Ghassan Chehaibar
email: ghassan.chehaibar@bull.net

Meriem Zidouni
email: meriem.zidouni@bull.net

Radu Mateescu
email: radu.mateescu@inria.fr

Modeling Multiprocessor Cache Protocol Impact on MPI Performance

This paper presents a modeling method particularly suited to analyze interactions between Message Passing Interface MPI library execution and distributed cache coherence protocol. The method is applied to the Ping-Pong benchmark. In addition to overall performance figures like message exchange latency, it also provides detailed analysis elements such as cache miss counts per variable. It is based on formal modeling where functional aspects and performance aspects are integrated by composition and can be refined independently. A key modeling point is that the cache coherence protocol implies that the duration of an access to a variable is not static but is state-dependent. Our Ping-Pong model allows comparison of different primitive implementations in the context of different cache coherence protocols. We applied this approach using Interactive Markov Chain theory and its implementation in the CADP toolbox.

Introduction

The range of high-end servers designed and manufactured by BULL includes multiprocessor systems dedicated to highperformance computing (HPC), providing an implementation of the Message Passing Interface (MPI) library [START_REF] Snir | MPI: The Complete Reference (2 volumes)[END_REF]. Such an HPC system is a network of multiprocessors, each implementing a Cache-Coherent Distributed Shared Memory (CC-DSM) architecture. In the message-passing paradigm, processes do not share data but communicate and synchronize by means of MPI primitives. The data of these primitives are shared between processes, which implies that the performance of the library is impacted by cache coherence protocol behavior.

The work presented in this paper is motivated by our need to understand the impact of cache coherence protocol on MPI library performance in order to optimize the library implementation. We are interested not only in the overall performance given by a benchmark execution, we also look for analysis elements such as individual variable miss counts.

Section 2 details the motivation of this research and explains why, instead of simulation, we have chosen formal modeling using the CADP toolbox that supports Interactive Markov Chains (IMC) theory. Section 3 describes the modeling method through its application to the Ping-Pong benchmark. We model a software layer comprising the benchmark and MPI primitives algorithms on top of a hardware layer comprising the topological mapping of processes and cache coherence protocol. The main aspect a model should capture is that, at a given time, the latency of an access done by one process depends on the distributed states of all other process caches. The software, the hardware, and the performance aspects are integrated using composition. Section 4 analyzes the results of the Ping-Pong performance evaluation obtained by varying three parameters: processor mapping onto architecture, primitive algorithms and cache coherence protocol. Section 5 concludes this paper and gives future work directions.

Motivation and related work

MPI optimization is an extensively investigated domain along various directions: optimizing implementation on a generic architecture like a cluster [START_REF] Liao | Collective caching: Application-aware client-side file caching[END_REF], [START_REF] Hoefler | A practically constanttime MPI broadcast algorithm for large-scale InfiniBand clusters with multicast[END_REF] or on a specific machine [START_REF] Gropp | A high-performance MPI implementation on a shared-memory vector supercomputer[END_REF], [START_REF] Feind | An ultrahigh performance MPI implementation on SGI R ccNUMA Altix R systems[END_REF]; or building configurable benchmarking tools [START_REF] Reussner | SKaMPI: A detailed, accurate MPI benchmark[END_REF]. All this work relies on measuring MPI benchmark performance on actual machines (already manufactured hardware), so that one can show that one implementation is more efficient than another. However, when we want to optimize an implementation for a CC-DSM architecture, we need to analyze its interaction with the cache coherence protocol in order to know how many misses occur and on which variables. This information either cannot be obtained with measurement or requires complex instrumentation. Another drawback of measurement is that optimization cannot be done during hardware development phase.

The goal of our research is to build a method particularly suited to analyzing interaction between MPI library execution and distributed cache coherence protocol. This method should allow our software teams to compare and analyze different implementations of the MPI library, providing overall performance figures and analysis elements such as cache miss counts per variable. We are not aware of any published work on this particular subject.

The process of arriving at an adequate performance model of a system is often considered an art [START_REF] Jain | The Art of Computer Systems Performance Analysis: Techniques for Experimental Design, Measurement, Simulation, and Modeling[END_REF] in itself. In our context, this is even more critical, because the performance properties depend heavily on the correct modeling of the functionality of the cache coherence protocol. Therefore, functional modeling and performance modeling need to be very tightly intertwined, and it is useful to have checkers to verify the correctness of the functional behavior at hand. Standard simulation environments such as Opnet (http://www.opnet.com), Omnet (http://www.omnetpp.org) or NS-2 (http://www.isi.edu/nsnam/ns), do not provide any support for this. Instead, in these environments, the model is coded in a loosely structured set of declarations and libraries, and often some C-code snippets are used to glue the components together. The results obtained by such studies are often not credible, as reported in [START_REF] Cavin | On the accuracy of manet simulators[END_REF], [START_REF] Riley | Simulating large networks: How big is big enough?[END_REF], [START_REF] Heidemann | Effects of detail in wireless network simulation[END_REF]. This is not a deficiency of the analysis technique (discrete event simulation), but the model construction process is badly supported, and hence one looses the view of what one is actually modeling (and thus analyzing).

In this paper we instead use a formal method, the ISOstandardized language LOTOS [START_REF] Iso/Iec | LOTOS -a formal description technique based on the temporal ordering of observational behaviour[END_REF], to model the functional aspects of our system. We formally verify the correctness of this model exploiting model checking capabilities of the tool CADP [START_REF] Garavel | CADP 2006: A toolbox for the construction and analysis of distributed processes[END_REF]. On top of that, we integrate performance aspects of the system using the same tool and technique [START_REF] Garavel | On combining functional verification and performance evaluation using CADP[END_REF], based on the IMC theory [START_REF] Hermanns | Interactive Markov Chains and the Quest for Quantified Quality[END_REF], which is a smooth extension of the theory underlying LOTOS. This modeling results in a performance model, a highly unstructured continuous time Markov chain, which we are confident properly reflects the functionality and the performance aspects of the system under study. We then use numerical analysis algorithms to calculate relevant performance figures. We could also use discrete-event simulation of a formal model as an alternative analysis technique, but this is currently not supported by CADP. The tight integration of performance and functionality considerations was first devised in the context of stochastic Petri nets [START_REF] Marsan | Modelling with Generalized Stochastic Petri Nets[END_REF], and indeed the use of a Petri-net based tool would have been an alternative; we are however not aware of a tool with the same model checking support as CADP provides.

Functional and performance modeling

This section describes the modeling process: first we translate the software program into a LOTOS model, then we compose this model with a process that represents the cache protocol and associates to each access its state-dependent transfer type. Finally we obtain a performance model by composition with a process that inserts "delay transitions".

Ping-Pong functional behavior

In this paper, we consider the MPI benchmark called Ping-Pong dedicated to measure the latency of a message transfer between two processes. It is composed of two processes; each process alternately sends and receives a message from the other. If Snd i→j denotes the emission of a message from P i to P j and Rcv i←j denotes the reception by P i of a message sent by P j , then Ping-Pong behavior is:

(Snd 0→1 ; Rcv 0←1 ) k ||(Rcv 1←0 ; Snd 1→0 ) k .
The delay ∆t of executing the loop k times is measured; since one loop turn corresponds to a round trip, that is two transfers, one transfer latency l is obtained by l = ∆t 2k . Each MPI send and receive primitive is a C procedure composed of assignments, tests, and loops accessing some variables in shared memory. From a functional viewpoint, the fact that memory is physically distributed and that an access to a variable may involve a transfer over the network is not relevant: only the values of variables are of interest. That is why we write a process Memory managing a storage Mem containing the values of variables, that can be accessed atomically in one transition. An access to a variable can be a load or a store and is performed by rendezvous with Memory process on a gate of the form:

Action ?P:Proc ?Op:Access ?Var:Address ?Val:Value;

where P is the identifier of the process performing the access, Op is the access type (load, store, test-and-set), Var is the name of the variable and Val is the value read or stored.

Each primitive algorithm is composed of assignments, ifthen-else, and while constructs. A straightforward translation of these instructions into Action gates gives two LOTOS procedures Send(Pi, Pj) and Receive(Pi, Pj). Then, each process of Ping-Pong is: and the functional behavior of the benchmark is:

(Proc0[Action] ||| Proc1[Action]) |[Action]| Memory[Action](Mem)
(";" is the sequential composition of processes, ||| is the free interleaving and |[A]| is synchronization on action A).

Cache coherence protocol impact

Our protocol is based on the classic 4-state protocol called MESI [START_REF] Papamarcos | A low-overhead coherence solution multiprocessor with private cache memories[END_REF] (acronym formed by the state initials): Modified, Exclusive, Shared, and Invalid. The cache coherence protocol is described in Table 1 for a load access and Table 2 for a store access. P i is the requesting processor and P j represents all other processors. The first two columns give the current cache states, and the next two ones give the new cache states after the data transfer. The fifth column gives the data transfer type, specifying the data provider (M means home memory) and occasional cache lookup or invalidation. We consider two protocol variants that differ only in handling a store miss when modified data exist (shown by the last two lines): in case A the requester goes into M state and the provider into I state; in case B they both go into S state.

These tables define a cache state transition function NewState(p, op, v, CurrentState) where p is the requesting processor, op is the access performed (load or store) and v the variable that is accessed. It is worth noting that cache It follows from NewState and Transfer definitions that the latency of an access to a given variable in a given process cannot be determined statically or locally because it does not depend only on its local cache state, or on variable or process mapping onto the architecture. It also depends on the global state of all caches in the system.

Inserting state dependent latencies

Once the functional model is built, the next step is to associate a duration to each access performed by the benchmark. In IMC a transition can be an "ordinary" immediate action, or a delay action labeled with "label; rate R", where R is a positive real and label any string (possibly empty). A transition S 1 → S 2 labeled with rate R indicates that the probability that this transition occurs at t ≤ x is 1 -e -Rx .

Applying this approach in LOTOS, in order to specify that an action A has a mean duration (or latency) L A , we write the sequence Begin A; Latency A; End A, where Begin A and End A are immediate actions and Latency A is a delay one. This distinction is not done at the LOTOS level but in the generated labeled transition system (LTS), where Latency A is renamed with Rate R or Label; Rate R, where R=1/L A : this gives a so-called stochastic LTS.

We will extend our functional model to introduce access latencies in two steps using process composition: first we associate to each access its transfer type, then we insert delay transitions as explained above. Concerning transfer types, we write a process Caches that maintains the global state of all caches for all variables and gives the transfer type associated to each access (as defined by the function Transfer of Section 3. Then we add the ?T:Transfertype on the gates of the functional behavior and we compose it with Caches, thus obtaining a functional model where accesses are labeled with their transfer types. In order to insert delay transitions as explained above, each occurrence of the gate Action in Send and Receive processes has to be split into a sequence Action;End action (we keep Action instead of Begin Action). Then the delay transitions are inserted by composition with the following process: In Memory and Caches processes, actions are not split because these rendezvous are an abstraction to provide variable values and cache states to the benchmark processes and do not represent actual transfers: no duration can be associated to them in these processes.

