Revised Ghent nosology.
\r\n\t
\r\n\tRecently in 2019, International Council on Systems Engineering (INCOSE) has released the latest version of the “Guidelines for the Utilization of ISO/IEC/IEEE 15288 in the Context of System of Systems (SoS) Engineering” to industry for review and comments. The document was developed under the Partner Standards Development Organization cooperation agreement between ISO and IEEE, as it was approved by Council Resolution 49/2007. This document provides guidance for the utilization of ISO/IEC/IEEE 15288 in the context of SoS in many domains, including healthcare, transportation, energy, defense, corporations, cities, and governments. This document treats an SoS as a system whose elements are managerially and/or operationally independent systems, and which together usually produce results that cannot be achieved by the individual systems alone. This INCOSE guide book perceives that SoS engineering demands a balance between linear procedural procedures for systematic activity and holistic nonlinear procedures due to additional complexity from SoS perspectives.
\r\n\tThe objective of this book is to provide a comprehensive reference on Systems-of-Systems Engineering, Modeling, Simulation and Analysis (MS&A) for engineers and researchers in both system engineering and advanced mathematical modeling fields.
\r\n\tThe book is organized in two parts, namely Part I and Part II. Part I presents an overview of SOS, SOS Engineering, SOS Enterprise Architecture (SOSEA) and SOS Enterprise (SOSE) Concept of Operations (CONOPS). Part II discusses SOSE MS&A approaches for assessing SOS Enterprise CONOPS (SOSE-CONOPS) and characterizing SOSE performance behavior. Part II focuses on advanced mathematical application concepts to address future complex space SOS challenges that require interdisciplinary research involving game theory, probability and statistics, non-linear programming and mathematical modeling components.
\r\n\tPart I should include topics related to the following areas:
\r\n\t- SOS and SOS Engineering Introduction
\r\n\t- Taxonomy of SOS
\r\n\t- SOS Enterprise (SOSE), SOSE CONOPS, Architecture Frameworks and Decision Support Tools
\r\n\tPart II should address the following research areas:
\r\n\t- SOS Modeling, Simulation & Analysis (SOS M&SA) Methods
\r\n\t- SOS Enterprise Architecture Design Frameworks and Decision Support Tools
\r\n\t- SOS Enterprise CONOPS Assessment Frameworks and Decision Support Tools.
Health in general is fundamental in humans, oral health plays an important role, and any alteration in it can influence the general welfare of individuals. Diseases of the oral cavity are very important due to its high incidence and prevalence according to the World Health Organization [1].
\nRegarding the epidemiology of the disease, we can say that from 5 to 15% of the population of the United States suffers from severe periodontitis [2]. Data from the Department of Health of Mexico mention that approximately 8.8% of the Mexican population has chronic periodontitis. This is more common among subjects 35 years of age and older, where it is estimated that the frequency is 22% [3].
\nPeriodontitis is a chronic inflammatory disease that compromises the integrity of the tissues that support the teeth, which include the gingiva, periodontal ligament, dental cement, and alveolar bone, and are collectively known as the periodontium [4, 5].
\nThis disease is caused by specific microorganisms or groups of specific microorganisms, which in the end produce a greater formation of probing depth, recession, or both. When these conditions remain, they cause the tissue to be destroyed and the tooth to be lost. This disturbs the mastication, phonation, and esthetics of the patient, which affect the quality of life [4].
\nThe traditional treatment for periodontitis decreases the microbial presence by means of the mechanical interruption and the elimination of the bacterial layers that form in the surfaces of the teeth and adjacent soft tissues [2].
\nIn the pathology of periodontitis, the clinical, radiographic, and histological characteristics of the gingival groove and pouch epithelium, the underlying connective tissue and the types of resident and infiltrating blood cells in the initial, early, established periodontal injury are known [6].
