susceptibility[END_REF] . SCAD had been reported in occasional patients with several rare vascular syndromes, mainly vascular Ehlers-Danlos syndrome (vEDS) [START_REF] Pepin | Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV)[END_REF][START_REF] Frank | The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome[END_REF] , Marfan 14 , and Loeys-Dietz syndromes [START_REF] Henkin | Spontaneous coronary artery dissection and its association with heritable connective tissue disorders[END_REF][START_REF] Garcia-Bermudez | Repeated Loss of Consciousness in a Young Woman: A Suspicious SMAD3 Mutation Underlying Spontaneous Coronary Artery Dissection[END_REF] . Other case reports described SCAD in association with polycystic kidney disease [START_REF] Klingenberg-Salachova | Spontaneous coronary artery dissection in polycystic kidney disease[END_REF] or Alport syndrome [START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF] . There is a large body of evidence from these extensively studied rare connective tissue disorders that supports arterial fragility with vascular dissection a recognized clinical risk among affected patients [START_REF] Saw | Spontaneous Coronary Artery Dissection: Clinical Outcomes and Risk of Recurrence[END_REF][START_REF] Saw | Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes[END_REF][START_REF] Lebrun | Spontaneous coronary artery dissection (SCAD): The underdiagnosed cardiac condition that plagues women[END_REF] (Figure 2). The clinical overlap between SCAD and these rare hereditary connective tissue disorders and aortopathies implied a shared genetic pathophysiology, involving highly penetrant mutations from a finite list of genes. These associations motivated a more systematic search for other rare mutations in genes causing these syndromes in SCAD patients.

In a series reported by Henkin et al. of 116 patients referred from a national SCAD referral center for medical genetics evaluation, 59 underwent panel-based gene sequencing. Of these, only three had mutations in genes associated with known connective tissue disorders including one patient with Marfan syndrome; one patient with vEDS alone and a third patient with vEDS who also had FMD [START_REF] Henkin | Spontaneous coronary artery dissection and its association with heritable connective tissue disorders[END_REF] . Another study by Kadaan et al. reported findings from 44 patients referred by a tertiary SCAD clinic for evaluation in a cardiovascular genetics clinic and selected for panel-based gene testing. Six patients (8.2%) had an identifiable genetic disorder associated with vascular disease, three patients with collagen type III alpha 1 chain gene (COL3A1) mutations causative for vEDS, one patient with LIM homeobox transcription factor 1 beta gene (LMX1B) mutation causative for Nail-patella syndrome, one with mutation in polycystin 1, transient receptor potential channel interacting gene (PKD1) causative for autosomal dominant polycystic kidney disease, and one with mutation in SMAD family member 3 gene (SMAD3) involved in Loeys-Dietz syndrome [START_REF] Kaadan | Prospective Cardiovascular Genetics Evaluation in Spontaneous Coronary Artery Dissection[END_REF] . Together, these two small studies suggested rare causal variants in COL3A1 as the most frequent genetic finding in SCAD patients [START_REF] Henkin | Spontaneous coronary artery dissection and its association with heritable connective tissue disorders[END_REF] .

In a more recent study by Verstraeten et al, targeted sequencing of a panel of 25 genes involved in thoracic and aortic aneurysm and dissection was applied to a cohort of 179 patients with SCAD±FMD and 102 patients with severe FMD only [START_REF] Verstraeten | Enrichment of Rare Variants in Loeys-Dietz Syndrome Genes in Spontaneous Coronary Artery Dissection but Not in Severe Fibromuscular Dysplasia[END_REF] . Using the public database of genetic variants in the general population (gnomAD) as a control set, the authors showed that SMAD family member 2 gene (SMAD2), a key transcriptional regulator of transforming growth factor (TGF)-beta signaling, reached significant enrichment for rare variants in patients with SCAD±FMD compared with the general population after applying a false discovery rate correction [START_REF] Verstraeten | Enrichment of Rare Variants in Loeys-Dietz Syndrome Genes in Spontaneous Coronary Artery Dissection but Not in Severe Fibromuscular Dysplasia[END_REF] . The authors also reported a significantly higher combined frequency of variants in all 6 Loeys-Dietz syndrome genes in SCAD but not FMD-only patients, although, other than SMAD2, these did not individually reach the corrected threshold for statistical significance [START_REF] Verstraeten | Enrichment of Rare Variants in Loeys-Dietz Syndrome Genes in Spontaneous Coronary Artery Dissection but Not in Severe Fibromuscular Dysplasia[END_REF] . Likely pathogenic variants in SCAD patients were also reported in COL3A1, filamin A gene (FLNA) and lysyl oxidase gene (LOX).