The model built above is very abstract, since it associates a one-shot latency to a transfer and it makes cache state transition one atomic event at the beginning of the transfer. In the real system, on a cache miss, the requesting processor issues a transaction that goes through many phases in the various agents of the architecture. Cache states are changed according to these phases. Actually the compositional way of inserting latencies allows us to easily refine the model to choose the needed abstraction level in order to improve accuracy. For instance, in order to split a transfer into two equal phases and put cache state update at the end of the first phase, we modify only processes Caches and Latency. We keep cache states unchanged when Action is fired and we add a specific event Update in these processes as follows: This shows how this modeling separates the functional aspect from the performance one: in this way, each aspect can be refined independently.

Formal verification

Once the LOTOS model is available, before exploiting it for performance evaluation, we assess its correct functioning using the formal verification tools of CADP toolbox based on equivalence checking and model checking. The following verifications are done:

• When all the actions of the model are hidden except the actions that send or receive a message and branching bisimulation is applied, we obtain a behavior equivalent to the Ping-Pong benchmark.

• Correct functioning of the cache coherence protocol is checked using safety properties written in regular alternation-free µ-calculus, the input language of the EVALUATOR [START_REF] Mateescu | Efficient on-the-fly modelchecking for regular alternation-free mu-calculus[END_REF] model checker of CADP.

• Correct functioning of the primitive algorithms, such as lock management, is also checked using temporal logic properties written in regular alternation-free µ-calculus.

Performance analysis

To perform numerical analysis, we generate the LTS of the model, then we rename transitions labeled Latency !P !V !T with P V T; rate R where R=1/L if L is the latency of a transfer of type T. BCG MIN minimization tool [START_REF] Hermanns | A set of performance and dependability analysis components for CADP[END_REF] is used to reduce LTS according to stochastic branching bi-simulation. The BCG STEADY tool [START_REF] Hermanns | A set of performance and dependability analysis components for CADP[END_REF] takes a stochastic LTS as input, and computes the corresponding equilibrium ("steady-state") probability distribution on a long run. Moreover, it also computes throughputs of the transitions bearing a given label, which is the only output we have used in this study.

Computing performance figures

In assessing Ping-Pong performance, two figures are of interest: latency of a message exchange, and number of misses on a given variable during this exchange, to analyze the impact of each variable used in the primitives implementation.

The mean latency between two consecutive occurrences of an event is the inverse of its throughput. So, in order to compute the latency of a message exchange in the Ping-Pong benchmark model, we add a Startj gate in the LOTOS specification at the beginning of Procj, and we compute L = 1/(2•F S ) where F S is the throughput of Start (see Section 3.1 for a justification of the factor 1/2).

In order to obtain the average number of misses on a given variable during a message exchange in Ping-Pong, we notice that a miss on a variable V corresponds to an occurrence of a miss transfer type, i.e. an action Latency !P !V !T where T is a miss case. But the mean number of occurrences of an event in a loop is the throughput of this event divided by the throughput of the occurrence of the loop. Then, if we call F(V, p) the sum of all throughputs of Latency !P !V !T, the number of misses on V during a message transfer in a given process is F(V, p)/F S .

Evaluation results

We evaluate the latency and cache miss numbers of Ping-Pong in several configurations in order to investigate the impact of various parameters on the performance of MPI library. A configuration is defined by three parameters:

1) A mapping of processors (with an associated variable mapping) onto the architecture. This is defined by inter-process distance (0, 1 or 2). Figure 1. Latency of a message exchange (called SR2 below) is a lock-free implementation, which replaces lists with fixed-size buffers, taking advantage of the fact that these buffers have a unique reader (similar to the algorithms described in [START_REF] Gropp | A high-performance MPI implementation on a shared-memory vector supercomputer[END_REF]). 3) A cache coherence protocol: there are two variants (A and B) defined in Section 3.2. Figure 1 gives the latency results for all cases: Xi curve where X=A or B, and i=1 or 2, represents the X protocol case with SRi algorithm. We also represent the measured latency in case A1 (noted MA1) on a Bull server. First we see that in A1 case, the difference between measured and evaluated latency ranges between 9% and 22%. However, let us stress that our objective is not to build a model that accurately predicts absolute experimental values, but to show that a fairly abstract model of a large-scale distributed cache coherence protocol has potential to compare configurations and to show right tendencies. As expected, latency increases when distance between processes increases, in all primitive and protocol cases.

The second less obvious result is that Protocol A is more efficient than Protocol B. Assume a process P 0 performs a load(V) and V is M in P 1 cache (this means that P 1 has already performed a store(V)). If load(V) brings V in E state in P 0 and makes it I in P 1 (Protocol A), any subsequent access by P 0 (load(V) or store(V)) is a hit, and any by P 1 is a miss. Now if load(V) makes V in S state in both caches (Protocol B), a subsequent load(V) is a hit, but store(V) is a miss in both processors. In the MPI library primitive implementation (in both cases SR1 and SR2), a process never performs a store(V) followed by a load(V), which is the favorable case of Protocol B; however, a process always performs store(V) after load(V), which is the favorable case of Protocol A.

The third result is that SR2 implementation is more efficient than SR1 one. This is explained by Figure 2, which gives the number of misses per kind of variables (packet, pointer or lock), in each configuration (Ptr-A1 curve gives the number of misses on pointer variables in A1 case, etc). We see that there are about 20 misses in a message transfer in case A1, where 20% are on packets, 45% on pointers and 35% on locks. In case A2, there are about 12 misses, where 32% are on packets and 68% on pointers (actually buffer index). These figures show that, in SR1, misses on list management variables (pointers and locks) play a major part in the overall latency of a message transfer: therefore a lock-free algorithm like SR2 is more efficient.

Modeling and evaluation cost

The model size is 797 lines of LOTOS and 1044 lines of C code (for efficiency reasons, data types are implemented in C). The generated LTS has 1,452,856 states. There are 450 lines of temporal logic properties. The state space generation, formal verification and performance evaluation are completed within a few minutes. This shows that in both development effort and execution time, this method is inexpensive and yet yields useful results.

Conclusion and future work

In this paper we presented, by means of its application to the Ping-Pong benchmark, a method to analyze the impact of cache coherence protocol on the MPI library performance in a CC-DSM architecture. The goal of this method is to help software teams optimize MPI implementation during hardware design phase and to analyze measurement afterwards. It is based on formal modeling that integrates functional and performance behaviors, using IMC extension of the LOTOS language supported by CADP toolbox. The model's functional behavior is formally verified, which cannot be done in simulation approach. The software aspect (benchmark and MPI library primitive), the hardware aspect (cache protocol and topological mapping), and the performance aspect (delay transitions) are in separate processes. Their integration is done by composition but each aspect can be refined independently. An abstraction of the hardware cache protocol allows to easily capture the fact that an access latency in one process depends on all cache states in the system. This is allowed by the compositional method of building the model and by the distinction of immediate transitions from delay transitions in IMC theory. It computes overall latency and above all cache miss count per variable, in different software and hardware configurations. These detailed figures allow to understand the weight of each access in the overall latency. The model is relatively small and its formal verification and performance evaluation are done within a few minutes. So even such an abstract model of a complex large-scale architecture has the potential to compare and analyze benchmark behavior.

Next step is to apply this method to predict additional figures like bandwidth; and to investigate modeling of other MPI primitives like the barrier one. Our long-term objective is to build a modeling tool that automates this method. It takes in input primitive and benchmark implementations written in some pseudo-code, cache coherence protocol and processor mapping, then automatically produces the LOTOS models and computes the performance figures.

  Proc0[Action] = Send(P0, P1);Receive (P0, P1);Proc0 and Proc1[Action] = Receive(P1, P0);Send(P1, P0);Proc1,

  2): Process Caches[Action](Cs:Cachestates, Map:Mapping): Noexit:= Action ?P:Proc ?Op:Access ?V:Address ?Val:Value ?T:Transfer [T == Transfer(P, Map, Op, V, Cs)]; Caches[Action](Newstate(P, Op, V, Cs), Map) Endproc

  Process Latency[Action, End action, Latency](P:Proc): Noexit := Action !P ?Op:Access ?V:Address ?Val:Value ?T:Transfer; Latency !P !V !T; End action !P; Latency[Action, End action, Latency](P) Endproc yielding the following processes: PLj[Action, End action, Latency]= Procj[Action, End action] |[Action, End action]| Latency[Action, End action, Latency](Pj) and the benchmark whole model is: Benchmark = ( PL0[Action, End action, Latency] ||| PL1[Action, End action, Latency] ) |[Action]| Memory[Action](Mem) |[Action]| Caches[Action](Cs, Map)

Figure 2 .

 2 Figure 2. Number of cache misses

Table 1 .

 1 Protocol for a load operation

	CurrentState	NewState	Data transfer type
	P i S/E/M I I I I	P j * I S E I	P i S/E/M E S S E	P j * I S S I	Hit (internal) M → P i M → P i M → P i with P j lookup P j → P i

Table 2 .

 2 Protocol for a store operation

	CurrentState	NewState	Data transfer type
	P i E/M I/S I/S I I I	P j I I S E M M	P i E/M M M M M S	P j I I I I I S	Hit (internal) M → P i M → P i with P j invalidation M → P i with P j invalidation P j → P i (Protocol A) P j → P i (Protocol B)

states in the real system are not modified atomically but the protocol should ensure that from a coherence viewpoint, the system behaves as though the NewState function is atomic. The tables also define a Transfer(p, op, v, CurrentState, vmap, pmap) function giving the data transfer type, which has two additional parameters vmap and pmap, describing respectively variable mapping in the distributed memory and process mapping onto processors. We consider the FAME architecture commercialized in the Bull NovaScale R "Intensive Line" servers (www.bull.com/novascale/intensive.php). It is a hierarchical CC-DSM architecture with three levels: at the top level a system is composed of modules, a module is composed of processing nodes, and a processing node contains processors connected with a bus and equipped with a memory piece. This gives three possible cases of distance (denoted d) between a requester and a data provider: in the same node (d = 0), in different nodes but in the same module (d = 1) and in different modules (d = 2). Therefore, Transfer function can take 13 possible values: 1 hit case and 12 miss cases. The miss cases are obtained by varying 3 parameters: distance between source and destination (3 values), source types (2 values: other cache or memory), handling in memory source case (3 cases: with other cache lookup, with invalidation, or none of them).