\nCurrently, the diagnosis requires rapidity, sensitivity, and specificity since determining the stage in which the patient is located is fundamental for a good treatment; for this reason molecules are currently being sought that vary when the person is healthy and when the person has the disease. However, despite all the researches that exist regarding chronic inflammation, the diagnosis of periodontitis is based on clinical measurements; these not only show low sensitivity and specificity as diagnostic tests but are also subjective and laborious. The objective of this chapter is to try to describe what a biomarker is, the types of biomarkers evaluated in periodontitis, the sources to obtain these biomarkers, and their usefulness.
\nThe definition of biomarkers as established by the National Institute of Health (NIH) is as follows: biomarkers are the biological, biochemical, anthropometric, physiological, etc. characteristics, which are objectively measurable, capable of identifying physiological or pathological processes, or a pharmacological response or a therapeutic intervention [7].
\nThere are different types of biomarkers; the ideal biomarker must be specific, sensitive, predictive, rapid, economical, noninvasive, and stable in vivo and in vitro. Additionally, it must have enough preclinical and clinical relevance to modify decisions regarding the pathological process in which applies [7].
\nBefore a biological marker is used in human health studies, its validation is fundamental; therefore, the selection and approval process requires careful consideration of specificity and sensitivity, establishing accuracy, precision, quality assurance, analytical procedure, and interpretation of measurement data, which must be compared with other variables [8].
\nBecause there are certain molecules, like trace elements, proteins (cytokines), and proteolytic enzymes, these have been considered as possible biomarkers of periodontal disease, we will try to discuss the relevance of these groups below.
\nInflammation has evolved as a protective response to an injury, is a primordial response that eliminates or neutralizes foreign organisms or materials, in general; the innate inflammatory response starts in minutes and, if all is well, resolves in a matter of hours. In contrast, chronic inflammation persists for weeks, months, or even years [9]. The inflammatory response that occurs in periodontal disease is mediated mainly by B and T lymphocytes, neutrophils, and monocytes/macrophages. These are activated to produce inflammatory mediators, including cytokines and chemokines [10]. Several pro-inflammatory cytokines including interleukins like IL-1, IL-6, IL-12, IL-17, IL-18, and IL-21; tumor necrosis factor alpha (TNFα); and interferon (IFN-γ) have been demonstrated to be involved in the pathogenesis of periodontitis [2].
\nThere is significant evidence showing that collagenases, along with other matrix metalloproteinases, play an important role in periodontal tissue destruction. The main group of enzymes responsible for the collagen and other protein degradation in extracellular matrix (ECM) is matrix metalloproteinases (MMPs) [11]. Several works have shown that matrix metalloproteinases are upregulated in periodontal inflammation; transcription of matrix metalloproteinase genes is very low in healthy periodontal tissue. In periodontal disease, secretion of specific matrix metalloproteinases is stimulated or downregulated by various cytokines [12].
\nThe importance of calcium in the development of periodontal disease has been recognized since the 1980s [13]. In addition to this, a relationship has been found between people who suffer from periodontitis and who also have osteoporosis [14].
\nAlkaline phosphatase (ALP) is an intracellular enzyme. It is considered that when this enzyme increases in saliva, it can be determined that there is inflammation and destruction of healthy tissues [15]. It is worth mentioning that other enzymes representative of tissue degradation are aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and acid phosphatase (ACP) [16].
\nPhosphorus is an essential element and plays an important role in multiple biological processes, due to the fact that maintaining physiological phosphate balance is of crucial biological importance for bone health [17]. Approximately 85% of phosphorus is in the bone, primarily compounded with calcium (Ca2+), the most abundant mineral in hydroxyapatite (HAP) crystals deposited on the collagen matrix [18].
\nThe importance of phosphate in periodontal disease has been observed in X-linked hypophosphatemia (XLH); this disease is a rare skeletal genetic illness in which increased phosphate in the kidney produces hypophosphatemia and prevents normal mineralization of the bone and bone dentine. In a study of 2017, it was observed that the frequency and severity of periodontitis increased in adults with XLH and that the severity varied according to the treatment of hypophosphatemia. Patients who benefited from early and continuous phosphate supplementation during childhood had less loss of periodontal attachment than patients with late or incomplete supplementation [19].