Genetic investigations of SCAD using exome and genome sequencing

Several exome and genome sequencing studies have recently been conducted in small pedigrees or sporadic series of SCAD patients. An exome sequencing study of 85 SCAD cases and 296 controls of Han Chinese origin implicated the TSR1 Ribosome Maturation Factor gene (TSR1) gene [START_REF] Sun | Association of TSR1 Variants and Spontaneous Coronary Artery Dissection[END_REF] . After removing variants with a minor allele frequency (MAF) <1% in public databases and selection of in silico predicted deleterious variants, a gene-based association test was implemented where TSR1 was the top associated gene. The authors replicated this result in a validation cohort of 53 SCAD patients and 201 healthy controls and confirmed a significant excess of rare coding variants in the TSR1 in SCAD patients compared to ethnically matched controls. Immunohistochemistry analysis further reported showing expression of TSR1 in human coronary arteries. We note however, that TSR1 is ubiquitously expressed in human tissues, (gtexportal.org, accessed July 2021). An important additional limitation acknowledged by the authors is the lack of exclusion of atherosclerotic causes of dissection, which may explain the surprisingly low percentage of women (~17% in this cohort) (Table 1). TSR1 is a key nucleo-cytoplasmic pre-40S ribosome biogenesis factor that is essential for the final maturation of 20S rRNA to 18S rRNA [START_REF] Hector | Snapshots of pre-rRNA structural flexibility reveal eukaryotic 40S assembly dynamics at nucleotide resolution[END_REF][START_REF] Turowski | Rio1 mediates ATP-dependent final maturation of 40S ribosomal subunits[END_REF][START_REF] Gelperin | Bms1p, a novel GTPbinding protein, and the related Tsr1p are required for distinct steps of 40S ribosome biogenesis in yeast[END_REF] . It is hypothesized to be a blocker that excludes binding with pre-40S particles of the GTPase eIF5B and the ATPase Rio1, and 60S subunit joining during the cytoplasmic maturation of the 40S ribosomal subunits [START_REF] Mccaughan | Pre-40S ribosome biogenesis factor Tsr1 is an inactive structural mimic of translational GTPases[END_REF] . The relevance of this molecular mechanism to coronary arterial dissection, is, at present, unclear. Additional limitations, also acknowledged by the authors, are the need for validation in an in vivo or at least in vitro model to functionally characterize the impact of the 6 rare mutations identified, the lack of segregation in larger pedigrees, the absence of FMD screening and the need for validation in additional ethnic backgrounds.

Using a similar strategy, Turley et al. [START_REF] Turley | Rare Missense Variants in TLN1 Are Associated With Familial and Sporadic Spontaneous Coronary Artery Dissection[END_REF] performed next-generation sequencing and targeted mutation screening in a family pedigree involving 5 individuals, of which 3 were affected across 2 generations and a large sporadic SCAD cohort of 675 unrelated individuals. The family study identified a rare missense variant in TLN1, encoding the cytoskeletal protein talin1, with additional rare missense variants in the sporadic cohort, implicating TLN1 as a novel susceptibility gene. Talin plays an important role in focal adhesions and integrin activation [START_REF] Elliott | The Structure of the talin head reveals a novel extended conformation of the FERM domain[END_REF] . TLN1 is also highly expressed in vascular tissues and endothelial cells [START_REF] Monkley | Endothelial cell talin1 is essential for embryonic angiogenesis[END_REF] . This suggests alterations in expression of TLN1 leading to reduced arterial wall integrity as a putative pathogenic mechanism relevant to SCAD. Limitations in this study include the small number of affected individuals in the familial cases and a lack of a precise estimation of the frequency of rare variants in the sporadic SCAD cohort for the entire gene, given that only a partial resequencing was undertaken restricted to mutations in a specific coding domain of the gene [START_REF] Turley | Rare Missense Variants in TLN1 Are Associated With Familial and Sporadic Spontaneous Coronary Artery Dissection[END_REF] . Whole genome sequencing has also been reported in a mother and daughter pair who shared a very rare (frequency of 4 × 10 -6 ) and cross species conserved mutation in an intercellular tight junction coding gene named F11R [START_REF] Fahey | The Intercellular Tight Junction and Spontaneous Coronary Artery Dissection[END_REF] .