  Then Latency process is modified this way:

	Process Caches[Action](Cs:Cachestates, Map:Mapping): Noexit:= Action ?P:Proc ?Op:Access ?V:Address ?Val:Value ?T:Transfer [T == Transfer(P, Map, Op, V, Cs)]; Caches[Action](Cs, Map) [] Update ?P:Proc ?Op:Access ?V:Address; Caches[Action](Newstate(P, Op, V, Cs), Map) Endproc
	Process Latency[Action, End action, Latency, Update](P:Proc): Noexit := Action !P ?Op:Access ?V:Address ?Val:Value ?T:Transfer; Latency !P !V !T !1; Update !P !Op !V; Latency !P !V !T !2; End action !P; Latency[Action, End action, Latency](P) Endproc

  2) An implementation of Send and Receive primitives.

		10.00
		9.00
		8.00
		7.00
	Latency (us)	3.00 4.00 5.00 6.00		B1 A1 MA1 B2 A2
		2.00
		1.00
		0.00
		0	1	2
			Distance
				The first one (called SR1 below), provided by MPICH v1.26 (www-unix.mcs.anl.gov/mpi/mpich1) is based on lists and locks: each process has a list of available packets (to use) and a list of incoming packets (re-ceived from the other process). These lists are accessed by locking them first. The second implementation

Acknowledgment

We are grateful to Holger Hermanns and Hubert Garavel for useful discussions. This research was supported by the MULTIVAL project of the MINALOGIC "Pôle de compétitivité". M. Zidouni's work is partially financed by French Research Ministry and European Social Fund.


Fanny Artaud
email: fanny.artaud@inserm.fr

PhD Pei-Chen Lee

PhD Graziella Mangone

MD, PhD Marie Vidailhet

PhD; Jean-Christophe Christophe Corvol

MD, PhD Alexis Elbaz

Longitudinal association between dopamine agonists and weight in Parkinson's disease

Keywords: Parkinson disease, dopamine agonists, body mass index, weight change, epidemiology, longitudinal analyses

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

INTRODUCTION

While weight tends to increase up to 80 years in the general population [START_REF] Dahl | Multifactorial analysis of changes in body mass index across the adult life course: a study with 65 years of follow-up[END_REF], weight loss is common in Parkinson's disease (PD) [START_REF] Ma | Weight Loss and Malnutrition in Patients with Parkinson's Disease: Current Knowledge and Future Prospects[END_REF][START_REF] Van Der Marck | Body mass index in Parkinson's disease: a meta-analysis[END_REF]. PD patients have lower weight than controls, and this difference increases with disease severity and duration [START_REF] Ma | Weight Loss and Malnutrition in Patients with Parkinson's Disease: Current Knowledge and Future Prospects[END_REF]. Several factors are involved, including increased energy expenditure, appetite loss, nausea, vomiting, and gastrointestinal function impairment.

There is however considerable heterogeneity in weight trajectories. While in the past PD was considered as a disease of malnutrition, individual patients may be nowadays overweight/obese [START_REF] Ma | Weight Loss and Malnutrition in Patients with Parkinson's Disease: Current Knowledge and Future Prospects[END_REF][START_REF] Kistner | Mechanisms of body weight fluctuations in Parkinson's disease[END_REF][START_REF] Wills | Association Between Change in Body Mass Index, Unified Parkinson's Disease Rating Scale Scores, and Survival Among Persons With Parkinson Disease: Secondary Analysis of Longitudinal Data From NINDS Exploratory Trials in Parkinson Disease Long-term Study 1[END_REF]. The global overweight epidemic may contribute to this observation. In addition, dopamine agonists (DA) are associated with impulse control disorders (ICDs) that may contribute to weight gain [START_REF] Corvol | Longitudinal analysis of impulse control disorders in Parkinson disease[END_REF].

Few studies investigated the longitudinal association between DA and weight; they were usually small with a short follow-up [START_REF] Kumru | Increase in body weight after pramipexole treatment in Parkinson's disease[END_REF][START_REF] Vikdahl | Weight gain and increased central obesity in the early phase of Parkinson's disease[END_REF][START_REF] Wills | Predictors of weight loss in early treated Parkinson's disease from the NET-PD LS-1 cohort[END_REF]. Our objectives were twofold. First, we used data from a prospective study of PD patients to examine the longitudinal association of DA use with weight trajectories and weight gain, while adjusting for levodopa (LD) use and disease severity. Second, we examined whether the association between DA use and weight change was explained by ICDs.

METHODS

Patients

The Drug Interacting with Genes in PD (DIGPD) study is a longitudinal cohort study of PD patients consecutively recruited (5/2009-7/2013) in four French university hospitals and four general hospitals. Eligible patients were PD patients (UK-Parkinson's Disease Society Brain Bank criteria, UKPDSBB [START_REF] Gibb | The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease[END_REF]) with ≤5 years disease duration at recruitment. Following the baseline visit, 5 additional annual evaluations were performed over 6 years by movement disorders specialists who checked whether patients fulfilled UKPDSBB criteria. Patients diagnosed with atypical parkinsonism over the follow-up (n=11) were excluded. As patients had short disease duration at baseline, none had deep brain stimulation (DBS); 7 patients with DBS over the follow-up were censored at time of DBS.

The study (clinicaltrials.gov NCT01564992) was approved by French regulatory authorities and an ethical committee; all patients gave written informed consent.

Variables

Height/weight were measured at baseline in all centers. Weight was measured at each visit in the Paris center only; analyses are therefore restricted to patients from this centre. Body mass index (BMI) was computed as weight (kg)/baseline height squared (m²).

At baseline, the full history of antiparkinsonian drug use since disease onset was obtained using medical records and prescriptions (start/end dates of all drugs, doses). At subsequent visits, history of all prescriptions since previous visits was obtained. DA and LD doses are expressed in LD equivalents (LED) [START_REF] Tomlinson | Systematic review of levodopa dose equivalency reporting in Parkinson's disease[END_REF].

Baseline characteristics included age, sex, education, and disease duration.

At each visit, cognitive function was assessed with the mini-mental state examination (MMSE). Patients reported all their medications (Anatomical Therapeutic Chemical classification-ATC). We identified antidepressants (ATC-N06A). Disease severity was assessed through the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS parts I-IV) and Hoehn and Yahr scale; movement disorder specialists assessed whether patients were on/off state. Dyskinesias were assessed using MDS-UPDRS part-IV.

Symptoms of dopaminergic dysregulation in the last 3 months before each visit were evaluated through semi-structured interviews (compulsive gambling [START_REF] Association | Diagnostic and Statistical Manual of Mental Disorders[END_REF], buying [START_REF] Evans | Impulsive and compulsive behaviors in Parkinson's disease[END_REF], eating [START_REF] Association | Diagnostic and Statistical Manual of Mental Disorders[END_REF], sexual behaviour [START_REF] Voon | Prevalence of repetitive and reward-seeking behaviors in Parkinson disease[END_REF]). ICDs were defined by at least one of these symptoms [START_REF] Corvol | Longitudinal analysis of impulse control disorders in Parkinson disease[END_REF].

Statistical analysis

Patients without any BMI measure or with missing covariates were excluded (Supplementary Figure 1).

Longitudinal trajectories of daily DA and LD dose

We modelled mean trajectories of daily DA and LD dose over the follow-up (in persons with at least one DA or LD prescription) using latent class mixed models for non-Gaussian longitudinal markers [START_REF] Proust-Lima | Joint modeling of repeated multivariate cognitive measures and competing risks of dementia and death: a latent process and latent class approach[END_REF]. Distributions of daily DA and LD dose were transformed using the Beta Cumulative Distribution Function link function that provided the best fit (Supplementary Figure 2). This approach assumes that the population is composed of G latent classes of patients (selected using the Bayesian information criterion). Models included time+time² and were adjusted for baseline age and disease duration. The intercept and slope (time+time²) were treated as random effects.

Longitudinal association of DA use with BMI change

We examined the longitudinal association of time-dependent DA use with BMI change using latent-process mixed models with random intercept and slope. The Beta Cumulative Distribution Function link function provided the best fit (Supplementary Figure 2). Models were adjusted for baseline age and disease duration, sex, education, and time-dependent LD use, severity (MDS-UPDRS part-III), on-off state, and dyskinesias (MDS-UPDRS part-IV).

Analyses are based on three different definitions of time-dependent DA and LD use:

(i) users vs. non-users in previous 12 months; (ii) mean daily dose over 12 months before each visit categorized at the median (based on all visits: DA=160mg, LD=300mg); (iii) trajectories of daily dose (defined above); for this model, the effect of DA and LD trajectories were not included at baseline, because they were not significantly associated with baseline BMI. Pvalues for trend were computed using mean daily doses and the trajectory number (0 to 3) as continuous variables. We examined whether associations were explained by compulsive eating or ICDs by adding them to the models as time-dependent covariates and computed the percentage reduction of regression coefficients.

We conducted several sensitivity analyses:

-Adjustment for time-dependent MMSE and use of other antiparkinsonian drugs (amantadine, anticholinergics, MAO-B inhibitors) or antidepressants.

-Because patients who dropped-out or died may be different compared to those who remained in the study, we took into account missing values due to drop-out or death through a joint model [START_REF] Rizopoulos | Joint Models for Longitudinal and Time-to-Event Data: With Applications in R[END_REF].

-The relation of DA and LD with BMI may be subject to time-dependent confounding by disease severity (Supplementary Figure 3).To address this issue, we used sequential conditional mean models [START_REF] Keogh | Analysis of Longitudinal Studies With Repeated Outcome Measures: Adjusting for Time-Dependent Confounding Using Conventional Methods[END_REF].

Incidence of weight gain over the follow-up

We used time-dependent Cox proportional hazards regression to estimate the hazard ratio (HR) of gaining ≥6kg (~1-standard deviation [SD] of the weight difference between baseline and end of follow-up) according to time-dependent DA and LD use. Patients were followed since baseline until the first visit with a weight gain of ≥6kg or last visit. Age was used as the time-scale; models were adjusted for baseline disease duration and height, and timedependent disease severity (MDS-UPDRS part-III), on-off state, and LD use; sex, education, and dyskinesias were not retained (not significant). We examined whether associations were explained by compulsive eating or ICDs by adding them as time-dependent covariates and computed the percentage reduction of regression coefficients.

Analyses were performed using SAS 9.4 (SAS Institute Inc, Cary, NC), and R 3.6 packages lcmm-1.9.1 [START_REF] Proust-Lima | Estimation of Extended Mixed Models Using Latent Classes and Latent Processes: The R Package lcmm[END_REF], JM-1.4-8 [START_REF] Rizopoulos | Joint Models for Longitudinal and Time-to-Event Data: With Applications in R[END_REF] (R-Foundation for Statistical Computing, Vienna); P-values are two-sided and those ≤.05 considered statistically significant.

