Additive Manufacturing-Based Supply Chain Configurations

*Silvana Gallinaro*

## **Abstract**

The topic of the chapter "Additive manufacturing-based supply chain configurations" is about the implementation of additive technologies in conventional supply chains and the possible supply chain configurations that can be generated. As a guideline in the field of supply chain management, this chapter suggests designing the AM-based supply chain configuration according to the supply chain strategy decided by the focal company of the supply chain. Two questions are not fully resolved in doctrine: the first concerns the measurement of the effects of additive manufacturing implementation in conventional companies and supply chains: the second, the relationship between the total average unit cost and the production volume of additive products. In agreement with some scholars, quantitative approach to the analysis of the impact of additive technologies in companies and supply chains is recommended, and the choice of a simulation method for ex-ante assessment of pros and cons of additive technologies over conventional ones is suggested. The goal of this chapter is twofold: to demonstrate that the superiority of additive manufacturing over conventional one cannot be discussed a priori, because it must be proven quantitatively on a case-by-case basis; to support the thesis according to which additive machines can achieve economies of scale.

**Keywords:** additive manufacturing, supply chain, simulation, economies of scale

## **1. Introduction**

Additive manufacturing (AM) does not take place by removing material from a solid, as in conventional or subtractive production, but by adding material, that is, by overlapping layers of materials (such as ceramics, metals, plastics, etc.) in sequence, starting from a 3D (virtual) design that contains all necessary information to create the product, generated using CAD design system or by scanning already an existing object in 3D (reverse engineering).

For additive machines to understand and process this information, a 3D design file must be converted into an STL file (Standard Triangulation Language). By means of a slicing program, information contained in STL file is converted into G-code (machine language). Each slice of an STL file represents a layer of the product to be made by overlapping and by means of an additive machine, using different methods of material extrusion and layer solidification [1, 2]. Time required by the additive manufacturing process depends on product size; specific additive technology adopted; raw material used and degree of precision required in product realization [2].

In fact, there are many additive technologies available to companies. Among these, 3D printing, often but erroneously, considered synonymous with additive manufacturing [3].

Additive raw materials can be in form of powders, filaments, liquids, or solids. Additive manufacturing processes also use food composites, such as pasta and chocolate, and metal-ceramics, but also materials that are difficult to process by means of traditional subtractive production processes, such as carbon alloys for high temperatures, as well as, more recently, "living" biological materials, such as cells and biological tissues [4, 5].

Additive machines require little manual labor and few operational skills, but they postulate new work skills (e.g., in design), rich in knowledge, generating new organizational roles and responsibilities. Likewise, they do not require production equipment, thus removing the costs of retooling machines. Additive production is, in fact, also called "fixture-less layered manufacturing" because it occurs simply by sending a digital 3D design file to an AM machine without equipping it with tools and molds.

By conveying the manufacturing process in a virtual environment, additive technologies enable digital transformation of manufacturing.

Implementation of additive technologies in companies and supply chains can produce destructive effects on traditional production paradigms and supply chain structures, foster disintermediation and production decentralization, making supply chains lighter or more concise [4–8]. As it will be better explained later on, effects produced by additive manufacturing implementation in conventional technology supply chains depend on the value chain strategy adopted by the focal company and, therefore, on the logistic tier affected by the chosen additive technology.

In the current stage of the evolutionary process they have reached, additive technologies have not yet completely replaced conventional ones. They often integrate, support, and coexist with conventional technologies in companies and supply chains [9], being used in productions with high product customization (e.g., in the healthcare sector) and/or characterized by low or uncontrollable demand (large spikes and dips in product demand) [10–12].

## **2. Implementation of additive manufacturing technologies in conventional companies**

## **2.1 Advantages of implementing additive technologies in conventional manufacturing-based companies**

As regards the implementation of additive manufacturing technologies, it is necessary to distinguish between two different and distinct levels of analysis: company and supply chain.

Implementation of additive technologies in business processes is the result of a strategic decision of pure or tailored postponement [13] in a context of cost-effectiveness: additive technologies entrust product differentiation to design activities of value creation, optimizing organizational flexibility and, at the same time, making production of units or small series of items requested in a discontinuous and unpredictable way and/or with complex geometries, cheaper than in conventional production [14].

A postponement is an approach to value creation process. It takes place when one or more value creation activities are postponed at the very moment of receivement of customer order: the goal is product customization [15]. The company that postpones value creation activities waits to know what the customer really wants (form), where

#### *Additive Manufacturing-Based Supply Chain Configurations DOI: http://dx.doi.org/10.5772/intechopen.110174*

he wants it (place), and when he wants it (time), before starting the design and/or production and/or delivery of the product, so that this is exactly as requested and/or delivered according to the customer's place and time requests.

In this regard, some scholars describe various types of postponement strategies, each of which is according to the specific activity that is postponed. Then, they talk about form postponement strategy, if manufacturing and/or design is delayed, place and time postponement strategy, if delivery is delayed [16–18].

Order penetration point (OPP)—also referred to as customer order decoupling point (CODP)—is defined as the stage in value chain where customer order enters and product differentiation takes place. The further upstream in value chain the customer's order is placed, the greater the degree of postponement adopted by the company, therefore the greater the differentiation and degree of customization of the product. Pure or tailored product customization is achieved if product design is postponed, allowing the customer to intervene in this phase of value creation.

Postponement strategies make company—but also, as it will be said later on, supply chains—efficient in dealing with demand uncertainty [17–19]: in fact, more precise information about form, time, and place of delivery of product, and also about the amount to be made, can be obtained during postponement period, making company able to satisfy demand in form/time and/or place required, therefore agile and flexible.

Therefore, it can be said that, in contexts of environmental uncertainty, efficient companies (and efficient value chains) are those oriented toward postponement strategies, and that efficiency goes through flexibility.

So, the degree of postponement adopted by a company is a function of the level of external uncertainty to be faced and managed.

In conclusion, postponement is the "keystone" of mass customization and a tool for managing environmental uncertainty [19, 20]. Company that adopts postponement in value creation process, demonstrates that it has strategic capabilities for achieving product differentiation in one of the stages of value creation, downstream or upstream of manufacturing [21].

Implementation of AM technologies in a company allows to entrust product differentiation to value design activities and satisfies organizational flexibility needs of all sorts. These value activities enable the company to pure customization, moving CODP up to the product concept stage.

About that, Olhger [22] and Verboeket and Krikke [23] specify that, when AM replaces conventional production in a value creation process, OPP tends to move upstream, in parallel generating the shift of make-to-stock (MtS) production logic toward make-to-order (MtO) or engineer-to-order (EtO) ones. In other words, additive manufacturing makes internalization of customers in value creation process concrete, which becomes "value co-creation with customer process" as a result [14].

Generally, the full participation of the customer in the value creation process takes place by means of co-design platforms. So, additive technologies reveal the potential for pure customization if co-design platforms are active [14, 20].

Numerous scholars have addressed the issue of the pros and cons of additive manufacturing compared to conventional one. To the aim of implementing an additive manufacturing technology in a company or in a supply chain, and as an indication of a decisional method, pros and cons of a hypothetic additive plant compared to actual conventional one have to be matched with each other in a trade-off evaluation.

The topic of implementation of additive technologies in a company will be dealt with in this paragraph, reserving the following one to that of the implementation of additive technologies in conventional supply chains.

Additive manufacturing allows the company to carry out product differentiation and customization "without extra costs" [24, 25] or makes customization "without penalty" possible [1] because—as it is known—it does not require product-unique equipment and molds, and since the digital redesign of products is not expensive. In additive manufacturing, the degrees of freedom in product creation are exponentially higher than those allowed by conventional production because manufacturing is not limited by the possibilities allowed by subtractive technologies. In other words, additive manufacturing generates products characterized by large freedom and high complexity of geometric features, which are difficult to achieve with conventional technologies.

Ready-made products come out of additive machines, without the need for component assembly, and increasing reliability of products with complex geometries which could be compromised by assembly of components in conventional production. Therefore and ceteris paribus, by avoiding assembly costs, additive manufacturing cuts production costs.

Additive machines can achieve time savings in the creation of pure or tailored customized products: product lead times do not include machine set-up times and component assembly times—despite the generally longer production times of additive machines compared to conventional ones.

Additive machines can also accelerate the time to market of radical and incremental product innovation, thanks to lowering production times of early products, with which to rapidly test and validate product ideas in target markets [20]. Furthermore, additive manufacturing is combined with virtual product prototyping by which to carry out virtual simulation tests, thus eliminating the phase of physical tests which requires time to create prototypes.

Therefore, digitization of manufacturing makes it lean and agile, allowing efficient and fast production on demand of single units or small batches of pure or tailored customized products: that is, additive manufacturing achieves economies of variety.

Additive manufacturing evokes a context of just-in-time production, also generating:

In short, additive production verifies a lower dependence on manual work and a greater dependence on skilled work with a high knowledge content, for which it can be said that additive production acts in favor of manufacturing reshoring [26–28].

To all those advantages of additive manufacturing compared to conventional one analyzed so far, we must add the ability of processing materials that cannot be processed with conventional technologies (such as carbon alloys for high temperatures, metal-ceramic, and food composites) or anomalous nature for conventional manufacturing (such as organic cells and tissues); longer life cycle of additive product compared to conventional one, thanks to simpler, cheaper, and faster design upgrades that can slow or revitalize the decline of the product in the market.

Lightened additive components—due to the possibility of being made hollow reduce fuel consumption of additive products (e.g., in the aerospace and aeronautical industries). In this sense, additive manufacturing has been labeled as functional for environmental sustainability.