\nAlthough the pH of the oral cavity is between 5 and 9, it is also known to vary widely depending on several factors. There are studies that report that there is a statistically significant correlation between pH and periodontal pocket formation [20].
\nPeriodontitis is an inflammatory disease of the supporting tissues of the teeth, it is defined as a complex infectious disease that results from the interaction of the bacterial infection and the response of the host to the bacterial challenge, and the disease is modified by environmental factors, acquired risk factors, and genetic susceptibility [21]. In recent years, the inflammatory response has been associated with oxidative stress, specifically with reactive oxygen species since it is considered to play a central role in the progression of many inflammatory diseases [22].
\nOxidative stress create multiple products in affected tissues, such as reactive oxygen species which are free radicals and other non-radical derivatives which are involved in normal cell metabolism [23], other metabolites can damage DNA such as 8-hydroxy2′-deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) which are two of the predominant forms of free radicals induced by oxidative lesions. In fact, 8-oxodG has been widely used as a biomarker for oxidative stress [24].
\nBone resorption is a basic physiological process that is central to the understanding of many key pathologies, with its most common oral manifestation seen as the alveolar bone destruction in periodontitis [25]. The osteoid matrix consists principally of collagen (90%), other smaller proteins, and proteoglycans. The main structural protein of the bone is type I collagen. Consequently, most available bone resorption markers are based on degradation products of type I collagen. According to Koizumi et al. [26], ICTP (telopeptide) is one of the best markers for clinical use.
\nNowadays, RNAs that do not code for protein have taken on great importance because, in addition to maintaining their importance in the determination of cellular phenotypes [27], now they are recognized as dynamic participants in the performance of cellular activities [28].
\nIt has been mentioned and demonstrated that miRNAs are involved in bone metabolism, in fact, some studies have shown that they are associated with the activator of the nuclear factor receptor kappa-B ligand (RANKL) induced osteoclastogenesis. Within these miRNAs, miR-223 [29] was the first to associate with periodontal tissue, although other miRNAs such as miR-15a, miR-29b, miR-125a, miR-146a, miR148 / 148a, miR-223 and miR-92 have been identified more recently as important in periodontal health and have even been considered potential biomarkers [30].
\nOther biomarkers have been analyzed to determine periodontitis. One of these is chondroitin sulfate, which is a natural glycosaminoglycan (GAG) present in the extracellular matrix [31]; chondroitin sulfate is recognized for its immunomodulatory effects, such as the reduction of nuclear translocation NF-κB, the decrease in the production of pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α), and the decrease in expression and activity of nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) [32]. Another molecule that has been proposed as a possible biomarker is MUC-4. Mucins are high-molecular-weight glycoproteins, are involved in diverse biological functions, are members of transmembrane mucin family, and are expressed in airway epithelial cells and body fluids like saliva, tear film, ear fluid, and breast milk [33]. It has been reported that the production of MUC-4 could be regulated by inflammatory cytokines [34].
\nSaliva is a seromucous secretion, consisting of 99% water; however, saliva is also composed of glycoproteins, phosphate ions, bicarbonate, sodium, chlorine, fluorine, calcium, and potassium and has a neutral pH [35], which forms a film of liquid consistency that covers the surface of the oral mucosa, with the purpose of lubricating it and keeping it moist among many other characteristics for the maintenance of oral health [36]. The composition of saliva varies from one place to another in the oral cavity of each individual [35]. If there are changes in its composition, there may be significant alterations in deterioration of the health of the host [37].
\nDue to the described characteristics of saliva, several authors have claimed that these salivary constituents may actually be useful indicators of both local and systemic disorders. These revelations have formed the basis of the field of saliva diagnosis and, therefore, have triggered research that culminated in the identification of saliva-based biomarkers for disorders ranging from cancer to infectious diseases [38]. In addition to the above, saliva has several advantages when compared to other sources for diagnosing diseases since saliva is easily collected and stored and ideal for early detection of disease as it contains specific soluble biological markers [39]. Saliva has been used to diagnose diseases as diverse as autoimmune disorders, cardiovascular diseases, diabetes, HIV, oral cancer, and oral diseases [40].