RESULTS

PD patients' characteristics

Of 374 patients included in the Paris center, we excluded 19 with missing BMI, treatments, or covariates, and retained 355 (Supplementary Figure 1); 66.5% of the patients attended ≥5 assessments, 25.9% attended 2-4 assessments, and 7.6% attended the baseline assessment only. 35 patients died over the follow-up, and of those who remained alive, 79 dropped-out before last visit (Supplementary Figure 1); there were no major baseline differences between patients who dropped-out and those who remained alive, while patients who died were older and used LD more frequently and at higher doses than patients who remained alive (Supplementary Table 1). Average follow-up was of 4.0 years (SD=1.7 years). Supplementary Table 2 shows patient's baseline characteristics. Baseline mean BMI was 26.0 kg/m² (SD=3.9); male sex, lower education, disease severity, ICDs, compulsive eating, and antidepressant use were associated with higher BMI. Fifty four (15.2%) patients were obese (BMI≥30) and 156 (43.9%) overweight (25≤BMI<30); 145 (40.8%) had normal BMI (BMI<25). Compared to patients who had not used DA in the previous 12 months, DA users were younger and more often male, had longer disease duration, used less frequently LD and at lower doses, and had more frequently ICDs and compulsive eating.

Longitudinal trajectories of DA and LD dose

Figure 1 shows trajectories of daily DA dose. Three trajectories were identified: low (decreasing, 18.5%), moderate (increasing-decreasing, 29.9%), and high (increasing, 51.6%).

Patients in the low dose trajectory were older, used more often LD, and had higher MDS-UPDRS part-I (Supplementary Table 3). Three trajectories were identified for LD dose (Supplementary Figure 4): lowincreasing (14.0%), increasing-decreasing (20.7%), high-increasing (65.4%).

Longitudinal association of DA use with BMI change

Overall, BMI decreased each year by -0.07 kg/m² (95% Confidence Interval [CI]=-0.12, -0.02). Female sex, higher education, and dyskinesias were associated with lower BMI throughout the follow-up (not shown). Age, baseline disease duration, and MDS-UPDRS Part III, and on-off state were not associated with BMI but forced in the analyses due to their association with treatments.

Analyses of the relation of DA and LD use with BMI are summarized in Table 1 (Model A) and Figure 2. Baseline BMI was similar in DA users and non-users (P=.62), while it was higher in LD users than non-users (P=.005) without a significant dose-effect relation (P-trend=.09); the difference in baseline BMI between DA and LD users was not statistically significant (P=.12). BMI increased over the follow-up in DA users compared to non-users (beta=0.13, P=.02), while it decreased in LD users compared to non-users (beta=-0.26, P<.001); the difference between DA and LD users was statistically significant (P<.001).

There was no interaction between DA and LD (P=.10). The dose-effect relation was more pronounced for LD (P<.001) than DA (P=.13); in DA users, there was no significant difference between patients below and above the median (P=.45), while in LD users, BMI decreased faster in patients above the median compared to those below (P<.001).

Regarding DA trajectories, compared to non-users, BMI did not increase significantly for the low trajectory (beta=0.12, P=.23) while associations became stronger for the moderate (beta=0.16, P=.08) and significant for the high (beta=0.29, P=.001; P-trend=.001) trajectories; BMI increase was more pronounced in the high trajectory compared to the moderate (P=.04) and low (P=.02) trajectories. For LD, compared to non-users, BMI decrease was not significant for the low-increasing trajectory (beta=-0.14, P=.28); it was more pronounced for the increasing-decreasing (beta=-0.28, P=.02) and high-increasing trajectories (beta=-0.22, P=.06; P-trend=0.09). There was no significant difference between high-increasing and lowincreasing (P=.26) or increasing-decreasing (P=.37) trajectories.

After adjustment for compulsive eating, associations between DA and BMI change decreased but remained present (Table 1, Model B); adjustment for ICDs led to a smaller attenuation (Supplementary Table 4). Adjustment had a weaker effect for LD than DA.

Conclusions were similar after adjustment for MMSE, use of other antiparkinsonian drugs (not shown) or antidepressants (Supplementary Table 5), and after taking into account death and drop-out (Supplementary Table 6).

After taking into account time-dependent confounding through sequential conditional mean models, BMI was higher in DA users than non-users at each visit (beta=0.35, P=.03); the difference increased as DA dose increased (P-trend=.02; Supplementary Table 7). The difference between LD users and non-users was not statistically significant (beta=-0.10, P=.45), but higher doses tended to be associated with lower BMI (P-trend=.01).

DA use and incidence of weight gain over the follow-up

Over the follow-up, 75 patients (11 never DA users, 64 ever DA users) gained ≥6kg. The cumulative incidence of weight gain of ≥6kg was 30.9% (95% CI=23.6-38.3); it was 14.8% (95% CI=2.7-26.8) in never DA users and 33.0% (95% CI=24.9-41.1) in ever DA users.

Incidence of weight gain of ≥6kg was 2.10-times higher in DA users compared to nonusers (P=.04), with a dose-effect relation (P-trend=.03; Table 2). Although LD users were less likely to gain weight, the association was not statistically significant (HR=0.60, P=.10; P-trend=.23).

Both ICDs and compulsive eating were associated with incidence of weight gain (Table 2). The HR for DA decreased by -15.9% after adjustment for compulsive eating but remained >1; the attenuation was weaker after adjustment for ICDs (-11.4%). For LD, compulsive eating and ICDs did not attenuate associations.

DISCUSSION

In this longitudinal study of PD patients, after adjustment for disease severity, dyskinesias, and age, DA users gained weight over the follow-up while LD users lost weight. Part of the association of DA use with weight gain was explained by compulsive eating.

According to a meta-analysis, PD patients had on average lower BMI than controls, although the difference was variable across studies; disease severity was associated with weight loss [START_REF] Van Der Marck | Body mass index in Parkinson's disease: a meta-analysis[END_REF]. A variety of factors are involved in weight loss in PD [START_REF] Kistner | Mechanisms of body weight fluctuations in Parkinson's disease[END_REF]. Metabolic studies suggest that increased energy expenditure related to rigidity, tremor, and dyskinesias are involved. Other factors include appetite loss, nausea, vomiting, and gastrointestinal function impairment. In addition, DA may lead to changes in eating behavior (e.g., binge eating) by activating the reward system [START_REF] Kistner | Mechanisms of body weight fluctuations in Parkinson's disease[END_REF][START_REF] Voon | Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update[END_REF].

Few studies investigated the longitudinal association between DA and weight change.

One study of 58 patients with short follow-up (3 years) did not find any association between DA (±LD compared to LD only) and BMI change [START_REF] Vikdahl | Weight gain and increased central obesity in the early phase of Parkinson's disease[END_REF]. In another study, LD use and baseline LED were associated with more rapid annual weight loss in 1619 patients over 7 years compared to DA use [START_REF] Wills | Predictors of weight loss in early treated Parkinson's disease from the NET-PD LS-1 cohort[END_REF]. In another study, the weight of 28 patients treated with pramipexole increased from 74.8±13.2 kg to 77.4±13.2 kg (P<.001) over 3 months [START_REF] Kumru | Increase in body weight after pramipexole treatment in Parkinson's disease[END_REF]. Finally, a randomized trial showed a significant increase of ~1 kg in the pramipexole group relative to placebo over 12 weeks [START_REF] Kieburtz | Parkinson Study Group Prami, Twice-daily, low-dose pramipexole in early Parkinson's disease: a randomized, placebo-controlled trial[END_REF].

Analyses based on the average daily DA dose did not show a clear dose-effect relation.

However, in analyses based on DA trajectories, patients in the high trajectory had the greatest weight gain over the follow-up, while it was less pronounced for the moderate trajectory and not significant for the low trajectory. These results highlight the interest of trajectory analyses; while, the mixed model uses the information on DA dose at each time point, trajectory analyses use information on DA dose throughout the follow-up. In the survival analysis, patients above the median DA dose over all the follow-up had a 2.4-fold increased risk of gaining ≥6kg. Even moderate weight gain in middle-age is associated with increased risk of incident cardiometabolic disease [START_REF] Kodama | Quantitative relationship between body weight gain in adulthood and incident type 2 diabetes: a meta-analysis[END_REF][START_REF] Jayedi | Adult weight gain and the risk of cardiovascular disease: a systematic review and dose-response meta-analysis of prospective cohort studies[END_REF] and cancer [START_REF] Emaus | Weight change in middle adulthood and breast cancer risk in the EPIC-PANACEA study[END_REF]. Larger studies are necessary to examine the relation between prolonged DA use and these outcomes in PD patients.

DA use is the main risk factor for ICDs, and compulsive eating is the most frequent ICD [START_REF] Corvol | Longitudinal analysis of impulse control disorders in Parkinson disease[END_REF]. After adjustment for compulsive eating, the associations between DA and weight gain decreased but remained present. It is possible that we measured imperfectly changes in eating behavior, as questions on ICDs referred to the three months prior to each visit, or that some patients did not report them. Alternatively, it is possible that other mechanisms may be involved in this association. For instance, both ergot and non-ergot DA can induce oedema [START_REF] Antonini | A reassessment of risks and benefits of dopamine agonists in Parkinson's disease[END_REF]. In the CALM-PD trial, pramipexole compared to LD was associated with a 3-fold increased risk of leg oedema; the 4-year incidence of leg oedema was 45% in pramipexole users [START_REF] Biglan | Parkinson Study Group, Risk factors for somnolence, edema, and hallucinations in early Parkinson disease[END_REF]. The etiology of DA-induced oedema is not well understood, but it has been hypothesized that DA could interfere with sympathetic nervous system regulation [START_REF] Biglan | Parkinson Study Group, Risk factors for somnolence, edema, and hallucinations in early Parkinson disease[END_REF], which also plays a key role in weight regulation [START_REF] Guarino | The Role of the Autonomic Nervous System in the Pathophysiology of Obesity[END_REF].

Regarding LD, while cross-sectional studies suggested that LD can be associated with ICDs [START_REF] Weintraub | Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients[END_REF], a previous longitudinal analysis of our data showed no association between LD and ICDs [START_REF] Corvol | Longitudinal analysis of impulse control disorders in Parkinson disease[END_REF]. In addition, in the present study, adjustment for compulsive eating or ICDs had a weaker effect on BMI change for LD than DA.

Disease severity represents a time-dependent confounder of the relation between DA or LD use and BMI (Supplementary Figure 3). Analyses were adjusted for time-dependent disease severity, as well as LD use and dyskinesias which also correlate with severity. In addition, we used a statistical method designed to handle time-dependant confounding that confirmed that BMI was higher by ~0.5kg/m² in DA users compared to non-users, with a dose-effect relationship [START_REF] Keogh | Analysis of Longitudinal Studies With Repeated Outcome Measures: Adjusting for Time-Dependent Confounding Using Conventional Methods[END_REF].

