The shift towards the future of manufacturing is a main stake for companies to remain competitive. This paper proposes to manage this shift in a global manner through an enhanced co-evolution model. It takes into account the main enterprise domains that have to 'co-evolve': product, manufacturing and information system. The model also integrates the role of the strategy and of the human workforce which are crucial in the Factory of the Future context. We identify the modeling constructs required to support an efficient co-evolution management.

I. INTRODUCTION

In order to fully realize their potential, modern organizations have stepped up their efforts to bring better practices and advanced performance for industrial evolution associated to the concepts of Factory of the Future (FoF) [START_REF] Welber | Factory of the future[END_REF], Smart Factory [START_REF] Lucke | Smart factory -A step towards the next generation of manufacturing[END_REF] or even Industry 4.0 [START_REF] Drath | Industrie 4.0: Hit or Hype? [Industry Forum[END_REF]. A big issue for organizations is to manage this transition from a given situation towards a target evolved scenario. The promise that parallels this transition is set against a wide range of technological, organizational and societal challenges [START_REF] Thoben | Editorial: System-integrated Intelligence -New Challenges for Product and Production Engineering in the Context of Industry 4.0[END_REF].

In the last decades, research agendas have been devoted to develop new methods, techniques and tools to master the transformation of industries. These works have generally adopted a focus on techno-centred issues, and less attention has been paid to approaches allowing a global engineering point of view.

Factory of the Future as the counterpart of Industry 4.0smart factory aims at improving the overall performance of the factory through developing communication within the company. In order to manage such a transformation, the role of human workers [START_REF] Moeuf | The industrial management of SMEs in the era of Industry 4.0[END_REF] and the evolution of the Information System (IS) [START_REF] Haddara | The Readiness of ERP Systems for the Factory of the Future[END_REF] are major concerns to be tackled.

The goal we are striving is to conceive an approach that helps to ensure the transition from a specific situation to a situation that reaches the context of FoF. In this line of action, the model developed by Tolio, et al. [START_REF] Tolio | SPECIES-Co-evolution of products, processes and production systems[END_REF] is promising since it considers a co-evolution problem including product, process and production system. As stated by the authors, the management of co-evolution will allow manufacturing companies 'to operate at a point that preserves the feasibility *Research supported by CONACYT Flor De A. Marti N. is with the ICube Laboratory -INSA 24 bld de la Victoire 67084 Strasbourg Cedex France (phone: +33783403106; e-mail: flor-de-asis.marti-nieto@etu.unistra.fr).

Virginie Goepp is with ICube Laboratory -INSA 24 bld de la Victoire 67084 Strasbourg Cedex France (e-mail: virginie.goepp@insastrasbourg.fr).

Emmanuel Caillaud is with the ICube Laboratory -Unistra 3 rue de l'Université 67000 Strasbourg France (e-mail: caillaud@unistra.fr). and profitability of the performed processes in spite of the dynamic context' alike FoF's.

Therefore, in this study we are interested in co-evolution as a mean to successfully exploit these interactions to orchestrate the desired transformation. However, the model proposed by Tolio et al. does not aim at enabling the management of co-evolution. Indeed, the scope of proposed model provide a coarse definition of the entities considered to co-evolve. Therefore, it limits the range of decisions and their interdependencies enabling to ensure a successful transformation. Moreover, the model lacks the explicit representation of strategic decisions on which these management choices rely on (i.e. to match the firm's business with the dynamics of the environment) [START_REF] Karimi | Strategic Planning for Information Systems: Requirements and Information Engineering Methods[END_REF][START_REF] Papadakis | Strategic Decision-Making Processes: The Role of Management and Context[END_REF]. Therefore, in this paper we propose an enhanced coevolution model built on the co-evolution model proposed by Tolio, et al. [START_REF] Tolio | SPECIES-Co-evolution of products, processes and production systems[END_REF]. We analyze, identify and develop the missing elements required to conceive a co-evolution modelling approach enabling to design a path to achieve a desired future industrial scenario. The novelty of our co-evolution model regards the following statements:

• The operational application of our co-evolution model through the use of enterprise modelling techniques.

• The consideration of strategic dimension; the integration of the IS domain to address required choices concerning Information Technologies (IT), as well as the impact on the role of human workforce.

In fact, our co-evolution model strives to take a step further in terms of strategic alignment to effectively cope with the complexity of manufacturing businesses towards higher competitiveness as required for FoF. This paper is structured as follows. In section 2 we detail the original model. We also discuss its strengths and limitations to deal with the co-evolution management as required for the transition to the Factory of the Future and how the model can be adapted to this objective. In section 3, we first modify and complete the original model by exploiting the Strategic Alignment Model (SAM) [START_REF] Henderson | Strategic Alignment: Leveraging Information Technology for Transforming Organizations[END_REF] and the related work of Avila, et al. [START_REF] Avila | Towards and extended alignment model for a complete alignment of manufacturing information systems[END_REF] about the E-SAM. Then, we detail the content of this model with the corresponding enterprise modeling constructs stemming from ISO 19440 [START_REF]Enterprise Integration-Constructs for enterprise modelling[END_REF]. Conclusions and perspectives are drawn in section 4.

Factory of the Future: The industrial transition through the prism of co-evolution*

Flor de A. Marti Nieto, Virginie Goepp, Emmanuel Caillaud

II. INITIAL CO-EVOLUTION MODEL ANALYSIS

A. Co-evolution Model Overview

The work of Tolio, et al. [START_REF] Tolio | SPECIES-Co-evolution of products, processes and production systems[END_REF] is based on the "co-evolution paradigm". This paradigm is defined as: "the repeated configuration of products, process and production system over time". To manage co-evolution, they proposed a model that allows to delimit a space where co-evolution management approaches, tools and problems can be mapped. The model takes a geometrical shape represented by a triangular prism (See Figure 1). The edges of the prism stand for the three "configuration entities" (P3S): products, process and production system. The prism includes a vertical axis to represent the evolution axis. At any level of the evolution axis, the triangular cross-section represents the integration space among the three entities.

B. Co-Evolution Management Process

The Co-Evolution Management process of the original co-evolution model is considered as a configuration activity of the product, process and production system entities. Authors propose two metrics to evaluate a given configuration approach enabling to choose the one fitting the best to a specific configuration context. These metrics are the integration level and the evolution level. The integration level aims at analyzing the way a given approach enables to work out a configuration solution. It is mapped within the integration space of the model. The evolution level is the capability of a configuration approach to take into account potential evolutions of the entities. It is mapped at the vertical axis through check points in order to evaluate the configuration approach at a given time period.

C. General Analysis and Conclusions concerning the Coevolution Model

Tolio, et al. [START_REF] Tolio | SPECIES-Co-evolution of products, processes and production systems[END_REF] consider co-evolution as the repeated configuration of the product, process and production System entities. The authors show that this co-evolution is crucial in environments subject to continuous changes like the context of FoF, in which we are interested. The related management consists in choosing the configuration approach fitting the best to a given situation. In other words, the co-evolution model they propose is used to map and analyze existing configuration approaches. This provides a global overview of the existing approaches but does not provide an effective support to manage the potential interactions between the entities to be configured. Therefore, in our view, the co-evolution model can be exploited to manage these interactions. It can help to understand and manage the multi-level interactions that explain competition and change across the organization, considering also their interdependencies like found in biological evolution [START_REF] Abatecola | Darwinism, organizational evolution and survival: key challenges for future research[END_REF][START_REF] Penn | Coevolutionary and Symbiotic Relationships in Design, Manufacturing and Enterprise[END_REF]. However, if the co-evolution is used in this sense, entities subject to configuration have to be further detailed especially the characteristics required to make design decisions. Correlations among them and with respect to higher decision levels of the organization must be taken into account. Furthermore, the strategic dimension is has to be more explicitly depicted in the model. Therefore, in order to guide the co-evolution towards FoF's, we aim to complete the proposed co-evolution model with the following aspects that we consider necessary to address: 1) the explicit consideration of the role of the Information System (IS) within the model, not only from its the technological function (i.e. IT functionality) but from its key role at the center of the major managerial functions adding value to the firm's processes and 2) the consideration of strategic dimension since it involves the pattern of decisions that leads the activities of the firm into a specific direction [START_REF] Hayes | Restoring our Competitive Edge: Competing Through Manufacturing[END_REF].

By developing these objectives, we argue that a more powerful co-evolution model can be built and further applied as an effective management tool towards a FoF environment. The next section will explain the resulting restructuring of the model involving new domains' decision areas for both internal and external levels of analysis.

