L Avella
email: lavella@uniovi.es

D Vazquez-Bustelo

E Fernandez

CUMULATIVE MANUFACTURING CAPABILITIES: AN EXTENDED MODEL AND NEW EMPIRICAL EVIDENCE

Keywords: MANUFACTURING STRATEGY, OPERATIONS STRATEGY, EMPIRICAL manufacturing strategy, manufacturing capabilities, trade-offs, sand cone model, environmental protection

There has been intense debate in the manufacturing strategy literature on the way in which firms work on different manufacturing capabilities, with two opposing approaches considered -the trade-off model and the sand cone model. Analysis of these models has essentially been based on study of the links amongst four classic manufacturing capabilities (quality, delivery, flexibility and cost efficiency) and has obviated the need to consider environmental protection as an important manufacturing capability. This study analyses the theoretical arguments and the prior empirical evidence on the two models, and proposes and tests an extended sand cone model which includes the environmental protection objective alongside the four traditional ones. The research uses structural equation modelling and data from a sample of 274 manufacturers to contribute additional empirical evidence on the existence of cumulative effects amongst manufacturing capabilities. It is observed that the predominant strategic model in these firms is one of multiple, non-incompatible capabilities with cumulative effects according to the following sequence: quality, delivery, flexibility, environmental protection and cost efficiency.

is then presented and the measurement variables used are tested. Finally, after analysis of the results obtained, the main conclusions are drawn and limitations and possible future research lines are mentioned.

BACKGROUND

Manufacturing objectives

Since the field of manufacturing strategy was first set up, four basic manufacturing objectives have been considered: cost efficiency, quality, flexibility and delivery [START_REF] Skinner | Manufacturing -Missing link in corporate strategy[END_REF][START_REF] Skinner | The focused factory[END_REF][START_REF] Hayes | How should you organize manufacturing?[END_REF][START_REF] Hayes | Restoring Our Competitive Edge[END_REF]amongst others).

Although the objectives of innovation [START_REF] Dangayach | Practice of manufacturing strategy: evidence from select Indian automobile companies[END_REF] and service were also considered, they have not been generally accepted in the literature. This is because some components of flexibility, such as change and volume, also promote innovation [START_REF] De Toni | Manufacturing Flexibility: A Literature Review[END_REF], and because service can be considered as a component of quality [START_REF] Garvin | Quality on the line[END_REF]. In recent years, environmental protection has started to be included amongst manufacturing objectives, on the same terms as the four objectives mentioned above [START_REF] Handfield | Green value chain practices in the furniture industry[END_REF][START_REF] Angell | Integrating environmental issues into the mainstream. An agenda for research in operations management[END_REF].

It cannot be denied that, in the past, environmental protection matters were considered a restriction for the manufacturing area. Therefore, the only link between the environmental protection factor and manufacturing was the installation of control or end-of-process technologies -those which eliminate any waste produced-which, by their very nature, did not require the consideration of environmental protection matters as a production objective [START_REF] Newman | An empirical exploration of the relationship between manufacturing strategy and environmental management. Two complementary models[END_REF].

But today manufacturing objectives are considered to have an effect on the environmental protection result and vice versa. So, flexibility leads to a reduction in inventories and therefore fewer products are spoilt while fewer resources are used. Also, products can be better adapted to environmental protection needs [START_REF] Klassen | An international comparison of environmental management in operations. The impact of manufacturing flexibility in the US and Germany[END_REF]. Improved quality stabilizes production processes, eliminating reprocessing tasks and saving energy and resources [START_REF] Rosenzweig | Towards a theory of competitive progression. Evidence from high-tech manufacturing[END_REF]. Moreover, quality management systems have synergies with environmental protection management [START_REF] Kitazawa | The relationship between ISO 14001 and continuous source reduction programs[END_REF]. Cost reductions can also be achieved, amongst other actions, through savings in energy and by recycling products (Porter andvan der Linde, 1995a, 1995b). And a reduction in delivery time not only reduces inventories but also shortens internal product transport time, eliminating the need for repeat consignments (because deliveries are reliable). This too saves energy [START_REF] Koufteros | Examining the competitive capabilities of manufacturing firms[END_REF]. Environmental protection practices also affect manufacturing objectives. The use of production processes that consume fewer production inputs or less energy and make use of any waste generated helps reduce costs (Shrivastava, 1995a). Ecoefficiency or reduced costs through more efficient use of resources [START_REF] Gupta | Environmental operations management. An opportunity for improvement[END_REF] is based on the premise that any contamination produced by the firm is a symptom of inefficiency. Moreover, environmental protection management practices affect total quality tools and this causes a move towards total quality environmental management (TQEM) [START_REF] Welford | Linking quality and the environment: A strategy for the implementation of environmental management systems[END_REF], to the extent that the ISO 9000:2000 includes environmental protection aspects. Contamination prevention technologies may provide the production flexibility that firms need if they are to offer products that will not come up against environmental protection restrictions. Also, environmental protection practices can be used for adding value to products by reducing delivery time [START_REF] Newman | An empirical exploration of the relationship between manufacturing strategy and environmental management. Two complementary models[END_REF]. Therefore, [START_REF] Angell | Integrating environmental issues into the mainstream. An agenda for research in operations management[END_REF] suggested that, in the long term, the environmental protection objective should be included at the same level as the other manufacturing objectives thus making them endemic in the production process rather than seeing them only as external restrictions. Moreover, in the short term, they recommended that firms should reflect environmental protection aspects in tactical changes while the management should promote their inclusion in the process in the long term. However, few studies have considered the position of production departments regarding this topic and the effects of such considerations on their results.

This study therefore considers the four traditional objectives (cost efficiency, quality, flexibility and delivery) and includes the environmental protection as the fifth objective in testing the prevailing objective model in firms.

These five general objectives are broken down into 22 categories (Table 1).

Trying to avoid terminological confusion, in this paper, for each manufacturing objective, we use the term "competitive priority" referring to priority granted or emphasis placed to each manufacturing objective (importance). Whereas, we define "manufacturing capability" as the strength or advantage developed regarding the industry average or relative to primary competitors (performance).

INSERT TABLE 1

Models for improving manufacturing objectives

Most of the literature on manufacturing strategy is based on the model of incompatibilities -or trade-offs to use the term devised by [START_REF] Skinner | Manufacturing -Missing link in corporate strategy[END_REF] preference or priority is given to one manufacturing objective over others. Manufacturing only one product, a factory might pursue different manufacturing objectives but, furthermore, many objectives might arise because a single factory manufactures: a) products that are at different stages of their life cycle, and b) products that meet different market needs. In this last case, this multiplicity reflects the result of manufacturing two or more products in the same factory to meet different objectives. When products, processes, levels of skills and customer requirements are added, the production department tends to increase its size and, especially, to establish different objectives to meet different market needs [START_REF] Skinner | The focused factory[END_REF].

The traditional strategic approach is that the different objectives are incompatible [START_REF] Hofer | Strategy Formulation. Analytical Concepts[END_REF], because they consider it is difficult and risky for a firm to try to compete by offering high performance results in all its objectives. Firms that aim to be exceptional in many objectives end up being worse than those which focus their efforts on a single objective. In the manufacturing field, [START_REF] Skinner | Manufacturing -Missing link in corporate strategy[END_REF] proposed that each manufacturing department (factory or strategic manufacturing unit) should focus on one or, at the most, two of the various possible objectives. [START_REF] Skinner | Manufacturing -Missing link in corporate strategy[END_REF] called this explicit, priority objective the 'manufacturing task', although the more usual term is 'competitive priority'. The manufacturing task (or competitive priority) should be maintained over time and indicates to a certain extent that achieving this objective is more important than achieving others.

There is thus a synergy effect within the production department, with the actions of the various responsibility centres being oriented in the same direction [START_REF] Hayes | How should you organize manufacturing?[END_REF]. Some researchers move away from the trade-off model and defend achieving a balance amongst different objectives. They assume there is a link -not a conflict-between long and short term objectives (Banks and Wheelwright, 1979). Following this argument, Huge and [START_REF] Anderson | Structural equation modeling in practice: A review and recommended two-step approach[END_REF] consider that the various objectives can be improved simultaneously because they do not oppose each other and they can be reached in a concerted way. So, based on the experience of Japanese manufacturers, it has been noted that some firms tend to simultaneously achieve acceptable performance levels in the various manufacturing objectives, thus eliminating trade-offs [START_REF] Hayes | Beyond the world class. The new manufacturing strategy[END_REF].