We have also recently described rare loss-of-function (LoF) mutations in FMD and SCAD [START_REF] Georges | Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia[END_REF] of the prostacyclin receptor gene (PTGIR), a G protein coupled receptor with a cardioprotective function and an established role in atherothrombosis [START_REF] Majed | Molecular mechanisms regulating the vascular prostacyclin pathways and their adaptation during pregnancy and in the newborn[END_REF] . Specifically, four FMD and two SCAD patients carried a nonsynonymous (L67P, rs1397542892) and LoF (Q163X, rs199560500) variant alleles, which were found to significantly delay or totally impair cAMP signaling, respectively, after stimulation by iloprost, an agonist of the prostacyclin receptor [START_REF] Georges | Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia[END_REF] . SCAD patients carrying PTGIR LoFs did not present with FMD in other arterial beds. This observation may suggest that the pathological impact of these mutations could be different in SCAD and FMD. There are numerous potentially relevant mechanisms where prostacyclin signaling is a key pathway, mainly in vasodilation, fibrosis, smooth muscle cells proliferation and platelet aggregation [START_REF] Georges | Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia[END_REF] .

The largest sequenced cohort of patients reported to date included 384 SCAD survivors who were analyzed alongside 13,722 controls from the UK Biobank 7 . This study aimed to assess the diagnostic yield of rare variant genetic testing in sporadic patients and was the first to comprehensively investigate whole genome sequencing from SCAD patients for coding (exome-wide) and indel genomic variants [START_REF] Carss | Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation from Genome Sequencing[END_REF] . Pathogenic variants (according to American College of Genetics and Genomics guidelines) were identified in 14 (3.6%) patients, mostly in established genes harboring mutations previously described in SCAD or one of its related hereditary connective tissue disorders or arteriopathies. Variants were identified in COL3A1 (n=2), PKD1 (n=5) and SMAD3 (n=2), TGFB2 (n=2), LOX (n=1), myosin light chain kinase gene MYLK (n=1) and YY1 associated protein 1 gene YY1AP1 (n=1) [START_REF] Carss | Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation from Genome Sequencing[END_REF] . Interestingly, two heterozygote variants were identified in YY1AP1, where homozygote or compound heterozygote mutations have been reported in Grange syndrome, a condition with FMD-like vascular features [START_REF] Guo | Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease[END_REF] . The authors did not have access to haplotype phased genotypes in the SCAD patients to precisely define the genetic model for this gene. This study used an interesting strategy based on a machine learning method for gene prioritization that identified 10 genes relevant to SCAD with ultra-rare variants, which included all those manually defined. Finally, using gene-set enrichment analysis, the authors reported an intriguing enrichment for variants in the loop of Henle development genes, driven mainly by the five individuals carrying variants in PKD1. In addition to previous reports [START_REF] Kaadan | Prospective Cardiovascular Genetics Evaluation in Spontaneous Coronary Artery Dissection[END_REF] , this result suggests the existence of a potential genetically driven association between SCAD and renal genetic disorders that deserves further investigation to clarify the molecular and cellular mechanisms shared by these two diseases.

Clinical testing for rare genetic variants in SCAD

Altogether, inherited arteriopathies and heritable connective tissue disorders appear to account for 4 to 10% of SCAD. The current consensus is not to recommend genetic testing in the absence of features from physical examination, imaging or family history suggestive of an associated heritable disorder [START_REF] Hayes | Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association[END_REF] . Testing all prevalent cases of SCAD would be a potential source of stress for the large proportion of patients with negative results or worse, findings of uncertain significance. Nonetheless, even 4% is a relatively high proportion that might benefit from having a molecular diagnosis for severe vascular syndromes such as vEDS. A genetic diagnosis in such patients might alter clinical management through enhanced awareness of the potential risk of vascular complications in other arterial beds. Furthermore, pedigree screening these cases could allow additional affected members of the patient families to benefit from awareness of their putative vascular risk.