From the above, it follows that additive manufacturing can generate greater value for the customer and, therefore, a greater willingness to pay a higher price to obtain highly customized products, whose unit production costs and delivery times are lower than those conventional manufacturing would be able to achieve [29].

## **2.2 Disadvantages of implementing additive manufacturing in conventional manufacturing-based companies**

As anticipated, alongside the advantages (pros) of additive manufacturing over conventional manufacturing, there are numerous disadvantages (cons) that must be measured and compared with the aforementioned advantages in trade-off analysis.

First of all, absence of economies of scale of additive machines. In fact, a widespread thesis among scholars is that additive machines would not allow economies of scale because the average unit additive product cost tends to be invariable as production amounts vary.

In our opinion, the reasoning about economies of scale denied by additive technologies is more complex. Total variable costs of additive manufacturing tend to be higher than total fixed ones, but this does not justify the constant average total unit cost of the additive products as production increases. What is undoubted is that additive technologies make it possible to achieve the minimum efficient scale in correspondence with a very low number of units produced. It is known that the minimum efficient scale is high when the level of fixed capital required for production is high. The higher the minimum efficient scale, the smaller the number of firms on the market. This is valid for conventional technology machines, whose minimum efficient scale is reached in correspondence with a large number of products. All this confirms that additive technologies make the level of capital to be invested to do business low. As a result, additive technologies are able to expand the number of smaller efficient production structures present in a territorial context, because the level of fixed capital required to do business tends to be smaller than that required by conventional production.

Therefore, unlike conventional machines, additive ones are efficient in highly customized unit productions or in low-volume ones, and the convenience of using them in manufacturing processes decreases as demand grows up. Persistent limits of additive machines—such as low throughput times and poor quality standardization of products—are the causes that prevent digital manufacturing from achieving economies of scale. Nothing prevents these limits from being exceeded in the near future.

Another disadvantage of additive manufacturing is the non-standardizability quality of additive products and spare parts in terms of strength, durability, consistency, safety, accuracy, and consequent low certainty of reproducibility of products and spare parts [8], which often generates post-processing costs of products and components (e.g., costs of polishing the surface of products) [30]. Lack of shared quality standards makes quality assurance and product warranty difficult.

Disadvantages of additive manufacturing match with advantages in a trade-off evaluation are also difficulties in finding and the high cost of additive materials;

difficulties of their technical integration [26, 31], as well as high prices of additive machines to be used in production cycles.

In additive manufacturing, the hourly cost of subordinate labor tends to be higher than in the conventional one because the former has a higher skill content [31].

Moreover, there is a non-secondary problem of lack of clarity of intellectual and industrial property of additive product designs, which can represent a bottleneck for the implementation of additive technologies.

At last, the high energy consumption of additive manufacturing and material preparation processes must be considered, as well as the size limits of additive components or end-use products caused by the size limits of AM machines [32].

**Table 1** shows the summary table of the pros and cons (advantages and disadvantages) of additive manufacturing compared to conventional one.

#### **Table 1.**

*Advantages and disadvantages of implementing AM technologies in conventional companies.*

## **3. Implementation of additive technologies in conventional supply chains: AM-based supply chain configurations**

## **3.1 Centralized additive configurations**

If shared across multiple organizations, value creation occurs in a supply chain, which is the value system that integrates intra-organizational value chains.

The implementation of additive manufacturing technologies in conventional technology supply chains generates different AM-based supply chain configurations, depending on the supply chain strategy pursued by the focal company (manufacturer). Therefore, as a guideline in the field of supply chain management, it is suggested to design the AM-based supply chain setup according to the supply chain strategy chosen by the focal company. In other words, the AM-based supply chain setup should be designed to implement the chosen supply chain.

The adoption of additive manufacturing in conventional supply chains, in fact, implements not only and not always product customization strategies, but always occurs at the individual company level, but often cost optimization supply chain strategies.

The supply chain strategy determines the level of the supply chain affected by the implementation of additive technologies: the lower the level of the supply chain affected by the implementation of additive technology, the greater the customization of the product guaranteed to the customer, the faster the delivery time, but the lower the cost savings. Thus, it can be argued that supply chain strategies determine its basic configurations, which are as follows:

AM machines centrally located in a supply chain typically eliminate inventory of components and spare parts that are infrequently or occasionally required by internal and external customers (low-demand products or products with large peaks and drops in demand) and whose response time to demand is not critical [12, 31]. In other words, the central warehouse of components or spare parts of this type is replaced by centralized production capacity and inventory of materials and 3D files for additive manufacturing [28]. The costs of storing raw materials and files for additive manufacturing are lower than those of components with large peaks and dips in demand, so the overall inventory packing and storage costs of centralized AM-based supply chains are likely to be lower than those of conventional supply chains.

#### **Table 2.**

*Centralized additive configurations.*

The presence of a centralized additive production capacity reduces the risk of stock-out of safety components and spare parts and increases the possibility of their customization.

On the other hand, costs for fixed investments and the dependence of the supply chain on suppliers of raw materials are growing. The costs of additive machines are high as well as energy consumption, while the impact of additive technologies on the total transport costs of the supply chain must be measured and evaluated according to the specific contextual situation.

Below is a synthesis of the analysis so far (**Table 2**).

#### **3.2 Decentralized additive configurations**

Implementation of additive technologies in production facilities close to places where end-use products are used, that is, close to the external or internal customers, draw AM-based decentralized supply chains and support product customization strategies. Bypassing component suppliers and end-use product distributors, AM-based decentralized configurations reduce the number of tiers in the supply chain Therefore, they embody the disintermediation of the supply chains, generating reductions in logistics costs, however in the face of the multiplication of local investments in the supply chain which must therefore be justified by local demands to be met in a specific way and in a short time.

In a nutshell, investments in decentralized additive machines increase the fixed production costs of the supply chain and lower the costs that depend on the logistic levels (e.g., transport costs, warehouse costs).

The lower total stock-keeping costs of AM-based decentralized supply chains, compared to traditional ones, are determined despite the greater presence of inventories of raw materials, often in the form of powders or liquids, instead of inventories of components and sub-assemblies, which are bulkier and more expensive than materials. It follows that whether on the one hand, it is possible to observe a minimum dependence of the decentralized supply chains on the suppliers of components, on the other hand, a greater dependence of the same supply chains on the suppliers of additive raw materials is generated.

#### *Additive Manufacturing-Based Supply Chain Configurations DOI: http://dx.doi.org/10.5772/intechopen.110174*

Decentralized supply chains based on additive technologies tend to guarantee shorter delivery times of products compared to centralized ones, as a consequence not only of the reduction of logistic tiers, but also of the proximity of AM machines to end users of products or spare parts. Furthermore, it should be considered that, in decentralized AM-based supply, the decrease in transport costs is determined not only by the disintermediation of the supply chains (the decrease in the number of tiers) and by the proximity of the AM machines to the end customers, but also by the object itself of the transport (raw material rather than components and end-use products.)

As a result, the risks of transport damage to components and products are reduced.

*Coeteris paribus*, by reducing transport and realizing manufacturing in situ, disintermediation of supply chains guarantees lower consumption of fossil fuels and lower carbon dioxide emissions.

Although additive machines consume electricity to a large extent, the total balance in terms of environmental sustainability of AM-based supply chains is proven as tendentially positive by numerous studies—also thanks to the lower weight of vehicles (aircrafts and cars) that have hollow and light components.

Decentralized AM-based supply chains serving the plurality of local markets have also been defined as mini-factory networks [14, 35]. Mini-factories are local production facilities close to the end customers. Additive manufacturing technologies, with which each mini-factory is equipped, reduce customization costs. In addition to production activities, each mini-factory carries out sales and customer assistance, often also digital product design activities. Networks of mini-factories are enterprises of pure and tailored customization [13]. Proximity of the mini-factory to the customer or a local market allows the focal company della supply chain to access customer knowledge which is highly strategic for the purpose of creating customized or highly customer-specific products, but also for innovative processes.

By favoring short delivery times and low costs of production of personalized or unique products, mini-factories embody lean agile factory principles.

As aforementioned, the decision to invest in distributed AM machines—which are expensive at the current stage of development that additive technologies have reached—must be economically justified by the existence of local demands, even if low and fluctuating, which must be satisfied in a personalized way and in a short time, as in the case of spare parts requested in aeronautics or biomedical sectors (heart valves, prostheses, dental implants) [9, 26] or be motivated by demands from places difficult to reach by conventional means of transportation [9, 24, 36]: so, additive manufacturing is certainly the enabling technology of space economy.

The decentralized implementation of digital additive manufacturing technologies in a supply chain implies the replacement (total or partial) of warehouses of components and sub-assembly systems, spare parts, and end-use products, not only with warehouses of raw materials, but also with "virtual warehouses" of digital design files. Raw materials and design files travel faster and more efficiently than physical materials, components and products, along supply chain tiers—the latter reduced in number—and no specific local knowledge is required for on-site production: designs submitted to decentralized production structures through IT infrastructures, incorporate necessary knowledge for product realization. Therefore, as a precondition, implementation of additive technologies in decentralized supply chains requires huge investments in ICT infrastructure, capable of supporting the production and circulation of knowledge incorporated in designs in supply chains themselves. In fact, the lack or weakness of ICT infrastructure of a supply chain is to be considered bottleneck, which hinders the implementation of additive technologies [23].

#### **Table 3.**

*Decentralized additive configurations.*

Additive manufacturing also requires customer digital design knowledge and skills: to be made on demand, that is, according to customer-specific requests, additive products must be designed on the basis of co-design platforms that carry out co-creation of value with customer.