Certain authors consider that balance amongst objectives can be achieved in a sequential (cumulative) way using the 'sand cone model' developed by [START_REF] Ferdows | Lasting improvements in manufacturing performance. In search of a new theory[END_REF]. This approach considers that every factory should focus on a single objective at any single moment in time, as there is a logical sequence that should be followed, in order to achieve substantial improvements in all of them. More specifically, the initial The model determines that the falling sand broadens at the base while rising in height. In fact, the broadening of the base is related to continuous improvement, because it is a question of improving the objectives reached while trying to achieve the next one. Since the objectives have an accumulative nature and are based on those that have already been achieved, there is no incompatibility preventing them from being achieved. If manufacturing objectives are achieved in this sequential way, they can provide the firm with a powerful and sustainable competitive advantage because they are based on consistent management practices that are consistent over time and cannot, therefore, be replicated easily or fast by competitors. This approach is based on an original idea by [START_REF] Nakane | Manufacturing Futures Survey in Japan. A comparative survey 1983-1986[END_REF], although the sequence varies: quality, dependability, cost efficiency and flexibility. However, quality management specialists introduced the idea that quality should receive priority and, until a suitable level has been reached in quality, no steps should be taken to achieve the other objectives. The competitive progression theory [START_REF] Roth | Winning in global markets. Neo-operations strategies in U.S. and Japanese manufacturing[END_REF][START_REF] Roth | Neo-Operations strategy. Linking capabilities-based competition to technology[END_REF] gives a theoretical explanation as well as additional empirical evidence for the sand cone model. This theory states that combined, sustainable manufacturing capabilities accumulate in a forward sequential progression -from quality to delivery, flexibility and cost efficiency-by means of an innovation cycle that leads towards strategic agility.

Finally, the studies that empirically test the sand cone model, in an explicit way, include [START_REF] Noble | Manufacturing strategy. Testing the cumulative model in a multiple country context[END_REF], [START_REF] White | A meta-analysis model of manufacturing capabilities[END_REF], [START_REF] Kathuria | Competitive priorities and managerial performance. A taxonomy of small manufacturers[END_REF], [START_REF] Corbett | Searching for the sandcone in the GMRG data[END_REF], [START_REF] Koufteros | Examining the competitive capabilities of manufacturing firms[END_REF], [START_REF] Rosenzweig | Towards a theory of competitive progression. Evidence from high-tech manufacturing[END_REF], [START_REF] Größler | An empirical model of the relationships between manufacturing capabilities[END_REF], [START_REF] Rosenzweig | Is the tradeoffs model dead?. Evidence using modified metaanalysis methods[END_REF], [START_REF] Amoako-Gyampah | Examining cumulative capabilities in a developing economy[END_REF], [START_REF] Wang | When the sand cone model meets SMEs[END_REF], [START_REF] Boon-Itt | The relationships between manufacturing capabilities: An empirical analysis in Thai automotive industry[END_REF]. [START_REF] Flynn | An exploratory study of the nature of cumulative capabilities[END_REF] find empirical evidence of the link between the accumulation of some manufacturing capabilities and the production department performance, but their results do not support the sand cone model. [START_REF] Filippini | Trade-off and compatibility between performance: definitions and empirical evidence[END_REF] state that there is evidence of high levels of compatibility among different types of manufacturing performance but is not possible to consider that trade-off model has been overcome.

In spite of the theoretical arguments and the empirical evidence against the trade-off model, some authors consider that it can be applied in certain circumstances. They even maintain that it is possible to combine the two 6 models (trade-off and sand cone) as they offer complementary approaches. It should be stressed in this connection that manufacturing capabilities depend on the technology used. If the factory operates below the technological frontier of its manufacturing possibilities, it can improve in all the objectives simultaneously. When it reaches the frontier, trade-offs occur. But if the frontier moves, there will be further room for simultaneously achieving the objectives [START_REF] Clark | Competing through manufacturing and the new manufacturing paradigm. Is manufacturing strategy passé?[END_REF][START_REF] Schmenner | On theory in Operations Management[END_REF]. As stated by [START_REF] Skinner | Missing the links in manufacturing strategy[END_REF], changing technology changes the trade-offs and the links between the design of a manufacturing system and the objectives. In other words, a factory that uses a manufacturing system that is within the technological standard for the industry (at the technological frontier) cannot expect to improve two or more objectives simultaneously [START_REF] Ferdows | Lasting improvements in manufacturing performance. In search of a new theory[END_REF]). [START_REF] Lapré | Performance improvement paths in the U.S. Airline Industry. Linking trade-offs to asset frontiers[END_REF] provide empirical evidence from the airline industry that the sand cone model is applicable when firms are operating further away from their asset frontiers, although trade-offs occur when operating close to asset frontiers.

An extended sand-cone model: Research hypotheses

Based on a review of the literature, the aim of this study is to test, in a sample of manufacturers located in Spain, whether or not there are trade-offs amongst the manufacturing capabilities, that is, whether firms are able to achieve excellent results in several manufacturing objectives simultaneously and also whether the different manufacturing capabilities strengthen each other. Considering the literature on the environmental protection objective and the interactions between it and the four traditional manufacturing objectives [START_REF] Del Brío | Competitive effects from eco-manufacturing strategy. Influencing factors[END_REF], in our research the sequence is completed by including the environmental protection as the fifth manufacturing objective.

De [START_REF] De Burgos | Environmental performance as an operations objective[END_REF] explain the need for including the environmental protection as an objective for the production department, and state that there are direct links between the environmental protection strategy and the production department. The authors point to the existence of synergies between environmental protection and improvement programs and activities and operating methods and practices. They also indicate that environmental protection management programs should be implemented taking into account and supporting manufacturing strategy. This means that the objectives for the operations area should be expanded to include environmental protection considerations. [START_REF] Angell | Environmental and Operations Management face the future[END_REF] proposes that inclusion of the environment protection as a manufacturing objective could be the first step towards achieving a sustainable environmental protection strategy. Reduction of the environmental impact should be considered, at least partially, a matter for the production department [START_REF] Angell | Integrating environmental issues into the mainstream. An agenda for research in operations management[END_REF].

Previous studies have analysed the impact of the results of environmental protection management on the production department (see, for example, [START_REF] Gupta | Environmental operations management. An opportunity for improvement[END_REF][START_REF] Klassen | An international comparison of environmental management in operations. The impact of manufacturing flexibility in the US and Germany[END_REF], identifying possible synergies between environmental protection improvement and manufacturing objectives. De Burgos and Céspedes (2001) state that it would be interesting to analyse the link between this environmental protection objective and the other manufacturing objectives as well as the existence of a possible logical sequence for achieving lasting improvements in the manufacturing objectives in the long term.

Regarding this sequence and on the basis of previous studies [START_REF] Noble | Manufacturing strategy. Testing the cumulative model in a multiple country context[END_REF][START_REF] Ferdows | Lasting improvements in manufacturing performance. In search of a new theory[END_REF][START_REF] Rosenzweig | Towards a theory of competitive progression. Evidence from high-tech manufacturing[END_REF], it can be assumed that improvements in quality serve as a basis for the improvement of the other objectives. Specifically, quality is hypothesized to have a significant positive relation with delivery. Delivery refers to a firm's ability to provide fast and dependable deliveries; therefore, it comprises two elements: a) speed, and b) reliability. [START_REF] Schroeder | Manufacturing performance trade-offs: an empirical investigation[END_REF] argue that conformance quality will drive higher levels of on-time deliveries and fast deliveries. When a factory improves its quality, its processes become more stable and reliable and less time and cost are needed for re-processing tasks [START_REF] Rosenzweig | Towards a theory of competitive progression. Evidence from high-tech manufacturing[END_REF].

When quality improves, the number of items requiring re-work becomes smaller. This allows materials to move more swiftly and consistently through a process and cycle times to become more predictable. Reductions in the lead time, set-up time and delivery time depend on the reliability of the processes and on a consistently high product quality level [START_REF] Sakakibara | The impact of just in time manufacturing and its infrastructure on manufacturing performance[END_REF]. Consistent with this, [START_REF] Wacker | The complementary nature of manufacturing goals by their relationship to throughput time: a theory of internal variability of production systems[END_REF][START_REF] Wacker | A theoretical model of manufacturing lead-times and their relationship to a manufacturing goal hierarchy[END_REF] mathematically demonstrates that a reduction in defect rates can have a positive effect on throughput time and delivery reliability, a compatible relationship that has also been reported by other authors [START_REF] Schroeder | Manufacturing performance trade-offs: an empirical investigation[END_REF][START_REF] Vickery | Dimensions of manufacturing strength in the furniture industry[END_REF][START_REF] Safizadeh | Alternative paradigms in manufacturing strategy[END_REF]. Taking this into account, it could be argued that a production process with high levels of internal quality may facilitate delivery commitments (quoted and/or forecasted) based on the process output (Sarmiento et al., 2007). In other words, higher levels of quality may lead to enhanced delivery, so the following hypothesis is established: H1: Improving quality has a direct, positive effect on delivery. In fact, some studies show that delivery reliability and various dimensions of flexibility (e.g. product mix and volume changes) may be compatible and are positively associated [START_REF] Vickery | Dimensions of manufacturing strength in the furniture industry[END_REF].

High-speed manufacturing improves flexibility in that less time is needed for responding to different external influences and adjusting to changes in requirements or specifications [START_REF] Milling | Time as a success factor for operations management -an empirical analysis based on the World Class Manufacturing -Project[END_REF]. Corbett and Van Wassenhove (1993) assert that if the organization is unable to meet due dates under normal circumstances, it will be unable to react flexibly to unforeseen volume fluctuations in demand. This is consistent with the comments by [START_REF] Wacker | The complementary nature of manufacturing goals by their relationship to throughput time: a theory of internal variability of production systems[END_REF] who argues that, as throughput time increases, a firm becomes less productive and less able to respond to changes in output mix and customer demand responsiveness. Therefore, the following hypothesis is established: H2: Improving delivery has a direct, positive effect on flexibility.