SCAD as a complex genetic disease involving common genetic variation

The low yield in genetic testing for SCAD using existing panels of genes involved in rare vascular diseases and genome sequencing studies has motivated the investigation of the role of common genetic variants. The first supporting evidence came from a study demonstrating the association between SCAD and the common variant rs9349379 (MAF=0.40 in unselected populations). This variant was known to have a role in the genetic susceptibility to coronary artery disease, 53 FMD 54 , migraine [START_REF] Freilinger | Genome-wide association analysis identifies susceptibility loci for migraine without aura[END_REF] and cervical artery dissection [START_REF] Debette | Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection[END_REF] and is located in the intronic sequence of the phosphatase and actin regulator 1 gene (PHACTR1) [START_REF] Adlam | Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection[END_REF] . The association study combined four case control studies involving >1000 patients and 3500 controls from Europe and the USA. This showed that the same effect allele (rs9349379-A), reported to associate with FMD, cervical artery dissection and migraine significantly increased the genetic risk of SCAD [START_REF] Adlam | Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection[END_REF] . Recently, a first single-center genome-wide association study (GWAS) in SCAD was conducted in women of European ancestry [START_REF] Turley | Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection[END_REF] . The authors investigated ~5 million genotyped and imputed common variants in the discovery study of 484 patients and 1,477 controls, and followed-up 10 loci in an independent set of 180 cases and 340 controls. They identified a total of five replicated risk loci, including PHACTR1, at the genome-wide significance level, and several high-profile positional candidate genes. The strongest association signal was detected within chromosome 1q21.3 locus, with at least 25 genes mapping within the associated region of 400 kilobases defined by the authors. Based on eQTL analyses in arteries from GTEx and enhancer annotation, they reported mitochondrial ribosomal protein S21 gene (MRPS21), extracellular matrix protein 1 gene (ECM1) and ADAMTS like 4 gene (ADAMTSL4) as the most likely candidates. MRPS21 is involved in oxidative phosphorylation and its putative role in artery dissection is unclear. However, ECM1 and ADAMTSL4, which encodes secreted glycoproteins, could both play a potential role in cell-cell and cell-extracellular matrix adhesion to maintain artery integrity. An independent SCAD GWAS reported a similar association result on chromosome 1q21.3 based on two case control studies including 433 patients and 8470 controls. The authors performed colocalization analyses using expression data from the genotype and expression portal GTEx and reported ADAMTSL4 as the potential candidate gene in this locus [START_REF] Saw | Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction[END_REF] . Both GWAS reported association signals in the LDL receptor related protein 1 gene (LRP1) at 12q13.3, involving an intronic variant rs11172113 that significantly correlated with this gene expression in several artery tissues from GTEx [START_REF] Saw | Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction[END_REF][START_REF] Turley | Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection[END_REF] . Another locus was reported on Chr 21q22.11 locus, where several genes which show evidence of expression in arteries are potentially involved [START_REF] Saw | Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction[END_REF][START_REF] Turley | Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection[END_REF] . Turley et al., argued given the increasingly understood biological roles of long non-coding RNAs that LINC00310 might be the most likely candidate at this locus. On the other hand, Saw et al., performed co-localization analysis using gene expression in arteries and the association with SCAD at this locus and pointed to two candidates: MRPS6 encoding a mitochondrial ribomosomal protein S6 and KCNE2 encoding potassium voltagegated channel subfamily E regulatory subunit 2. Larger studies, involving ideally other ethnic backgrounds will certainly be needed to narrow down the causal variants and genes at this locus. One additional SCAD locus was identified by Turley et al. in the fibrillin gene (FBN1) at the 15q21.1 locus 12 . This association signal is driven by several common variants spanning a large linkage disequilibrium region that includes FBN1, a gene that harbors rare and private mutations causative of Marfan Syndrome. As highlighted by the authors, the protein encoded by ADAMTSL4, the best candidate gene at the 1q21.3 locus, binds to FBN1 and promotes microfibril assembly [START_REF] Hubmacher | ADAMTS proteins as modulators of microfibril formation and function[END_REF] . FBN1 was reported to be higher in plasma from 70 SCAD patients, compared to that in 70 non-SCAD patients who experienced AMI, or 70 healthy controls, and of relatively promising value in prognosis prediction of cardiovascular events during follow-up of SCAD patients 58 FBN1 is an important molecule which forms the backbone of the microfibrils in elastic tissues in the coronary artery wall and is involved in TGF-beta activation and signaling. Altogether, current genetic association studies of common variants provide evidence for a polygenic risk underlying most SCAD. Ongoing efforts to combine larger samples are expected to increase the current list of genetic susceptibility loci and, combined with deeper integrative functional annotation, may help to improve the resolution at current and future risk loci. No study to date has investigated potential genetic differences between angiographic subtypes although increasing evidence suggests these appearances represent different temporal phases of the same disease process rather than distinct clinical phenotypes. [START_REF] Jackson | Spontaneous Coronary Artery Dissection: Pathophysiological Insights From Optical Coherence Tomography[END_REF][START_REF] Waterbury | Early Natural History of Spontaneous Coronary Artery Dissection[END_REF][START_REF] Mori | Clinical Outcomes By Angiographic Type Of Spontaneous Coronary Artery Dissection[END_REF]