Particular attention should be paid to the underlying choices regarding the role of human. Choices of the human dimension namely their competencies and skills will be included in our co-evolution model. In the further discussion will also argue how our contribution can potentially cover the dynamics of choices concerning the development of human beings in response to the objectives of the changing organization.

III. PROPOSAL OF AN ENHANCED CO-EVOLUTION MODEL

In this section, we present in detail the completed coevolution model taking the model presented in [START_REF] Tolio | SPECIES-Co-evolution of products, processes and production systems[END_REF] as a starting point. To succeed in, we rely on:

• A detailed analysis of the P3S entities of the already defined model to set up the domains of our enhanced co-evolution model.

• The Strategic Alignment Model (SAM) of Henderson and Venkatraman [START_REF] Henderson | Strategic alignment: Leveraging information technology for transforming organizations[END_REF] enabling to integrate the strategic dimension into our model.

• Enterprise Modeling (EM) techniques which provide means to describe process oriented systems and decompose them into manageable parts [START_REF] Zelm | The CIMOSA business modelling process[END_REF]. We exploit the ISO standards for EM: ISO 19440 [START_REF]Enterprise Integration-Constructs for enterprise modelling[END_REF] to define the modeling constructs required to represent the domains of our model.

A. Definition of the new domains of the co-evolution model

Redefinition of the P3S entities into domains of the enhanced co-evolution model: Our first concern aims at complementing the co-evolution view as depicted in the model which considers three basic entities: the product, the process and the production system. According to the definition of the entities, it is assumed that interactions only result from the transforming process that relates the input and the output of a system. As such, the model reduces the scope of co-evolution to the physical process through which an output, namely a product is obtained by means of a performed production system.

So, we consider this proposal as a preliminary effort that provides direction for addressing co-evolution to a broader context that complies with the range of activities and decisions. In this context, we suggest to redefine the proposed entities into domains. Into each domain we can thus specify the set of decisions that should mutually co-evolve for enabling 'as-is' reengineering. Moreover, by defining functional domains like product design, product manufacturing etc., their specific composition can be captured for users requests and possible interrelations can be clearly focused. From the Enterprise Modelling viewpoint this is a modular way allowing to deal with the overall system complexity [START_REF] Berio | Enterprise Modelling with CIMOSA: Functional and organizational aspects[END_REF]. Therefore, two main domains are derived based on the entities of the original model:

• The Product Design domain is composed of the product entity. Nevertheless, we propose to expand the initial concept to consider the processes of product development like appropriate design methods which can affect manufacturing costs or productivity. Indeed, product design, both as an outcome and a process is relevant for organizational success [START_REF] Chen | The Design Imperative[END_REF].

• The Manufacturing domain bundles the process and the production system into the same domain. This is because both are closely related since they rely on each other to carry out the transformation for a product. The concepts emphasize this aspect as they define the process as the logical procedures executed by the production system and this latter as a set of resources and policies that in turn allow the execution of the processes.

Definition of the Information System (IS) domain of the enhanced co-evolution model:

According to our objective we add the IS domain to tackle the decisions regarding the setup of the IS matching the needs of the enterprise. The IS has a key role on organization to support the execution of operational, managerial and executive-level processes. Furthermore, IS academics broadly agree that IS has to be considered as an entire functional domain on its own, being at the core of business process and Information Technology (IT) evolutions. As result, IS needs to be aligned with the business activity and new technologies in order to create value for the organization and effectively support innovation [START_REF] Ferreira | Digital Organization -a new challenge in the Information Systems Curriculum[END_REF].

Integration of the Strategic Dimension

Concerning the strategic dimension, we exploit the Strategic Alignment Model (SAM) proposed in [START_REF] Henderson | Strategic Alignment: Leveraging Information Technology for Transforming Organizations[END_REF]. This is one of the first frameworks that considers simultaneously the strategic and implementation levels of analysis. The authors detail these levels as follows:

• The external level, also called the 'strategic level' deals with the arena in which the firm competes, their attributes that differentiate it from its competitors, the decisions regarding product-market offering as well as "make-versus-buy" decisions, including partnerships and alliances.

• The internal level, also called the 'structural level' concerns the implementation choices related to the logic of the administrative structure and the specific rationale for the design and redesign of critical business process, and the resources to operate and manage it.

As the distinction made by the SAM, we split each domain of our co-evolution model into two levels: the internal level and the external one. The definition of the domains has to include the content of each domain to support co-evolution management as defined in section 2.C. This is done in section 3.C exploiting the E-SAM proposed by Avila, et al. [START_REF] Avila | Towards and extended alignment model for a complete alignment of manufacturing information systems[END_REF] which add two domains to the classical SAM: product design and production. We use these domains in our model.

B. Internal Structure of Domains

The general sub-domain structure of the E-SAM is the same as the one of the SAM with three components per subdomain: [START_REF] Welber | Factory of the future[END_REF] The scope (or perimeter), competencies and governance in the external level; (2) The infrastructure, skills and process in the internal level. We use the same component structure for the six sub-domains of our co-evolution model because the decisions specified are common to the concerns we aim to tackle for the internal and external level of the coevolution approach.

As a result, the Erreur ! Source du renvoi introuvable. shows the general structure of the proposed co-evolution model. The next section details the content of each component.

C. Modeling the Components of the Co-evolution Model

As the modeling purposes differ between the internal and the external level, the way to model them also differs.

Modeling of the Strategical level of the Co-evolution:

Since the external level is related to the strategies, their modeling must enable to represent the strategic behavior of companies in the form of decisions or activities that are in harmony with the enterprise activities performed. This aspect is already tackled by the set of decisions of the domain's components within the E-SAM. So, for this level we exploit them as presented in Table 1. Modeling of the Structural level of the Co-evolution: Coevolution management requires structured modeling of the internal level. Therefore, we propose to exploit modeling constructs of EM defined in ISO 19440 [START_REF]Enterprise Integration-Constructs for enterprise modelling[END_REF] by mapping them with the internal components of the co-evolution model, as they do not fit naturally into each other. We take into account guidance on a previous mapping presented in [START_REF] Goepp | A Systematic Evaluation of the SAM according to Enterprise Architecture Framework Requirements[END_REF] between the components of the SAM and the constructs of ISO 19440 [START_REF]Enterprise Integration-Constructs for enterprise modelling[END_REF]. The results of our mapping are detailed in Table 2 Following the results of the mapping, the first four constructs of the function view correspond to the processes of the product design, manufacturing and IS domain. These four constructs: Domain, Business Process, Enterprise Activity and Event, represent the functional aspects of the enterprise, meaning their processes and activities.

The next four constructs of the information view involve information-related entities used and obtained during enterprise operations. The Enterprise Object and Object view constructs refer to the inputs and outputs of enterprise activities or enterprise object, respectively. As such, these constructs are mapped to the processes of our domains since they have to be defined for the process operation. They are also mapped to the architecture of the IS domain since they refer to the definition of the data architecture. Regarding the constructs of Product and Order, both are specializations of the Enterprise object construct. Concerning the Product, this construct is represented as the output of an enterprise's process. Products have to be described within the process component of the manufacturing and product design domain where it is mapped. The Order construct represents the 'information for planning and control of a business process in an enterprise'. It may be also the end-result of a business process used to describe a further activity. As a result, we map it to the process component of the product design and manufacturing for which orders have to be described.

In the resource view, we consider the Resource construct and its specialization. The Functional entity construct describes required capabilities that any enterprise activity needs in order to take place. They include the equipment, facilities, people and organizational groupings, as well as equipment for data processing. As such, both resource and functional entity constructs are mapped to the infrastructure of manufacturing and IS. Operational capabilities or skills provided by a resource or required by the enterprise activity are also described here and are mapped to the skills component of each domain. Regarding the Capability construct, it describes attributes related to the identified resources like constraints that have to do with processing such as tooling dimensions, data processing or time restrictions. As a result, capability construct match with the architecture of manufacturing and IS but it is not linked to the product design domain.

The organizational view represents the organization, organizational relationships and decision-making responsibilities in the enterprise operation. The construct of Organizational unit refers to the roles and responsibilities to perform human tasks within a given hierarchical structure. Thus, we map this construct to the skills component and the design structure of the product design domain. Similarly, the construct of Organizational cell is mapped to the design structure component since it refers to the hierarchical structure of an enterprise like divisions and departments. At last, the Decision Centre construct deals with decision system modeling. In our view, this construct is not linked to any modeling concern of the co-evolution model's components.