In agreement with other studies [START_REF] Wills | Predictors of weight loss in early treated Parkinson's disease from the NET-PD LS-1 cohort[END_REF][START_REF] Sharma | Cascade of levodopa dose and weight-related dyskinesia in Parkinson's disease (LD-WD-PD cascade)[END_REF][START_REF] Palhagen | Does L-dopa treatment contribute to reduction in body weight in elderly patients with Parkinson's disease?[END_REF], LD use was associated with decreasing BMI in the linear mixed model, although this pattern was less significant for LD trajectories, using survival analysis, and after adjusting for time-dependent confounding.

Our study has limitations. First, patients were included in referral centers and relatively young. Because DA are more frequently used in younger patients, this may contribute to overestimate weight gain frequency. Second, the proportion of patients who died or dropped-out before the end of follow-up was not negligible. However, there were no major differences between patients who dropped-out and remained alive, and a statistical method that takes into account missing values due to drop-out or death led to similar conclusions. Third, previous studies showed that DBS leads to weight gain [START_REF] Kistner | Mechanisms of body weight fluctuations in Parkinson's disease[END_REF]. Few patients underwent DBS over the follow-up, and they were censored at the time of surgery; we were therefore unable to examine the relation between DBS and weight change. Fourth, MDS-UPDRS part-III was measured on-or off-state, and analyses were adjusted for this variable. At each visit, >80% of patients were on-state which leads to underestimate disease severity, but in a similar way for all patients and visits and independently of BMI. We repeated our analyses after adjusting for time-dependent Hoehn and Yahr and results were unchanged (not shown). Fifth, one study of 7 patients on DA showed that in 5 patients who lowered the dose or discontinued treatment, no further weight gain occurred [START_REF] Nirenberg | Compulsive eating and weight gain related to dopamine agonist use[END_REF]. The small number of patients who discontinued DA in our study did not allow us to examine whether BMI declined after discontinuation. Finally, BMI at each visit was computed based on baseline height, leading to underestimate BMI if height decreased significantly over the follow-up. In a French study (n=1,520, 65-85 years), the 10-year change in height was -2.0 cm (95% CI: -2.2, -1.9); therefore, a strong impact on our findings is unlikely [START_REF] Elbaz | The gait speed advantage of taller stature is lost with age[END_REF].

The main strength of our study is the longitudinal annual assessment of a relatively large cohort of PD patients that allowed us to take into account the full history of DA use and BMI change over 6 years. We used a flexible statistical approach that captures nonlinear trajectories [START_REF] Proust-Lima | Estimation of Extended Mixed Models Using Latent Classes and Latent Processes: The R Package lcmm[END_REF], and carried out a number of sensitivity analyses that confirmed the robustness of our findings.

Our study emphasizes the need to carefully monitor changes in eating behavior and weight as PD progresses, particularly weight gain in DA users and weight loss in LD users. -Graziella Mangone reports no disclosures.

ACKNOWLEDGMENT

-Marie Vidailhet reports no disclosures.

-Jean-Christophe Corvol holds stock options in B&A Therapeutics; is a consultant for Theranexus, BrainEver, and Air Liquide; received research grants from Actelion, 2-Predicted trajectories of BMI according to daily DA dose categorized at the median (time-dependent). The curves correspond to the average trajectory of BMI in patients who never took DA over the follow-up (blue) and in patients with DA doses below (green) or above (red) the median throughout the follow-up.

3-Predicted trajectories of BMI according to trajectories of daily DA dose over the follow-up. The curves correspond to the average trajectory of BMI in patients according to their trajectory of daily DA dose (defined in Figure 1). Table 1. Longitudinal associations of use of dopamine agonists (DA) and levodopa (LD) with the latent process of change of body mass index (BMI, kg/m²) over the follow-up before (model A) and after adjustment for compulsive eating (model B).

  The authors thank the Assistance Publique Hôpitaux de Paris (APHP), and the Unité de Recherche Clinique (URC) of the Pitié-Salpêtrière Hospital for their support in sponsoring this cohort. The authors thank contributors of the DIGPD Study Group who helped with the recruitment or assessment of patients at the Pitié-Salpêtrière Hospital: Julia Muellner (coinvestigator), Julia Kraemmer (coinvestigator), Eve Benchetrit (neuropsychologist), Fanny Pineau (neuropsychologist), and Julie Socha (neuropsychologist). DIGPD Study Group: Florence Cormier-Dequaire, MD, Olivier Rascol, MD, Franck Durif, MD, Pascal Derkinderen, MD, Ana-Raquel Marques, MD, Frédéric Bourdain, MD, Jean-Philippe Brandel, MD, Fernando Pico, MD, Lucette Lacomblez, MD, Cecilia Bonnet, MD, Christine Brefel-Courbon, MD, Fabienne Ory-Magne, MD, David Grabli, MD, Stephan Klebe, MD, Hana You, MD, Valérie Mesnage, MD, Alexis Brice, MD. STUDY FUNDING This project was funded by grants from the French Ministry of Health (Programme Hospitalier de Recherche Clinique, AOR0810) and from the French Drug Agency (Agence Nationale de Sécurité et des Médicaments, ANSM-2013). DISCLOSURES -Fanny Artaud reports no disclosures. -Pei-Chen Lee is supported in part by the Taiwan Ministry of Science and Technology (MOST 107-2314-B-227-009-MY3) and by the Taipei City Hospital (10801-62-008).

Figure 1 .

 1 Figure 1. Trajectories of the daily dose of dopamine agonists (DAs) with 95% pointwise confidence intervals Daily DA dose was assessed annually; at each time point, it is defined as the daily dose over the previous 12 months. 95% pointwise confidence intervals were obtained by a Monte Carlo method.

Figure 2 .

 2 Figure 2. Predicted trajectories of body mass index (BMI) with 95% pointwise confidence intervals according to use of dopamine agonists (DAs) Regression coefficients of the corresponding models are shown in Table 1 (Model A). 1-Predicted trajectories of BMI according to DA use (time-dependent). The curves correspond to the average trajectory of BMI in patients who never took DA during the follow-up (blue) and in patients who remained on DA throughout the follow-up (red).

Data availability

Anonymized data will be shared by request from any qualified investigator.

Ipsen, Clevexel, Sanofi-Aventis, Michael J. Fox Foundation, France Parkinson, French Ministry of Health (ANR: MeMoDeep, MoDysk; PHRC Grants AOM_10-078, AOR-08-10); consultant honoraria from Abbvie, Lundbeck, BMS, Pfizer, Zambon, and Amarantus; and travel grants from MDS, Teva, Novartis, and UCB.

-Alexis Elbaz reports funding for grants from ANSM (Agence nationale de sécurité du médicament et des produits de santé, ANR (agence nationale de la recherche), and Anses (Agence nationale de sécurité sanitaire de l'alimentation).

CONTRIBUTIONS

Fanny Artaud: Study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of manuscript for intellectual content.

Pei-Chen Lee: Interpretation of data, critical revision of manuscript for intellectual content.

Graziella Mangone: Acquisition and interpretation of data, critical revision of manuscript for intellectual content.

Marie Vidailhet: Interpretation of data, critical revision of manuscript for intellectual content.

64 (1.00, 2.68) .05 --DA, dopamine agonist; LD, levodopa. Inc, incidence. Hazard ratios (HR) and 95% confidence intervals (CI) were computed using time-dependent Cox proportional hazards models. Age is used as the time-scale. a Model A is adjusted for disease duration at baseline, height at baseline, time-dependent MDS-UPDRS III, and time-dependent on-off state; sex, education, and dyskinesias were not retained in the survival model because they were not associated significantly with the outcome. b Model B = Model A + time-dependent compulsive eating. c Model C = Model A + time-dependent ICDs. d Percentage reduction in the association between DA and weight gain after adjustment for compulsive eating (∆=100×(βModel B-βModel A)/βModel A) or ICDs (∆=100×(βModel C-βModel A)/βModel A). e P-trend.


Bourmaud

A Demont

J Quentin

A Bourmaud

Keywords: Emergency medical services, Musculoskeletal disorders, Physical therapy (specialty), Referral and consultation

est destinée au dépôt

Résumé

Position du problème Les affections musculosquelettiques sont confrontées à une augmentation de leur prévalence, principalement en raison de la sédentarité. Des données probantes fortes soutiennent le recours précoce à un traitement de première ligne incluant la kinésithérapie. De nouveaux modèles innovants en soins primaires et aux urgences ont été développés et utilisent les compétences du masseur-kinésithérapeute pour la prise en charge précoce et de première ligne des patients souffrant d'affections musculosquelettiques. L'objectif de cette revue était d'identifier et de décrire les études évaluant les modèles de soins intégrant l'accès direct à la kinésithérapie en soins primaires et aux urgences pour les patients présentant une affection musculosquelettique et proposer des perspectives sur l'application de ces deux modèles en France.

Méthodes

Une revue de la littérature a été réalisée à partir de l'inclusion d'études provenant de quatre bases de données scientifiques, PubMed, CINAHL, Embase et PEDro. Les articles recherchés devaient traiter de l'efficacité clinique ou de l'efficience de ces modèles de soins dans un contexte de soins primaires ou d'urgence. Une méthode narrative de revue de la littérature a été utilisée. La synthèse porte sur l'analyse qualitative des études incluses.

Résultats

Au total, 39 études ont été incluses dans cette revue : 19 sur l'évaluation de l'accès direct à la kinésithérapie en soins primaires et 20 sur l'évaluation de l'accès direct aux urgences. Celles-ci rapportaient que les différents modèles de soins intégrant l'accès direct en soins primaires ou aux urgences fournissaient de meilleurs résultats en termes de qualité et d'accès aux soins tout en maintenant une sécurité similaire. La méthodologie des études incluses a cependant été estimée comme de qualité hétérogène.