Manufacturing flexibility, by enabling efficient adaptation to change and uncertainty, can support environmental practices [START_REF] Klassen | An international comparison of environmental management in operations. The impact of manufacturing flexibility in the US and Germany[END_REF]. Improving innovation in both products and processes promotes the incorporation of more flexible, more environment-friendly technology. It also enables the development of maketo-order production systems that can operate with lower inventory levels. Such systems reduce shrinkage and limit the obsolescence of stored products which otherwise would have to be eliminated, reprocessed or recycled, and this reduces environmental impact. Moreover, production systems involving more flexible processes (such as just-in-time) may promote the adoption of more advanced environmental practices which might improve the company's overall environmental situation [START_REF] Del Brío | Competitive effects from eco-manufacturing strategy. Influencing factors[END_REF]. This argument is to some extent consistent with studies that have empirically noted synergies amongst some lean manufacturing processes and environmental practices [START_REF] King | Lean and green? An empirical examination of the relationship berween lean production and environmental performance[END_REF][START_REF] Rothenberg | Lean green and the quest for superior environmental performance[END_REF]. The following hypothesis is therefore posed: H3: Improving flexibility has a direct, positive effect on the environmental protection objective. Direct synergies can also be observed between environmental protection and cost reduction. For example, the development of an overall pollution prevention strategy (which only requires limited additional investments, compared with add-on equipment for an end-of-pipe strategy) may result in reduced operating costs and efficiency improvements [START_REF] Wagner | How to reconcile environmental and economic performance to improve corporate sustainability: Corporate environmental strategies in the European paper industry[END_REF]. Additionally, the introduction of technologies that aim to improve firms' environmental protection situation (for example, reducing energy consumption during the production process) or the re-examination of the actual production processes also help to save costs (Porter andvan der Linde, 1995a, 1995b;Angel and Klassen, 1999). This was exemplified by [START_REF] Dorfman | Environmental Dividends: Cutting More Chemical Wastes[END_REF], who reported annual cost savings of $740,000 at Ciba-Geigy's dyestuff plant in New Jersey as a result of re-examining its wastewater streams and operating processes and replacing some production components. Similarly, [START_REF] Sheridan | Attacking wastes and saving money…Some of the time[END_REF] reported how 3M implemented a new production technique that allowed it to reduce hazardous wastes by 10 tons per year at almost no cost, yielding annual savings of more than $200,000. [START_REF] Van Wassenhove | How green is your manufacturing strategy[END_REF] reported how AT&T saved US$1.4 million on recycling efforts alone, whereas the Gulf Coast Acid Team, a task force of employees at Dow Chemical, recommended installation of a state-of-the-art recycling system that resulted in an annual saving of US$20 million.

Solving environmental problems can also yield benefits in terms of lower costs due to reduced downtime. [START_REF] Parkinson | Reducing wastes can be cost-effective[END_REF] described how installing higher quality monitoring equipment allowed DuPont to reduce production interruptions and the associated wasteful production start-ups in many chemical production processes, thus reducing waste generation as well as downtime.

The implementation of environmental initiatives aiming to substitute materials, reuse or recycle production inputs, use less packaging, reduce storage, make work conditions safer, improve monitoring and maintenance, etc., may lead to higher resource productivity (Porter and van der Linde, 1995b). [START_REF] Basta | A casebook of successful waste reduction projects[END_REF] reported several cases of successful waste reduction projects in the chemical industry that illustrate the positive effects of "green" initiatives on cost savings. With regard to certain ecological products, it is possible to go even further, with firms recovering waste products for re-manufacturing, thus achieving a cost reduction advantage [START_REF] Ayres | Ecoefficiency, asset recovery and remanufacturing[END_REF]. As pointed out by Porter and van der Linde (1995b), solving environmental problems by using recyclable products can lead to designs that allow valuable materials to be recovered more easily after disposal of the product; in this case, whoever takes back used products -either the customer or the manufacturer-gains greater value. Environmental management may also improve firms' process excellence by using environmental management tools which support identification of eco-efficiency potential and successful implementation of eco-efficiency enhancing measures [START_REF] Wagner | Umweltmanagement in Deutschen Unternehem. Der aktuelle Satand der Praxis (Environmental Management in Practice)[END_REF]. In this way, as shown empirically by [START_REF] Carter | Interorganizational determinants of environmental purchasing. Initial evidence from the consumer products industries[END_REF], environmental protection improvement, which in turn helps make the firm eco-efficient, leads to reduced costs [START_REF] Gupta | Environmental operations management. An opportunity for improvement[END_REF]. Or, to state this in more formal terms: H4: Environmental protection improvement has a direct, positive effect on cost efficiency.

The hypotheses H1-H4 capture the direct effects of improving a given capability on the capability succeeding it in the depicted progression. However, the literature suggests that the development of these capabilities in this successive fashion may lead to indirect and cumulative effects. As previous authors suggest [START_REF] Nakane | Manufacturing Futures Survey in Japan. A comparative survey 1983-1986[END_REF][START_REF] Ferdows | Lasting improvements in manufacturing performance. In search of a new theory[END_REF]Schmenner and Swink, 1988;[START_REF] Swink | Manufacturing strategy: propositions, current research, renewed directions[END_REF][START_REF] Flynn | An exploratory study of the nature of cumulative capabilities[END_REF], quality can be viewed as the foundation for the development of cumulative capabilities. The literature documents many cases and examples that illustrate the positive effect of quality on other manufacturing capabilities. Quality management systems have synergies with flexibility and environmental protection management [START_REF] Kitazawa | The relationship between ISO 14001 and continuous source reduction programs[END_REF]. The quality improvement stabilizes production processes, eliminating reprocessing tasks and saving energy and resources [START_REF] Rosenzweig | Towards a theory of competitive progression. Evidence from high-tech manufacturing[END_REF]. A reduction in lead times not only reduces inventories but also shortens internal product transport time, eliminating the need for repeat consignments (because deliveries are reliable), which also saves energy [START_REF] Koufteros | Examining the competitive capabilities of manufacturing firms[END_REF] and reduces costs. Flexibility leads to a reduction in inventories and therefore fewer products are spoilt while fewer resources are used, which contributes to environmental protection and cost savings. Consequently, contrary to the theory that trade-offs exist among manufacturing capabilities, cost efficiency in production can be achieved more easily through improvements in other capabilities. Therefore, considering the shared (or common) process variance between enhancement in one capability and improvement in the others, it is possible to assume the existence of positive indirect effects amongst them [START_REF] Rosenzweig | Towards a theory of competitive progression. Evidence from high-tech manufacturing[END_REF]. This leads to the following hypotheses:

Research design and sample characteristics

The information needed for the study was obtained from a survey conducted on 1,234 manufacturers that in 2003 were located in Spain and employed over 100 workers, according to the Amadeus-SABI database. The selection of firms was based on two-digit ISIC codes, including codes 24 and 28 to 36. A detailed description of the research instrument and the sample analysed can be seen at [START_REF] Vázquez-Bustelo | Agility drivers, enablers and outcomes. Empirical test of an integrated agile manufacturing model[END_REF] The questionnaire used was designed on the basis of the existing literature and the conclusions obtained from a previous case study [START_REF] Vázquez-Bustelo | Agile manufacturing. Industrial case studies in Spain[END_REF]. It was revised by four experts in operations management and two experts in survey design. With the aim of checking its validity and improving its design, a pre-test was also done on a small sample of firms drawn from the population.

The information needed for the study relates to the production function in firms, so the questionnaire was addressed to the plant/operations/manufacturing manager or other similar position, and the strategic manufacturing unit was identified as the unit of analysis. Each strategic manufacturing unit corresponds to a firm, or a division or plant within a firm, with defined business and manufacturing strategies. A total of 283 valid questionnaires were returned corresponding to 274 different firms and representing a valid response rate of 22.2%. Using a Student T-test, the last 25% of respondents were compared to earlier ones and no statistically significant differences were found in key variables at the 5% level. Based on the assumption that late respondents are similar to non-respondents [START_REF] Armstrong | Estimating non response bias in mail surveys[END_REF], non-response bias does not appear to be a major problem in this research.

Measurement of variables

For each of the 22 items of the five manufacturing objectives considered in this research (Table 1), managers were asked to indicate on a five-point scale (1 = poor/lower; 3 = average; 5 = excellent/higher), the strength or advantage developed in comparison to its competitors. In this way we measure manufacturing capability in each dimension of the five manufacturing objectives considered in this research.

Before testing the hypotheses, the metric properties of the scales for the five manufacturing capabilities were evaluated, that is, the unidimensionality, reliability and validity.