D. Considerations on human role from the resource view

One of the fundamental aspects to consider concerns the implications of organization' changes on human beings' skills and experience. The importance of that matter has triggered the setting of an agenda in the European Union, which is known as the Lisbon Strategy, to achieve the most competitive and dynamic knowledge-based economy in the world [START_REF]Presidency conclusions-Lisbon European Council[END_REF]. [START_REF]Enterprise Integration-Constructs for enterprise modelling[END_REF] In our contribution, we consider human role by exploiting the decision set of 'competencies' and 'skills' as defined in the E-SAM. As a result, we can address human's role by modelling it as a resource within high and low levels of the organization. For this purpose, we follow the modelling standard ISO 19440 [START_REF]Enterprise Integration-Constructs for enterprise modelling[END_REF] through the predefined 'resource view'. The resource view allows to represent the roles and responsibilities of human resources. Thus, based on the established standard, we can integrate in the co-evolution model decisions of the profile required to perform a task, including the required capacities that must be fulfilled as skills and functions. In this way, we are able to handle the dynamics of the human's role in response to strategic and structural rearrangements. Moreover, we can consider the necessary alignment of the perceived skills' gap in relation to the desired state that the organization seeks to meet.

IV. CONCLUSIONS AND PERSPECTIVES

Organizations are struggling to keep the pace with evolutions whereby they have to make co-evolve their subsystems. That's why co-evolution becomes relevant in order to enact successful engineering changes while maintaining the coherence along the whole business structure. Relying on the work of Tolio, et al. [START_REF] Tolio | SPECIES-Co-evolution of products, processes and production systems[END_REF], in this paper we have consolidated a co-evolution model with the aim to help firms to foster adaptation looking towards nextgeneration factories.

Taking the prior model as starting point, we have pointed out that co-evolution must take an integrated approach of the key interdependencies that can lead firms to change and adapt themselves to future contexts. As a result, our first contribution is to build up three key domains: product design, manufacturing and IS as the ones interacting within the prism of coevolution.

According to [START_REF] Tolio | SPECIES-Co-evolution of products, processes and production systems[END_REF], from a co-evolution stance, successful transition results from the strategic and operational management of engineering changes that propagate to the different levels of the organization. Consistent with this notion, we have defined two levels of analysis for each domain: the internal and external level. The interdependencies between each other, specifically the way they can be modelled and managed over the time are the main motivation behind this work. As a result, we have taken into account the strategic links that were missing. Furthermore, the role of human workforce can be addressed through the domain's content related to the competences and skills of human resources. The definition of the two-level structure is made in analogy with the SAM [START_REF] Henderson | Strategic Alignment: Leveraging Information Technology for Transforming Organizations[END_REF] while the content's detail of the resulting 6 sub-domains is based on the E-SAM [START_REF] Avila | Towards and extended alignment model for a complete alignment of manufacturing information systems[END_REF].

Taking a step further in completing the co-evolution model, we have exploited the modeling constructs for enterprise models of ISO 19440 [START_REF]Enterprise Integration-Constructs for enterprise modelling[END_REF]. Hence, we have mapped the standardized constructs to the content of the internal sub-domains. By making this we provide a common modelling representation that opens up further research on extending co-evolution for architectural contexts of an organization.

More importantly, the generic constructs related to the view Resource and the Organizational view allow us to describe and create instances of the profile skills that human beings deliver. As such, the impact of human factors can be considered in the co-evolution from the current to the desired state. Furthermore, a further development could be pursued by refining constructs in the Resource view to include specific management concerns related for example to the planning of the personnel or the assignment of the workplaces.

To effectively support co-evolution management, we will further choose relevant modeling languages to formally represent the processes of the internal sub-domains. For instance, BPMN (Business Process Modeling Notation) [START_REF]Business Process Model and Notation[END_REF]and UML (Unified Modeling Language) [START_REF]OMG UML version 2.5.1[END_REF] are both widely recognized standards with support from many tools. The first one focuses on business process modeling including visual description like workflows that allows to analyze the business process in detail. As such, BPMN can efficiently drive the translation from the conceptual design to their implementation. The second modeling language, UML, supports software applications and software architecture modeling.

The precedent efforts represent the first stage of our work. In further steps we will consider the managerial implications that can arise from the instantiation of the co-evolution model related to a current and future organization state (i.e. "As-Is" and "To-Be" business process). To do so, we aim to identify potential relationships across the domain's models, meaning domain-to-domain interactions as well as those between their internal components. Further, we will characterize these interactions and build "co-evolution sequences" in terms of the attributes of the specific relationship (i.e. the direction from one specific domain to another) and their degree of impact (i.e. poor, necessary, insufficient). Empirical evidence will be necessary to validate the completed co-evolution approach.

The time dimension is an integrative part of the coevolution model since changes are propagated at different time intervals with respect to each of the domains. Conceptually, time has been represented in the original model through a vertical axis plotted at the center of the triangular prism of the P3S entities (see Figure 1). We have kept this representation in order to depict how the new defined domains of the firm co-evolve over time. From a macroscopic point of view, this evolution axis should also take place within a prism having our redefined domains at the edges.

Figure 1 .

 1 Figure 1. Graphical representation of the co-evolution model (Tolio et al., 2010)

Figure 1 .

 1 Figure 1. The detailed representation of the completed Co-evolution model

TABLE 1 .

 1 DECISION-BASED MODELING OF STRATEGIC LEVEL OF THE CO-

EVOLUTION MODEL External Structure

of Domains in the Enhanced Co-evolution Model Product Manufacturing IS

		Technological	Production	Current or new
		integration: New	Technologies	ITs
		Design	Types of technologies	IS governance
		Technologies	Degree of	IS strategic
		Distinctive	systematization	alliances and
		Product's features:	Degree of automation	partnerships
	Scope	Structure, Functionality, Performance,	Degree of interconnection Product's types
		Quality	Product variety and
			scope
			Time to market of new
			products
			Final product
			complexity
		Partnership for	Vertical Integration	Partnership for
	Governance	Design: Alliances, Partnership, Outsourcing Design Policies: Competitiveness	Make -or-buy decisions Alliances Upstream Integration	IT Alliances Joint venture with vendors Join research
		/Profitability,		and
		Product Life cycle		development
		Design	Production Capacity	Systemic
		Competencies:	Size, Location of	Competencies
	Competencies	Innovative Design, Design of customized products, Design of modular products, Design of serial	Facilities Capacity Level of reliability Level of flexibility	System reliability Cost-performance levels Inter-
		products		connectivity
				Flexibility

TABLE 2 .

 2 MAPPING MADE BETWEEN THE INTERNAL COMPONENTS OF THE CO-EVOLUTION MODEL AND THE MODELING LANGUAGE CONSTRUCTS FROMISO 19440


Xuan Wu
email: xuan.wu@ensam.eu

Virginie Goepp
email: virginie.goepp@insa-strasbourg.fr

Ali Siadat
email: ali.siadat@ensam.eu

Cyber Physical Production Systems: A Review of Design and Implementation Approaches

Keywords: Cyber physical production systems, design approach, implementation approach, industrial engineering, 5C architecture

Cyber Physical System (CPS) is a very crucial and promising technology in Industry 4.0 context. The application of CPS in the production and manufacturing environment gave rise to the term Cyber Physical Production Systems (CPPSs). CPPSs hold great potential to make production systems become intelligent, resilient and self-adaptive by utilizing the cyber world to realize the distributed collaboration in the physical world. There is growing interest in CPPSs, yet there is a scarcity of review to document the current status of CPPSs. This review aims to classify the current research activities within CPPSs field with a special focus on design and implementation approaches in view of industrial engineering and to analyze research gaps based on the literature review. Findings of this review can be used as the basis for future research in CPPSs and related topics.

I. INTRODUCTION

The manufacturing industry is facing well-known trends, such as highly customized products, increasing product complexity and shorter product lifecycles. Industry 4.0 and smart factory as the most widespread industrial paradigms, appear on the scene. Industry 4.0 is a general term that includes a series of different technologies, with the Cyber-Physical Systems (CPS) as the core technology [START_REF] Longo | Smart operators in industry 4.0: A human-centered approach to enhance operators' capabilities and competencies within the new smart factory context[END_REF]. Smart factories utilize the CPS technology to monitor the physical world and make decentralized decisions in the virtual world [START_REF] Lee | A cyber-physical systems architecture for Industry 4.0-based manufacturing systems[END_REF]. Therefore, we can note that the common enabler behind Industry 4.0 and the smart factory is actually the CPS. There are many different definitions of CPS depending on the application scenario. The core idea of CPS is the fusion of the real world and the virtual world by implementing the interaction between physical components and cyber components in distributed networks. CPS have been applied in many fields such as the civil infrastructure the healthcare, the smart home, and so on [START_REF] Giraldo | Security and Privacy in Cyber-Physical Systems: A Survey of Surveys[END_REF]. This paper focuses on the specific application of CPS in the production environment, namely Cyber-Physical Production Systems (CPPSs).