Therefore, a first summary can be drawn from the analysis carried out so far: additive technologies centrally located in a supply chain generally reduce the costs of central component or spare parts warehouses whose response times to demand are not critical, replacing them with fixed investments in machines additive and with warehouses of raw materials and 3D files for additive manufacturing; decentralized additive technologies lower the number of supply chain levels, and therefore all those costs that depend on that number (e.g., transport costs and warehouse costs of the entire supply chain). It can be said that the lower the level of supply chain affected by additive technology implementation, the greater product customization guaranteed to the customer, but the lower cost savings ensured.

**Table 3** shows the summary of the pros and cons of decentralized AM-based supply chains versus conventional ones, based on the analysis so far.

#### **3.3 Hub additive configurations**

In between the two aforementioned structural configurations are hub configurations.

In logistics, the concept of supply hub is well-established in conventional manufacturing [17]. From the point of view of conventional technology supply chains, the concept of hub refers to supply of components or sub-assemblies to local production plants. Hub functions as a buffer of components for the manufacturing plants in a just-in-time context [6, 17, 37]. In fact, the purpose of supply hub is to satisfy downstream demand in a timely and regular manner, and this occurs both thanks to its proximity to the main plant and by assembling parts purchased from upstream suppliers into sub-assemblies

to send downstream [38]. Therefore, the use of a supply hub reduces supply risks and investments in equipment and labor of the entire supply chain compared with structural solutions that involve the direct supply of components from external suppliers. As a result, the complexity of operations at the supply chain level is reduced.

In a nutshell, in multilevel supply chains, a consolidation hub enables smooth and reliable supply of components or sub-assemblies to manufacturing plants and lowering structural costs. All this fosters transition of manufacturing in a just-in-time (JIT) context [37].

Supply hub can belong to one supply chain or serves multiple ones. In the latter case, higher volumes of off-the-shelf components purchased and high production volumes of sub-assemblies supplied to local locations, greatly reduce end-use product unit costs.

In an additive manufacturing context, hub configuration refers to an intermediate supply chain structure between fully centralized configuration and fully distributed one. Hub's AM machines are located in a logistic tier between the main plant and local manufacturing plants. They are oriented toward the realization of various strategic objectives, some of which are pursued by AM-based centralized supply chains, others by decentralized ones.

Therefore hub configuration has some of the main advantages of a centralized manufacturing supply chain configuration (e.g., it requires fewer machines and less manpower to meet total demand than a decentralized supply chain configuration, and thus guarantees better utilization of production capacity), but also some advantages of decentralized configuration compared to the centralized one (lower transport costs and faster, cheaper and smoothly supplies) [2].

## **4. The decision-making process for the implementation of additive technologies in conventional structures: method guidelines**

Distributed or decentralized AM-based supply chains are likely to be more concise than traditional ones—and also than centralized AM-based ones: they cut off component suppliers and distributors, but become more dependent on raw material suppliers. It is known that raw materials for additive manufacturing are expensive, but generate lower inventory costs than the components and end-use products ones. Raw material costs are variable production costs; instead, component, spare part, and product costs include fixed costs. Because decentralized AM-based supply chains have fewer layers than conventional ones, and centralized AM-based ones, the transportation costs of the former are likely to be lower than the latter.

All things being equal, in AM-based supply chains variable production costs are higher than in conventional ones, due to material and labor costs, assessed by Li et al. [31] as higher than those incurred by a supply chain based on subtractive technology. In fact, as anticipated in the previous pages, additive technologies generate a change in the required work roles: less manual work, less knowledge related to machines, but new design and operational roles, generally more expensive than the manual ones of subtractive production.

As regards fixed costs of production, Li et al [31] point out that supply chains based on additive technologies may not be cost-effective compared to those based on conventional technologies: costs of AM machines are still high today and multiply in the case of distributed production.

In our opinion, it should also be considered that additive machines undergo rapid obsolescence due to the acceleration of technological innovation in this field of application, so the incidence of fixed costs on additive product unit cost tends to be more high a fortiori.

Based on what has been described in the previous paragraphs, it can be argued that, although additive manufacturing has many advantages over the conventional one, this is not enough to support the superiority of AM-based companies or supply chains over conventional ones in any business situation and environmental context. In fact, on the basis of the analysis so far, it can be noticed that there are negative quantitative interactions between pros and cons of additive manufacturing, that make AM-based company or supply chain not always feasible or appropriate.

All this for saying that the advantages and disadvantages of implementing additive technologies in conventional companies or supply chains have to be measured ex-ante and assessed in trade-off to decide about additive manufacturing choice.

As guidelines of company or supply chain management, in order to design a decision-making process for the implementation of additive technologies in organizational structures based on conventional technologies, a number of decisions are suggested: firstly, which method of simulation of company or supply chain based on additive manufacturing to adopt, then which specific additive technology to implement. With regards to supply chains, the focal company also has to decide at which level of the supply chain to implement additive manufacturing, that is, which AM-based supply chain configuration to adopt. In the previous pages, we have argued that the logistical level of the conventional supply chain affected by the implementation of additive technologies depends on the supply chain strategy decided by the focal company, in other words, the configuration of the AM-based supply chain that comes about depends on the chosen supply chain strategy.

The decision-making process for the implementation of additive technologies in conventional companies or supply chains always requires the choice of a simulation method on the basis of which to build AM-based company or supply chain models from which to derive cost functions to be compared with those of the status quo. The comparison between the aforementioned cost functions substantiates the ex-ante and trade-off assessment of the advantages and disadvantages of the additive option. Furthermore, the decision-making process described up to now must be repeated for all the different and possible additive technologies that can be adopted, because the effects that each of them can produce on conventional companies or supply chains can be so different as to imply different decisions.

In another study of ours [21], we specified that only a small number of scholars deal with the evaluation of the pros and cons of the implementation of AM from a quantitative point of view, thus filling a gap present in the studies on additive technologies. Among them are Li et al. [31], who suggest that the choice of one supply chain configuration can only be taken by resorting to mathematical simulation models of supply chains from which to derive functions of quantitative variables to be compared, mainly cost functions.

## **5. Conclusions**

## **5.1 Recent advances**

• Centralized implementation of additive technologies in a conventional supply chain lightens and simplifies its structure without changing the number of logistic tiers (component supplier-manufacturer-distributor-customer), because

### *Additive Manufacturing-Based Supply Chain Configurations DOI: http://dx.doi.org/10.5772/intechopen.110174*

it reduces the intervention of suppliers of components and spare parts required fluctuating and in small quantities by the manufacturer. The result is reduced inventory costs, as centralized additive machines reduce the risk of stock-out of discontinuously requested, low-quantity spare parts and components. In a centralized AM-based supply chain, inventory costs are therefore likely to be lower than in a conventional one, although they are partly replaced by AM machine costs. Product customization is allowed not only by the assembly of modules but also by the potential of additive machines. The production context is that of modularity. Balance between the advantages and disadvantages of a centralized additive choice has to be measured to decide on its implementation.

Referring to Verboeket and Krikke [23], we specify that the replacement of the central warehouse with centralized additive machines can represent a first step in the process of implementing additive technologies in supply chains and that, over time, a configuration centralized AM can evolve into a distributed one.

## **5.2 Future directions**

The development of additive manufacturing technologies is moving toward the maturity stage, therefore, a rapid improvement in the technical characteristics of additive machines on which economies of scale depend, such as throughput time and standardization of production, is likely.

As a result, an increasingly vast adoption of additive machines in companies and supply chains is foreseeable, accompanied by a progressive decrease in prices.

Nowadays the consumer increasingly wants to participate in the business process of value creation, postulating personalization, short delivery times, and, at the same time, convenient prices. Additive technologies allow for the most suitable product solution for this market context.

#### *Advances in 3D Printing*

The near future is a complete outsourcing of the production process to the consumer. So, distributed manufacturing can be considered an intermediate stage in the evolutionary process of manufacturing toward pure customized production made directly by the consumer, using design files downloaded from open design platforms, and by home printers or nearby 3D printing shops [39].

## **Author details**

Silvana Gallinaro Department of Economics and Statistics, University of Turin, Turin, Italy

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[20] Gallinaro S. Produzione. Torino: Giappichelli; 2015

[21] Gallinaro S. Catene di fornitura basate sulla produzione additiva. ImpresaProgetto – Electronic Journal of Management. 2021;**1**:1-28

[22] Olhager J. Strategic positioning of the order penetration point. International Journal of Production Economics. 2003;**85**(3):319-329

[23] Verboeket V, Krikke H. The disruptive impact of additive manufacturing on supply chains: A literature study, conceptual framework and research agenda. Computers in Industry. 2019;**111**:91-107

[24] Holmström J, Liotta G, Chaudhuri A. Sustainability outcomes through direct digital manufacturing-based operational practices: A design theory approach. Journal of Cleaner Production. 2017;**167**:951-961

[25] Weller C, Kleer R, Piller FT. Economic implications of 3D printing: Market structure models in light of additive manufacturing revisited. International Journal of Production Economics. 2015;**164**:43-56

[26] Berman B. 3-D printing: The New Industrial Revolution. Business Horizons. 2012;**55**(2):155-162

[27] Fratocchi L, Ancarani A, Barbieri P, Di Mauro C, Nassimbeni G, Sartor M, et al. Motivations of manufacturing reshoring: An interpretative framework. International Journal of Physical Distribution and Logistics Management. 2016;**46**(2):98-127