Exploratory factor analysis was carried out using Varimax rotation to determine the dimensions underlying the set of variables in each scale (Table 2). The 22 variables were grouped in five factors relating to cost efficiency (4 items), flexibility (6 items), quality (5 items), delivery (3 items) and environmental protection (4 items) with factor loadings above 0.5 and a percentage of total accumulated explained variance of over 50%.

INSERT TABLE 2

After exploratory factor analysis, confirmatory factor analysis (CFA) was carried out by means of structural equations, using the EQS statistical package, which confirmed the composition of the scales identified in the previous exploratory factor analyses for the manufacturing capabilities -strength developed in each of the manufacturing objectives-(Table 3).

INSERT TABLE 3

In order to analyse reliability, Cronbach's alpha coefficient and the composite reliability coefficient were calculated (Table 3). Cronbach's alpha coefficient in all cases was over 0.7, the criterion usually considered to identify strict internal consistency. In all cases the composite reliability coefficient was over the minimum level of 0.6 recommended by [START_REF] Bagozzi | On the evaluation of structural equation models[END_REF]. After studying the unidimensionality and testing for reliability, the content, convergent and discriminant validity were analysed. Content validity indicates that the items considered are suitable for representing the concepts to be analysed. The 18 measures used for the four traditional manufacturing objectives (cost efficiency, quality, flexibility and delivery) are an adaptation of those used in the Global Manufacturing Futures Survey Project-GMFSP [START_REF] Miller | Global Benchmarking in Manufacturing[END_REF] and are consistent with the measures used in other empirical studies on manufacturing strategy [START_REF] Roth | Neo-Operations strategy. Linking capabilities-based competition to technology[END_REF][START_REF] Corbett | A comparative study of the operations strategies of globally-and domestically-oriented New Zealand manufacturing firms[END_REF][START_REF] Avella | Taxonomy of the manufacturing strategies of large Spanish industrial companies[END_REF]Gilgeous, 2001, among others). The items used for measuring the environmental protection objective are also based on the extant literature (Porter and van der Linde, 1995a;Shrivastava, 1995aShrivastava, , 1995b;;[START_REF] Gupta | Environmental operations management. An opportunity for improvement[END_REF][START_REF] Newman | An empirical exploration of the relationship between manufacturing strategy and environmental management. Two complementary models[END_REF][START_REF] Ayres | Ecoefficiency, asset recovery and remanufacturing[END_REF][START_REF] Klassen | An international comparison of environmental management in operations. The impact of manufacturing flexibility in the US and Germany[END_REF][START_REF] Angell | Integrating environmental issues into the mainstream. An agenda for research in operations management[END_REF][START_REF] Kitazawa | The relationship between ISO 14001 and continuous source reduction programs[END_REF]. Only those categories in which the manufacturing area is directly responsible are included.

Since the scales were built on the basis of the previous literature and therefore include items used in scales that had already been validated for measuring similar concepts and assessed by case studies and the questionnaire pre-test, it was considered that each item had the necessary content validity.

Convergent validity measures the degree to which the different scales used to measure a latent factor are correlated. It can be assessed from the measurement model by determining whether each indicator's estimated pattern coefficient on its posited underlying construct factor is significant [START_REF] Anderson | Structural equation modeling in practice: A review and recommended two-step approach[END_REF].

Following Anderson and Gerbing's method, the lambda coefficients that measure the relation between the observed and the latent variable were analysed observing that all the standardized factor loadings were statistically significant at a 95% confidence level (t>1.96, weak condition) and exceeded 0.5 (strong condition) (Table 3).

The discriminant validity measures the degree to which the specified latent factors differ even though they are correlated. It was tested by calculating and examining the confidence interval of the paired correlations among the latent variables (i.e., +/-two standard errors; [START_REF] Marcoulides | Modern methods for business research[END_REF]. As shown in Table 3, the discriminant validity of the scales can be confirmed because none of these confidence intervals contains the value 1.0 at 95% confidence [START_REF] Bagozzi | Representing and testing organizational theories: A holistic construal[END_REF][START_REF] Anderson | Structural equation modeling in practice: A review and recommended two-step approach[END_REF][START_REF] Torkzadeh | Confirmatory analysis of a computer self-efficacy instrument[END_REF]. However, the idea of the existence of synergies or reinforcements amongst the various objectives suggests that the factors that measure the objectives should have a certain degree of correlation.

INSERT TABLE 4

RESULTS

In order to analyse the data and test the hypotheses, a structural equation model was used. This methodology allowed us to carry out statistical validation of the model proposed by means of simultaneous analysis of the whole system of variables involved and their links, determining the degree to which the analysis is consistent with the data. Use of this technique allows the researcher to simultaneously compare many equations and explore both the direct and indirect effects of the variables, offering a more precise measure of the overall effect of one variable on another.

If the chi-square test is considered in isolation, the model does not reach the recommended criterion for good fit.

However, the possibility of using the chi-square test is limited and has been questioned in the literature [START_REF] Bagozzi | On the evaluation of structural equation models[END_REF] because it does not take into account the complexity of the model tested.

To solve this limitation, its value should be divided by the degrees of freedom. This quotient should be 3 or below, a criterion which is achieved in this model (S-B χ 2 / df = 1.95 < 3). The values reached by other robust indices (BBNNFI = 0.921 > 0.9) (CFI = 0.930 > 0.9) (IFI = 0.931 > 0.9) (RMSEA = 0.058 < 0.08) also support the model's goodness of fit and allow us to confirm the plausibility of the links proposed between the variables involved.

The estimated value and the sign of the links (direct and indirect effects) between the five manufacturing objectives are shown in Table 5.

INSERT TABLE 5

The results of testing the model support the hypothesis that improved manufacturing objectives can be achieved progressively and without incompatibility or direct trade-offs between them. The results of the multi-variant analysis offer evidence that backs up the theory of the sequential or sand cone model (Figure 2).

INSERT FIGURE 2

The specific link between quality and delivery (H1) is backed by the empirical evidence that points to the existence of a direct, positive, significant link at 99% confidence between the former and the latter (t value = 9.040). Similar results can be observed for the other hypotheses that indicate direct effects amongst the remaining manufacturing objectives. They show that greater delivery speed and dependability has a positive effect on flexibility (p< 0.01), thus supporting hypothesis H2. The data also support hypothesis H3, noting a direct, positive, significant effect (t value = 5.543) of flexibility on environmental protection. Finally, the t value of the non-standard coefficient 0.348 illustrates the existence of a direct, positive, and significant effect (p< 0.01) of environmental protection on cost efficiency, which supports hypothesis H4.

Table 5 shows that a higher level in quality has an indirect effect on cost efficiency (p< 0.01) through an improvement in the delivery, flexibility and environmental protection. These results support hypotheses H5a, H5b, H5c. With regard to H6a, H6b, the results indicate that improved delivery have an indirect, positive effect on cost efficiency (t value = 3.219), through increased flexibility and environmental protection improvement (p< 0.01).

Finally, the results support the last of the hypotheses (H7), indicating that flexibility has an indirect effect on cost efficiency (p< 0.01) as a result of greater environmental protection.

DISCUSSION

Our results point out that not only can trade-offs be avoided altogether, but in fact one capability would enhance another. Specifically, our findings provide empirical evidence supporting an extended sand cone model which includes the environmental protection objective alongside the four traditional manufacturing capabilities -quality, delivery, flexibility and cost efficiency. Our data show the system of simultaneous dependence that exists in the process of improving these five manufacturing capabilities and suggest that it is possible to reject the existence of trade-offs or incompatibilities among them, thus providing empirical support for the cumulative aspects of the manufacturing capabilities analysed.

Nowadays, compared to their competitors, excellent manufacturers seem to achieve better quality, to be more dependable, more flexible, and more environment conscious and, in spite of all that, to achieve cost efficiency.

Maybe the pursuit of intelligent production-competition strategies that try to overcome the traditional duality of cost leadership or differentiation [START_REF] Bullinger | Intelligent production-competition strategies for production enterprises[END_REF], the generalized implementation of advanced manufacturing technologies (AMT) and other world-class practices and organisational improvements (New, 1992) have helped such firms to concurrently develop multiple capabilities avoiding trade-offs between them.

These findings are in line with the arguments of previous authors [START_REF] Ferdows | Lasting improvements in manufacturing performance. In search of a new theory[END_REF][START_REF] Swink | Manufacturing strategy: propositions, current research, renewed directions[END_REF][START_REF] Schmenner | On theory in Operations Management[END_REF] and also support the idea that addressing capabilities in a particular sequence enables improvements to be made in other capabilities. The relationship among capabilities suggested in our model and our results would appear to have some theoretical and practical implications.

From a theoretical point of view, this paper highlights the need to adopt an integrated perspective for environmental operations management, and justify the need to include environmental protection as a dimension of operations performance in manufacturing strategy studies. The paper contributes to the field of operations management by exploring the direct and indirect connections between capabilities for a large sample of manufacturers. Our findings on the relationship among manufacturing capabilities and their sequence may offer a way of better understanding manufacturing competence, which determine manufacturing's contribution to the success of a firm.