Fig. 1 shows the change of the number of journal articles and conference articles within the CPPSs field until the end of 2018 in the ISI Web of Science which is one of the most extensive citation databases that includes various publishing houses such as Elsevier, Springer, and IEEE. Considering some authors may use the term CPS and "manufacturing/production systems" to illustrate the research work within the CPPSs field. We set up our bibliographical research using three topics "cyber physical system(s) AND manufacturing systems" OR "cyber physical system(s) AND production systems" OR "cyber physical production system(s)". we note that the research work on CPPSs in literature starts from 2012. The total number of articles, the number of conference articles and journal articles are distinguished by the red solid line, black round dotted line and green dashed line. For the total number of articles, a rapid growth can be noticed from 2012 to 2017. There is a slight decline in 2018 because the journal articles have not been fully published. What is even more remarkable is that the number of journal articles has increased significantly in the last few years. The aim of this figure is to show that the CPPS has been widely studied in literature and the research trend is expected to increase in the upcoming years. As CPPSs is a relatively new term, there is no standard and agreed definition. Most of the researchers just simply describe the concept of CPPSs as the application of CPS in the manufacturing and production field. The most cited, detailed explanation of this concept was given by [START_REF] Monostori | Cyber-physical systems in manufacturing[END_REF]: "CPPSs consist of autonomous and cooperative elements and sub-systems that are getting into connection with each other in situation dependent ways, on and across all levels of production, from processes through machines up to production and logistics networks". In this definition, we can conclude several points: (i) CPPSs are systems of systems, more than just isolated systems because of complex interactions among them; (ii) These systems includes autonomous and cooperative elements and can be connected or decoupled according to different situation, which means the subsystems are independent and reconfigurable; (iii) The connection between systems impacts all levels of production lifecycle from manufacturing to logistics. However, in this definition, two important concepts are missing: knowledge management and human resources. On the one hand, knowledge is key for decision making and an automated continuous improvement of CPPSs' operations. On the other hand, although CPPSs can work in an automatic way, humans should have a central and key role instead of being replaced by technologies because humans are the most flexible one who can handle exceptional situations and control the systems when needed. The following definition, suggested by [START_REF] Ribeiro | Cyber-physical production systems' design challenges[END_REF], emphasized the missing points: "A CPPS is a composition of human resources, production equipment and aggregated products towards which it establishes one or several cyber-physically formulated interaction interfaces. These interfaces are used for monitoring and control of the CPPS operations as well as to tap into the knowledge generated both by the human resources, and the equipment, during the production process as well as knowledge generated by its aggregated products throughout their life-cycle." These two definitions complement each other and cover various aspects of CPPSs.

The notion of CPPSs is very wide and aggregate many different research disciplines. Its development can be categorized into three distinct communities in parallel: (i) The industrial engineering community, mainly focuses on CPPSs engineering and implementation approaches, by adopting systems engineering methods. (ii) The computer science community, mainly concentrates on information technology and development methods of software systems. (iii) The electrical engineering community, mainly focuses on hardware in CPPSs, such as sensors. In this paper, we study CPPSs in view of industrial engineering.

CPPSs can be regarded as a significant evolution in the manufacturing and production systems. The challenge in the future is to prove the advantages CPPSs bring to the industry. Therefore, it is important to develop approaches for the design and implementation of CPPSs. Many methods on specific technical issues emerge in recent years. However, as far as we know, there is a lack of efforts to review the design and implementation approaches of CPPSs. The rapidly growing interest from both academics and practitioners in CPPSs has urged such need to help newcomers have a general understanding of this emergent research area and therefore choose the proper approaches in future studies. Therefore, the purpose of this paper is to review the design and implementation approaches of CPPSs in literature and to analyze research gaps.

II. REVIEW OF CPPS DESIGN AND IMPLEMENTATION APPROACHES

After reading the journal articles we found in section I, classifications for CPPSs design and implementation approaches were set up manually instead of automatically by some tools. Within the scope of this paper, it is not possible to integrate all the articles. Therefore, our study exhibits some representative articles to explain the classifications and show the current developments available in literature.

A. CPPSs design approaches

The design of CPPS is extremely challenging due to the involvement of multiple fields and the complex interactions in distributed environments. In this regard, modelling & simulation approaches are the most popular and useful ones for CPPSs design. We identify four modelling approaches as follows.

1

) Architecture-based modelling approaches

In view of industrial engineering, an architecture should address the organizational structure of a system including its design principles, components and relationships. There are some established architectures and standards that can be used as the references for the conceptual design of CPPSs. The Reference Architectural Model Industrial (RAMI 4.0) and the Industrial Internet Reference Architecture (IIRA) are two of the most popular and widely recognized architectures.

The RAMI 4.0 [START_REF] Adolphs | Status report-reference architecture model industrie 4.0 (rami4.0)[END_REF] describes the connection between IT, manufacturers/plants and product life cycle by using a layer model (including three axes: the layer axis, value stream axis, and hierarchy axis). It formalizes manufacturing resources as 'Industry 4.0 component' [START_REF] Spec | 91345: Referenz-Architekturmodell Industrie 4.0 (RAMI4. 0)[END_REF] which comprises asset and Asset Administration Shell (AAS). The asset can be anything in the physical world, e.g. a sensor. The AAS is the mapping of assets to the virtual world and illustrates its functionalities. With reference to the RAMI 4.0, a multi-level method for modelling CPPSs was proposed in [START_REF] Kannengiesser | Multi-level, viewpointoriented engineering of cyber-physical production systems: an approach based on Industry 4.0, system architecture and semantic web standards[END_REF], where RAMI 4.0 was used on the meta-model level, the model level, and the instance level to form a concrete CPPS. This contributed to the lifecycle management.

The IIRA [START_REF] Lin | Industrial Internet Reference Architecture[END_REF] is a standard architecture of designing Industrial Internet Systems (IIS), which is developed by the industrial internet consortium. With reference to the IIRA function viewpoint, a three-tier architecture that includes the edge, platform and enterprise tier was presented, as in [START_REF] Rojas | Enabling connectivity of cyber-physical production systems: a conceptual framework[END_REF]. RAMI 4.0 and IIRA synthesize the three kinds of integrations (vertical integration, horizontal integration and end-to-end integration), and also consider the whole life cycle, which refer to as promising architectures for CPPSs. However, they are not sufficient architectures because they did not address how humans interacted with CPPSs.

2

) Agent-based modelling & simulation approaches

The term agent refers to an intelligent entity that can perform tasks autonomously [START_REF] Ming | A CORBA-based agent-driven design for distributed intelligent manufacturing systems[END_REF]. An agent enjoys very similar properties with a CPPS, which is characterized by autonomy, flexibility, robustness, adaptability and so on. Thus, the agent-based modelling & simulation approaches can be seen as a very promising means for simulating characteristics of complex CPPSs. For example, a simulation approach was presented in [START_REF] Ilsen | Optimizing energy consumption in a decentralized manufacturing system[END_REF] that evaluated the self-organizing potential of CPPSs.

The interaction of multiple agents can form decentralized systems, called Multi Agent Systems (MAS), which is a popular architecture for the design of distributed CPPSs [START_REF] Yang | An agent-based framework for collaboration among critical mechanical devices working in a cluster[END_REF]. A MAS is are often applied for distributed production planning and control of CPPSs, as in [START_REF] Vrabič | Distributed control with rationally bounded agents in cyber-physical production systems[END_REF], [START_REF] Jiang | Distributed dynamic scheduling for cyber-physical production systems based on a multi-agent system[END_REF]. Although MAS brings many benefits, there are still some limitations. In the CPPSs, each resource (such as machines) represents an intelligent agent, and these agents can negotiate among themselves to cope with unexpected interrupts, so as to make the system more resilient. But it will also make the system become complicated, which will be difficult to be managed. therefore, a simple management method to realize interaction is needed.

