**Irene Vargianniti 1 and Kostas Karpouzis 2,\***

Received: 25 September 2020; Accepted: 14 October 2020; Published: 22 October 2020

**Abstract:** The goal of this paper is to utilize available big and open data sets to create content for a board and a digital game and implement an educational environment to improve students' familiarity with concepts and relations in the data and, in the process, academic performance and engagement. To this end, we used Wikipedia data to generate content for a Monopoly clone called Geopoly and designed a game-based learning experiment. Our research examines whether this game had any impact on the students' performance, which is related to identifying implied ranking and grouping mechanisms in the game, whether performance is correlated with interest and whether performance differs across genders. Student performance and knowledge about the relationships contained in the data improved significantly after playing the game, while the positive correlation between student interest and performance illustrated the relationship between them. This was also verified by a digital version of the game, evaluated by the students during the COVID-19 pandemic; initial results revealed that students found the game more attractive and rewarding than a traditional geography lesson.

**Keywords:** big data; open data; game-based learning; education; geography; board games; monopoly

## **1. Introduction**

## *1.1. Big Data in (and for) Education*

In recent years, the abundance of online learning solutions both for children and adults has increased interest in taking advantage of the data they create. Data related to school attendance, performance, engagement and other factors are too big to handle using conventional processing techniques; in addition to this, they offer the opportunity to identify relationships and trends, which may not be otherwise evident, using data mining algorithms. As a result, the field of data analytics seems to be the most appropriate means to exploit them [1], mostly to predict student performance or interest [2], visualize information in a dashboard [3], either for school usage or for policy makers [4] or even to identify cognitive states in real-time, such as interest and fatigue [5]. In this context, ethics awareness becomes of the essence, since data mining, especially in social media, has been criticized as a channel which caters for targeted advertising and may promote dubious behavioral shifts; given that big data effectively expands the scope of educational measurement [6], it is important to educate young students about the underlying mechanics, the source of available big data (not necessarily related to education) and the means to easily collect meaningful and dependable data sets. In our work, we utilize a Game-Based Learning (GBL) approach to educate young students not only with respect to a specific school course, but also about the relationships between different entities from a Big Data set; this is also of great importance, in order to ensure that Big Data can be used and interpreted correctly [7–9].

World geography provides a handy introduction to Big Data for young students, since it incorporates diverse solitary information (e.g., Points of Interest, names of persons, etc.) and relational data, such as population and size; the latter is of major importance, since it can be used to illustrate ranking and grouping concepts between different entities (mainly countries or continents). Research shows that geographical education fosters critical thinking and increases environmental awareness [10–12]. Such skills can be cultivated by playing games, since cooperation, communication and critical thinking flourish in a playful environment, while games highly engage players and motivate the students [13–15]. Game-based learning [16] is designed to balance the content and mechanics of the game with the players' ability to transfer the concepts described in the game to the real world [17]; Prensky reports ([18]) that education and play are, indeed, interrelated. Conventional learning offers rich educational content, but little involvement, as opposed to games that sometimes promote fun, entertainment and flow, in exchange for reusable, transferable knowledge [19]. Moreover, the narrative of a game is manifested through goals and objectives that students have to accomplish in order to progress and succeed in it. Engagement is associated with learning outcomes [20–22] and motivation is considered games' fundamental elements [23]. Therefore, the game design process must be thorough, in order to engage and motivate students [24,25]. Even though literature reports quite a few examples of games having a positive effect on learning [26], this is not always the case [20]. Interest and fun can go hand in hand with learning, if we integrate educational games in the classroom, regardless of the students age group [27–30]. Today's generation have the unique opportunity to go beyond traditional means of education [31], hence, educators should use games to make learning fun and exciting but also more effective.

#### *1.2. Monopoly as a Serious Game*

Monopoly is one of the five most popular board games, licensed in more than 100 countries and printed in 37 languages [32]. Hasbro has produced or licensed different versions for cities, towns and regions and even for TV shows and Hollywood films. Custom-made Monopoly sets even played a role in World War II, when the British Secret Intelligence Service cooperated with the game's UK manufacturer to include genuine maps, compasses are real money, instead of the game's items, to sets delivered to prisoners via the Red Cross. Even though it is mostly considered an entertainment game, it was designed as an educational game, back in the early 20th century, by American game designer and author Elizabeth "Lizzie" Magie. Magie believed in the ideas of Henry George, an American political economist and journalist, who thought that land and natural resources should belong to the people who rent them, but never own them. Her game, called "Landlord's Game" consisted of a board with different properties, each with the distinct purchase price and rental value: in this context, the government charges tax not on profit or labor, but on the possession of land and whatever profit people can create through the investment of accumulated capital stays with them. Landlord's Game was initially rejected by one of the leading game manufacturers in the U.S. and was finally published by Parker Brothers in 1935, under the name "Monopoly" [33].