SCAD as a genetically distinct cause of AMI sharing some genetic loci with other vascular diseases

Recent advances in the investigation of SCAD have provided evidence that the genetic basis of this condition is distinct from atherosclerotic AMI. A first example came from the PHACTR1 risk variant where the rs9349379-A allele confers risk for both SCAD and FMD [START_REF] Adlam | Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection[END_REF] . PHACTR1 is a highly pleiotropic risk locus for a large number of vascular disorders, including cervical artery dissection and migraine, two neurovascular conditions concomitant with SCAD (Figure 2). Similarly, rs11172113 at the LRP1 locus is also an established risk locus for both migraine and SCAD [START_REF] Freilinger | Genome-wide association analysis identifies susceptibility loci for migraine without aura[END_REF] . Interestingly, despite SCAD being a cause of AMI, the alternative rs9349379-G allele in PHACTR1 is associated with increased risk for classical coronary artery disease and atherosclerotic AMI, including in an analysis restricted to women only [START_REF] Adlam | Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection[END_REF] . This finding of an opposing direction of effect of SCAD and atherosclerotic AMI variants was further supported using a SCAD polygenic risk score calculated from GWAS data, which was found to be associated with protection from AMI in the UK biobank data [START_REF] Saw | Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction[END_REF] . Insights about the mechanisms behind these differences may arise from future investigation into SCAD risk variants and particularly any putative sex hormone mediated regulation of expression. Furthermore, the association signal in FBN1 in the Mayo Clinic SCAD GWAS, also overlaps with that previously reported for sporadic thoracic aortic aneurysm and dissection [START_REF] Lemaire | Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1[END_REF] . This was the first common genetic locus with this aortopathy to be reported. Variants associated in both diseases are in strong linkage disequilibrium, and whether the same causal allele is at play both in thoracic aortic aneurysm and SCAD was not reported.

Conclusions

Significant advances have been made in our understanding of the genetic basis of SCAD in the last five years. SCAD may occasionally result from rare genetic variants, generally in genes implicated in inherited arteriopathies or connective tissue disorders. This accounts for 4 to 10% of patients, depending on the degree of patient selection prior to genetic testing. Routine genetic testing is not current consensus practice in the field but this may be reconsidered as more information becomes available. The results of recent genetic studies suggest both rare and common genetic factors are implicated in the predisposition to SCAD. We highlight diverse biological mechanisms related to artery integrity, shared with several associated arteriopathies including FMD, cervical artery dissection, migraine and adult polycystic kidney disease. Finally, most of the described studies were limited in power, which has restricted the current yield from gene and loci discovery studies. Therefore, huge efforts are still needed to unravel the full genetic basis of this under-recognized cause of AMI. Despite the challenging complexity of diagnosis, use of larger cohorts of patients, with a special emphasis on including more diverse ethnicities will likely uncover additional molecular mechanisms of SCAD. The integration of transcriptomic and proteomic datasets combined with the development of cell systems and small animal genetic models are also expected to help develop future mechanisminformed therapeutic interventions.