Conclusion

Les études portant sur ces nouveaux modèles de soins intégrant l'accès direct à la kinésithérapie en soins primaires et aux urgences permettent de retenir deux enseignements : ils n'ont pas vocation à remplacer le médecin et encouragent la collaboration entre professionnels de la santé afin d'améliorer l'accès pour les patients à des soins efficients. Il convient de s'intéresser désormais aux facteurs de dissémination permettant d'assurer l'efficience de ces modèles innovants dans d'autres pays, comme la France. [START_REF] Iorio | A survey of primary care physician practice patterns and adherence to acute low back problem guidelines[END_REF][START_REF] Fullen | Adherence of Irish general practitioners to European guidelines for acute low back pain: a prospective pilot study[END_REF][START_REF] Fritz | Does adherence to the guideline recommendation for active treatments improve the quality of care for patients with acute low back pain delivered by physical therapists?[END_REF]. La formation initiale des médecins généralistes et des médecins urgentistes a été identifiée comme répondant à un objectif d'identification des pathologies graves pouvant causer une symptomatologie musculosquelettique [START_REF] Akesson | Improved education in musculoskeletal conditions is necessary for all doctors[END_REF]. Mais l'interrogatoire approfondi et la réalisation d'un diagnostic clinique dans le champ musculosquelettique font peu partie de leurs acquis, qui sont par contre enseignés en formation initiale de masso-kinésithérapie selon les recommandations de la Confédération mondiale de la physiothérapie et la dernière réforme de la formation initiale des MK [START_REF]World Confederation for Physical Therapy[END_REF][START_REF]World Confederation for Physical Therapy[END_REF][25].

Mots clés

Plusieurs pays ont posé l'hypothèse que devant l'augmentation du nombre de consultations pour un symptôme relevant d'une affection musculosquelettique, une utilisation étendue des soins de kinésithérapie était une des solutions au fonctionnement optimal du système de santé, d'autant plus que les étiologies identifiées sont en majorité bénignes [START_REF] Briggs | Reducing the global burden of musculoskeletal conditions[END_REF]. De nombreuses études soutiennent la nécessité de l'utilisation précoce et en première intention de traitements tels que la kinésithérapie pour ces patients [START_REF] Lin | What does best practice care for musculoskeletal pain look like? Eleven consistent recommendations from high-quality clinical practice guidelines: systematic review[END_REF][START_REF] Liu | Immediate Physical Therapy Initiation in Patients With Acute Low Back Pain Is Associated With a Reduction in Downstream Health Care Utilization and Costs[END_REF].

Ainsi, l'hypothèse pourrait être posée que pour la France aussi, un nouveau parcours de soins pour ces patients, dans un contexte de soins primaires ou d'urgence, pourrait contribuer à un meilleur accès aux soins et à une meilleure qualité des soins.

Objectif

Cet article a pour objectif de réaliser une synthèse des études évaluant les modèles de soins intégrant l'accès direct à la kinésithérapie avec le MK comme praticien de premier recours pour la prise en charge des patients présentant une affection musculosquelettique dans un contexte de soins primaires ou d'urgence et de proposer des perspectives sur son application en France.

Méthodes

Cet article est une revue narrative conduite à partir des études identifiées comme évaluant l'efficacité des modèles de soins intégrant l'accès direct à la kinésithérapie pour la prise en charge des affections musculosquelettiques dans un contexte de soins primaires ou d'urgence. Les évaluations recherchées portaient sur l'efficacité clinique (douleur, fonction et qualité de vie), la satisfaction du patient, l'utilisation des ressources en santé (prescription de médicaments, d'imagerie et recours aux avis de médecins spécialistes) et les coûts de santé.

Bases de données et équation de recherche

Quatre bases de données ont été utilisées pour la recherche de la littérature pertinente :

Sélection des documents

Les titres et résumés de l'ensemble des articles identifiés à partir de la stratégie de recherche ont été inclus par les deux premiers auteurs pour déterminer leur éligibilité basée sur les critères d'inclusion suivants :

-tous types d'études de type article original (étude de cohorte, étude contrôlée randomisée, étude observationnelle…) et de type synthèse qualitative ou quantitative de la littérature (revue systématique avec ou sans méta-analyse) ;

-population de patients présentant une affection musculosquelettique ;

-population de patients consultant directement un MK sans référencement préalable ;

-modèle de soin dans lequel le MK exerce soit en ville dans un contexte de soins primaires, soit à l'hôpital dans un contexte d'urgence (première ligne de soin) ;

-évaluant au moins un des critères de jugement suivants : efficacité clinique (critères objectifs et/ou déclarés par les patients), utilisation des ressources en santé et/ou coûts de santé ;

-accessible en texte intégral ;

-en langue française ou anglaise.

Les critères d'exclusion des études étaient un des types suivants d'études :

-étude de cas, série de cas, éditorial ou acte de congrès ;

-patients consultant un MK suite à un référencement préalable par un autre professionnel de santé ;

-incluant l'intervention d'un MK en seconde ligne de soin ;

-évaluant un autre type de critères de jugement ;

-autre langue que le français ou l'anglais.

Analyse et synthèse des articles

La synthèse des données extraites a été réalisée à partir des revues systématiques et des articles originaux inclus en rapportant le type d'étude, la population concernée, le contexte de soin, sa qualité méthodologique et les principaux résultats.

L'analyse des études incluses dans la revue et qui n'étaient pas retrouvées dans les revues systématiques identifiées a été réalisée de façon qualitative et parallèle par les deux premiers auteurs à l'aide de l'outil d'analyse de biais méthodologiques « Quality Assessment Tool for Quantitative Studies » [START_REF] Thomas | A process for systematically reviewing the literature: providing the research evidence for public health nursing interventions[END_REF]. Les analyses ont secondairement été mises en commun. Lors de désaccords d'analyse ou d'interprétation, la solution était obtenue par débats avec le troisième auteur puis consensus. Au regard de la qualité méthodologique des revues systématiques incluses dans cette revue, il n'a pas été réalisé d'analyse de la qualité méthodologique des études incluses par celles-ci.

Résultats

Pour clarifier la terminologie utilisée entre les différents modèles de soins exposés cidessous, la Confédération mondiale de la physiothérapie (WCPT) a produit une déclaration politique, dénommée "Direct access and patient/client self-referral to physical therapy" révisée en 2019 [START_REF]Policy statement: Direct access and patient/client self-referral to physical therapy n[END_REF]. L'accès direct à la kinésithérapie y est défini comme la possibilité donnée aux patients de se référer eux-mêmes à un MK sans avoir à consulter d'abord un autre professionnel de santé, ou sans qu'un autre professionnel ne leur ordonne de se référer au MK. Les deux premiers pays à avoir introduit ce modèle en soins primaires sont l'Australie en 1976 et le Royaume-Uni en 1977 [START_REF] Galley | Ethical principles and patient referral[END_REF][START_REF] Galley | Patient referral and the physiotherapist[END_REF][START_REF] Galley | Physiotherapists as first-contact practitioners--New challenges and responsibilities in Australia[END_REF][START_REF] Kruger | Patient referral and the physiotherapist: three decades later[END_REF]. De nombreux pays l'ont mis en oeuvre ultérieurement dans leur système de santé tels que les Pays-Bas [START_REF] Leemrijse | Direct Access to Physical Therapy in the Netherlands: Results From the First Year in Community-Based Physical Therapy[END_REF], la Suède [START_REF] Bornhöft | Health effects of direct triaging to physiotherapists in primary care for patients with musculoskeletal disorders: a pragmatic randomized controlled trial[END_REF], les Etats-Unis [START_REF] Domholdt | Direct Access Use by Experienced Therapists in States with Direct Access[END_REF], le Canada [START_REF] Deslauriers | Access to publicly funded outpatient physiotherapy services in Quebec: waiting lists and management strategies[END_REF], la Norvège [START_REF]World Confederation for Physical Therapy. Norwegian physical therapists celebrate direct access for patients -WCPT News n[END_REF],

Singapour, la Jamaïque, l'Afrique du Sud et l'Autriche [START_REF] Kruger | Patient referral and the physiotherapist: three decades later[END_REF].

Modèle de soins intégrant l'accès direct à la kinésithérapie pour la prise en charge en soins primaires des patients présentant une affection musculosquelettique

Au total, 19 études ont été identifiées concernant l'évaluation de l'accès direct à la kinésithérapie en soins primaires. Une seule étude de qualité modérée a été publiée postérieurement [START_REF] Bishop | Providing patients with direct access to musculoskeletal physiotherapy: The impact on general practice musculoskeletal workload and resource use. The STEMS-2 study[END_REF] à la revue systématique la plus récente publiée en 2019 évaluant l'impact de ce modèle de soin en termes de résultats cliniques (douleur, fonction, qualité de vie et évènements indésirables), d'utilisation des services de santé, de coûts économiques des soins de santé et de satisfaction des patients [START_REF] Demont | The impact of direct access physiotherapy compared to primary care physician led usual care for patients with musculoskeletal disorders: a systematic review of the literature[END_REF]. Concernant la méthodologie des 19 études, il a été retrouvé : 2 études contrôlées randomisées [START_REF] Bornhöft | Health effects of direct triaging to physiotherapists in primary care for patients with musculoskeletal disorders: a pragmatic randomized controlled trial[END_REF][START_REF] Bishop | STEMS pilot trial: a pilot cluster randomised controlled trial to investigate the addition of patient direct access to physiotherapy to usual GP-led primary care for adults with musculoskeletal pain[END_REF],

2 études non randomisées [START_REF] Bishop | Providing patients with direct access to musculoskeletal physiotherapy: The impact on general practice musculoskeletal workload and resource use. The STEMS-2 study[END_REF][START_REF] Holdsworth | Are patients who refer themselves to physiotherapy different from those referred by GPs? Results of a national trial[END_REF] Certains de ces enseignements sont pleinement intégrés dans le programme de formation initiale des MK et d'autres relèvent de compétences médicales pouvant être déléguées dans ce modèle de soin.

Discussion

Bien que de tels modèles de soins intégrant l'accès direct à la kinésithérapie dans des contextes de soins primaires [START_REF] Demont | The impact of direct access physiotherapy compared to primary care physician led usual care for patients with musculoskeletal disorders: a systematic review of the literature[END_REF] ou d'urgence [START_REF] Matifat | Benefits of Musculoskeletal Physical Therapy in Emergency Departments: A Systematic Review[END_REF] aient été évalués dans plusieurs pays présentant des systèmes de santé différents, les études retrouvées étaient de méthodologie hétérogène. Au-delà des bénéfices retrouvés par de tels modèles, leur mise en oeuvre implique d'abord et avant tout une grande capacité à répondre aux évolutions de la demande de soins de la population.

Enjeux de la mise en oeuvre de modèles de soins intégrant l'accès direct à la kinésithérapie en France

L'ensemble des pays ayant évalué l'impact de ces modèles de soins pour les patients présentant une affection musculosquelettique a rapporté des bénéfices pour les patients,

  CINAHL, Embase, Medline et PEDro. Cette recherche a été réalisée pour identifier les articles en anglais et en français et publiés jusqu'à mai 2020. Les mots clés utilisés ont été basés sur les critères PICO et sont détaillés dans le Tableau 1. La stratégie de recherche a utilisé la combinaison de mots clés pour la population (patients présentant une affection musculosquelettique), l'intervention (accès direct à la kinésithérapie en soins primaires ou en service d'urgence), le comparateur (soins usuels) et les critères de jugement détaillés ci-dessus. Des recherches manuelles de références d'articles et de précédentes revues systématiques ont été réalisées.