Monopoly employs several game objects and mechanics that associate them, the most prominent of which includes investing in property and re-using collected rent to build houses and hotels to increase the value of rent collected by visitors. In addition to property deeds, which correspond to street names in most Hasbro editions, players may invest in railroad stations and utility companies; as is the case with street properties, collecting more of the same kind increases the rent collected by visitors, along with the owner's chances of winning. Some of the squares in the board correspond to Chance cards, which may entail players paying taxes (players who have invested in many properties may be hurt substantially) or fund collection (redistribution of wealth) or even send players to Jail, where no rent can be collected by visitors in their properties. Chance cards, along with the use of dice that provide how many squares each player advances in each round, introduce a chance element; despite that, the dominant strategy to increase a player's chances of winning is to move early, invest in many properties and try to save funds to invest in more expensive properties, usually positioned

towards the end of the boards. In general, positioning of street properties on the board implies a ranking mechanism: the price to invest in each property increases as one moves along the board and, in turn, the rent collected by visitors and, hence, the player's return on investment, increases as well [34].

#### *1.3. The Monopoly Game in Education*

The original properties and game mechanics included on Monopoly cater for quite a few educational uses, the most obvious of them having to do with how to save and spend money in order to invest and that investments in property may not always lead to fiscal success. There are also mechanics related to social play, with players being able to lend money to bail out their friends and prevent them from going bankrupt and leaving the game.

Another obvious use has been in the context of land and lodging development: O'Halloran and Deale [35] designed a version of Monopoly, along with the relevant teaching material, where the objective is to maximize one's asset value by developing hotels and then blocks of hotels. An interesting addition to the usual game mechanics of the original game was that, as the game was played over a semester, players had the opportunity to research the actual real estate value of each property, as well as other emerging information regarding the market, and inform their property development decisions accordingly.

In the context of accounting education, Tanner and Lindquist extended Knechel's [36] idea and used Monopoly as a business simulation for a team-based project for university students. Students would form four-person teams, form a virtual company, agree on a mutual strategy and then face other "companies" in games of 24 turns per player. After the game, the members of each company analyzed the company's transactions as a whole, set up an accounting record and used a general ledger to keep track for each type of transaction: salaries, depreciation expenses, interest expenses and tax expenses. After the evaluation of the game, authors concluded that "students' attitudes towards financial accounting and learning, mutual concern and perceived achievement were very positive at the completion of the project" [37]. Shanklin and Ehlen [38] also worked with the original idea and saw that "the use of an engaging and unusual medium early in the principles course helps students build confidence and provides positive reinforcement of understanding in a course that undergraduate business students do not always enjoy".

Besides including Monopoly in courses where its mechanics make immediate sense, the game has been used in the context of other disciplines as well. Hastunar et al. [39] designed a modified version of the game, referring to food and everyday objects, instead of properties, and to points, instead of money, to teach English to students of 7th grade in Indonesia, while Inal and Cagiltay [40] assessed Monopoly, among other games, with children aged 7 to 9, noting the "clear and immediate feedback of the game" which resulted in increased flow.

An interesting concept, not necessarily restricted to school education, is that of creating Monopoly boards from open data. Gustafsson Friberger defines data games as "as games where gameplay and/or game content is based on real-world data external to the game, and where gameplay supports the exploration of and learning from this data" [41]; in the case of open data games, most of the game content (images, text, Points of Interest, etc.) comes from sources freely available for use, such as a governmental organization, NGO or data aggregator (e.g., Google's Public Data Explorer [42] and the European Union's Open Data Portal [43]). Dissemination of open data is important, since it can provide a substantial basis for argumentation in public speaking or policy making; in the context of education, it strengthens the connection between the concepts and facts taught at school with everyday life, and empowers students to make informed decisions in their life [27]. Friberger and Togelius [44] analyzed thoroughly the different kinds of information which can be used as properties in this context, from geographic data, which is typically readily available and easy to visualize, to demographic, which can be sensitive (in terms of politics). They mention that real-time infrastructure data, such as

flight information, are becoming increasingly available and may be more appealing to avid game players since it helps them relate to the actual providers of the data.