Since our findings suggest that improvement in certain manufacturing capabilities can amplify certain other capabilities, managers can conclude that developing multiple capabilities simultaneously is possible and desirable. Our model also suggest to practitioners that an efficient development path to overall improvement in manufacturing capabilities exist, and it can be used as a guide when constructing manufacturing strategies and designing programmes to improve performance of manufacturing systems. The sequence, strength and direction of the tested relationships between the five manufacturing capabilities considered in our paper may play a major role conducting firm's resource allocation and leading the emphasis placed by managers on the improvement of different capabilities. Particularly, our findings suggest that improvements on the quality dimension have a strong positive impact on improvements on delivery capabilities and, by supporting delivery, capabilities on a higher level (e.g. flexibility, environmental protection and cost efficiency) jointly benefit from achievements on quality. Thus, as the other capabilities benefit from quality, management attention should first be directed toward achieving and then expanding it. Quality management (control, assurance and improvement) may serve a primary building block for gaining cumulative capabilities. This assertion is consistent with previous studies that observe quality management to form a strong foundation for cumulative capabilities [START_REF] Flynn | An exploratory study of the nature of cumulative capabilities[END_REF].

Quality-related principles, initiatives, practices and action programmes (e.g. Process Statistical Control, ISO 9000, kaizen, six sigma, TQM, quality circles, QFD, etc.) may function as drivers to enhance supportive links between the manufacturing capabilities. One explanation may be related to the fact that the work processes associated with quality management may also have interdependent properties, or "process commonalities" that overlap with other management practices related with the enhancement of different capabilities. Thus, the improvement of one capability maybe acts synergistically to automatically modify other capabilities with which it shares common processes [START_REF] Rosenzweig | Towards a theory of competitive progression. Evidence from high-tech manufacturing[END_REF]. This argument can be a plausible explanation of the indirect links and cumulative effects observed in the structure of capabilities presented in our paper. After achieving the quality-related objective and while quality efforts are further expanded, attention should be directed toward the improvement of delivery capabilities. Delivery (dependability and speed) is closely related to organisational integration, supply chain management and lean manufacturing [START_REF] Flynn | An exploratory study of the nature of cumulative capabilities[END_REF]. In this second layer, management should focus their strategic initiatives on developing effective supplier relationships and incorporating external supply chain management practices internally. Relationship-building initiatives such as just-in-time (JIT) manufacturing, supplier certification and customer integration, for example, can clearly change delivery reliability and speed, and synergistically amplify other capabilities on a higher level, such as flexibility, environmental protection or cost efficiency. Once significant performance has been achieved in quality and delivery and while pursuing these objectives further, resources may be directed toward improving manufacturing flexibility by proper product-process integration and close coordination between manufacturing activities and suppliers and/or customers. In this third layer, the activities initiated during the previous stages of the improvement progression facilitate the possibility of changing manufacturing volume to meet fluctuations in demand without incurring high penalties, and enhance skills in both modifying the characteristics of existing products or processes, and placing new products on the market fast. A close coordination with suppliers that provide slack capacity, absorb demand fluctuations or exchange technological expertise, and the information sharing and degree of process integration with customers may be key for directly acquiring flexibility capability and affecting the remaining capabilities indirectly. While efforts continue toward achieving and expanding quality, delivery and flexibility, attention can then be directed toward improving environmental protection. Since environmental protection as strategic capability is supported by other capabilities and reinforce each other [START_REF] De Burgos | Environmental performance as an operations objective[END_REF], managers should develop policies and implement environmental management programmes with similarities and synergies with the strategic operations initiatives already in place. Proactive environmental strategies (e.g. Design for environment (DfE), total quality environment management (TQEM), life cycle assessment (LCA), total recycling, source reduction/pollution-prevention (SR/P2), or zero emissions) would have a positive affect on cost cutting via waste reduction and other factors that reflect an eco-efficient approach.

CONCLUSIONS

The purpose of this study was to determine which model for improving manufacturing objectives prevails in firms.

Are there incompatibilities (trade-offs) among the different manufacturing capabilities? Or, on the contrary, are firms able to obtain high scores in several manufacturing objectives simultaneously and do the various manufacturing capabilities strengthen each other?

The study began with a review of the literature and the design of a model structuring the links among the five key manufacturing objectives -quality, delivery, flexibility, environmental protection and cost efficiency. After drawing up a precise definition of these objectives, the measurement scales for the constructs were validated, and the set of links proposed was tested using structural equation modelling. The results of the multi-variant analysis showed that the predominant model in these firms is one of multiple, non-incompatible capabilities with cumulative effects according to the following sequence: quality, delivery, flexibility, environmental protection and cost efficiency. It was noted that the five manufacturing objectives considered in the research not only are not incompatible with each other but that improvements in quality have a positive effect on delivery, flexibility, environmental protection and cost efficiency as do each of the objectives on the others, so they strengthen each other and produce cumulative effects.

Thus, this study makes a dual contribution. On the one hand, it offers additional empirical evidence on the existence of cumulative links amongst the four classic manufacturing objectives: quality, delivery, flexibility and cost efficiency, as suggested both by the sand cone model [START_REF] Ferdows | Lasting improvements in manufacturing performance. In search of a new theory[END_REF]) and the competitive progression theory [START_REF] Roth | Neo-Operations strategy. Linking capabilities-based competition to technology[END_REF][START_REF] Rosenzweig | Towards a theory of competitive progression. Evidence from high-tech manufacturing[END_REF]. On the other, it adopts an integrated perspective for environmental operations management, validating an extended sand cone model which considers environmental protection management alongside the four traditional objectives.

In spite of its contribution, the study has certain limitations that represent challenges for further research. On the theoretical side, the absence of trade-offs among the capabilities may be explained by the fact that the manufacturing units studied are positioned further from their performance, technological or assets frontier [START_REF] Schmenner | On theory in Operations Management[END_REF][START_REF] Rosenzweig | Towards a theory of competitive progression. Evidence from high-tech manufacturing[END_REF]. However, our research does not consider the viewpoint of performance frontiers, an aspect that should be addressed in future research. Since we did not include the consideration of contingencies as [START_REF] Swink | Manufacturing strategy: propositions, current research, renewed directions[END_REF] suggest, and did not compare the influence of different structures of capabilities on business performance (measured, for example by market share, ROI or other indices) one has to be careful to interpret the specific structure of operations-based capabilities presented in this paper as the "one best way" to firm's competitiveness and success. This paper also uses a conceptualization of environmental protection mainly focused on internal issues, although an internal perspective to environmental protection may be insufficient to actually improve a firm's environmental objective.

On the methodological side, obtaining information by means of a survey may generate doubts about the validity of the information provided by respondents. This problem may be solved by obtaining information from more than one source for each unit of analysis (that is to say, from more than one respondent), but this research did not consider this possibility, as it would have had important negative effects on the response rate. For this reason, single respondent bias can be considered a limitation for this empirical research. This study also uses managerial perceptions to measure the manufacturing capabilities. Perceptual measures of performance have often been used to measure operational performance because of the difficulty associated with obtaining comparable, objective measures for large samples. Objective measures are not normally available at the manufacturing level, or firms are reluctant to facilitate such information. Although this approach is a common procedure in management research, objective measures might improve the validity of our results. The lack of objective measures to complement the subjective/perceptual measures used can be considered a limitation.

Also, this research adopts a cross-cutting approach when it considers the manufacturing strengths achieved by the firms analysed at a specific moment in time, which limits the discussion of causality. Although plausible theoretical inter-relationships among capabilities have been drawn from the literature, and prior research [START_REF] Noble | Manufacturing strategy. Testing the cumulative model in a multiple country context[END_REF][START_REF] Rosenzweig | Towards a theory of competitive progression. Evidence from high-tech manufacturing[END_REF] has stated that the path dependency of manufacturing capabilities generally holds over time, our inferences on a time sequence with respect to capability development should be interpreted with caution. Future research should carry out a longitudinal analysis of the link between the various manufacturing objectives, including environmental protection, in order to offer stronger empirical support for the time process-model of capabilities development. It should also adopt a contingent approach [START_REF] Noble | Manufacturing strategy. Testing the cumulative model in a multiple country context[END_REF][START_REF] Schaltegger | The link between 'green' and economic success: environmental management as the crucial trigger between environmental and economic performance[END_REF][START_REF] Flynn | An exploratory study of the nature of cumulative capabilities[END_REF][START_REF] Sousa | Contingency research in operations management practices[END_REF], evaluating the robustness of the results when considering context factors such as firm size and age, industry, type of production process, customer behaviour, business environment or national context and culture.

  -amongst its different objectives. This model is based on two basic premises: a) the factory has many objectives, and b) some objectives are incompatible with others. A trade-off means that

  placed on obtaining quality and, once a suitable quality level has been attained, then work should be begun on improving delivery. But at the same time, work should continue on quality. When a suitable standard has been reached for delivery, work should begin on flexibility, while continuing with the two objectives already reached. Finally, having reaching the desired level of flexibility, the focus should turn to cost efficiency.

  for manufacturing to adapt to changing market needs. This objective involves several facets (De Toni and Tonchia, 1998): a) the possibility of changing manufacturing volume to meet fluctuations in demand without any significant effect on cost efficiency -volume flexibility; b) the skill to modify the characteristics of existing products -product flexibility; and c) the skill to place new products on the market fastflexibility in innovation.