\nIn our review we observed that there are about 15 works that were dedicated to investigate the possible use of these proteins determined in saliva as biomarkers to determine periodontitis. We can say that of all the works, the majority focuses on comparing healthy groups with periodontitis; only three researches include the group of gingivitis, which indicates that this group should be used more for this type of studies. We need to remember that gingivitis is considered an intermediate stage that may or may not lead to periodontitis [41], and if the patient performs good dental hygiene in combination with the treatment, in general, progression to periodontitis can also be stopped [42].
\nOn the other hand, the cytokine that has been most explored and that better results have given as biomarkers to detect in saliva is the cytokine IL-1β [43, 44, 45, 46, 47, 48]; this must be due to the recognized importance of interleukin-1β, as an important mediator in the pathophysiology of periodontitis [49].
\nHowever, other cytokines such as IL-6 and IL-2 have also been explored [43, 44, 48, 50]; IL-6 is recognized for playing a role as a pro-inflammatory cytokine acting on bone resorption in the presence of infections [51]. Regarding IL-2, a study that investigated cytokine profiles at different stages of the development of periodontitis found that levels of mRNA for IL-2 were significantly associated with the phase of resolution of the disease [52]. This agrees with reports that IL-2 has been implicated in the stimulation of osteoclasts [53].
\nRegarding MCP-1, Gupta et al. [54] conducted a study in 45 patients with an average age of 43 years for healthy patients and 41 for patients with periodontitis, with results similar to Nisha et al. [55]. In both studies it was found that the levels of MCP-1 in saliva can be a good biomarker for the development of periodontal disease. One difference between the studies is that Nisha’s work included a group of patients with gingivitis, while Gupta’s study does not include it.
\nRegarding the possibility of using prostaglandin E2 (PGE2) as biomarkers in saliva to diagnose gingivitis, Syndergaard et al. [56] conducted a study with 80 participants, 40 without gingivitis and 40 with gingivitis, and found that the levels of PGE2 in the group with gingivitis were significantly higher compared with the control group. This study reported that PGE2 remained high after prophylaxis. As for other studies conducted with the purpose of comparing the concentrations of PGE2, Sanchez et al. [82] conducted a study in which the population was 74 adult subjects who were grouped according to the progress of the periodontal disease in mild, moderate, and severe; the conclusion was that the levels of PGE2 increase as the severity of the periodontal disease progressed. In addition a high sensitivity and specificity were reported.
\nWhen TNF-α is evaluated as a possible biomarker for the diagnosis of periodontitis, we found that there are discrepancies since in some studies, such as Eivazi et al. [57] who conducted a study with one healthy group and another with chronic periodontitis which reported that before and after starting treatment, the concentrations of TNF-α in saliva were higher in the healthy group than in the periodontitis group. In contrary to the results reported by Yue et al. [48], they found that TNF-α concentrations were higher in the saliva of patients with advanced periodontitis than in the saliva of healthy subjects. Yue’s study is supported by studies that investigate the loss of the alveolar bone since the concentration of TNF-α in subjects with alveolar resorption is low [58].
\nYue et al. [48] found that in the saliva of patients with aggressive periodontitis (AP) have higher levels of IFN-γ in the saliva compared to subjects without AP; this decrease was statistically significant throughout the course of treatment (p < 0.05).
\nMatrix metalloproteinases (MMPs) are key proteases involved in destructive periodontal diseases. A total of 23 MMPs have been described. These MMPs can be found in periodontal tissues as pro-forms, active forms, complex species, fragmented, and cell-bound species [59]. MMPs are the most important group of proteinases responsible for the degradation of extracellular matrix proteins during periodontitis, and any imbalance between MMPs and their inhibitors can trigger the degradation of the ECM, the basement membrane, and the alveolar bone [60].