In our work, we wanted to examine whether the implied relations between entities and data contained in the game mechanics of Monopoly would help students identify the same relations between entities from a Big Data set. The subject of European geography was a straightforward choice, because it refers to a variety of numerical and reference data, typically associated with commercial versions of Monopoly. In addition to that, Monopoly entities are grouped using different colors, and ranked with respect to rent prices; we attempted to take advantage of these mechanisms to increase the students' comprehension of the relative size and population of each country and train them to identify those relations in the data. An additional game mechanic has to do with the positioning of the Monopoly entities on the board: even though in the original game there is no reference to any geographic positioning, in Geopoly the four sides of the board correspond to the region of Europe where each country resides. In order to create the required data and populate the board, we developed an automated infrastructure to retrieve data (country names, size and population, and landmarks) from Wikipedia, and create the Geopoly board respecting the grouping and ranking processes described earlier. The same approach can also be used with other Big Data sets, such as plants and animals (used in [27] in the context of a "Top Trumps" card game), where different numerical attributes (e.g., size, weight or life expectancy) or grouping elements (e.g., scientific classification, type of habitat or conservation status) may be used. As a result, we can create different versions of Monopoly to both familiarize students with concepts and relationships in Big Data sets and also follow and examine the learning objectives of the school curriculum, making it easier to integrate such a game in formal education practices.


**Author details**

multitude of cellular processes, such as vesicle transport and protein degradation. In accord‐ ance with literature studies, *VCP* mutations represent one of the major genetic causes of frontotemporal dementia but, recently, a specific mutation in this gene (p.R191Q) has been detected in some cases of FALS [55]. In our analysis, we observed the differential expression of *VCP* in SALS patients (**Figure 5b**). Moreover, several studies have highlighted the existence of a link between alterations in VCP functionality and the toxic gain of function of full-length TDP-43 [56]. The latter is a DNA/RNA binding protein, involved in several processes, includ‐ ing transcription, pre-mRNA splicing, mRNA stability, and mRNA transport [57]. Because of various types of insults, such as dysregulation in calcium homeostasis and oxidative damage, TDP-43 can migrate from the nucleus to the cytoplasm which can cause sequestration of RNA stress granule as well as a loss or gain of splicing functions. Although several studies have focused their attention on the role of TDP-43 in ALS etiopathogenesis, additional investigations are needed. Recent literature data showed the presence of aberrant nuclear or cytoplasmic TDP-43 inclusions in the nervous tissue of ALS patients [58]. It is thus evident that the pharmacological modulation of VCP may represent a promising strategy for ALS treatment, also through the reduction of TDP-43-mediated motor neuron toxicity. Some VCP inhibitors (Vesnarinone and Xanthohumol) have, in fact, demonstrated how to prevent neuronal death

and inflammatory processes occurring in diverse neurological conditions [9].

ALS is a fatal neurodegenerative disease characterized by the influence of diverse mechanisms that interacting among each other promote the development and progression of the disease. Despite intensive research, ALS is still incurable and the only approved drug, Riluzole, conveys only modest benefits to patients. This clinical failure may be mainly due to the actual classification of ALS diseases, which is mainly based on clinical observation of symptoms and physical signs and does not take into account the complexity and heterogeneity of molecular

The advent of high-throughput techniques in the biomedical sciences has provided a frame‐ work for developing a new, more accurate, and refined "molecular taxonomy" of human diseases that implies the use of molecular data to classify patients into distinct subgroups with differing diagnostic, prognostic, or therapeutic implications. In our previous work, we used unsupervised hierarchical clustering to identify two subgroups of SALS patients, characterized by their gene expression pattern, and revealed new clues to pathogenesis and potential

We argue that, as it is already happening in the genomic cancer field, our genomic analysis in combination with other "omics" data will complement and augment existing phenotypic information, providing a much deeper understanding of etiopathogenic mechanisms, which may have been masked by considering SALS as a single entity, and facilitating the develop‐

ment of a more precise diagnosis and individualized treatments for ALS patients.

**5. Conclusion**

250 Update on Amyotrophic Lateral Sclerosis

therapeutic targets.

pathogenic mechanisms underlying ALS.