[28] Fratocchi L. Is 3D printing an enabling technology for manufacturing reshoring? In: Vecchi A, editor. Reshoring of Manufacturing: Drivers, Opportunities, and Challenges. Berlino: Springer; 2017:99-124

[29] Franke N, Piller FT. Value creation by toolkits for user innovation and design. The case of the watch market. The Journal of Product Innovation Management. 2004;**21**(6):401-415

[30] Chekurov S, Metsä-Kortelainenb S, Salmia M, Rodac I, Jussila A. The perceived value of additively manufactured digital spare parts in industry: An empirical investigation. International Journal of Production Economics. 2018;**205**:87-97

[31] Li Y, Jia G, Cheng Y, Hud Y. Additive manufacturing technology in spare parts supply chain: A comparative study. International Journal of Production Research. 2017;**55**(5):1498-1515

[32] Gebhardt A. Rapid Prototyping. Cincinnati: Hanser Gardner Publications Inc.; 2003

[33] Emelogu A, Marufuzzaman M, Thompson SM, Shamsaei N, Bian L. Additive manufacturing of biomedical implants: A feasibility assessment via supply-chain cost analysis. Additive Manufacturing. 2016;**11**:97-113

*Additive Manufacturing-Based Supply Chain Configurations DOI: http://dx.doi.org/10.5772/intechopen.110174*

[34] Holmström J, Partanen J, Tuomi J, Walter M. Rapid manufacturing in the spare parts supply chain: Alternative approaches to capacity deployment. Journal of Manufacturing Technology Management. 2010;**21**(6):687-697

[35] Reichwald R, Piller FT, Jager S, Zanner S. Economic evaluation of miniplants for mass customization. In: Piller FT, editor. The Customer Centric Enterprise. Advances in Mass Customization and Personalization. Berlin: Springer; 2003:51-69

[36] Ryan MJ, Eyers DR, Potter AT, Purvis L, Gosling J. 3D printing the future: Scenarios for supply chains reviewed. International Journal of Physical Distribution and Logistics Management. 2017;**47**(10):992-1014

[37] Naylor JB, Naim MM, Berry D. Leagility: Integrating the lean and agile manufacturing paradigm in the total supply chain. International Journal of Production Economics. 1999;**62**(1-2):107-118

[38] Creazza A, Dallari F, Melacini M. Evaluating logistics network configurations for a global supply chain. Supply Chain Management: An International Journal. 2010:**15**(2):154-164

[39] Rayna T, Striukova L. From rapid prototyping to home fabrication: How 3D printing is changing business model innovation. Technological Forecasting and Social Change. 2016;**102**:214-224

## *Edited by Ashutosh Sharma*

*Advances in 3D Printing* presents an overview of various types of advances in 3D printing. It discusses current research trends, problems, and applications of 3D printing processes and materials. The book also discusses advances in bioprinting, tissue generation, radiotherapy, and safety issues in health care. It showcases applications of 3D printing in digital design, body part surrogates, rheological models, airway stents, 3D-printed cermets, and more. It also discusses advances in biomimetic nanocomposite materials, intellectual property concerns, and safety issues in 3D printing technology.

Published in London, UK © 2023 IntechOpen © morgan23 / iStock

Advances in 3D Printing

Advances in 3D Printing

*Edited by Ashutosh Sharma*


**4. Foot-and-mouth disease control programme in India**

Due to heavy morbidity in susceptible livestock population and negative social and economic impact of the Foot-and-mouth disease, Indian government has started progressive control pathway for FMD according to the protocols given by

Office Internationale-des-Epizooties (OIE)/Food and agriculture organisation (FAO) to minimise losses [17]. Progress for covering all the districts under the umbrella of FMDCP is presented in the **Tables 2** and **3** [18, 19].

The nine major activities that are being undertaken in the FMDCP are:

In order to check whether the FMD vaccine, used in the FMDCP (at six monthly intervals), elicited protective immune response in the vaccinated large ruminants, randomly collected serum samples are being tested (**Table 2**). Paired serum samples are collected (the first serum before vaccination and the second after 21–30 days post vaccination from the same animal). These serum samples are collected from randomly selected 10 villages in each district from 10 cattle and 10 buffaloes after every vaccination. That means there are two rounds of vaccination in the year and 200 samples will be collected from each category of animals, cattle and buffaloes. So, to conclude from every district around 400 serum samples will be tested to evaluate whether the large ruminants elicited enough neutralising antibody response and protective enough to thwart future FMD outbreaks. A table indicating various institutions that are related to FMD activities is presented (**Table 3**). There are around 733 districts in India and assuming that 400 samples are generated after the end of a year (a total number of estimated serum samples screened to check for neutralising antibody response against FMDV in a year: 733 × 400 = 2,93,200). From the year 2017–2018, all the districts were covered under FMDCP, so, data for two subsequent years 2017–2018 and 2018–2019 must be made available (for a total of 5,86,400 number of serum samples) to arrive to the logical conclusions regarding

**99**

*Foot-and-Mouth Disease in India: Past, Present and Future Outlook - A Review*

International Center on FMD, Arugul 2017 BSL3 + Ag facility

**Institutions Year Achievements and activities**

1943 Vaccination, Virus serotyping

1968 For FMD virus serotyping, Central FMD

throughout the country

India

and BSL3

tropism)

1971 For epidemiological studies on FMD, Facilities

2001 At Mukteshwar and a network of laboratories

2015 FAO reference center for FMD in South Asia, Member of a global FMD research alliance

1999 Vaccine manufacturing technology obtained from M/s. Wellcome foundation, United Kingdom, Has the capacity of producing 360 million trivalent doses of FMD vaccine and also exports the vaccine (Raksha Ovac, Raksha Triovac, Raksha Biovac), 80% and more vaccine for FMDCP in

2010 Quality control of FMD vaccine, Facilities of BSL2

2000 Epidemiology, Prediction, prevention and control of FMD threats, Weather based animal disease forecasting (National Animal Disease Referral Expert System- http://nivedi.res.in/Nadres\_v2/),

1988 BSL3 facility to produce animal vaccines, Supply vaccines to FAO and export vaccines (FUTVAC)

vaccines (Bio-FMD oil), Export

2010 Center for Agricultural Bioinformatics (FMD

Use of artificial intelligence

laboratory at Mukteshwar and three regional centers at Hisar, Hyderabad and Kolkata

and manpower for extensive FMD surveillance

located at various places in India, Diagnosis of FMD, Vaccine matching studies, Virus typing, Serological surveillance, Epidemiology

appropriate level of protective antibody response in the vaccinated animals. Early workers also commented on the weakness of the national eradication schemes in India [20]. Testing data of cattle and buffaloes from randomly selected villages as mentioned in the beginning are unavailable. Currently India is in the Stage 3 of

*Institutes/companies that are involved in FMD research/manufacturing of FMD vaccines in India (the year*

Biovet, Malur (http://biovet.in/) 2007 BSL3+ Ag production facility, Production of FMD

Intervet India Pvt. Ltd., Pune 2004 Production of FMD vaccines, Export

The annual report of the Directorate on FMD (2017–2018) elaborated in detail on the progress of bi-annual vaccinations in different states of the country. A total of 10,02,437 serum samples were tested to assess the level of immunity. Many of the Indian states indicated development of low level of herd immunity and hence the report emphasised on regular vaccinations in the states that have low herd

FAO's progressive control pathway (PCP) for control of FMD [21].

*DOI: http://dx.doi.org/10.5772/intechopen.93348*

Indian Veterinary Research Institute,

All India Co-ordinated Research Project,

All India Co-ordinated Research Project,

Project Directorate on Foot-and-mouth

Directorate of Foot-and-mouth disease, Mukteshwar (http://www.pdfmd.ernet.in/)

Indian Immunologicals Limited, Hyderabad (http://www.indimmune.com/businessunit/animal-health/vaccines/livestockvaccines), Established by National Dairy Development Board in 1982 (https:// www.nddb.coop/services/rdbiotech/

Chaudhary Charan Singh National Institute

Brilliant Biopharma Pvt. Ltd., Hyderabad (https://brilliantbiopharma.com/products/ foot-and-mouth-disease-vaccine-

Indian Agricultural Statistics Research

*represented establishment/start of functioning).*

Mukteshwar

Mukteshwar

Mukteshwar

immunology)

of Animal Health, Baghpat

20ml30ml100-ml/)

Institute, New Delhi

**Table 3.**

National Institute of Veterinary Epidemiology and Disease Informatics, Bangalore (https://nivedi.res.in/about-us) formerly Project Directorate on Animal Disease Monitoring and Surveillance

disease, Mukteshwar

**Table 2.** *Districts covered in FMD control programme.*

#### *Foot-and-Mouth Disease in India: Past, Present and Future Outlook - A Review DOI: http://dx.doi.org/10.5772/intechopen.93348*

**Table 3.**

*Some RNA Viruses*

Office Internationale-des-Epizooties (OIE)/Food and agriculture organisation (FAO) to minimise losses [17]. Progress for covering all the districts under the

The nine major activities that are being undertaken in the FMDCP are:

4.Sero-surveillance and monitoring of animal population on random basis.

7.Quality assessment of randomly collected samples from vaccine preparations.