Table 1. Summaries of articles published in the last five years (2015-2020) aiming to address the genetic basis of SCAD. Studies were cited in the order of year of publication (by November 2020). We display study design, summary of the main findings, number of SCAD patients studied, percentage of women and fibromuscular dysplasia among patients, and limitations we identified for each study. FMD: fibromuscular dysplasia. vEDS: vascular Ehlers Danlos syndrome. COL3A1: collagen type III alpha 1 chain, PKD1: polycystin 1, transient receptor potential channel interacting gene, SMAD3: SMAD family member 3 gene, PHACTR1: phosphatase and actin regulator 1 gene, TLN1: Talin1 gene, TSR1: TSR1 ribosome maturation factor gene, PTGIR: prostaglandin I2 receptor gene, ECM1: extracellular matrix protein 1 gene, ADAMTSL4: ADAMTS like 4 gene, FBN1: fibrillin 1 gene, LRP1: LDL Receptor related protein 1 gene, LINC00310: Long intergenic non-protein coding RNA 310, TGFB2: Transforming growth factor beta 2 gene, LOX: Lysyl oxidase protein gene, MYLK: Myosine light chain kinase gene, and YY1AP1: YY1 associated protein 1 gene. NA: not available. The study was inconclusive for several genes tested.

Year

Verstraeten 8 SCAD is reported in several connective tissue and rare aortopathies that mainly occur in Marfan and Ehlers Danlos syndromes. SCAD is also associated with common forms of vascular diseases, such as migraine and fibromuscular dysplasia, also more often diagnosed in women. Genetic factors are increasingly reported as an important cause of SCAD. Some of these causes are shared through rare and common genetic basis of the associated conditions.

SCAD event

Figure 1 .Figure 2 .

 12 Figure 1. Clinical imaging of SCAD. Coronary angiographic examples of SCAD using the Yip-Saw classification (A-E). (A) Type 1 SCAD with dual lumen appearance in the proximal left anterior descending coronary artery (arrow). (B) Type 2a SCAD with false lumen commencing just after the second diagonal branch of the left anterior descending coronary artery (solid arrow) recovery of a normal vessel calibre distally (beyond dotted arrow). (C) Type 2b SCAD extending from the mid left anterior descending coronary artery (solid arrow) distally with no recovery of a normal lumen calibre (dotted arrow). (D) Type 3 SCAD with appearances mimicking a focal atherosclerotic stenosis (arrow) and requiring intracoronary imaging for diagnostic confirmation. (E) Type 4 SCAD with an occlusion at the junction of the mid and distal thirds of the left anterior descending coronary artery (solid arrow) but with evidence of upstream tapered narrowing (dotted arrow). (F) Optical coherence tomography image showing the darker contrast-filled true lumen (TL) surrounded by the compressive false lumen (FL) haematoma. Images from patients consented to the UK SCAD Study (ISRCTN42661582; UK national research ethics service 14/EM/0056)

Acknowledgement

The authors thank Dr Linda Adlam for her input in optimizing the manuscript.

Funding sources

This work was funded by the European Commission ERC scheme (ERC-Stg-ROSALIND-716628), Fédération de Cardiologie (FFC-Dotation-BOUATIA-NAJI-2019), Fondation Coeur & Recherche and la Fondation Wagner (Fondation du Luxembourg) (GENET-IP-SCAD). DA is supported by BeatSCAD, the British Heart Foundation (BHF) [PG/13/96/3060], the National Institute for Health Research (NIHR) rare disease translational collaboration and the Leicester NIHR Biomedical Research Centre.

Disclosures

DA has received funding to support a clinical research fellow from Abbott vascular. He has also received funding from Astra Zeneca inc. for unrelated research and has conducted unrelated consultancy for GE inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.


Christian Verger

RDPLF annual report: Profile of peritoneal dialysis patients in France in 2022, synthetic raw results

Keywords: Registry, RDPLF, peritoneal dialysis, France, annual report

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

Summary

We present the main descriptive data of patients treated by peritoneal dialysis in France in 2022 in the form of tables and graphs. Patients from DROM-TOM and other French-speaking countries and regions of the RDPLF will be described in a future issue in order to group together regions with similar socio-economic and climatic characteristics.

Since the SARS-Cov2 epidemic in 2020 and the three years that followed, the number of patients treated by peritoneal dialysis in France has decreased by 6.7%, but with significant regional variations ranging from +20% to -30%.

Vascular (23.5%) and diabetic (20.5%) nephropathies are the most numerous.