3) Human-centered modelling approaches Nowadays, more and more researchers start to discover the importance of humans and they acknowledge humans should be central elements in CPPSs. Reference [START_REF] Pirvu | Engineering insights from an anthropocentric cyberphysical system: A case study for an assembly station[END_REF] presented an anthropocentric cyber-physical reference model that consisted of a physical component, cyber component and human component where the human was an element that affected the behaviors of the system throughout its whole life cycle. Moreover, humans embody the highly developed intelligence, such as understanding, learning and adapting, that can provide design knowledge for CPPSs, as explained in [START_REF] Francalanza | A knowledge-based tool for designing cyber physical production systems[END_REF], [START_REF] Engel | Ontology-assisted engineering of cyber-physical production systems in the field of process technology[END_REF]. In the CPPS paradigm, human tasks will be different. Workers will face plentiful computerized interfaces, make more complex decisions and coordinate the autonomous production. Collectively, the human work tasks, work areas and interaction ways with machines will be different. The objectives of CPPSs is not removing humans, but to fully involving humans by using their intelligence.

4) Modelling for integration approaches of specific design concerns

There are some modeling approaches that enable to integrate into the design of CPPSs' specific concerns such as process management, business strategies, different engineering stages, co-simulation and so on. One such example was provided by [START_REF] Neubauer | Subjectorientation as design language for integration across organisational control layers[END_REF], that depicted the Subjectoriented Process Management (S-BPM) approach for vertical integration of the business and production processes.

B. CPPSs Implementation Approaches

The 5C architecture of CPS, proposed by [START_REF] Lee | A cyber-physical systems architecture for Industry 4.0-based manufacturing systems[END_REF], provided a guideline for implementing CPSs from the initial data acquisition, to information gathered, to the final system control, and it can be extended to CPPSs. As shown in Fig. 2, it includes five levels: smart connection level, data-to-information conversion level, cyber level, cognition level and configuration level. The smart connection level (level I) is the physical world, levels II-IV are the cyber world, while the configuration level (level V) is the feedback from the cyber world to the physical world. We categorize the CPPSs implementation approaches through the lens of 5C levels.

1) Smart Connection Level

This level achieves integrations between different elements in the physical space such as sensors, controllers and machine tools.

There are two important factors in this level to improve the implementation of CPPSs. First, the communication in CPPSs demands standard protocols, interfaces and information model, such as the IEC 61499 standard. An example was presented in [START_REF] Urbina | Cyber-physical production system gateway based on a programmable SoC platform[END_REF], that establishes communication with different elements by integrating different interfaces and connections to sensors and actuators. Second, since different elements in CPPSs are able to generate huge amounts of data about the ongoing production processes, data acquisition approaches [START_REF] Silva | Universal parser for wireless sensor networks in industrial cyber physical production systems[END_REF] and data cleansing algorithms [START_REF] Deng | Data cleansing for energy-saving: a case of cyber-physical machine tools health monitoring system[END_REF] are research topics.

2

) Data-to-Information Conversion Level

This level converts data to meaningful information. Considering an increasing amount and complexity of data, tools and methodologies such as data processing [START_REF] Lee | Implementation of cyber-physical production systems for quality prediction and operation control in metal casting[END_REF], big data analysis [START_REF] Post | User-guided visual analysis of cyber-physical production systems[END_REF] and data mining approaches are proposed to get the valuable information.

3

) Cyber Level

This level is a central information hub, which aggregate all the information from various sources to form a cyber space. Some researchers noticed the importance of collaborative manufacturing network. One example was given by [START_REF] Mladineo | Selecting manufacturing partners in push and pull-type smart collaborative networks[END_REF], presenting an intelligent collaborative platform to manage the production network. With the current trend of increased connectivity to external networks, CPPSs are increasingly targeted by cyber-attacks. Therefore, the cyber security is another important research area. On the one hand, in the early attack stage, there should be ways to monitor and detect abnormal behavior [START_REF] Sandor | Cross-layer anomaly detection in industrial cyber-physical systems[END_REF]. On the other hand, defense mechanisms should be enhanced to ensure security [START_REF] Khalid | Security framework for industrial collaborative robotic cyber-physical systems[END_REF].

Moreover, a digital twin is the most important research focus at this level. Digital twin is the virtualization of the physical resources in the cyber world. The idea of a digital twin is widely used to simulate properties and behaviors of systems. Reference [START_REF] Bao | The modelling and operations for the digital twin in the context of manufacturing[END_REF] developed three digital twins (a product, a process and an operation digital twin) that can simulate the state and behaviour of the corresponding physical object for optimizing production processes.

4) Cognition Level: Since abundant information is available, this level can generate comprehensive knowledge of the system. The research focus is developing appropriate presentation tools that can show the knowledge to experts for further decisions making. One such example is illustrated in [START_REF] Pujo | Wireless holon network for job shop isoarchic control[END_REF]. Besides, in this level CPPSs are able to diagnose their own state and predict the potential failure, as in [START_REF] Niggemann | Data-driven anomaly detection in cyber-physical production systems[END_REF].

5) Configuration Level: The configuration level can apply the right decisions made in the cognition level to the physical space, therefore implementing a resilience control. It can achieve control and adjustment, especially the self-X properties (X is a placeholder for describing the desirable characteristics of a system in response to changing environments), such as self-adjustment, selfconfiguration and self-optimization, in response to external environmental changes. One such example was given in [START_REF] Grundstein | A new method for autonomous control of complex job shops -Integrating order release, sequencing and capacity control to meet due dates[END_REF], presenting an Autonomous Production Control method (APC) of manufacturing processes, which includes all control tasks and their interdependencies. The APC method acts autonomously and keeps the resilience of CPPSs.

III. DISCUSSION

As previously reviewed, there has been a great deal of efforts toward CPPSs design and implementation approaches. However, there are still research gaps. ➢ CPPSs change the traditional Computer Integrated Manufacturing (CIM) pyramid that has hierarchical layers into a decentralized architecture, which will have an impact on the structure of centralized Information Systems (IS). An IS-centric architecture for CPPSs should be designed, and the place and new role of IS in these architectures should be analyzed. ➢ The most significant difference between CPPSs and traditional production systems lies in the digital twin. In the digital twin, the physical object's change of state should have an automatic impact on the cyber object's state and vice versa. However, the concept of "Digital Twin" is easily confused with the concepts of "Digital Model" and "Digital Shadow" that don't implement the bidirectional dynamic impacts between physical objects and cyber objects. Therefore, the digital twin should be put into more research efforts. ➢ As [START_REF] Monostori | Cyber-physical systems in manufacturing[END_REF] pointed out, one of the most important characteristics of CPPSs is intelligence, which can be defined as follows: elements are able to acquire information from their surroundings and act autonomously. Intelligence can widely distribute throughout the entire CPPSs. The "connection level" and "data-to-information level" can achieve the intelligence through physical elements, such as machines, products and conveyors. In the "cyber level", the digital twin can achieve intelligence because it is dynamically linked to the physical object. In other words, the physical object's change of state will have an automatic impact on the cyber object's state and vice versa. This is the most significant difference between CPPSs and traditional production systems. However, the "cognition Level" and "configuration Level" haven't implemented the intelligence. ➢ The research efforts on the configuration level are extremely rare because this level has the highest requirements with self-X capabilities which is the most difficult to achieve. Moreover, the total integration of 5 levels in CPPSs does not exist currently within the scope of the authors' knowledge. ➢ The industrial practices of CPPSs are still at its infancy and difficult to implement. One of the major obstacles lies in the integrative link between CPPSs and Enterprise Information Systems (EIS) which rely on software such as the Manufacturing Execution System (MES). This link has long been, and often still is, confused with information technologies due to the influence of the computer science community. While it is true the link in its broad sense is surely first of all a technological one which leverages the latest information technologies to combine the digital and physical world, more importantly is an organizational link to better support the decision making and business processes. Therefore, this link is the integration of all elements including data, information technologies, people and business processes.

IV. CONCLUSION There has been a great deal of efforts from both academics and industry practitioners towards CPPSs, yet there is a scarcity of literature review to document the CPPSs design and implementation approaches. This paper provides such a review in view of industrial engineering to help researchers and practitioners have a general understanding of this emergent research area and therefore choose the proper approaches and technologies in future research.

In this paper, four different CPPSs design approaches are identified, focusing either on a specific way of modelling (architecture or agent-based, human-centered), or integration approaches from specific design concerns. Then, a review of CPPSs implementation approaches is identified through the lens of 5C architecture levels. At last, this paper analyzes the research gaps and points out possible directions for future research.

Fig. 1 .

 1 Fig. 1. Distribution of articles per year

Fig. 2 .

 2 Fig.2. 5C architecture for implementation of CPSs[START_REF] Lee | A cyber-physical systems architecture for Industry 4.0-based manufacturing systems[END_REF]

ACKNOWLEDGMENT

The first author Xuan WU was financially supported by the China Scholarship Council (CSC) under the Grant CSC N°201706020154.