In order to check whether the FMD vaccine, used in the FMDCP (at six monthly intervals), elicited protective immune response in the vaccinated large ruminants, randomly collected serum samples are being tested (**Table 2**). Paired serum samples are collected (the first serum before vaccination and the second after 21–30 days post vaccination from the same animal). These serum samples are collected from randomly selected 10 villages in each district from 10 cattle and 10 buffaloes after every vaccination. That means there are two rounds of vaccination in the year and 200 samples will be collected from each category of animals, cattle and buffaloes. So, to conclude from every district around 400 serum samples will be tested to evaluate whether the large ruminants elicited enough neutralising antibody response and protective enough to thwart future FMD outbreaks. A table indicating various institutions that are related to FMD activities is presented (**Table 3**). There are around 733 districts in India and assuming that 400 samples are generated after the end of a year (a total number of estimated serum samples screened to check for neutralising antibody response against FMDV in a year: 733 × 400 = 2,93,200). From the year 2017–2018, all the districts were covered under FMDCP, so, data for two subsequent years 2017–2018 and 2018–2019 must be made available (for a total of 5,86,400 number of serum samples) to arrive to the logical conclusions regarding

9.Recording/regulation of animal movement from unvaccinated areas.

**Year Districts included Species covered** 2003–2004 54 Cattle, buffalo

2019–2024 733 Cattle, buffalo, sheep, goats, pigs

2010–2011 Extended to 167 districts

2015–2016 415 2017–2018 All

*Districts covered in FMD control programme.*

umbrella of FMDCP is presented in the **Tables 2** and **3** [18, 19].

1.To vaccinate cattle and buffaloes at six monthly intervals.

2.Publicity and mass awareness campaigns.

6.Procurement of cold cabinets and vaccine.

8.Typing of FMDV in case of outbreaks.

3.Identification of target animals.

5.Mass vaccination.

**98**

**Table 2.**

*Institutes/companies that are involved in FMD research/manufacturing of FMD vaccines in India (the year represented establishment/start of functioning).*

appropriate level of protective antibody response in the vaccinated animals. Early workers also commented on the weakness of the national eradication schemes in India [20]. Testing data of cattle and buffaloes from randomly selected villages as mentioned in the beginning are unavailable. Currently India is in the Stage 3 of FAO's progressive control pathway (PCP) for control of FMD [21].

The annual report of the Directorate on FMD (2017–2018) elaborated in detail on the progress of bi-annual vaccinations in different states of the country. A total of 10,02,437 serum samples were tested to assess the level of immunity. Many of the Indian states indicated development of low level of herd immunity and hence the report emphasised on regular vaccinations in the states that have low herd

immunity. It was also stated that during the year 2017–2018, 21.2% cattle and buffalo and 18% sheep and goats tested positive in differentiation between infected and vaccinated animals [21]. These results when compared to the data available for the year 1995 (positivity in DIVA: 91% in cattle and buffalo and 74% in sheep and goats) indicated significant reduction in circulation of FMDV in livestock population. Thus, successful administration of FMDCP at official and ground levels and effective implementation of its mandate resulted in reduction of FMDV circulation in susceptible livestock population.

A total amount of ₹ 3.0653 billion was released by the central Government towards implementation of the control programme [12]. However, as per the data available, a total of 381.51 million livestock population (cattle and buffaloes) received the vaccine for protection against FMD in the country. Though, the state-wise data presented, for the vaccinations were not reflecting on percentages of cattle and buffalo vaccinated till date in that respective state and also for those animals yet to receive the vaccine.

### **5. Vaccines and vaccination for Foot-and-mouth disease in India**

In India, Directorate of FMD located at Mukteshwar in the state of Uttarakhand and its collaborating and regional centers across the country are involved in continuous survey, monitoring and collection of clinical samples for virus typing and isolation from susceptible livestock population during the disease outbreaks. After isolation of a particular type of FMDV, it is stored in the virus repository for further studies. Currently, the national FMDV repository has a total of 2,188 FMDV isolates (1,482, 325, 15 and 366 belonging to the types O, A, C and Asia1 respectively) [21]. Its tally of FMDV isolates is increasing each year. These FMDV isolates are used in genotyping studies by using latest molecular biological methods and other vaccine matching experiments.

A detail on FMD vaccines is available [22]. Vaccines are one of the very important tools in the control of FMD in India [23]. Previously, India used quadrivalent inactivated FMDV vaccines (containing FMDV antigens for types O, A, C and Asia1) to control the disease. The FMDV strains used in the production of inactivated FMDV antigens for trivalent vaccines (FUTVAC) are: for type O-IND/O/ R2/75, type A-IND/A/40/2000, type Asia1-IND/Asia1/63/72. The Directorate also monitors suitability of FMD antigens employed in the production of the FMD vaccines. After critical studies the directorate also recommends to the vaccine manufacturers in the country for any requirement of inclusion of suitable FMD strain of the particular FMDV type used in the vaccine production (which can confer better protection).

There were no reports in the country for the involvement of type C FMDV in the disease outbreaks hence FMDV antigen for type C was omitted from the vaccine. The absence of type C in the country may be due to implementation of vaccination programme in FMDCP or unknown reasons. At present, only trivalent inactivated FMDV vaccines are used in immunisation programmes of the livestock population in India.

India is continuously trying to increase its capability to produce sufficient doses of FMDV vaccines required in FMDCP to cover vaccination of small and large ruminants and pigs. Though, it is a big task to vaccinate susceptible livestock population but possible because of the good veterinary services [24]. Private vaccine manufacturers such as Intervet, Biovet and Brilliant Biopharma Pvt. Ltd. are ramping up the production of doses of FMD vaccines not only to cover its domestic needs but also for the export of vaccines to demanding countries. The Central Government of

**101**

**Figure 2.**

*Milk production in India (in million tonnes).*

*Foot-and-Mouth Disease in India: Past, Present and Future Outlook - A Review*

helped India to achieve first rank in milk production in the world.

antibiotic residue in the food animals and its products [27].

further spread [28, 29].

India extend financial help to the Indian states for procurement and administration of vaccines to the susceptible livestock population for prevention of FMD. Present vaccines are administered at six-monthly intervals to each animal to generate sufficient level of protective immunity. Some researchers suggest that increase in the antigenic mass of the vaccine may elicit higher level of protective antibodies in the vaccinated animals (which gives protection for longer duration). Though, it seems

During FMD outbreaks, there can be economic loss of up to 80.68% attributed to reduced milk yield. Hence, to contain economic losses due to FMD, vaccination to susceptible livestock population is must. India hosts 43 indigenous cattle breeds and 13 buffalo breeds (milch and draft purpose breeds). Apart from these well documented cattle and buffalo breeds, it also holds non-descript and crossbred cattle population. Large ruminants in India are reared mainly for milk production and also for the field work in the farmland. India ranks first in the production of milk (176.3 million tonnes in 2017–2018). Milk production in India from 1950 to 1951 onwards is presented (**Figure 2**). In the country work on FMD vaccination was started from the year 1943 onwards and many vaccine manufacturers are venturing into large scale production of doses of FMDV vaccines (**Table 3**). In FMDCP, all the susceptible livestock population is being covered for conferring protection against FMD through vaccinations and thereby mitigate economic losses including that from reduced milk yield. Hence, vaccination programmes in FMDCP indirectly

FMD outbreaks were reported even in vaccinated animals. It leads to doubt the quality of the vaccines and vaccinations [25, 26]. It creates unnecessary fears in the livestock owners. Though, timely vaccinations reduce the incidence of the disease outbreaks and thereby reduction in antibiotic requirements for the treatment of animals for those conditions that may arise due to involvement of secondary bacterial infections during the disease outbreaks. Eventually, vaccinations help to reduce

Availability of rapid diagnostic testing kits for FMD allows early detection of FMD which in turn will help in devising preventative and control strategies. Early detection will help in immediate segregation of diseased animals from healthy to minimise the spread of the infection. It also alarms Government bodies to vaccinate nearby animals in the periphery from the index case (ring vaccinations) to curtail

Critics are pointing on the fact that though vaccination is practiced in the country for prevention and control of FMD, yet, there is more than 20% of reactivity to FMD non-structural protein (NSP) 3AB3 indicative of FMDV exposure in field animals. They opined that vaccination has not resulted into generation of

*DOI: http://dx.doi.org/10.5772/intechopen.93348*

difficult as it will increase the cost of FMD vaccines.

#### *Foot-and-Mouth Disease in India: Past, Present and Future Outlook - A Review DOI: http://dx.doi.org/10.5772/intechopen.93348*

India extend financial help to the Indian states for procurement and administration of vaccines to the susceptible livestock population for prevention of FMD. Present vaccines are administered at six-monthly intervals to each animal to generate sufficient level of protective immunity. Some researchers suggest that increase in the antigenic mass of the vaccine may elicit higher level of protective antibodies in the vaccinated animals (which gives protection for longer duration). Though, it seems difficult as it will increase the cost of FMD vaccines.

During FMD outbreaks, there can be economic loss of up to 80.68% attributed to reduced milk yield. Hence, to contain economic losses due to FMD, vaccination to susceptible livestock population is must. India hosts 43 indigenous cattle breeds and 13 buffalo breeds (milch and draft purpose breeds). Apart from these well documented cattle and buffalo breeds, it also holds non-descript and crossbred cattle population. Large ruminants in India are reared mainly for milk production and also for the field work in the farmland. India ranks first in the production of milk (176.3 million tonnes in 2017–2018). Milk production in India from 1950 to 1951 onwards is presented (**Figure 2**). In the country work on FMD vaccination was started from the year 1943 onwards and many vaccine manufacturers are venturing into large scale production of doses of FMDV vaccines (**Table 3**). In FMDCP, all the susceptible livestock population is being covered for conferring protection against FMD through vaccinations and thereby mitigate economic losses including that from reduced milk yield. Hence, vaccination programmes in FMDCP indirectly helped India to achieve first rank in milk production in the world.