Giovanna Morello, Francesca Luisa Conforti, Antonio Gianmaria Spampinato and Sebastiano Cavallaro\*

\*Address all correspondence to<EMAIL_ADDRESS>
Institute of Neurological Sciences, Italian National Research Council, Catania and Mangone (CS), Italy


**6. Arterial graft failure**

The need for repeat revascularization is substantially reduced with the use of arterial conduits, since long-term patency is much higher compared to SVG. [66-68] In contrast to SVG, arterial grafts appear to be more resistant to the influence of atherogenic factors and incur only minor traumatic and ischemic lesions, since they are not removed from the blood circulation but are prepared locally, with few ligations and preservation of blood flow. [69] Since 1986, the LIMA has been used in more than 90% of CABG procedures. Less frequently, the RIMA is used. The early patency of a LIMA anastomosed to the left anterior descending (LAD) is reported to be almost 99%. [70] The mean patency of LIMA to coronary conduit at 5 years is reported 98%, at 10 years it is 95%, and at 15 years it is 88%. [71] Differences are observed between territory grafted, the 10 year LIMA patency to the LAD is reported to be 96% and to the circumflex (Cx) 89%. [72] The early patency of the RIMA anastomosed to major branches of the left circumflex artery is approximately 94%. [70] The mean RIMA patency at 5 years is reported to be 96%, at 10 years it is 81% and at 15 years it is 65%. [71] Again differences are observed, the RIMA graft patency to the LAD artery is 95% at 10 years and 90% at 15 years. Ten-year RIMA patency to the Cx marginal is 91%, right coronary artery is 84%, and posterior descending artery is 86%. [72] In situ RITA and free RITA had similar ten-year patency, 89% vs 91% respectively. RA patency is reported to range between 83% to 98% at 1 to 20 years but lower rates have been reported. [73] The patency rate estimated by the Kaplan-Meier method for the GEA conduit was 96.6% at 1 month, 91.4% at 1 year, 80.5% at 5 years, and 62.5% at 10 years. [74] Arterial grafts are not uniform in their biological characteristics and difference in the perioperative behaviour and in the long-term patency may be related to different characteristics. It should be taken into account in the use of arterial grafts that some grafts need more active pharma‐ cological intervention during and after operation to obtain satisfactory results.

Although, the IMA is the most used conduit to restore the blood flow to the LAD, it is less easy to use because of its complicated preparation and postoperative complications. Specific reasons for not to use the RIMA may include additional time to harvest, concerns over deep sternal wound infection, myocardial hypoperfusion, and unfamiliarity. Besides the potentially deleterious effect on the vascular supply of the forearm and hand, potential spasm and size matching to target coronary artery are the main drawback for the use of RA in CABG. [75,76]

is supplied by the vaso vasorum and in addition through the lumen, whereas the veins are only supplied by the vaso vasorum [64]; 3) the endothelium of the arteries may secrete more endothelium-derived relaxing factor [65]; 4) the structure of the artery is subject to high pressure, whereas the vein is subjected to low pressure. While the SVG have to adapt to the high pressure, the arterial grafts do not which may partly explain the difference in the long-

**Type I - Somatic arteries** Less spastic Internal mammary artery

**Type II - Splanchnic arteries** Spastic Gastroepiploic artery

**Type III - Limb arteries** Spastic Radial artery

**Table 1.** Functional classification of arterial grafts according to physiological and pharmacological contractility,

Inferior epigastric artery Subscapular artery

Splenic artery Inferior mesenteric artery

Ulnar artery Lateral femoral circumflex artery

Similar like SVG, the arterial grafts can also be divided into three layers: the intima, media, and adventitia. As a result of location at different parts of the body and supply to different organs, differences in gross anatomy among arterial grafts have been observed. Divergent anatomic structures of the arteries have been observed. One of the most obvious differences is that arteries such as the GEA, IEA, and RA contain more smooth muscle cells in their walls and are therefore less elastic compared to other arteries such as the IMA which may be more elastic because they contain more elastic laminae. [64] Such structure divergence may also

The need for repeat revascularization is substantially reduced with the use of arterial conduits, since long-term patency is much higher compared to SVG. [66-68] In contrast to SVG, arterial grafts appear to be more resistant to the influence of atherogenic factors and incur only minor traumatic and ischemic lesions, since they are not removed from the blood circulation but are prepared locally, with few ligations and preservation of blood flow. [69] Since 1986, the LIMA has been used in more than 90% of CABG procedures. Less frequently, the RIMA is used. The early patency of a LIMA anastomosed to the left anterior descending (LAD) is reported to be almost 99%. [70] The mean patency of LIMA to coronary conduit at 5 years is reported 98%, at 10 years it is 95%, and at 15 years it is 88%. [71] Differences are observed between territory

explain the difference in phsysiologic and pharmacologic reactivity.

term outcome.