1 .Comparator

 1 la communauté médicale et les organismes financeurs de la santé. Toutefois, bien que la Confédération mondiale de la physiothérapie ait établi des lignes directrices concernant les compétences à acquérir pour un exercice autonome du MK[START_REF]World Confederation for Physical Therapy. WCPT guideline for physical therapist professional entry level education n[END_REF], il existe de nombreuses différences entre les cursus de formation des différents pays dans lesquels les études ont été menées comparativement à la France. Ces différences peuvent inclure d'une part le nombre d'années d'études pour obtenir le diplôme autorisant l'exercice et d'autre part le nombre d'heures théoriques et pratiques pour l'acquisition de certaines compétences essentielles à la pratique autonome du MK en accès direct. Tout écart par rapport aux recommandations de formation -et donc tout manque de compétences -met en jeu la sécurité, l'efficacité et l'efficience d'un modèle dans lequel les patients accéderaient directement à ces services[START_REF] Moffatt | Physiotherapy-as-first-point-of-contact-service for patients with musculoskeletal complaints: understanding the challenges of implementation[END_REF][START_REF]The Musculoskeletal Services Framework: a joint responsibility-doing it differently[END_REF]. Les compétences indispensables impliquent des connaissances approfondies sur[START_REF]World Confederation for Physical Therapy[END_REF] :• la sémiologie médicale concernant les pathologies secondaires provoquant une symptomatologie musculosquelettique ;• le raisonnement clinique ;• l'évaluation clinique et la prise de décision concertée incluant l'identification des drapeaux rouges chez les patients et le choix d'orientation vers un spécialiste,• l'exercice collaboratif dans un environnement pluri-professionnel incluant la communication et le leadership.Afin de garantir une qualité des soins optimale à ces patients, la mise à jour continuelle de la formation initiale ainsi qu'une potentielle certification des MK en activité semblent nécessaires.La profession de MK, née en France en 1946, abrite aujourd'hui plusieurs générations de professionnels, issus de différents programmes de formation initiale. Certains MK ont été formés avec un modèle antérieur à 1989, d'autres, -la majorité-ont suivi la formation initiale selon le programme de 1989 [84], et une minorité a été formée avec le programme récemment réformé de 2015[25]. Bien que ces connaissances indispensables aient été incluses dans la dernière réforme de la formation initiale, il est supposé une variété de compétences parmi ces professionnels, principalement chez ceux ne s'étant pas mis à jour dans le cadre du développement professionnel continu dans la prise en charge des patients présentant une symptomatologie musculosquelettique. Cette hétérogénéité interroge sur les différences de compétences des professionnels lors de la mise en oeuvre de tels modèles de soins intégrant l'accès direct à la kinésithérapie, ce qui sera le cas en France. Le diplôme d'état obtenu à l'issue de la formation initiale permet en théorie aux MK d'exercer dans la totalité de leur champ de compétences (musculosquelettique, neurologie, cardiopulmonaire, pelvi-périnéologie, vestibulaire, etc…). Nombreux sont les professionnels qui choisissent d'orienter leur exercice avec une pratique spécifique, recourant au développement professionnel continu. La sécurité des patients et la performance de l'identification des signes de gravité réalisée par les MK dans le champ musculosquelettique doivent donc être questionnées car elles peuvent être compromises par des compétences insuffisantes à identifier chez ces patients des pathologies ne relevant pas de leurs compétences et impliquant une réorientation vers un médecin.Plusieurs dispositifs législatifs et réglementaires ont été mis en place en France par le législateur pour introduire le transfert de compétence et la délégation de tâche entre les professionnels de santé dans le but d'améliorer la prise en charge des patients. Les protocoles de coopération entre professionnels de santé ont été introduits en France grâce à la loi relative à l'hôpital, aux patients, à la santé et aux territoires, parue en 2009[START_REF] Loi | du 21 juillet 2009 portant réforme de l'hôpital et relative aux patients[END_REF]. Validés par la Haute Autorité de santé, ils permettent de mettre en place, dans un cadre précis, un transfert de compétences ou une délégation de tâche d'un corps professionnel à un autre[86]. La mesure présentée par Madame Agnès Buzyn dans le Pacte de refondation des urgences, visant à faciliter l'expérimentation de modèles de soins intégrant l'accès direct à la kinésithérapie pour les patients présentant une lombalgie aiguë ou une entorse de la cheville, s'inscrit dans le cadre de ces protocoles.5.2. Perspectives posées par la mise en oeuvre de modèles de soins intégrant l'accès direct à la kinésithérapie en FranceSuite à l'annonce du Pacte de refondation des urgences par Madame Agnès Buzyn, plusieurs modèles de soins peuvent être proposés et combinés, à l'image de ceux existants dans d'autres pays, pour répondre au désengorgement des urgences médicales et ainsi contribuer à l'amélioration de la prise en charge des patients présentant une affection musculosquelettique.Le premier modèle, existant déjà dans plusieurs pays tels que le Royaume-Uni[START_REF] Morris | The value of accident and emergency based physiotherapy services[END_REF][START_REF] Kempson | Physiotherapy in an accident and emergency department[END_REF], l'Australie[START_REF] Kruger | Patient referral and the physiotherapist: three decades later[END_REF] et les Etats-Unis[START_REF] Greathouse | The United States Army physical therapy experience: evaluation and treatment of patients with neuromusculoskeletal disorders[END_REF], viserait à proposer un accès direct à la kinésithérapie exerçée dans une équipe pluridisciplinaire d'un service d'urgence médicale en structure hospitalière. Ce modèle est dépendant de la capacité de l'établissement hospitalier de recruter un ou plusieurs MK pour leur équipe médicale d'urgence. Selon une enquête menée en 2018 par le Conseil national de l'Ordre des masseurskinésithérapeutes, 3090 postes de MK salariés ne seraient pas pourvus dans les 3820 établissements de santé en 2018 (données extrapolées à partir des 240 réponses obtenues des établissements de santé interrogés)[START_REF] Pinsault | Enquête nationale sur l'exercice salarié de la kinésithérapie en France[END_REF]. La mise en place d'un tel modèle de soins pourrait être un des leviers pour attirer de nouveaux MK dans les établissements hospitaliers.Le second modèle consisterait à augmenter l'offre de soins primaires proposée aux patients présentant une affection musculosquelettique en leur permettant de consulter directement un MK, sans référencement préalable d'un médecin. Bien qu'il soit désormais autorisé aux MK de mettre en place deux protocoles de coopération visant aux prises en charge du traumatisme en torsion de la cheville pour le premier et de la douleur lombaire aiguë inférieure à quatre semaines pour le second dans le cadre d'une structure pluri professionnelle[START_REF]Prise en charge de la douleur lombaire aiguë inférieure à 4 semaines par le masseurkinésithérapeute dans le cadre d'une structure pluri-professionnelle[END_REF][START_REF]Prise en charge du traumatisme en torsion de la cheville par le masseur-kinésithérapeute dans le cadre d'une structure pluri-professionnelle[END_REF], l'accès direct à ce professionnel n'est pas étendu à l'ensemble des affections musculosquelettiques et ne permettra pas d'utiliser le plein potentiel de ce parcours de soin innovant.Le troisième modèle consisterait à orienter les patients présentant une affection musculosquelettique aiguë (suspicion d'entorse de la cheville après un traumatisme et lombalgie aiguë par exemple) vers un MK de ville à partir de plateformes téléphoniques pour désengorger les urgences comme par exemple le service d'aide médicale urgente (Samu) ou à l'aide d'un dispositif de permanence des soins ambulatoires pendant et audelà des horaires habituels de consultations des MK[START_REF] Loi | du 21 juillet 2009 portant réforme de l'hôpital et relative aux patients[END_REF]. Un algorithme d'aide à la décision pourrait être utilisé par la personne en contact avec le patient, pour définir le niveau de risque : élevé s'il présente une suspicion de pathologie jugée comme grave justifiant un recours aux urgences médicales, ou modéré/faible s'il présente une suspicion de pathologie jugée comme bénigne justifiant le recours à un MK de ville. Bien que ce modèle incluant un triage téléphonique existe par exemple au Royaume-Uni, leur système de gestion des appels d'urgence présente des différences avec celui utilisé en France, telle que l'utilisation d'un index basé sur cinq niveaux pour définir l'urgence de la réponse à apporter, et en limite donc sa comparaison[START_REF] Morris | Effectiveness of a physiotherapy-initiated telephone triage of orthopedic waitlist patients[END_REF][START_REF] Salisbury | A pragmatic randomised controlled trial of the effectiveness and cost-effectiveness of "PhysioDirect" telephone assessment and advice services for physiotherapy[END_REF].La facilitation du recours à ces services par les patients pourrait être permise par leur remboursement dans ces nouveaux modèles de soins par l'Assurance maladie obligatoire et les Assurances maladies complémentaires afin d'en faciliter l'accès à l'ensemble de la population. de la demande de soin de la population, l'augmentation de la sédentarité et les enjeux contemporains de notre système de santé impliquent une réorganisation continuelle des modèles de soins proposés aux patients présentant diverses conditions pathologiques dont les affections musculosquelettiques. Ces nouveaux modèles de soins intégrant l'accès direct à la kinésithérapie ne visent pas à remplacer le médecin intervenant en soins primaires ou aux urgences mais à améliorer la collaboration entre les professionnels de santé de soins primaires et dans un contexte d'urgence pour améliorer l'accès, la qualité des soins et l'efficience du parcours de soin du patient. L'évolution des pratiques de soins en France est nécessaire pour permettre à l'ensemble de la population d'accéder au « bon traitement », au « bon moment », au « bon endroit » et pour le « bon patient ». La recherche devrait ainsi s'intéresser aux facteurs de réussite et d'efficacité de la dissémination de ces modèles innovants à d'autres pays, telle que la France.Déclaration de liens d'intérêtsLes auteurs déclarent ne pas avoir de liens d'intérêts.TableauCritères PICO pour la recherche de la littérature (Population, Intervention, Comparator, Usual care model including prescribed physiotherapy services in secondary careOutcomesClinical patient outcomes (pain, function and quality of life), patient satisfaction, health care resources use and health care costs