FMD outbreaks were reported even in vaccinated animals. It leads to doubt the quality of the vaccines and vaccinations [25, 26]. It creates unnecessary fears in the livestock owners. Though, timely vaccinations reduce the incidence of the disease outbreaks and thereby reduction in antibiotic requirements for the treatment of animals for those conditions that may arise due to involvement of secondary bacterial infections during the disease outbreaks. Eventually, vaccinations help to reduce antibiotic residue in the food animals and its products [27].

Availability of rapid diagnostic testing kits for FMD allows early detection of FMD which in turn will help in devising preventative and control strategies. Early detection will help in immediate segregation of diseased animals from healthy to minimise the spread of the infection. It also alarms Government bodies to vaccinate nearby animals in the periphery from the index case (ring vaccinations) to curtail further spread [28, 29].

Critics are pointing on the fact that though vaccination is practiced in the country for prevention and control of FMD, yet, there is more than 20% of reactivity to FMD non-structural protein (NSP) 3AB3 indicative of FMDV exposure in field animals. They opined that vaccination has not resulted into generation of

**Figure 2.** *Milk production in India (in million tonnes).*

*Some RNA Viruses*

in susceptible livestock population.

animals yet to receive the vaccine.

matching experiments.

protection).

in India.

immunity. It was also stated that during the year 2017–2018, 21.2% cattle and buffalo and 18% sheep and goats tested positive in differentiation between infected and vaccinated animals [21]. These results when compared to the data available for the year 1995 (positivity in DIVA: 91% in cattle and buffalo and 74% in sheep and goats) indicated significant reduction in circulation of FMDV in livestock population. Thus, successful administration of FMDCP at official and ground levels and effective implementation of its mandate resulted in reduction of FMDV circulation

A total amount of ₹ 3.0653 billion was released by the central Government towards implementation of the control programme [12]. However, as per the data available, a total of 381.51 million livestock population (cattle and buffaloes) received the vaccine for protection against FMD in the country. Though, the state-wise data presented, for the vaccinations were not reflecting on percentages of cattle and buffalo vaccinated till date in that respective state and also for those

**5. Vaccines and vaccination for Foot-and-mouth disease in India**

In India, Directorate of FMD located at Mukteshwar in the state of Uttarakhand and its collaborating and regional centers across the country are involved in continuous survey, monitoring and collection of clinical samples for virus typing and isolation from susceptible livestock population during the disease outbreaks. After isolation of a particular type of FMDV, it is stored in the virus repository for further studies. Currently, the national FMDV repository has a total of 2,188 FMDV isolates (1,482, 325, 15 and 366 belonging to the types O, A, C and Asia1 respectively) [21]. Its tally of FMDV isolates is increasing each year. These FMDV isolates are used in genotyping studies by using latest molecular biological methods and other vaccine

A detail on FMD vaccines is available [22]. Vaccines are one of the very important tools in the control of FMD in India [23]. Previously, India used quadrivalent inactivated FMDV vaccines (containing FMDV antigens for types O, A, C and Asia1) to control the disease. The FMDV strains used in the production of inactivated FMDV antigens for trivalent vaccines (FUTVAC) are: for type O-IND/O/ R2/75, type A-IND/A/40/2000, type Asia1-IND/Asia1/63/72. The Directorate also monitors suitability of FMD antigens employed in the production of the FMD vaccines. After critical studies the directorate also recommends to the vaccine manufacturers in the country for any requirement of inclusion of suitable FMD strain of the particular FMDV type used in the vaccine production (which can confer better

There were no reports in the country for the involvement of type C FMDV in the disease outbreaks hence FMDV antigen for type C was omitted from the vaccine. The absence of type C in the country may be due to implementation of vaccination programme in FMDCP or unknown reasons. At present, only trivalent inactivated FMDV vaccines are used in immunisation programmes of the livestock population

India is continuously trying to increase its capability to produce sufficient doses of FMDV vaccines required in FMDCP to cover vaccination of small and large ruminants and pigs. Though, it is a big task to vaccinate susceptible livestock population but possible because of the good veterinary services [24]. Private vaccine manufacturers such as Intervet, Biovet and Brilliant Biopharma Pvt. Ltd. are ramping up the production of doses of FMD vaccines not only to cover its domestic needs but also for the export of vaccines to demanding countries. The Central Government of

**100**

sufficient levels of protective immunity in the animals and poor vaccine quality. To check FMDV vaccine quality, Government of India has set up a vaccine quality testing facility at Baghpat (**Table 3**). FMDV has RNA as a genomic material. During the process of viral replication, there are chances of mutations in the FMDV genome and sometimes it may be possible that the antibodies generated after the vaccination may not be able to neutralise the circulating strain of the FMDV. Apart from this, there are many factors like persistent FMDV infections, nutritional status of the host, parasitic infestation of the host and other miscellaneous complexities prevalent in field conditions of such a vast country which can have its impact on the vaccination programme [30]. Still, FMDCP in India achieved a success in terms of reduction in FMD outbreaks as discussed below.

## **6. Reduction in Foot-and-mouth disease outbreaks reported in India**

Foot-and-mouth disease control programme (FMDCP) is led by Department of Animal Husbandry Dairying and Fisheries, Government of India. Due to continuous efforts to prevent and control the FMDV infection in susceptible livestock population especially large ruminants, there is significant reduction in number of FMD outbreaks reported during the years 2012–2018 to that of the FMD outbreaks reported during the years 2002–2012 (**Figure 3**). Reduction in the number of outbreaks reported is largely due to comprehensive sero-monitoring, epidemiological investigations, increased diagnostic capabilities, trained manpower, competency in vaccine manufacturing capacity to cover the livestock population in the vaccination programme and Government push.

In 2019, fully central Government backed National Animal Disease Control Programme (NADCP) of ₹ 126.52 billion was launched to vaccinate 600 million animals to control FMD and Brucellosis. It is hoped that with this continuous efforts and interest of the authorities and guidelines formulated, there will be implementation of the FMDCP more effectively and efficiently [31, 32] resulting into further reduction in the incidence of the disease and ultimately eradication.

However, there must be positive criticism in few regards. As the data stated that there is no incidence of FMD in Madhya Pradesh during the year 2017–2018 but the adjoining states to Madhya Pradesh, Rajasthan, Gujarat and Uttar Pradesh reporting

**103**

**7. Discussion**

*Foot-and-Mouth Disease in India: Past, Present and Future Outlook - A Review*

the disease? Migratory small ruminants and camels are used to reach Madhya Pradesh from Rajasthan. Cattle are being procured from Gujarat, yet astonishingly the state is not reporting any incidence of FMD for the last few years. Ironically, it reported about 18% reactivity to non-structural proteins (NSP) and as a corollary more is the presence of anti-NSP antibodies, more will be the incidence of FMD. That's not holding true in this case. It can be concluded that the FMD incidence is underreported in this case. The author is a witness to a farm visit, where the cattle owner was not aware even about the vaccination practices in his last 30 years of livestock rearing. Similarly, in one of the other studies FMD was reported at Bulandshahr in Uttar Pradesh where mortalities had happened even in vaccinated animals but at a lower level than the unvaccinated ones in the year 2015 [33]. As there will be reduction in the number of outbreaks reported in a state various known and unknown pressures would play a role in hiding any further positive cases of FMD. Few random visits of authorities from a different state can be planned during vaccinations and further monitoring. Hence availability of a dedicated contact number as envisioned in NADCP for reporting the outbreak by common man or livestock owner will bring more transparency. Since each one of the eligible cattle, buffalo, sheep, goats and pigs will receive vaccine for protection against FMD, the processes of vaccinations, blood collections and follow up needed to be fully recorded digitally. The internet data is cheapest in India, presently. So, location tracing applications can be developed and used to monitor actions of vaccinators and other workers. In India, declaration of monetary incentives for reporting about the incidence of the disease will not only bring more transparency in reporting the disease but also serve a great cause to prevent and control it. If an outbreak of FMD is noticed at a place, it needed to be reported immediately as per the FMDCP. But at the field level due to unawareness of significance of reporting an outbreak and unexplained pressures experienced by the workers, sometimes, at some places, it may go unreported. Hence it is desirable to spread awareness among common man and livestock owners regarding the programme. This programme is yet to popularize, countrywide, in livestock owners in respect to the basic understanding of the disease and its prevention and control. As there are still few pockets of the farmers left who are not willing to vaccinate their animals [33]. Such farmers needed to be identified and must be penalised else all the good of the control programme would be in danger. More coverage by the print and press media is needed to spread mass awareness. Once you start any programme subsequently it will be closely watched by the benefactor and also common public for the progressive outcome. Moreover, recently FMD outbreaks even in the vaccinated animals population raise unwarranted doubts in the animal owners unless they are better addressed about the epidemiology and transmission of the disease in a better way. Earlier states may also be reluctant to disclose the incidence of the disease due to further compliance to the provisions of the Prevention and Control of Infectious and Contagious Diseases in Animals Act, 2009. Awareness about the disease in a household is very important. A household's health-seeking behaviour influences

*DOI: http://dx.doi.org/10.5772/intechopen.93348*

selection into preventative care interventions [34].