198 Artery Bypass

anatomical, and embryological characteristic

**6. Arterial graft failure**

Although all arterial grafts may develop vasospasm, it develops more frequently in the GEA and RA, than the IMA and IEA. [13,77] Two types of vasoconstrictors are found to be important spasmogens in arterial grafts. [78] Type I vasoconstrictors are the most potent and they strongly contracts arterial grafts even when the endothelium is intact. The constrictors are endothelin, prostanoids such as thromboxane A2 and prostaglandin F2α, and alpha1-adrenoceptor agonists. Type II vasoconstrictors induce only weak vasoconstriction when the endothelium is intact, but play an important role in the spasm of arterial grafts when the endothelium is destroyed by surgical manipulation. Type II vasoconstrictor is 5-hydroxytryptamine.

Early IMA graft failure is attributed to technical errors and distal anastomosis. [79,80] Non‐ technical factors that may affect the patency of the arterial graft are high levels of LDL cholesterol and triglycerides, and high levels of lipoprotein(a), a thrombogenic molecule that is related to the hypercoagulable state. Other classical risk factors for coronary artery disease, such as diabetes mellitus, smoking and hypertension may also affect the patency of the arterial graft. Age may be of influence the quality of the arterial graft.

Furthermore, competitive flow and low-flow profoundly affect graft patency. Low-grade graft stenoses in the target artery proximally are a major cause of competitive flow which may lead to a decrease in antegrade flow in the arterial graft causing early failure ('disuse athrophy'). The SVG and IMA are more tolerant than the RA and GEA conduits. This is likely to be related to biological differences as the RA and GEA have a thick layer of smooth muscle or poor endothelial function in these muscular conduits. Therefore, it is recommended to avoid grafting target arteries with a stenosis less than 90% with RA grafts. [81]

Atherosclerosis in arterial grafts can develop before coronary grafting when the graft is in the in situ native position, or after. The incidence of atherosclerosis in native arteries in the in situ position in the four major arterial grafts is low, especially in the IMA. [64] The incidence of atherosclerosis in bypass grafts is also low, in IMA grafts even as late 15 to 21 years after CABG. [67,82] However, the degree of stenosis in the native vessel is a major predictor of IMA graft patency. The observed association between non-significant stenosis of the native artery and high occlusion rate of the arterial bypass conduit raises concerns about the use of IMA in the treatment of native vessels with only mild or moderate stenosis. [83] In addition, the target vessel for the IEA must be one that is completely occluded or severely stenotic, with low coronary resistance, and in territories not totally infarcted to avoid "string sign" (conduit <1 mm diameter). Although the incidence of atherosclerosis is low in arterial grafts, 2 other morphologic changes may be present in arterial graft, fibrointimal proliferation and fibrosis representing organized thrombus. [84] The presence of fibrointimal proliferation is associated with long-term IMA graft narrowing and may be an important factor for late graft failure. Despite hypertension was associated with increased fibrointimal proliferation in SVG, this correlation could not be found in IMA grafts. [84]

and controlling serum glucose in diabetic patients. The bypass angioplasty revascularization investigation (BARI) trial illustrated that intensive risk-factor modification and hypolipid medication use slows atherosclerosis progression within native coronary arteries of CABGtreated patients and may to a lesser extent improve long-term patency of surgical conduits. [89] *Antiplatelet therapy* - Antiplatelet therapy is recommended following CABG since it improves SVG patency and clinical outcomes. The 2008 EACTS guideline on antiplatelet and anticoa‐ gulation management in cardiac surgery [90] recommends that aspirin should be given postoperatively to all patients without contra-indications after CABG in order to improve the long-term patency of SVG. The recommended dose given is 150—325 mg. Several studies have shown a trend towards maximal benefit with 325 mg/day in the first year. [91-95] In contrast, there is no evidence that the use of aspirin after coronary artery bypass grafting improved the patency of arterial grafts. However, aspirin may be recommended on the basis of improved