MD Pietro Addeo

Vincent Noblet

Benoit Naegel

Philippe Bachellier

Large-for-size orthotopic liver transplantation: a systematic review of definitions, outcomes and solutions

Background:

We systematically reviewed the literature on definitions and outcomes of large-forsize (LFS) syndrome in orthotopic liver transplantation (LT).

Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Cochrane library, PUBMED, and Embase were searched (January 1990-January 2019) for studies reporting LFS in LT. Primary outcomes were definitions and mortality of LFS LT.

Results: Eleven studies reporting patients with LFS LT were identified. Four different formulas (Graft-recipient weight ratio (GRWR), Body surface area index (BSAi), Donor standardized total liver volume (sTLV)-recipient sTLV ratio, and Graft-weight/Right anteroposterior distance (RAP) ratio) with their critical thresholds were found. There were 81 patients (54% women) with a median weight and height of 62.5 kg (range, 40-105 kg) and 165 cm (range, 145-180 cm). The median graft weight was 1772 g (range, 1290-2400 g), and the median GWRW was 2.77% (range, 2. 1-4.00%). Graft venous outflow obstruction was described in seven patients(8.6%). At the time of LT, fascial closure was not achieved in 24 patients (29.6%) and the graft size was reduced by a liver resection in three patients(3.7%). Thirteen deaths (16%) were reported in the first 90 postoperative days with two patients undergoing re-transplant.

Conclusions: LFS LT remains heterogeneously defined but characterized by high mortality rates despite the use of tailored surgical solutions (graft reduction and open abdomen). A composite definition is proposed in order to better describe LFS clinical syndrome.

Introduction

Currently, the allocation of a liver graft to a recipient is based on scores that give priority to the severity of liver disease more than to the anthropometrics of the donor and recipient [START_REF] Tschuor | Allocation of Liver Grafts Worldwide Is there a best System?[END_REF] . Discrepancies in appropriate matching between the donor and the recipient can lead to implantation of an excessively large liver graft into a small recipient cavity [START_REF] Fukazawa | Size mismatch in liver transplantation[END_REF] . This condition, known as large-for-size (LFS) liver transplantation (LT), has been widely described in pediatric LT [START_REF] Kiuchi | Impact of graft size mismatching on graft prognosis in liver transplantation from living donors[END_REF] . The implantation of an LFS liver graft in babies was characterized by immediate hemodynamic instability, increased vascular complications and decreased survival [START_REF] Kiuchi | Impact of graft size mismatching on graft prognosis in liver transplantation from living donors[END_REF][START_REF] Oikawa | Graft weight/recipient body weight ratio (G/R ratio) in living-related liver transplantation for pediatric patients: abdominal wall closure in cases with a large G/R ratio[END_REF][START_REF] Ersoy | Effect of Graft Weight to Recipient Body Weight Ratio on Hemodynamic and Metabolic Parameters in Pediatric Liver Transplant: A Retrospective Analysis[END_REF] . When dealing with orthotopic LT in adults, the occurrence of an LFS LT remains theoretically rare because of a larger recipient cavity and the greater availability of adult deceased liver donors. However, transplant surgeons still can face an LFS graft because of the increased prevalence of obesity among the donor population, the urgent need for a liver graft (i.e. fulminant liver failure, urgent re-transplantation), and the inherent limitations given by the anthropometrics of some recipients. Recently, the occurrence of LFS has been described even in adult LTs as a possible consequence of an extreme anthropometrics mismatch between a donor and a recipient [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF] . A recent study reported a postoperative mortality rate up to 40% for LFS LTs and other studies demonstrated a decreased graft and recipient survival [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF][START_REF] Fukazawa | Body surface area index predicts outcome in orthotopic liver transplantation[END_REF][START_REF] Fukazawa | Detrimental graft survival of sizemismatched graft for high model for end-stage liver disease recipients in liver transplantation[END_REF] . However, a uniform definition for LFS syndrome is currently lacking and little is known about outcomes of LFS LT in adults as well as technical solutions when facing this clinical scenario. The aim of this study was, therefore, to systematically review the literature regarding on LFS LTs in adults.

Patients and Methods

Search Strategy

The EMBASE, MEDLINE, and COCHRANE central databases were systematically searched from January 1990 through December 2018 for articles describing cases of LFS LTs in adult. The search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and limited to manuscripts written in English. The following phrases were used as search terms: "large-for-size," "size mismatch," each phrase was combined with "liver transplantation" or "orthotopic liver transplantation."

Article Selection and Data Extraction

Potentially eligible articles were screened by two independent investigators. The exclusion criteria included articles describing: 1) LFS occurring after LT in pediatric patients; 2) LFS using a liver graft procured from a living donor in either an adult or pediatric recipient; 3) patients undergoing staged wound closure for causes other than donor-recipient size mismatch (e.g. bowel edema, massive coagulopathy and/or fluids resuscitations, and planned reoperation); and 4) registry studies.

Discrepancies between the two investigators were resolved via consensus. The full text of the selected articles was analyzed for eligibility. The authors of the articles were contacted when additional information was needed. The primary outcomes of this review were definitions and mortality of LFS LT. Secondary outcomes were morbidity and solutions used in presence of LFS in LT. Data regarding the study period, number of patients, patients and donor characteristics, surgical complications, morbidity and mortality of LT were extracted from the included articles. All the data were extracted using a standardized extraction form.

Statistical Analysis

The methodological limitations and the volume of incomplete data hampered the meta-analysis.

Continuous data were expressed as mean ± standard deviation (SD) and range or the median and range, as appropriate. Categorical variables were presented as numbers and percentages.

Differences between groups were assessed using the chi-squared or Fisher's exact test (categorical variables) and the Wilcoxon rank sum test or the Student's t-test (continuous variables). This review is largely descriptive because of the small sample size.

Results

Physiopathology and Definitions

LFS in adult LT has been defined by the transplantation of a large liver graft into a small cavity. In both murine and porcine models, LFS transplantation has been characterized by higher serum levels of transaminases and potassium following reperfusion resulting from ischemic hepatocyte injury 3,9- 11 . These kinds of injuries have been related to the following: 1) poor liver reperfusion because of the large donor-recipient mismatch, which leaves a large poorly perfused area of liver parenchyma;

2) poor hemodynamic tolerance after unclamping the portal vein and the inferior vena cava; 3) kinking of the reconnected vessels because of the steric mismatch between a large donor graft and the recipient portal and inferior vena cava; 4) direct mechanical compression by the recipient abdominal cavity (costal margin, diaphragm, and nearby organs) over a large liver graft 5,9-12 . These injuries have been thought to be responsible for severe allograft dysfunction with consequently poorer recipient and graft survival in both animals and humans (Figure 1). Four different formulas with their critical established threshold for defining LFS LT have been described and are reported in Table 1 [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF][START_REF] Fukazawa | Body surface area index predicts outcome in orthotopic liver transplantation[END_REF][START_REF] Levesque | Influence of larger graft weight to recipient weight on the post-liver transplantation course[END_REF][START_REF] Croome | A novel objective method for deceased donor and recipient size matching in liver transplantation[END_REF] . Two of these formulas were based on a ratio between the donor graft weight and the recipient weight [START_REF] Levesque | Influence of larger graft weight to recipient weight on the post-liver transplantation course[END_REF] or the antero-posterior diameter of the abdominal cavity [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF] . One formula was based on a ratio between the standardized liver volume of the donor and the recipient [START_REF] Croome | A novel objective method for deceased donor and recipient size matching in liver transplantation[END_REF] . The last formula used a ratio between the body surface area (BSA) of the donor and the recipient [START_REF] Fukazawa | Body surface area index predicts outcome in orthotopic liver transplantation[END_REF] .

A universally accepted definition of a clinical syndrome related to LFS was not available because these different formulas evaluated different main outcomes including early graft dysfunction [START_REF] Olthoff | Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors[END_REF] , pulmonary complications [START_REF] Levesque | Influence of larger graft weight to recipient weight on the post-liver transplantation course[END_REF] , and graft and patient survival [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF][START_REF] Croome | A novel objective method for deceased donor and recipient size matching in liver transplantation[END_REF] . Only one of these formulas combined the clinical condition represented by the impossibility of closing the abdominal wall because of a severe mismatch between the donor and recipient at the end of LT with early allograft dysfunction and/or death and/or the need for re-transplantation [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF] .