India is having a huge experience in recording of the data of its citizens and generating identity cards. Sometimes these cards are essential to have access to and avail certain facilities by its citizens. National level coding of individual designated livestock (if not for all) where efforts to create disease free zones are on can be implemented. Migratory flocks of small ruminants and of other animals

**Figure 3.** *FMD outbreaks/incidences in India.*

#### *Foot-and-Mouth Disease in India: Past, Present and Future Outlook - A Review DOI: http://dx.doi.org/10.5772/intechopen.93348*

the disease? Migratory small ruminants and camels are used to reach Madhya Pradesh from Rajasthan. Cattle are being procured from Gujarat, yet astonishingly the state is not reporting any incidence of FMD for the last few years. Ironically, it reported about 18% reactivity to non-structural proteins (NSP) and as a corollary more is the presence of anti-NSP antibodies, more will be the incidence of FMD. That's not holding true in this case. It can be concluded that the FMD incidence is underreported in this case. The author is a witness to a farm visit, where the cattle owner was not aware even about the vaccination practices in his last 30 years of livestock rearing. Similarly, in one of the other studies FMD was reported at Bulandshahr in Uttar Pradesh where mortalities had happened even in vaccinated animals but at a lower level than the unvaccinated ones in the year 2015 [33].

As there will be reduction in the number of outbreaks reported in a state various known and unknown pressures would play a role in hiding any further positive cases of FMD. Few random visits of authorities from a different state can be planned during vaccinations and further monitoring. Hence availability of a dedicated contact number as envisioned in NADCP for reporting the outbreak by common man or livestock owner will bring more transparency. Since each one of the eligible cattle, buffalo, sheep, goats and pigs will receive vaccine for protection against FMD, the processes of vaccinations, blood collections and follow up needed to be fully recorded digitally. The internet data is cheapest in India, presently. So, location tracing applications can be developed and used to monitor actions of vaccinators and other workers. In India, declaration of monetary incentives for reporting about the incidence of the disease will not only bring more transparency in reporting the disease but also serve a great cause to prevent and control it.

If an outbreak of FMD is noticed at a place, it needed to be reported immediately as per the FMDCP. But at the field level due to unawareness of significance of reporting an outbreak and unexplained pressures experienced by the workers, sometimes, at some places, it may go unreported. Hence it is desirable to spread awareness among common man and livestock owners regarding the programme. This programme is yet to popularize, countrywide, in livestock owners in respect to the basic understanding of the disease and its prevention and control. As there are still few pockets of the farmers left who are not willing to vaccinate their animals [33]. Such farmers needed to be identified and must be penalised else all the good of the control programme would be in danger. More coverage by the print and press media is needed to spread mass awareness. Once you start any programme subsequently it will be closely watched by the benefactor and also common public for the progressive outcome. Moreover, recently FMD outbreaks even in the vaccinated animals population raise unwarranted doubts in the animal owners unless they are better addressed about the epidemiology and transmission of the disease in a better way. Earlier states may also be reluctant to disclose the incidence of the disease due to further compliance to the provisions of the Prevention and Control of Infectious and Contagious Diseases in Animals Act, 2009. Awareness about the disease in a household is very important. A household's health-seeking behaviour influences selection into preventative care interventions [34].

### **7. Discussion**

India is having a huge experience in recording of the data of its citizens and generating identity cards. Sometimes these cards are essential to have access to and avail certain facilities by its citizens. National level coding of individual designated livestock (if not for all) where efforts to create disease free zones are on can be implemented. Migratory flocks of small ruminants and of other animals

*Some RNA Viruses*

sufficient levels of protective immunity in the animals and poor vaccine quality. To check FMDV vaccine quality, Government of India has set up a vaccine quality testing facility at Baghpat (**Table 3**). FMDV has RNA as a genomic material. During the process of viral replication, there are chances of mutations in the FMDV genome and sometimes it may be possible that the antibodies generated after the vaccination may not be able to neutralise the circulating strain of the FMDV. Apart from this, there are many factors like persistent FMDV infections, nutritional status of the host, parasitic infestation of the host and other miscellaneous complexities prevalent in field conditions of such a vast country which can have its impact on the vaccination programme [30]. Still, FMDCP in India achieved a success in terms of

**6. Reduction in Foot-and-mouth disease outbreaks reported in India**

Foot-and-mouth disease control programme (FMDCP) is led by Department of Animal Husbandry Dairying and Fisheries, Government of India. Due to continuous efforts to prevent and control the FMDV infection in susceptible livestock population especially large ruminants, there is significant reduction in number of FMD outbreaks reported during the years 2012–2018 to that of the FMD outbreaks reported during the years 2002–2012 (**Figure 3**). Reduction in the number of outbreaks reported is largely due to comprehensive sero-monitoring, epidemiological investigations, increased diagnostic capabilities, trained manpower, competency in vaccine manufacturing capacity to cover the livestock population in the vaccination

In 2019, fully central Government backed National Animal Disease Control Programme (NADCP) of ₹ 126.52 billion was launched to vaccinate 600 million animals to control FMD and Brucellosis. It is hoped that with this continuous efforts and interest of the authorities and guidelines formulated, there will be implementation of the FMDCP more effectively and efficiently [31, 32] resulting into further

However, there must be positive criticism in few regards. As the data stated that there is no incidence of FMD in Madhya Pradesh during the year 2017–2018 but the adjoining states to Madhya Pradesh, Rajasthan, Gujarat and Uttar Pradesh reporting

reduction in the incidence of the disease and ultimately eradication.

reduction in FMD outbreaks as discussed below.

programme and Government push.

**102**

**Figure 3.**

*FMD outbreaks/incidences in India.*

needed to be identified and given a free pass to trace their journey. Mithun and Yaks are also susceptible for FMD but they have been kept aside from the control programme. Services of State veterinary colleges needed to be utilised in a better way and funded to for the set up of extension camps and activities which spread awareness among livestock owners. However, enthusiasm shown by veterinarians to spread awareness in the livestock owners about free FMDV vaccinations from remote locations of India in Reasi, Jammu is widely appreciated (the veterinary official took para-gliding to spread FMD awareness in the mountainous region!). There are very few reports available on impact of the FMDCP in the control of FMD [35]. Haryana state is also going to undertake trials of combined vaccines of FMD and Haemorrhagic septicaemia (HS). These combined vaccines are shown to elicit better immunity. Then the question to NADCP will be why they have chosen only Haryana for testing combined vaccines and not chosen entire country? It will be wise to go with combined vaccines for FMD and HS in the NADCP, since it will reduce the cost of vaccination and handling of the animals, save manpower, brings in additional expert manpower involved in HS research and increase its outreach. International community is closely watching the scenario as there was a report indicating transboundry movement of FMD to Sri Lanka from India [36]. So, FMD vaccines needed to be of superior quality which can confer higher level of protection by eliciting neutralising antibodies. The inactivated FMDV vaccines used in FMDCP in India, require cold chain maintenance from its production to administration in the animals. Sometimes vaccine failures can be due to improper storage of the vaccines. Presently, there is no way to confirm whether the cold chain is maintained during transportation of the vaccines or not. Vaccines can be incorporated with certain indicators whose colour may change irreversibly when exposed to higher temperatures. Secrecy is being maintained to disclose vaccine quality testing data and only few authorities are designated for the testing. Rather processes of vaccine quality testing needed to be digitally recorded and must have real time access to any viewers for positive criticism. To clear any doubts in the minds of the public due to recent controversies in vaccine manufacturing and quality control, apart from the designated national agencies for quality testing of the FMD vaccines, services of any third party national agency and if need be, international agency must be hired wherever applicable. There needed to be more coordination among institutions to share real time data for the public. Such reporting and real time sharing of the data needed to be encouraged and talked upon to relish any success stories to inspire for and to learn any lessons otherwise. Newer and newer vistas must be explored [37]. However practices based on indigenous knowledge for control and treatment of FMD from rural India is well documented [38].


**Author details**

Serhan Haner Dinar Uygulamalı Bilimler Yüksekokulu, Afyon Kocatepe University, Afyonkarahisar, Turkey

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*The Effects of Mill Conditions on Breakage Parameters of Quartz Sand in the District… DOI: http://dx.doi.org/10.5772/intechopen.102554*


**7.4.3 Category # 3 – Detail**

Verb extensions included in this category were viewed as providing specific details relative to the overall topic or theme of the annotation. In an ideal situation, such details would hinge on indicators identified in the Overview. For the purpose of this analysis however, there was no backward linkage and extensions were included in this category based solely on the criteria outlined above. It should also be noted that in all cases the entire verb extension constituted the detail.


*6.2. Theoretical Contributions*

The results of this study make the following three theoretical contributions. First, according to the Chicago School of Industrial Economics Theory, the larger the scale of an industry, the higher its efficiency and innovation ability [50] but the sustainable development theory puts limits the growth. Macao is a small economy. The gambling industry dominates more than half of the whole economy. It has negative externalities, so it is easily affected by the external environment and has a siphon effect on other industries. Therefore, the continuous expansion of the gambling industry is unsustainable for the industry itself and the overall economy and society. Macao and some other international cities that position gambling and tourism as a pillar industry has always advocated for moderate diversification of the industry. Therefore, this study discusses how to assess the achievement of a moderately diverse economy in a small economy and how to obtain quantitative and appropriate scales to achieve economically sustainable development in the small economy.

Second, this study confirms that the scale of the current gambling industry in Macao is in line with the theory of congestion of production factors, which states that overdevelopment of a dominant industry will reduce its own efficiency and harm the development of other industries [51]. In recent years, the scale of the gambling industry has expanded and its efficiency has declined. This study shows that controlling the gambling industry in an appropriate scale can improve its efficiency. This study also shows that a stable transition from gambling industry to non-gambling industry can achieve a moderate economic diversification.