Treatment of Coronary Artery Bypass Graft Failure

http://dx.doi.org/10.5772/54928

201

The optimal timing of the first dose of aspirin for patients after CABG was investigated in a meta-analysis of 12 studies and found that the benefit of aspirin was optimal if started at 6 h after surgery. [96] Although, the largest risk reduction was observed when aspirin was given at 1 h after operation, there was a non-significant increase in the rate of re-operation in this group. [91] In contrast, there was no benefit found in giving aspirin if starting more than 48 h

Whether clopidogrel given in addition of aspirin to high-risk patients after CABG would reduce thrombotic complications was evaluated in several studies. Registry data showed that adding clopidogrel to aspirin was independently associated with a decrease in recur‐ rence of anginal complaints and adverse cardiac events following off-pump CABG. Nonetheless, clopidogrel use beyond 30 days did not show a significant effect on adverse cardiac events. [98] In the randomized CASCADE (Clopidogrel After Surgery for Coro‐ nary Artery Disease) study, aspirin monotherapy was compared with aspirin plus clopi‐ dogrel in 113 patients undergoing CABG and SVG intimal hyperplasia was determined by intravascular ultrasound at 1 year. [99] Compared with aspirin monotherapy, the combination of aspirin plus clopidogrel did not significantly reduce SVG intimal hyper‐ plasia 1 year after CABG. Although the study was not powered for clinical outcomes, there was no significant difference in SVG patency or cardiovascular events, neither was there a difference in the incidence of major bleeding between the 2 treatment groups at 1 year. Moreover, the superiority of clopidogrel over aspirin for optimising graft patency after CABG has not been established and thus aspirin should be regarded as the drug of

postoperatively. [97] Practically, Aspirin should be commenced within 24 h of CABG.

first choice, however, clopidogrel is an acceptable alternative to aspirin. [90]

In patients whom underwent CABG for ACS subgroup analyses of the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) and CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) study provides supportive evidence to prescribe clopi‐ dogrel for 9 to 12 months in addition to aspirin. [100,101] In patients undergoing coronary bypass surgery with a coronary stent in situ implanted within 1 year, clopidogrel should be continued if the stented vessel has not been grafted. Finally, in patients with SVG failure treated

survival of patients in general who have atherosclerotic disease.


**5. Prospective**

Chl fluorescence techniques will continue to play a major role on HTPP. Among these, imaging-PAM techniques will play a pivotal role, although specific cases will require different technological solutions. Moreover, field HTPP, which is expected to be fostered in the forthcoming years, will require technologies not dependent on sample dark adaptations and able to operate at medium-range distance, where the family of techniques based on LIF may play a role. Finally, the development of low-cost HTPP platforms [128], required to improve plant breeding in developing countries, is expected to make use of the less expensive Chl measurement techniques, namely passive fluorescence. On the other hand, high-technology in-house HTPP platforms are expected to make simultaneously use of different Chl fluores‐ cence techniques, integrated in a systems approach to plant phenomics.


**2. Methodology**

An electronic bibliographic search was carried out in three databases namely Pubmed central, Google Scholar, Ebsco, focusing on genetic studies related to periodontics. Books on genetics and periodontics were additionally referred for writing the book review.


**6. Take Home Messages**

Mechanical loads are one of the most potent regulators of muscle mass and the maintenance of muscle mass plays a critical role in health and quality of life. In Table 1 we have summarized the major structural adaptations that have been implicated in the mechanical load-induced growth of skeletal muscle. Based on our review, we have also considered whether each of these adaptations makes a substantive contribution to the overall growth process, as well as the level of evidence that is available to support that conclusion. The table also lists some of the major gaps in knowledge that we identified during our review of the literature. Importantly, this is not meant to be an exhaustive summary, and exclusion from the table does not indicate that a given adaptation or gap in knowledge is unimportant (e.g., satellite cell fusion, are satellite cells necessary for mechanical load-induced growth, etc.).

**Table 1.** The Structural Adaptations that Drive the Mechanical Load-Induced Growth of Skeletal Muscle.

As documented in this review, several of the adaptations that we consider as having weak supporting evidence have been engrained in the literature as "textbook" mechanisms (e.g., the longitudinal growth of myofibers is driven by the addition of new sarcomeres at the ends of myofibers, new myofibrils are formed via myofibril splitting, etc.). We hope that after reading this review, the reader appreciates how little we actually know about the structural adaptations that drive skeletal muscle growth, and the number of extremely fundamental gaps in knowledge that remain to be filled.

**Author Contributions:** K.W.J., S.M.P. and T.A.H.; all contributed to the writing of this manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** The research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number AR074932 to SMP and TAH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

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