Outcomes

The initial search resulted in 175 studies. However, only 11 studies

(US [n=34], France [n=40], Korea [n=1], China [n=1], India [n=1], Japan [n=1],
and Italy [n=3]) matched the inclusion criteria [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF][START_REF] Fukazawa | Body surface area index predicts outcome in orthotopic liver transplantation[END_REF][START_REF] Levesque | Influence of larger graft weight to recipient weight on the post-liver transplantation course[END_REF][START_REF] Brustia | Negative wound therapy to manage large-for-size liver graft mismatch[END_REF][START_REF] Eldeen | Passing loop" technique: a new modification of the piggyback technique tailored to voluminous liver grafts--case report[END_REF][START_REF] Jacob | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF][START_REF] Jafri | Temporary silastic mesh closure for adult liver transplantation: a safe alternative for the difficult abdomen[END_REF][START_REF] Kim | Performing a Right Hemihepatectomy Sequentially After Deceased Donor Liver Transplantation--The Solution for a Large-for-size Graft: A Case Report[END_REF][START_REF] Lim | Hepatic venous outflow obstruction after whole liver transplantation of large-for-size graft: versatile intra-operative management[END_REF][START_REF] Nagatsu | In Situ Posterior Graft Segmentectomy for Large-for-Size Syndrome in Deceased Donor Liver Transplantation in Adults: A Case Report[END_REF][START_REF] Donataccio | A Simple and New Device to Avoid Hepatic Venous Outflow Obstruction in Adult Liver Transplantation[END_REF] (Figure 2). The majority of the studies were published after the year 2010. There were 81 recipients with a median age of 48.5 years (range, 19-67 years) who underwent LFS LT. There were 39 women, which represented 54% of the recipients with available data regarding gender (39 out of 72). The median recipient weight and height were 62.5 kg (range, 40-105 kg) and 165 cm (range, 145-180 cm). Indications for LT are presented in Table 2, and fulminant liver failure and emergent liver re-transplantation were indications in ten patients (12.3%). The median graft weight was 1772 g (range, 1290-2400 g), the percentage of male donors ranged from 0 to 100%, and when reported, the median GWRW was 2.77% (range, 2.1-4.00). Table 3 shows postoperative outcomes of LT. To decrease the abdominal pressure, the abdominal wall was not closed in 24 patients and it was managed using negative pressure wound therapy in 12 patients, skin-only closure in three patients, and bridging mesh in seven patients (two were not described) [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF][START_REF] Levesque | Influence of larger graft weight to recipient weight on the post-liver transplantation course[END_REF][START_REF] Brustia | Negative wound therapy to manage large-for-size liver graft mismatch[END_REF][START_REF] Jacob | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF][START_REF] Jafri | Temporary silastic mesh closure for adult liver transplantation: a safe alternative for the difficult abdomen[END_REF][START_REF] Lim | Hepatic venous outflow obstruction after whole liver transplantation of large-for-size graft: versatile intra-operative management[END_REF] . Three liver resections were performed to reduce the graft size (one right hepatectomy, one right posterior sectionectomy, one left lobectomy) [START_REF] Eldeen | Passing loop" technique: a new modification of the piggyback technique tailored to voluminous liver grafts--case report[END_REF][START_REF] Kim | Performing a Right Hemihepatectomy Sequentially After Deceased Donor Liver Transplantation--The Solution for a Large-for-size Graft: A Case Report[END_REF][START_REF] Nagatsu | In Situ Posterior Graft Segmentectomy for Large-for-Size Syndrome in Deceased Donor Liver Transplantation in Adults: A Case Report[END_REF] . Venous outflow obstruction by the large liver graft was described in seven patients intraoperatively (n=5) [START_REF] Lim | Hepatic venous outflow obstruction after whole liver transplantation of large-for-size graft: versatile intra-operative management[END_REF] or in the immediate postoperative period (n=1), and it was managed by the placement of breast implants (n=2), pads (n=1), surgical gloves filled of saline solution (n=3), fascial closure with bridging mesh (n=1), or a "passing loop" caval anastomosis (n=1) [START_REF] Eldeen | Passing loop" technique: a new modification of the piggyback technique tailored to voluminous liver grafts--case report[END_REF][START_REF] Lim | Hepatic venous outflow obstruction after whole liver transplantation of large-for-size graft: versatile intra-operative management[END_REF] . Thirteen deaths (16%) were reported in the first 90 postoperative days, with two patients undergoing re-transplantation.

Discussion

The current systematic review confirmed that LFS syndrome in adult LT patients remains rare but has a high related mortality despite tailored surgical solutions such as an open abdomen and graft reduction.

Appropriate matching between donors and recipients is of paramount importance to avoid LFS.

From the analyzed pooled data LFSs appeared more frequently in small recipients (median height 165 cm) with large grafts (median weight 1772).The rare occurrence of this condition in adult LT compared to pediatric LT is related to the greater availability of adult liver grafts, the compliance of the abdominal cavity in adults, and the condition of the recipients, which may allow some waiting time to find a graft tailored to their abdominal cavity. However, the urgent need for a liver graft, such as in acute liver failure, can push the transplant team's choice toward using larger liver grafts (Figure 3). In this review, acute or fulminant liver failure was the most frequent indication for LT in ten out of 13 patients who were reported in three studies [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF][START_REF] Brustia | Negative wound therapy to manage large-for-size liver graft mismatch[END_REF][START_REF] Nagatsu | In Situ Posterior Graft Segmentectomy for Large-for-Size Syndrome in Deceased Donor Liver Transplantation in Adults: A Case Report[END_REF] . Patients with fulminant liver failure are more likely to have normal liver morphology and no ascites, which represents a favorable milieu for an anthropometric mismatch. LFS was also reported for re-transplantation where the previous surgery and strong adhesions could contribute to the shortage of space in the abdominal cavity [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF][START_REF] Brustia | Negative wound therapy to manage large-for-size liver graft mismatch[END_REF] .

There is currently no universally accepted definition of LFS. However the increasing number of the reports over the last ten years captured by the current review underlines probably the increase awareness of this specific problem and reflects the more liberal policy in accepting larger liver grafts. This could be also reflecting the worldwide epidemic of obesity and metabolic syndrome. We found four different definitions related to the analysis of different outcomes. Three of these formulas, the BSAi, the GRWR, and the STLV, associated the presence of a larger liver graft with early liver graft dysfunction or an increased rate of pulmonary complications [START_REF] Fukazawa | Body surface area index predicts outcome in orthotopic liver transplantation[END_REF][START_REF] Levesque | Influence of larger graft weight to recipient weight on the post-liver transplantation course[END_REF][START_REF] Croome | A novel objective method for deceased donor and recipient size matching in liver transplantation[END_REF] . In these three studies, no mention was made of the direct mechanical consequences that were related to the discrepancies between the small recipient abdominal cavity and the large graft. In addition, graft dysfunction and pulmonary morbidity can also be related to several other factors besides the presence of a large liver graft. Variability has also been reported when calculating the BSA, the STL, and the BMI ratio in predicting the occurrence of LFS because of the high variability of the recipient's weight in cirrhotic patients [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF] . In fact all the studied morphological index (GWRW, STLV, BSAi) have their intrinsic limitation. For example, the weight of a given recipient (WR) can be largely influenced by the presence of diffuse edema and ascites or conversely by extreme malnutrition and sarcopenia. The BSA could be influenced also by the same weight variation. The formula using the standard liver volume could also be influenced by the variability in case of hypertrophic or hypotrophic cirrhotic liver and the presence of previous operation. Finally the presence of ascites could potentially increase the volume of a limited small abdominal cavity and challenge all these formulas (Figure 4). Imaging-based donor-recipient matching, whenever possible, should be pursued in order to avoid mismatch.

Recently, Allard et al. conducted a short study that showed a correlation between the clinical occurrence of the inability to close the abdomen at the end of the LT and a morphological mismatch between the donor and the recipient. They found that the combination of a female recipient and a male donor with a GW/RAP ratio >100 was associated with the highest risk of LFS syndrome, which is characterized by the highest mortality rate. This study was the first to introduce a morphological measure (RAP) that might anticipate the occurrence of a mismatch in the presence of liver grafts. The same authors found that this ratio was better than the BSAi and the sTLV for predicting the occurrence of LFS syndrome [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF] . However, the wide application of this method requires immediate access to the most recent CT scan results of a potential recipient.

A universal and easily applicable formula could not be proposed even after an extensive review of the literature also because the potential outcomes associated to the presence of large graft were different. Intuitively, when describing a clinical scenario associated to the presence of a large liver graft several conditions should be associated in a composite definition. First the presence of mechanical consequences related to a liver graft larger than the reciepint liver cavity. These could include: the impossibility of closing the abdomen, and/or the presence of venous congestion (after having excluded all the other causes) and/or localized mechanical-associated liver areas of ischemia. Secondly, the presence of biological consequences should be present such as early allograft dysfunction, massive cytolysis and/or primary non-function. Third, the need for a graftdirected treatment such as re-laparotomy and/or graft reduction and/or open abdomen and/or retransplantation.