The average age for CAPD is 70 years and 58 years for APD 36% of patients are assisted by a nurse and 5% by a family member.

The average waiting time for transplant patients was 20 months.

There is a great difference in the technique of catheter placement with a catheter survival of 72% at 5 years. Depuis l'épidemie de SARS-Cov2, en 2020 et les trois années qui ont suivi le nombre de patients traités par dialyse péritonéale en France a diminué de 6,7 % en France mais avec des variations régionales importantes variant de +20% à -30%.

Bulletin de la Dialyse à Domicile

Les néphropathies vasculaires (23,5%) et diabétiques (20,5%) sont les plus nombreuses.

L'âge moyen en DPCA est de 70 ans et de 58 ans en DPA 36% des patients sont assistés par une infirmière et 5% par un membre de la famille.

Le délai d'attente des patients transplantés a été de 20 mois en moyenne.

On observe une grande différence dans les techniques de pose de cathéter avec une survie des cathéters 72% à 5 ans.

INTRODUCTION

The purpose of this document is to summarize with graphics ad tables the main descriptive elements obtained from the database of the Peritoneal Dialysis and Home Hemodialysis Registry (RDPLF) in metropolitan France in 2022. No discussion is intended in this report, which is primarily intended to provide background material for readers to illustrate their own work or presentations.

These tables and charts may be freely copied provided that this document is cited with its DOI.

The originals can also be obtained as PowerPoint files from the RDPLF secretariat.

COMPLETENESS

  RDPLF annual report: Profile of peritoneal dialysis patients in France in 2022, synthetic raw results (RRapport annuel RDPLF : profil des patients en dialyse péritonéale en France en 2022 , résultats bruts et synthétiques) Christian Verger et Emmanuel Fabre Registre de dialyse péritonéale et hémodialyse à domicile de langue française (RDPLF, Pontoise (France)

  The Réseau Epidemiologie Information en Nephrologie (REIN) is comprehensive for France, it is possible to know the completeness of peritoneal dialysis (PD) patients included in the RDPLF by comparing the number of patients treated on December 31 in each database. According to the 2019 REIN report [1] 97.8% of French patients were included in 2020. On January 1, 2022 the number of treated patients was identical in both registries (personal communication Cécile Couchoud and Mathilde Lassalle). The RDPLF database is structured in several modules described elsewhere [2,3]. Various tables and graphs included in this text were also obtained from the RDPLF open access statistical analysis web module [4]. DESCRIPTION OF THE POPULATION Number of prevalent patients in 2022 (treated at least 1 day): 3955 patients

other than glucose Non-diabetic patients diabetic patients

  Information on catheters in 2022 was provided for 2900 catheters and represents 73% of catheters used during this period in France.

			www.bdd.rdplf.org Volume 6, n° 1, April 2023
			v6i1.77293 v6i1.77293 https://doi.org/10.25796/bdd.v6i1.77293
			ISSN 2607-9917 ISSN 2607-9917 ISSN 2607-9917
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	30,0% No other solution than glucose Icodextrine Amino-acids Icodextrine+amino-acids	Pourcentage 24,2% 57,7% 2,1% 15,9%	27,6% 16,6% 52,0% 3,4% 28,0%	Langue Française RDPLF
	0,6% 0,4% 0-16 16-20 20-30 30-40 40-50 50-60 60-70 70-80 80-90 90-100 2,6% 5,0% 8,1% 14,8% 22,7% 17,3% 0,9% Extraperitoneal section 0,0% 5,0% 10,0% 20,0% 25,0% 15,0% Intraperitoneal section Percentages Straight Straight 22,8% Swan Neck Straight 28,2% Straight Coil 24,7% Swan Neck Coil 21,7%	Dialyse Péritonéale de Registre de journal officiel du
	not registered	Non registered	2,6%
	Figure 3. Age distribution of patients treated with PD in France in 2022, in metropolitan France, all methods combined. Transplantation status number Percentage Pre-transplant assessment not done 86 3,4% Note: 6% of catheters have a weighted tip
	TREATMENT BEFORE PD Pre-transplant assessment not finished 395 Anesthesia technique (indicated for 2332 catheters):	15,7%
	-non-dialysed: 3113 (80.4%) -hemodialysed: 626 (16.2%) (of which 11 in self-dialysis and 2 in home hemodialysis) -transplantated: 135 (3.4%) Autonomous 2316 Registered on waiting list 665 26,5% -General anesthesia: 87.2 59% Nurse assisted 1409 Not transplantable 896 35,7% -Local anesthesia: 7.5 36% Family assisted 203 5% Asisted (withou precision) 21 1% Transplantation refused by patient 213 -Spinal: 0.3 8,5% Temporaly contra-indication 254 10,1% -TAP block: 5%.
	Missing data	8	<1%
	RDPLF 2022 annual report RDPLF 2022 annual report RDPLF 2022 annual report