Finally, Macao needs to have sustainably economic diversification including the sustainable development of the gambling industry. Economic diversification aims to speed up the growth of economic outputs from a range of industries. It leads to a consequence of long-term economic growth which provides economic well-being in much longer-term through the notion of economic sustainability. For having economic sustainability, economic diversification is not just the economic development of certain industries. It involves technical and institutional arrangements by which output is produced and distributed [52]. Thus, we need to determine how to influence the other industries under the premise of sustainable development of the gambling industry. To develop a robust and stable economy, Macao's gambling industry should appropriately adjust its scale and diversify as much as possible to adjust to the development status that is most suitable to achieve sustainable development and the continued development of other industries. This study contributes to sustainability study a model that can be used to reveal the optimal level of development of gaming industry in order to create conditions for economic diversification in Macao. This model can also be used to calculate the appropriate scale for one industry to optimally develop economic diversification in other cities.


**Diagnosis of Lower Genital Tract Disease**

Editors

**Fabio Bottari Anna Daniela Iacobone**

Basel ' Beijing ' Wuhan ' Barcelona ' Belgrade ' Novi Sad ' Cluj ' Manchester

*Editors* Fabio Bottari Division of Laboratory Medicine European Institute of Oncology IRCCS Milan Italy

Anna Daniela Iacobone Preventive Gynecology Unit European Institute of Oncology IRCCS Milan Italy

*Editorial Office* MDPI St. Alban-Anlage 66 4052 Basel, Switzerland

This is a reprint of articles from the Special Issue published online in the open access journal *Diagnostics* (ISSN 2075-4418) (available at: www.mdpi.com/journal/diagnostics/special issues/ Lower Genital Tract Disease).

For citation purposes, cite each article independently as indicated on the article page online and as indicated below:

Lastname, A.A.; Lastname, B.B. Article Title. *Journal Name* **Year**, *Volume Number*, Page Range.

**ISBN 978-3-0365-9297-8 (Hbk) ISBN 978-3-0365-9296-1 (PDF) doi.org/10.3390/books978-3-0365-9296-1**

© 2023 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) license.


*2.1. Subjects' Characteristics*

A total cohort of 50 subjects was enrolled. At HRCT scan, two patients showed a "probable UIP" pattern and were consequently excluded from the study. The remaining 48 subjects, 37 female (77.1%) and 11 males (22.9%) were included in the study. The three study groups were composed by a total of 21, 10 and 17 ACPA-positive subjects without evidence of arthritis (ND), early RA (ERA) and long-standing RA (LSRA), respectively. Patients did not suffer from other significant comorbidities. The demographic, clinical and laboratory characteristics are summarized in Table 1. Within the LSRA group, eight patients (47.1%) were already on treatment with methotrexate (MTX), four patients (23.5%) were taking sulphasalazine and three patients (17.6%) hydroxychloroquine, either as monotherapy or as combination therapy. For the laboratory evaluation, 22 healthy control subjects (HC) were also enrolled, 15 females (68.2%) and 7 males (31.8%), the mean age being 47.3 ± 10.5 years.

**Table 1.** Demographic, clinical features and autoantibodies of enrolled subjects.

Data are reported as mean ± SD, unless stated otherwise. *p* values intended for comparisons between ND, ERA, LSRA and HC (whenever applicable) subgroups of participants. †: post hoc test *p* < 0.05 vs. ERA. Abbreviations: ND, no disease subjects; ERA, early rheumatoid arthritis patients; LSRA, long standing rheumatoid arthritis patients; HC, healthy controls; BMI, body mass index; ACPA, anti-citrullinated proteins antibodies; RF, rheumatoid factor.

#### *2.2. Lung Function and Physiological Responses to Exercise*

The results of the main PFT and CPET parameters are shown in Table 2.

**Table 2.** Selected pulmonary functional responses measured at rest and during exercise testing.

Data are reported as mean ± SD. *P* values intended for comparisons between ND, ERA and LSRA subgroups of participants. \*: post hoc test *p* < 0.05 vs. ND; Reduced DLCO: DLCO < 80% of predicted value; reduced exercise tolerance: V'O2 peak < 80% of predicted value; impaired ventilatory efficiency: V'E/V'CO2 a θL > 34 and/or V'E/V'CO2 slope > 30. Abbreviations: ND, no disease subjects; ERA, early rheumatoid arthritis patients; LSRA, long standing rheumatoid arthritis patients; FEV1, forced expiratory volume; FVC, forced vital capacity; TLC, total lung capacity; DLCO, diffusing lung capacity for carbon monoxide; KCO, transfer coefficient of the lung; V'O2, oxygen uptake; V'CO2, carbon dioxide output; V'E, minute ventilation; θL, lactate threshold; eMVV, estimated maximal voluntary ventilation; SpO2, peripheral capillary oxygen saturation; ΔSpO2, peak-rest change in peripheral capillary oxygen saturation.

Reduced DLCO (i.e., <80% predicted value) was observed in 57.1%, 50% and 64.7% of ND, ERA and LSRA subjects, respectively (*p* = 0.747). There were no significant differences between groups in the examined PFT parameters, even after correction for smoking status. FEV1, when expressed as percentage of predicted value, was significantly lower in patients who were current or former smokers compared to non-smokers (*p* = 0.018). DLCO values in current and former smokers were not different from those of never smoker subjects.

All patients achieved maximal effort during CPET. Mean work rate at peak exercise was 105 ± 32.5 W (76.1 ± 15.4% predicted value). Reduced exercise tolerance, defined as V'O2 peak < 80% predicted value, was found in 19 out of 48 (39.6%) patients. Even if not significantly different, ND and ERA subjects showed lower rates of exercise intolerance than LSRA. Anticipated θL (i.e., V'O2 at θL < 40% predicted V'O2 peak), indicating impaired aerobic fitness, was observed in six (12.5%) subjects, with no difference among subgroups. No abnormalities in cardiovascular responses were found, neither within the whole group nor among each subgroup.

Overall, there was no sign of ventilatory limitation, average V'E peak being 49.8 ± 12% eMVV. In this regard, none of the recruited patients showed V'E peak values > 85% eMVV. Mean VT was 1.8 ± 0.5 L at peak exercise, corresponding to 50.0 ± 10.0% of FVC, confirming the absence of ventilatory constraints during exercise. Apparently, no differences in breathing patterns were observed between subgroups.

Peak SpO2 fell within normal values for all groups, although a significant trend in progressive reduction was found between groups (97.7 ± 1.1% vs 97.6 ± 1.2% vs 96.8 ± 1.7% among ND, ERA and LSRA patients, respectively; *p* = 0.008). Significant haemoglobin desaturation (peak—rest change in SpO2 > 4%) was found only in one patient with LSRA.

Impaired ventilatory efficiency, defined as V'E/V'CO2 at θL > 34 and/or V'E/V'CO2 slope > 30, was found in about one third of the study group. The highest frequency was registered among LSRA patients (41.2%); however, no significant differences were observed in the rate of reduced ventilatory efficiency among the three subgroups.

#### *2.3. Laboratory Results*

There were no significant differences in ACPA and RF levels between the groups. Significantly higher values of RF were registered among subjects from all the three groups with reduced exercise tolerance (263.8 ± 216.5 IU/L vs 119.4 ± 171.71 IU/ L; *p* = 0.019) and with impaired ventilatory efficiency (326.6 ± 282.9 IU/ L vs 90.8 ± 98.6 IU/ L; *p* = 0.015). No further relations were observed between ACPA and RF levels and pulmonary function at rest and during exercise.

SPD serum levels were significantly higher among study group subjects compared with HC (158.5 ± 132.3 ng/mL vs. 61.27 ± 34.11 ng/mL; *p* < 0.0001). Similarly, subgroup analysis revealed higher SPD levels within the ND (132.1 ± 125.1 ng/mL; *p* = 0.023), ERA (181.1 ± 151.3 ng/mL; *p* = 0.003) and LSRA subgroups (176.1 ± 131.8 ng/mL; *p* < 0.0001) compared with HC (61.2 ± 34.1 ng/mL) (Figure 1). No difference was observed between patient groups; nonetheless, a significant trend in increasing levels of SPD was noticed from ND to LSRA (*p* = 0.004). There were no differences in SPD levels based on smoking history (i.e., current, former or never smoker). However, significantly higher levels of SPD were present in ACPA-positive never smokers (ND+ERA+LSRA) compared with healthy controls (142.2 ± 94.1 ng/mL vs 61.2 ± 34.1 ng/mL; *p* < 0.0001). In the LSRA group, no difference was found in SPD serum levels concerning treatment with MTX.

**Figure 1.** Comparison of SPD serum levels between ACPA-positive subjects and healthy controls. \*: *p* < 0.05; \*\*: *p* < 0.005; \*\*\*: *p* < 0.0005. Abbreviations: SPD, surfactant protein D; HC, healthy controls; ND, no disease subjects; ERA, early rheumatoid arthritis patients; LSRA, long standing rheumatoid arthritis patients.

SPD levels were inversely related to V'O2 peak (expressed as percentage of predicted value; *p* = 0.024; rho = −0.32), V'O2 at θL (percentage of predicted V'O2 peak; *p* = 0.013; rho = −0.36) and peak SpO2 (*p* = 0.008; rho = −0.38). As observed for RF, SPD levels were also shown to be significantly higher among patients with reduced exercise ventilatory efficiency (V'E/V'CO2 a θL > 34) (250.8 ± 155.3 ng/mL vs. 141.2 ± 121.9 ng/mL; *p* = 0.007). A similar result was also observed when limiting the analysis to ND patients (351.15 ± 219 ng/mL vs 93.5 ± 44.9 ng/mL; *p* = 0.01).