H5a:

  Improving quality has an indirect, positive effect on flexibility by improving delivery. H5b: Improving quality has an indirect, positive effect on environmental protection by improving delivery and flexibility. quality has an indirect, positive effect on cost efficiency by improving delivery, flexibility and environmental protection. H6a: Improving delivery has an indirect, positive effect on environmental protection by improving flexibility. H6b: Improving delivery has an indirect, positive effect on cost efficiency by improving flexibility and environmental protection. H7: Improving flexibility has an indirect, positive effect on cost efficiency by improving environmental protection. The theoretical reasoning presented above leads us to consider a cumulative manufacturing capabilities model, depicted in Figure 1, showing a progression in the achievement of quality, delivery, flexibility, environmental protection and cost efficiency capabilities. By empirically testing this model, we try to answer the following research question: Do firms accumulate manufacturing capabilities by following the sequence of quality, delivery, flexibility, environmental protection, and cost efficiency, in such a way that the performance achieved in each objective allows improvements in the others?

  Figure 1. Manufacturing capabilities cumulative model

  =397.33 (d.f. 203) p = 0.000 BBNNFI = 0.921 CFI = 0.930 IFI = 0.931 RMSEA = 0.058

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  Table 4 shows the correlation matrix amongst the various objectives. The results presented indicate that the correlations between the objectives are 14 moderate, in no case above 0.7. This allows us to conclude that the factors measure different concepts and can be treated as different statistical objects.

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Estimated cumulative model

				H 6b
				H 6a
	H 1	H 2	H 3		H 4
	Quality	Delivery	Flexibility	Environmenta l protection	Cost efficiency
	H 5a r F o	H 5b		H 7
	Direct effects Indirect effects P e		H 5c
		e r
	.084* .413* v R e Figure 2. Quality .634* .585* .242* i e Flexibility Delivery w Environmental protection	.348*	Cost efficiency
	Direct effects	.370*	.153*	.053*	.144* O n l y
	Indirect effects

Table 1 . Competitive manufacturing objectives

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Table 2 . Exploratory factor analysis

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				Manufacturing objectives
	I t e m s			Factors
		1	2	3	4	5
	Cost efficiency1	.083	.128	.077	.784	.151
	Cost efficiency2	-.028	.077	.111	.758	.162
	Cost efficiency3	.162	.136	.119	.643	.087
	Cost efficiency4	.216	.093	.149	.583	.133
	Flex1	.114	.684	.211	.276	-.017
	Flex2	.117	.590	.340	.214	-.072
	Flex3	.098	.536	.212	.325	.229
	Flex4	.109	.777	.125	.127	.140
	Flex5	.059	.708	.129	-.087	.155

Table 3 . Confirmatory factor analysis

 3

	Reliability	Discriminant validity

Table 4 . Correlation matrix between objectives

 4

		Delivery	Flexibility	Environmental protection	Cost efficiency
	Quality	0.612	0.480		0.437	0.606
	Delivery	1.00	0.531		0.418	0.557
	Flexibility		1.00		0.370	0.465
	Environmental protection				1.00	0.347
	Cost efficiency					1.00
	Note: All the correlations are significant at 99% (p<0.01)
		Measures of the model's goodness of fit (Robust Method)
	S-B χ χ χ χ 2, = 303.58 (d.f. 197) p = 0.000	BBNNFI = 0.955	CFI = 0.962	IFI = 0.962	RMSEA = 0.044

Table 5 . Breakdown of effects: direct and indirect effects. Standard coefficients and goodness of fit (robust statistics) ON…

 5

		Delivery			Flexibility	Environmental protection	Cost efficiency
	EFFECT OF…	Direct	Indirect	Direct	Indirect	Direct	Indirect	Direct	Indirect

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ACKNOWLEDGEMENTS

The authors would like to thank the Editor and the anonymous referees for their helpful comments and suggestions. The authors also would like to thank Spanish Ministerio de Ciencia y Tecnologıa (SEJ2006-04753/ECON) in its financial support. A preliminary version of this paper was published as Working Paper Nº. 371/2008 in Colección de Documentos de Trabajo de la Fundación de las Cajas de Ahorros (FUNCAS).


J I Wyatt

Keywords:

teaching and research institutions in France or abroad, or from public or private research centers.

Liver transplant pathology -messages for the non-specialist

There are about 650 liver transplants per year in 7 centres in the UK, with a 5 year survival rate of 75-80% (1) and about 7000 patients alive with a transplanted liver. Patients may live a distance from the transplant centre, and long term follow-up may be shared with the local hepatologist; histopathologists outside the transplant centre may therefore receive late post-transplant biopsies.

These biopsies are challenging with a wide differential diagnosis. Because of the importance of comparison with previous biopsies and of good clinic-pathological correlation, it is recommended that post-transplant biopsies are always referred to the pathologist at the transplant centre(2) However, the local pathologist often provides the initial opinion. This article focuses on these late biopsies, where the differential diagnosis broadens beyond the preservation/reperfusion changes, acute rejection and effects of surgical/post operative complications that dominate the first 3 months post-transplant.

The purpose of this article is twofold. Specifically as a guide to pathologists working outside transplant centres who may receive late post transplant liver biopsies. Also generally, to emphasize the three stage approach -(i) global pattern recognition, (ii) systematic evaluation of biopsy features, (iii) importance of clinical context -necessary in liver biopsy interpretation. In this regard, transplant biopsies are a subset of medical liver biopsies reviewed at the liver centre; understanding when and how the original clinico-pathological diagnoses are revised should enable some pitfalls to be avoided [START_REF] Bejarano | Second opinion pathology in liver biopsy interpretation[END_REF].

Late post transplant liver biopsies are obtained to investigate changes in liver enzymes/function tests, or as protocol biopsies particularly in hepatitis C or teenage patients. Like all medical liver biopsies, they may show a kaleidoscope of alterations including inflammation, structural changes, fibrosis, and cellular changes in hepatocytes and cholangiocytes, from which it is the task of the histopathologist, in collaboration with the hepatologist, to deduce the most appropriate clinicopathological explanation. Biopsy histology is one of an array of diagnostic tests (with biochemistry, immunology, virology and imaging) available to the hepatologist, and the histopathologist's role in the team is less often to make a single specific diagnosis, and more to guide further investigations, distinguish among potential causes of liver injury, and/or compare with previous biopsies Liver transplantation pathology is comprehensively reviewed in standard texts(4) and review articles [START_REF] Demetris | Liver allograft rejection: an overview of morphologic findings[END_REF][START_REF] Jones | Interpretation of biopsy findings in the transplant liver[END_REF][START_REF] Hübscher | Transplantation pathology[END_REF]. There are excellent recent reviews that give detailed accounts of the different diagnostic entities underlying liver biopsy alterations [START_REF] Adeyi | Liver allograft pathology: approach to interpretation of needle biopsies with clinicopathological correlation[END_REF][START_REF] Hübscher | Transplantation pathology[END_REF]. This article is more a 'where to start?' strategy for a non-specialist. The description of diagnostic patterns in liver disease by Bateman(10) in a previous Histopathology review also emphasised the three stage approach to medical liver biopsy diagnosis, in the non-transplant setting.

In general, biopsies will show some degree of inflammatory infiltrate, which may be accompanied by some fibrosis or architectural distortion and ductular reaction, and perhaps with some steatosis or cholestasis. In 2006, the Banff Working Group produced a helpful publication on the interpretation of late post transplant biopsies [START_REF] Banff | Liver biopsy interpretation for causes of late liver allograft dysfunction[END_REF]. This focuses on the differential diagnosis of inflammatory changes, based on the distribution, severity and nature of the inflammation among seven different compartments of the liver biopsy. Their tabulated summary is reproduced here with permission (table 1), and colour and shading has been added to emphasise the characteristics of the different pathologies. It is a helpful structure that (by excluding rejection from the list of differentials) can be equally applied in a non-transplant setting.

Most diseases leading to liver transplantation in adults can recur in the graft (not so in children where the majority of transplants are done for biliary atresia or inherited metabolic disease). The differential diagnosis in adult liver transplant biopsies includes rejection, recurrent disease, surgical complications (vascular and biliary) and de novo liver disease including autoimmune hepatitis, infection and drug reaction. As the Banff authors comment [START_REF] Banff | Liver biopsy interpretation for causes of late liver allograft dysfunction[END_REF], 'interpretation of these biopsies can be quite difficult...' There are caveats -more than one insult can contribute to the liver injury, and features of many overlap. In general, the more severe the inflammation, the more likely the pathologist can resolve it into one or more definite diagnoses -mild and patchy disease is likely to be non-specific histologically, and its significance only attributable by detailed clinical correlation, or apparent in retrospect.

Portal inflammation

Some degree of portal inflammation in usual in post transplant biopsies -determining its significance depends on the distribution, severity and composition of the inflammation and associated interface activity.