journal officiel du Registre de Dialyse Péritonéale de Langue Française RDPLF www.rdplf.org www.bdd.rdplf.org Volume 6, n° 1, April 2023 https://doi.org/10.25796/bdd.Figure 2. Nephropathies of peritoneal dialysis patients in France in 2022 MODALITES DE DIALYSE PERITONEALE DIABETES AUTONOMY journal officiel du Registre de Dialyse Péritonéale de Langue Française RDPLF www.rdplf.org www.bdd.rdplf.org Volume 6, n° 1, April 2023 https://doi.org/10.25796/bdd. Table II. Autonomy of peritoneal dialysis patients in metropolitan France in 2022 Figure 4. Age distribution of patients treated with APD and CAPD in metropolitan France in 2022 Figure 5. diabetic status and treatment of patients treated with PD in metropolitan France in 2022 Solutions  Table I. Dialysis solutions used in addition to glucose-based solutions TRANSPLANTATION journal officiel du Registre de Dialyse Péritonéale de Langue Française RDPLF www.rdplf.org www.bdd.rdplf.org Volume 6, n° 1, April 2023 https://doi.org/10.25796/bdd.v6i1.77293 ISSN 2607-9917 RDPLF 2022 annual report Figure 7. autonomy by PD modality Figure 6. Autonomy by patient according to age  Tableau III. Transplant status of patients in metropolitan France treated with PD in 2022 CATHETERS Figure 8 . Waiting times since the start of PD for patients transplanted in 2022 in France  Table IV : shapes of the catheters

used Catheter placement technique (reported for 2900 catheters):

	-Laparotomy : 57%.
	-Laparoscopy: 41.27%.
	-Percutaneous Trocard: 1.37
	-Percutaneous peelable dilator: 0.34
	Percentage of buried catheters using the Moncrief technique: 4.38%
	Nasal staphylococcus aureus carriage
	-not tested: n=2011 (69.3%)
	-tested: n=889 (30.7%)
	-positive: 15
	-negative: 85
	Actuarial survival (Kaplan-Meier) of peritoneal dialysis catheters (years 2013 to 2023)
	(dates are censored at the date of transfer to another method, death or transplantation)
	-12 months: 97% ± 07
	-24 months: 84.8% ± 1%.
	-36 months: 80.7% ± 1.2
	-48 months: 76.7 ± 1.6%.
	-60 months : 72.1± 1.1%.

DATA FROM THE NURSING SECTION OF THE DATA BASE 45% of RDPLF centers participate to the optional data-base module on nursing, the re- sults below represent some of the data available in 2022 journal officiel du Registre de Dialyse Péritonéale de Langue Française RDPLF www

  .rdplf.org www.bdd.rdplf.org Volume 6, n° 1, April 2023 https://doi.org/10.25796/bdd.v6i1.77293 ISSN 2607-9917

RDPLF 2022 annual report Figure 9. 96,7 % des patients ont été formés après la pose du cathéter et 3,3 % avant. Parmi ceux formés après la pose du cathéter , le délais entre pose et début de formations est très variable, avec une durée médiane de 19 jours

www.bdd.rdplf.org Volume 6, n° 1, April 2023 https://doi.org/10.25796/bdd.v6i1.77293 ISSN 2607-9917

Acknowledgments : We warmly thank the medical and nursing teams who regularly register their data in the RDPLF and thanks to whom these data are possible. We are at their disposal to help them in any work they would like to undertake with the database.

Peer reviewing : The figures, tables, and figures in this document are raw data extracted from the database, without interpretation, available to readers as a starting point for encouraging future research projects. They have not been subjected to peer.

Authoship : CV wrote the text and did the analysis. EF participated in the creation of the graphics and the output of the results.