  plus faible dans le modèle de soin intégrant l'accès direct à la kinésithérapie comparativement au modèle usuel[START_REF] Alkhouri | Impact of the primary contact physiotherapy practitioner role on emergency department care for patients with musculoskeletal injuries in New South Wales[END_REF][START_REF] Pugh | Dedicated emergency department physical therapy is associated with reduced imaging, opioid administration, and length of stay: A prospective observational study[END_REF][START_REF] Sayer | Advanced musculoskeletal physiotherapists are effective and safe in managing patients with acute low back pain presenting to emergency departments[END_REF][START_REF] Kinsella | Management of patients brought in by ambulance to the emergency department: role of the Advanced Musculoskeletal Physiotherapist[END_REF][START_REF] Matifat | Benefits of Musculoskeletal Physical Therapy in Emergency Departments: A Systematic Review[END_REF][START_REF] Taylor | Primary contact physiotherapy in emergency departments can reduce length of stay for patients with peripheral musculoskeletal injuries compared with secondary contact physiotherapy: a prospective non-randomised controlled trial[END_REF]. La charge de travail des médecins urgentistes était réduite et leur permettait d'accorder plus de temps aux patients présentant une condition pathologique grave[START_REF] Alkhouri | Impact of the primary contact physiotherapy practitioner role on emergency department care for patients with musculoskeletal injuries in New South Wales[END_REF][START_REF] Kinsella | Management of patients brought in by ambulance to the emergency department: role of the Advanced Musculoskeletal Physiotherapist[END_REF][START_REF] Matifat | Benefits of Musculoskeletal Physical Therapy in Emergency Departments: A Systematic Review[END_REF][START_REF] Morris | The value of accident and emergency based physiotherapy services[END_REF]. Une seule étude randomisée

	taille d'effet jugée comme élevée >0,8) [35,41,42,46,47], du handicap et une amélioration
	de la qualité de vie (meilleurs résultats rapportés par le questionnaire EQ-5D-5L
	[44,50,52,53]), une réduction des coûts de santé [42,44,45,49,57], un recours plus faible
	aux médicaments et aux examens d'imagerie [45] et une augmentation de la satisfaction
	des patients [43,46,47,52]. monocentrique a porté sur les coûts de santé montrant que les résultats des deux
	L'étude de Bishop et al. publiée en 2020 rapporte toutefois des résultats contradictoires modèles ne présentaient pas de différence statistiquement significative [66]. Enfin, la
	entre le groupe accès direct à la kinésithérapie et celui dont les soins sont dirigés par le concordance diagnostique entre les MK et les médecins urgentistes était retrouvée bonne
	médecin généraliste [39]. Aucune différence n'a été mise en évidence entre les deux (κ=0,81 ; 95% IC: 0,71-0,90) [58]. Un haut niveau de satisfaction des patients reçus
	groupes en matière de charge de travail des médecins généralistes. Les auteurs ont directement par les kinésithérapeutes en service d'urgence a été observé [59,63].
	suggéré que les kinésithérapeutes participant à l'étude ont eu recours majoritairement à La prise en charge des patients atteints d'affections musculosquelettiques dans un
	une approche biomédicale contribuant à maintenir un recours élevé aux consultations de contexte spécifique d'urgence exige des compétences professionnelles qui dépassent le
	médecine générale.
	Royaume-Uni (n=8), Italie (n=1) et Suède (n=3). Elles portaient en moyenne sur 21 207
	patients (minimum 72 patients, maximum 89 150 patients). Les études incluses portaient
	sur le périmètre des recours aux services de soins primaires et présentaient les La revue systématique de Matifat et al. mettait en évidence que la prise en charge de ces
	conséquences systémiques de l'adoption d'un modèle intégrant l'accès direct à la patients par des MK était retrouvée appropriée concernant les résultats cliniques
	kinésithérapie : augmentation du temps médical des MG accordé aux patients présentant (douleur, fonction et qualité de vie), les services de santé utilisés et la satisfaction des
	des pathologies complexes [42,46,50] et amélioration de la qualité des soins fournis par patients. Les résultats cliniques étaient retrouvés comparables entre les patients pris en
	les MK aux patients concernés par des affections musculosquelettiques charge par les MK et les urgentistes [67,68]. Les quatre études de méthodologie
	[35,41,42,44,46,50,50,52,53]. Les études incluses ne rapportaient aucun événement hétérogène portant sur la sécurité des hypothèses diagnostiques et des options de triage
	indésirable chez les patients pris en charge en accès direct par un MK [35,41,42,48,55]. des patients rapportaient l'absence d'événement indésirable associé aux MK exerçant
	aux urgences. La prescription de médicament et le recours aux autres services de santé

et 15 études observationnelles

[START_REF] Leemrijse | Direct Access to Physical Therapy in the Netherlands: Results From the First Year in Community-Based Physical Therapy[END_REF][START_REF] Webster | Self-referral, access and physiotherapy: patients' knowledge and attitudes-results of a national trial[END_REF][START_REF] Goodwin | Physiotherapy as a first point of contact in general practice: a solution to a growing problem?[END_REF][START_REF] Holdsworth | What are the costs to NHS Scotland of self-referral to physiotherapy? Results of a national trial[END_REF][START_REF] Mallett | Is physiotherapy self-referral with telephone triage viable, cost-effective and beneficial to musculoskeletal outpatients in a primary care setting?[END_REF][START_REF] Overman | Physical therapy care for low back pain. Monitored program of first-contact nonphysician care[END_REF][START_REF] Moore | Risk Determination for Patients With Direct Access to Physical Therapy in Military Health Care Facilities[END_REF][START_REF] Pendergast | A Comparison of Health Care Use for Physician-Referred and Self-Referred Episodes of Outpatient Physical Therapy[END_REF][START_REF] Holdsworth | Direct access to physiotherapy in primary care: now?-and into the future?[END_REF][START_REF] Bornhöft | Physiotherapy in Primary Care Triage -the effects on utilization of medical services at primary health care clinics by patients and subgroups of patients with musculoskeletal disorders: a case-control study[END_REF][START_REF] Ludvigsson | Evaluation of physiotherapists as primary assessors of patients with musculoskeletal disorders seeking primary health care[END_REF][START_REF] Brooks | Is a prescriptive or an open referral related to physical therapy outcomes in patients with lumbar spine-related problems?[END_REF][START_REF] Swinkels | An overview of 5 years of patient self-referral for physical therapy in the Netherlands[END_REF][START_REF] Mintken | Direct Access to Physical Therapy Services Is Safe in a University Student Health Center Setting[END_REF][START_REF] Downie | Physiotherapist as an alternative to a GP for musculoskeletal conditions: a 2-year service evaluation of UK primary care data[END_REF]

. La méthodologie des études incluses a été retrouvée de qualité faible à modérée au « Quality Assessment Tool for Quantitative Studies ». Toutes ces études incluaient des patients adultes présentant diverses affections musculosquelettiques et consultant en soins primaires et ont été réalisées dans cinq pays, Etats-Unis (n=5), Pays-Bas (n=2), Dans les 18 études comparatives incluses dans la revue systématique de Demont et al.

[START_REF] Demont | The impact of direct access physiotherapy compared to primary care physician led usual care for patients with musculoskeletal disorders: a systematic review of the literature[END_REF]

, par rapport au parcours de soins habituel (orientation du patient d'un médecin vers un MK), l'accès direct à la kinésithérapie est un modèle retrouvé comme présentant plusieurs bénéfices telles qu'une réduction de la douleur (non significative mais avec une

4.2. Modèle de soins intégrant l'accès direct à la kinésithérapie dans un contexte d'urgence pour la prise en charge des patients présentant une affection musculosquelettique

Au total, 20 études ont été identifiées comme portant sur l'évaluation de l'accès direct à la kinésithérapie pour des patients consultant aux urgences dont 5

[START_REF] Matifat | Concordance between physiotherapists and physicians for care of patients with musculoskeletal disorders presenting to the emergency department[END_REF][START_REF] Alkhouri | Impact of the primary contact physiotherapy practitioner role on emergency department care for patients with musculoskeletal injuries in New South Wales[END_REF][START_REF] Pugh | Dedicated emergency department physical therapy is associated with reduced imaging, opioid administration, and length of stay: A prospective observational study[END_REF][START_REF] Sayer | Advanced musculoskeletal physiotherapists are effective and safe in managing patients with acute low back pain presenting to emergency departments[END_REF][START_REF] Kinsella | Management of patients brought in by ambulance to the emergency department: role of the Advanced Musculoskeletal Physiotherapist[END_REF]

publiées postérieurement à la dernière revue systématique de Matifat et al. incluant les 15 autres

[START_REF] Matifat | Benefits of Musculoskeletal Physical Therapy in Emergency Departments: A Systematic Review[END_REF]

. Concernant la méthodologie des 20 études, il a été retrouvé : 3 études contrôlées randomisées

[START_REF] Lau | Early physiotherapy intervention in an Accident and Emergency Department reduces pain and improves satisfaction for patients with acute low back pain: a randomised trial[END_REF][START_REF] Mcclellan | A randomised trial comparing the clinical effectiveness of different emergency department healthcare professionals in soft tissue injury management[END_REF][START_REF] Richardson | Randomised controlled trial and cost consequences study comparing initial physiotherapy assessment and management with routine practice for selected patients in an accident and emergency department of an acute hospital[END_REF]

, 2 études quasi-expérimentales

[START_REF] Mcclellan | Effect of an extended scope physiotherapy service on patient satisfaction and the outcome of soft tissue injuries in an adult emergency department[END_REF][START_REF] Taylor | Primary contact physiotherapy in emergency departments can reduce length of stay for patients with peripheral musculoskeletal injuries compared with secondary contact physiotherapy: a prospective non-randomised controlled trial[END_REF]

et 15 études observationnelles [58-62,69-78]. Toutes ces études incluaient des patients adultes présentant diverses affections musculosquelettiques et consultant un service d'urgence et ont été réalisées dans quatre pays, Etats-Unis (n=5), Australie (n=13), Canada (n=1) et Chine (n=1). Elles portaient en moyenne sur 1912 patients (minimum 110 patients, maximum 14 452 patients). (demande d'avis d'un médecin spécialisé et/ou prescriptions d'imageries) étaient retrouvés plus faible chez les patients vus par le MK comparativement à ceux vus par le médecin urgentiste [59-61,63]. Le temps d'attente des patients consultant aux urgences était retrouvé cadre traditionnel de pratique des MK. Un niveau de compétences avancées et une expérience clinique sont nécessaires pour légitimer leur pratique avancée. Fennelly et al. rapporte que onze enseignements ont été identifiées au sein des onze programmes de formation délivrés au Royaume-Uni, au Canada et en Australie permettant aux MK l'acquisition de compétences avancées pour exercer dans un contexte de soin comme celui des urgences [80] : Recherche et pratiques fondées sur des données probantes, Evaluation et diagnostic, Pharmacologie, Kinésithérapie dans le champ musculosquelettique, Leadership et Gestion des services, Raisonnement clinique et Prise de décision concertée, Éducation et Mentorat clinique, Radiologie, Communication et Compétences Interprofessionnelles, Thérapie par injection, Enjeux professionnels.