Allograft rejection:

Histopathologists outside transplant centres may be tempted to diagnose rejection in any post transplant biopsy that shows inflammation. However in practice, rejection is a relatively rare diagnosis in late post transplant biopsies, and the diagnosis requires clinical corroboration. Other causes of portal inflammation need to be considered. In particular, hepatitis C and autoimmune hepatitis can show features that overlap closely with acute (cellular) rejection [START_REF] Souza | Morphologic features resembling transplant rejection in core biopsies of native livers from patients with Hepatitis C[END_REF], and biliary disease with chronic (ductopaenic) rejection (each considered further below).

In liver transplantation, most episodes of acute cellular rejection occur in the first few weeks following transplant, but it may occur at any time. The classic triad of portal tract features(13) -mixed inflammatory infiltrate including large lymphocytes and eosinophils, bile duct damage and venular endothelial inflammation (endotheliitis) are illustrated in fig 1 .   While this can be seen in late biopsies, the features are usually modified towards less portal vein endotheliitis, fewer lymphoblasts and eosinophils in the portal infiltrate, and more central perivenulitis (see below) (8.9.11). Of this triad, endotheliitis is the most specific feature for rejection, and its presence results in the inclusion of rejection in the differential [START_REF] Banff | Liver biopsy interpretation for causes of late liver allograft dysfunction[END_REF]. Conceptually, the distinction between rejection (based on immune reactions to MHC antigens) and AIH (reaction to non-MHC graft antigen) is confusing, and pragmatically clinical management of 'immune related graft injury' with enhanced immunosuppression does not necessitate a distinction to be made at the time of biopsy interpretation, although this may become apparent subsequently.

Viral hepatitis

Cirrhosis due to hepatitis C is now the commonest reason for liver transplant in most programmes. Unless the virus was eradicated before transplant, re-infection of the graft is universal, and circulating viral titres return to pre-transplant levels within a few days(14). This is followed usually after 3-6 weeks by histologically apparent hepatitis, and the rate of progression of fibrosis in chronic hepatitis C is accelerated compared with infection in nontransplant patients(15). However, the rate of progression is very variable, depending on the interplay of virus, host, donor and environmental factors. Older donors, donor steatosis, rejection episodes and their treatment, and severity of early hepatitis are factors associated with rapid progression to cirrhosis which is present in about 20% recipients by 5 years [START_REF] Adeyi | Liver allograft pathology: approach to interpretation of needle biopsies with clinicopathological correlation[END_REF]15). Protocol biopsies are often done (e.g. annually) to detect and treat patients with rapid fibrosis. The complex clinical decisions about treating hepatitis C and managing immunosuppression are made in transplant centres, and so biopsies performed elsewhere should be sent to the centre for review.

In general, histological features of recurrent hepatitis C are similar to non-transplant livers, and can be reported in the same way, e.g. with an Ishak Histopathology Activity Index (HAI) score [START_REF] Ishak | Hisotlogical grading and staging of chronic hepatitis[END_REF] or Metavir score [START_REF] French | METAVIR co-operative study group. Intraovbserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C[END_REF]. The task of the histopathologist is two-fold -i) are the biopsy features all attributable to hepatitis C, or is there another pathological process foreshortening the time to developing cirrhosis. In some, this may be associated with plasma cells and interface hepatitis -histological features of autoimmune hepatitis that may be associated with raised IgG and autoantibodies [START_REF] Khettry | Patterns of recurrent hepatitis C after liver transplantation in a recent cohort of patients[END_REF].

The second pattern of aggressive recurrent disease is characterised by portal and sinusoidal fibrosis swollen hepatocytes and bilirubinostasis in a patient with very high viral load [START_REF] Dixon | Early histologic changes in fibrosing cholestatic hepatitis C[END_REF].

In these patients the inadequacy of the immune response is believed to leave the liver susceptible to unopposed cytopathic effects of the virus; quasispecies are stable, due to the lack of immune-driven viral evolution(20). The histological differential diagnosis of the cholestasis and portal fibrosis is with biliary disease, and clinical context is important in resolving this.

Biliary pathology

In the transplant setting, the differential diagnosis of biliary disease is wide, and includes ductopaenic chronic rejection, anastomotic stricture, ischaemic cholangiopathy and recurrent primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). The key to diagnosing these is recognition of the 'biliary Gestalt'(11) -a combination of ductular reaction, portal and periportal fibrosis, +/-small bile duct loss, periportal oedema, and copper-associated protein deposition in periportal hepatocytes (fig 4). Recognition of this constellation of features grows with experience, but the one concrete objective component namely granules of copper-associated protein positive on the Shikata Orcein stain is a reliable pointer that should always prompt consideration of chronic biliary pathology. Since it can be patchy (localised around portal tracts affected by or upstream from bile duct injury/ loss) it repays searching.

The role of the pathologist is to suggest the presence of a chronic biliary pathology -this prompts further investigation with imaging, and review of clinical reasons for this complication. This may be recurrence of original disease -PSC or PBC, or bile duct stricture.

Bile ducts are supplied by the hepatic artery, and non-anastomotic biliary strictures form as a result of failed healing of ischaemic injury either due to hepatic artery thrombosis or late presentation of an injury originating at the time of transplantation. Grafts with prolonged ischaemic time, non-heart beating donor, split liver or live related donor grafts and paediatric transplants [START_REF] Demetris | Wound healing in the biliary tree of liver allografts[END_REF] are associated with an increased risk of late biliary complication.

The histology closely mimics PSC, including variation among portal areas and therefore susceptibility to sampling error. Ductopaenic chronic rejection, by contrast, classically results in ductopaenia without the biliary gestalt described above, although this may develop over time [START_REF] Demetris | Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection[END_REF]. Ductopaenic Histologically, early ductopaenic chronic rejection is present when more than 50% tracts contain bile ducts, but these show 'senescent' changes of irregular or atrophic appearing epithelium; in this situation portal inflammation is relatively mild, but targeting residual ducts, and sparing already ductopaenic tracts (fig 4). In the late stage there is >50% ductopaenia associated with perivenular bilirubinostasis, and often zone 3 hepatocyte loss and fibrosis [START_REF] Demetris | Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection[END_REF].

Parenchymal inflammation

A key observation in parenchymal necroinflammatory activity is the distinction between diffuse lobular hepatitis, which as in non-transplant patients may be from recurrent viral hepatitis , autoimmune or drug related, from localised perivenular (zone 3) inflammation [START_REF] Banff | Liver biopsy interpretation for causes of late liver allograft dysfunction[END_REF][START_REF] Krasinskas | The prevalence and natural history of untreated isolated central perivenulitis in adult allograft livers[END_REF]. The latter is named 'perivenulitis' and comprises sinusoidal inflammation and hepatocyte dropout localised to acinar zone 3, often accompanied by hepatic vein endotheliitis (fig 6). This is likely to be a rejection process even if there are no portal tract features of rejection (isolated central perivenulitis) [START_REF] Hübscher | Central perivenulitis: a common and potentially important finding in late posttransplant liver biopsies[END_REF], although alternative causes, especially autoimmune hepatitis, need to be considered. This pattern of late rejection is associated with an increased risk of progression to ductopaenic chronic rejection.

Sinusoidal dilatation

Perivenular sinusoidal dilatation and congestion associated with liver plate atrophy has a differential diagnosis that includes venous outflow obstruction due to hepatic vein anastomotic stenosis, veno-occlusion associated with previous perivenulitis, drug-related causes particularly azathioprine [START_REF] Hübscher | Transplantation pathology[END_REF], and vascular disturbance due to imbalance of hepatic artery and portal vein perfusion. This histological feature prompts clinical evaluation of these potential causes.

Fatty change

Fatty change is not a feature of transplant-specific complications, but has the same differential as in the non-transplant setting. Recurrence of original disease if that were

Fibrosis

The histopathologist's assessment of the presence, pattern and degree of fibrosis is the same as in non-transplant biopsies. Fibrosis tends to be more a feature of non-rejection complications, especially recurrent disease such as hepatitis C, or the biliary pattern of fibrosis that develops in patients with biliary disease. It gives a global indication of the severity of late post-transplant liver disease, at a time when re-transplantation may be under consideration.