Anthropological differences between genders favor the occurrence of LFS. Previous studies demonstrated that male donors have larger liver grafts than females, and females usually have a smaller abdominal cavity than males [START_REF] Chouker | Estimation of liver size for liver transplantation: the impact of age and gender[END_REF] . Not surprisingly, in the current systematic review, most LFS were reported in female recipients. Therefore, relatively low median recipient heights and weights were observed. Even if most donors were male in the current study, the lack of data did not allow us to quantify the exact incidence of the combination of a male donor graft that is used in a female recipient.

Transplanting a large graft into a small cavity can be associated with direct compression by nearby structures. Immediate outflow obstruction was reported in seven patients as a consequence of retrohepatic inferior vena cava compression by a large graft when performing a piggy-back LT with a side-to-side caval anastomosis [START_REF] Lim | Hepatic venous outflow obstruction after whole liver transplantation of large-for-size graft: versatile intra-operative management[END_REF][START_REF] Donataccio | A Simple and New Device to Avoid Hepatic Venous Outflow Obstruction in Adult Liver Transplantation[END_REF] . This complication was managed by rotating the graft and releasing the compression on the IVC by mechanical means (prosthesis, pads, and filled gloves) and/or leaving the abdomen open [START_REF] Lim | Hepatic venous outflow obstruction after whole liver transplantation of large-for-size graft: versatile intra-operative management[END_REF] . Other authors described a systematic caval resection when implantation of a LFS graft was anticipated, which could be a reasonable technique [START_REF] Levesque | Influence of larger graft weight to recipient weight on the post-liver transplantation course[END_REF] . Caval resection was still the technique used in six out of ten cases of extreme LFS, as reported by Allard et al. [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF] Another technical option could be of fashioning two caval anastomosis: one above and the other below the large liver graft (passing-loop technique). [START_REF] Eldeen | Passing loop" technique: a new modification of the piggyback technique tailored to voluminous liver grafts--case report[END_REF] Definitely the alternative technical option could be to reduce the graft volume via liver resection. Not surprisingly, this was rarely performed, with only three cases reported in the current review, and the right liver resections (posterior section and the right liver) were the most prevalent.

These resections were performed in situ and characterized by high blood losses (935 and 14,000 mL) [START_REF] Eldeen | Passing loop" technique: a new modification of the piggyback technique tailored to voluminous liver grafts--case report[END_REF][START_REF] Kim | Performing a Right Hemihepatectomy Sequentially After Deceased Donor Liver Transplantation--The Solution for a Large-for-size Graft: A Case Report[END_REF][START_REF] Nagatsu | In Situ Posterior Graft Segmentectomy for Large-for-Size Syndrome in Deceased Donor Liver Transplantation in Adults: A Case Report[END_REF] . The scarce number of graft reductions could be explained certainly by the fact that LFS in these cases was described intraoperatively and maybe other cases of potential LFS were prevented by ex-situ reduction.

Leaving the abdomen open was the most prevalent method of managing the mismatch between a large graft and a small cavity. In some studies, a bridging mesh and exclusive cutaneous closure were the most frequently used technique, while more recently, negative pressure wound therapy (NPWT) was the most common technique that was used to manage the open abdomen [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF][START_REF] Brustia | Negative wound therapy to manage large-for-size liver graft mismatch[END_REF] . This technique immediately releases abdominal tension, avoids compartment syndrome, and postpones definitive closure of the fascial plane while allowing time for edema resorption.

However, for severe LFS, definitive fascial closure was not possible in some cases [START_REF] Allard | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF] .

The current review found a high mortality rate (16%) in the first 90 days after LFS LT. Graft failure with multiorgan dysfunction and infections were the most common cause of death but vascular complications were not more common than in the general LT population. It is more likely that most of these deaths were related to the occurrence of an LFS syndrome with more prolonged hospitalization and more infections and consequent multiorgan dysfunction because death related to graft necrosis and mechanical complications were rarely reported [START_REF] Jacob | Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication[END_REF] .

From a practical point of view several approaches could be suggested after reviewing the literature. First, the chance of mismatch should be reduced by tailoring the choice of the graft to the recipient conditions. Predictive formulas of STL and CT scan of the donors should be used when facing the choice of a liver graft. Additionally, more recent images of the recipient should be reviewed in order to exactly determine the dimensions of the recipient's cavity which are related to several factors (liver volume, presence of ascites, adhesions, etc).

Secondly when size mismatch cannot be avoided because of the urgent need for a graft several technical tricks could be useful. First, in our opinion the abdominal incision should be lowered downward that will avoid that a large graft falls into the middle of high right subcostal incision. Secondly during recipient hepatectomy, in order to avoid bowel edema leading to further reduction of the abdominal space, a temporary portosystemic derivation could be performed whenever spontaneous shunts are hemodynamic inefficacious. Third, once at the end of hepatectomy transplant surgeons face a limited space for graft implantation, graft reduction should be planned ex-situ in order to reduce bleeding of in situ reduction. The choice of the liver segments to be resected will be based on the morphology of the liver and that of the recipient cavity. Left lobe or the right liver could be alternatively removed according to the morphology of the recipient.

Fourth, when LFS is evident at the end of the transplant NPWT with an open abdomen should be employed and the definitive closure of the fascia will be delayed in a progressive way.

NPTW will allow sufficient time to adequately resuscitation of the patient to reduce edema.

The current systematic review has several limitations. First, the relatively long interval of time that was analyzed and the small number of cases that were reported made a meaningful analysis difficult. Second, the lack of a uniform definition of LFS introduced a noteworthy selection bias. It is more likely that most of the patients with severe LFS were not even reported because of the rarity of this condition. A multicentric study could help to determine the exact incidence and mortality of LFS. Third, a detailed morphological analysis of the recipients' abdominal cavity was lacking in all studies while the liver graft weight was available in most cases. An analysis of the recipients' abdominal cavity characteristics could have added more value to this analysis.

Conclusions

The LFS syndrome after LT remains an ill-defined but life-threatening condition despite the use of tailored surgical solutions (graft reduction and open abdomen). Its occurrence seems mostly prevalent in small-size recipients who have an acute need for a liver graft. Leaving the abdomen open could help in the acute setting to release the abdominal tension and avoid the occurrence of severe mechanical consequences. A composite definition is herein proposed in order to better define the LFS clinical syndrome. Once a uniform definition will be adopted, the exact threshold of the different anthropometric (BSA, STLV, GWRW) and liver measures (Graft weight, Graft volume) associated with the LFS syndrome could be defined. Further multicentric studies gathering the data of patients with LFS LTs could help to extensively clarify risk factors and outcomes of this condition.

Figure 1 :

 1 Figure 1: Schematic breakout of hypothesized mechanism leading to a clinical evident "large-

Figure 2 :

 2 Figure 2: PRISMA selection for study selection

Figure 3 :

 3 Figure 3: Postoperative CT scan of a LFS LT in a 57-year-old man receiving an urgent re-

Figure 4 :

 4 Figure 4: Schematic breakout of the shortcomings of the current formulas in predicting LFS in

Table 1 :

 1 Definitions used for large-for-size liver transplantation.

	Author	Year	Formulas	Definition	Outcomes
	Fukazawa K	2011 Body surface area donor/ Body	BSA>1,24	Early allograft
			surface area recipient		dysfunction and
			(BSAi)		90-day graft
					failure
	Levesque E	2013	Graft-recipient weight ratio	GWRW>2.5%	Respiratory
			(GRWR)		complications
	Croome KP	2015 Donor standardized total liver	sTLV ratio>1,25	Early allograft
			volume (sTLV)-recipient sTLV		dysfunction
			ratio
	Allard MA	2017	Graft-weight/Right	GW/RAP>100	Impossibility to
			anteroposterior distance (RAP)		close the
			ratio		abdomen with
					1) EAD and/or 2)
					death; and/or 3)
					urgent re-
					transplantation.

Table 2 :

 2 Preoperative characteristics of patients undergoing liver transplantation developing LFS syndrome.

Table 3 :

 3 Postoperative characteristics of patients undergoing liver transplantation developing LFS syndrome.

	Author	Year	EA	GWR	Open	Morbi	Vascular	Biliary	Retransplan	Dea	Dea
		of Publica tion	D	W (%)	abdo men	dity	complicat ions	complicat ions	tation	th 90 day s	th 1 yea r

Acknowledgements

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