Conclusion

A structured approach to biopsy evaluation and clinical discussion is essential for optimising the value of transplant biopsies, just as it is with non-transplant liver biopsies. The distribution and severity of histological features listed in table 1 forms the basis of the histological diagnosis which set in the clinical context will lead to further investigation and/or a change in patient management. As the cohort of long term liver transplant survivors grows, more histopathologists outside transplant centres will receive their biopsies. This article is intended to support them in their initial assessment. However, it remains very important also to refer the biopsy to the patient's transplant centre for review by the transplant team. This is the first message of the title. The others -systematic approach through initial pattern recognition, evaluation of individual features, integration with clinical context (and comparison with previous biopsies) are generic to all medical liver biopsies. This is necessary for ensuring the risk of the biopsy procedure is justified by its optimal diagnostic benefit [START_REF] Rockey | AASLD Position Paper:Liver Biopsy[END_REF].

  transplant pathology for the effect of intervention. A diagnosis of rejection is often made by non-specialist clinicians and pathologists, but is actually rather rarely the cause of late dysfunction unless there is a change in immunosuppression.

  diagnosis. The clinical context, especially a recent change in immunosuppression, is important. Histopathological evidence of rejection will prompt adjustment of immunosuppression, and consequent improvement in liver function tests gives helpful corroboration of the diagnosis. transplant pathology Histological features of recurrent or de novo autoimmune hepatitis (AIH) in the graft overlap with those of late acute rejection; autoimmune hepatitis should be suspected if plasma cells are a conspicuous component of portal and interface hepatitis (fig 2). Conversely, liver transplant patients may have liver autoantibodies without other features of AIH. Minimal diagnostic criteria for allograft AIH are interface hepatitis, a significant titre (>1 in 160) liver autoantibodies, hypergammaglobulinaemia, and exclusion of drug or virus related hepatitis and rejection

  transplant pathology present (e.g. rejection, duct obstruction)? and ii) to document the grade and stage of chronic hepatitis.Histological features of hepatitis C in non-transplant liver biopsies include bile duct inflammation, eosinophils and endotheliitis[START_REF] Souza | Morphologic features resembling transplant rejection in core biopsies of native livers from patients with Hepatitis C[END_REF], and so distinguishing an additional component of acute rejection will be difficult. Presence of portal lymphoid aggregates and diffuse lobular disarray with apoptotic hepatocytes are features of hepatitis C-associated inflammation (fig3), in which context a mild degree of rejection-like portal tract inflammation may also be attributed to hepatitis C. The presence of disproportionate portal features of rejection, especially in the clinical context of reduced immunosuppression and not a particularly high viral titre, is an indication for clinical treatment of rejection. This is a trade off between risks to the graft of rejection versus risks of worsening hepatitis C by increasing immunosuppression.Rapid histological progression of hepatitis C has two patterns[START_REF] Adeyi | Liver allograft pathology: approach to interpretation of needle biopsies with clinicopathological correlation[END_REF][START_REF] Hübscher | Transplantation pathology[END_REF]15). More commonly there is high viral load with maintained immune response resulting in an accelerated version of the natural history of hepatitis C. In these transplant patients, the massive initial infection of the graft, vulnerability of an older/steatotic graft, and established immune response to hepatitis C modified by immunosuppression can account for aggressive disease,

  transplant pathology Hepatitis B (recurrent or new) is rarely a problem in post transplant biopsies, because the infection is controlled in recipients by immunoglobulin and antiviral treatment. If this is unsuccessful, the histological patterns of viral hepatitis B are of a chronic hepatitis, which like hepatitis C can progress more rapidly than in a non-transplant patient, or rarely these days a cytopathic 'fibrosing cholestatic hepatitis' (21).

  transplant pathology rejection progressing to graft loss has now become rare, due to the recognition and improved management of late acute rejection, and early chronic rejection(24) (fig4).

  transplant pathology alcoholic, non-alcoholic fatty liver disease, or hepatitis C (particularly genotype 3) is the commonest cause.

  Histological features most commonly detected with various causes of late liver allograft dysfunction. (from: Banff Working Group, Histopathology 2006). The colour coding has been added to emphasise the histological features: red = severity/intensity; blue = distribution -patchy or diffuse; brown = inflammatory cell type; green = associated biliary features. The shaded boxes indicate the principal abnormalities of the six main differential diagnoses in post transplant biopsies showing inflammatory pathology.

Fig 1 :

 1 Fig 1: Acute rejection. The classic triad of portal tract features of acute cellular rejection, as seen in early post transplant biopsies. The portal inflammation is polymorphous, including eosinophils and large lymphocytes ('rejection-type' infiltrate). The bile duct inflammation can include lymphocytes and/or neutrophils (long arrow). In endotheliitis, lymphocytes attach to venous endothelium and then migrate beneath it, lifting it (open arrows). Inset = hepatic vein and zone 3 hepatocytes; in late post transplant biopsies, endotheliitis is often more evident in hepatic veins than illustrated in this early biopsy.

Fig 2 :Fig 3 :

 23 Fig 2: Autoimmune hepatitis. Portal inflammation and interface hepatitis. The portal inflammation is lymphocytic with prominent plasma cells (inset), and associated with interface hepatitis, but the portal vein and bile duct (arrow) do not show features of rejection. De novo autoimmune hepatitis in a patient 9 years post transplant for acute seronegative hepatitis

Fig 4 :

 4 Fig 4: Biliary gestalt in a patient with non-anastomotic bile duct stricture. 4a: portal features of biliary obstruction, affecting part of the portal tract circumference (right side of picture).The portal area is expanded by ductular reaction with increased small ductular profiles in

Fig 5 :Fig 6 .

 56 Fig 5: chronic rejection. 5a: the portal inflammation is mild but targets the bile duct 5b: bile with senescent changes in the epithelium (arrow); these are most readily appreciated on a PASD stain. 5c: CK7 stain is useful in identifying ductopaenic portal tracts.

Page 14 of 23 Published 3 Figure 1 Page 15 of 23 Published

 233123 Figure 1Page 15 of[START_REF] Demetris | Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection[END_REF]

Figure 2 Page 16 of 23 Published

 223 Figure 2

Figure 3 .

 3 Figure 3. Page 17 of 23

  Fig 4a

  Fig 4bPage 19 of[START_REF] Demetris | Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection[END_REF]

Figure 5a Page 20 of 23 Published

 5a23 Figure 5a

  Fig 5bPage 21 of[START_REF] Demetris | Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection[END_REF]

Fig 5c Page 22 of 23 Published

 23 Fig 5c

  Fig 6.

Table 1 .

 1

	Histopathological features	autoimmune hepatitis	acute rejection	chronic rejection	chronic viral hepatitis B&C	Primary biliary cirrhosis	PSC/biliary stricture1.
	1 distribution, severity, and composition of portal inflammation	usually diffuse; predominantly mononuclear of varying intensity: often prominent plasma cell component	usually diffuse: variable intensity: mixed 'rejection-type' infiltrate	Patchy: usually minimal or mild lymphoplasmacytic	Patchy: variable intensity: predominantly mononuclear: nodular aggregates	Noticeably patchy and variable intensity: predominantly mononuclear: nodular aggregates and granulomas	Usually patchy to diffuse depending on stage: mild neutrophilic, eosinophilic, or occasionally mononuclear predominant
	2. Presence and type of interface activity	Prominent and defining feature is usually necroinflammatory-type: often plasma cell-rich	Focally present and mild necroinflammatory type	minimal to absent	variable: usually not prominent: necroinflammatory-and ductular-type	important features later in disease development: ductular and necro-inflammatory-type with copper deposition	prominent and defining feature: ductular-type with portal and periportal oedema
	3. Bile duct inflammation and damage	variable: if present, involves a minority of bile ducts	present and usually involves a majority of bile ducts	focal ongoing lymphocytic bile duct damage: inflammation wanes with duct loss	variable: if present, involves a minority of bile ducts	granulomatous or focally severe lymphocytic cholangitis is diagnostic in proper setting	periductal lamellar oedema: 'fibrous cholangitis': acute cholangitis: multiple intra-portal ductal profiles
	4. biliary epithelial senescence changes and small bile duct loss	absent or involves only a minority of ducts/portal tracts, but may be focally severe	absent or involves only a minority of ducts	senescence/atrophy/ atypia involve a majority of remaining ducts	absent or involves only a minority of ducts	small bile duct loss associated with ductular reaction	small bile duct loss associated with ductular reaction
	5. perivenular mononuclear inflammation and/or hepatocyte dropout	variable: can involve a majority of perivenular regions, similar to cell-rich rejection; may be plasma	variable, if defining feature should involve a inflammation of vein subendothelial majority of perivenular regions: may also show	usually present but variable	variable but generally regions mild: if present, involves a minority of perivenular	variable, but generally regions mild: if present, involves a minority of perivenular	absent
	6. lobular findings and necroinflammatory activity	variable severity: rosettes may be present and/or prominent	variable: if present, concentrated in perivenular regions	variable: if present, concentrated in perivenular regions	disarray variable: variable severity: necroinflammatory activity	mild disarray: features parenchymal granulomas: periportal copper deposition and cholestasis are late	disarray unusual: neutrophil clusters +/-cholestasis
	7. pattern of fibrosis during progression toward cirrhosis	usually macronodular: posthepatitic pattern	rare	uncommon, if present, usually a venocentric biliary pattern over time pattern, may evolve to	usually macronodular, micronodular hepatitic pattern: may be	biliary pattern	biliary pattern

Published on behalf of the British Division of the International Academy of Pathology Histopathology

Ramírez S, Pérez-Del-Pulgar S, Forns X. Virology and pathogenesis of hepatitis C virus recurrence. Liver Transpl. 2008 Oct;14 Suppl 2:S27-35.

Davies SE, Portmann BC, O'Grady JG, et al. Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. Hepatology. 1991 Jan;13(1):150-7