\nIn this way and due to the importance of MMPs, several researchers have been dedicated to try to determine if MMPs are opportune as biomarkers. Gursoy et al. [61] did a study with the objective of detecting possible markers of periodontitis in saliva, with high sensitivity and specificity; to determine this, the salivary concentrations of MMP-8, MMP-9, and MMP-13 among others were measured in 230 subjects. The concentrations of MMP-8, MMP-9, and MMP-13 in saliva were higher in subjects with generalized periodontitis than in controls; however, according to the authors, MMP-8 was the only marker capable of differentiating subjects with severe bone loss of those who presented mild bone loss, so they consider that MMP-8 is a strong candidate to detect alveolar bone destruction [61]. These results were corroborated by Rathnayake et al. [46] who found that MMP-8 could be used as a marker of periodontal disease in large patient populations. An interesting fact that they reported is that smokers compared to non-smokers showed slightly lower concentrations of MMP-8.
\nAnother interesting fact regarding MMP-8 by Ebersole et al. [25] in a study that included 30 healthy volunteers and 50 patients diagnosed with chronic periodontitis is that MMP-8 (among others) was investigated as a biomarker associated with inflammatory and destructive processes of periodontal disease and reported that the levels of MMP-8 of patients who have periodontitis are very different from the normal levels found in healthy subjects and showed a particular diagnostic potential.
\nMorelli et al. [50] examined 168 participants and found higher salivary levels of matrix metalloproteinases, MMP-3, MMP-8, and MMP-9, in diseased groups compared to healthy. In the same year, Miricescu et al. [62] carried out a study where 20 patients were also included with chronic periodontitis and 20 controls and different biomarkers were evaluated including matrix MMP-8, and as a result it was found that the levels of MMP-8 were significantly increased in patients with chronic periodontitis compared to controls.
\nEbersole et al. [43] conducted a study that included 65 healthy subjects, 43 subjects with gingivitis, and 101 subjects with periodontitis. In this study, the levels of MMP-8 very similar to the previous studies stood out in a significant way in the group of periodontitis compared to those of gingivitis and healthy subjects. In a more categorical way, Borujeni et al. [63] reported that MMP-8 provides a substantial sensitivity with which physicians can use the test for MMP-8 and thus detect periodontitis in their patients.
\nSimilarly, Gupta et al. [64] made an investigation with the objective of establishing MMP-8 as a noninvasive marker for the early diagnosis of chronic periodontitis. The study included 40 subjects who were divided into two groups: 20 healthy subjects and 20 patients with chronic periodontitis. The results of this study demonstrate high concentrations of MMP-8 in individuals with chronic periodontitis.
\nAlready Lira et al. [65] continued to explore the importance of MMP-8 and conducted a study that aimed to evaluate the levels of markers related to innate immunity, the MMP-8 in the saliva from patients with aggressive generalized periodontitis, and patients with gingivitis and healthy. In the saliva, MMP-8 levels were higher in aggressive periodontitis than in healthy patients; in this way it is reaffirmed that MMP-8 can be an important biomarker of periodontitis.
\nOther researchers such as Virtanen et al. [66] continued to look for other metalloproteinases as potential biomarkers, and some reaffirm that the salivary concentrations of matrix metalloproteinases such as MMP-8 and MMP-9 are slightly higher in patients with periodontitis, although they report that the differences between the groups were not significant. Interestingly, this group reports that MMP-13 values were significantly higher in the group without periodontitis compared to patients with periodontitis and also report that the concentration of MMP-13 may have some gender implications in periodontitis.
\nFollowing with the MMP-8, Mauramo et al. [67] studied whether the levels of MMP-8 in the saliva are associated with periodontitis in 258 subjects. Periodontitis was more frequent among subjects with high levels of MMP-8 in the saliva. The highest levels of salivary MMP-8 were associated with any periodontal diagnosis (mild, moderate, or severe). They concluded that elevated levels of MMP-8 in the saliva are associated with periodontitis in a normal adult population.
\nWhen we search for studies that have explored the detection of calcium present in saliva as a biomarker, we find that while some studies report the usefulness of calcium because the subjects in the periodontitis group had significantly higher levels of salivary calcium than gingivitis and healthy group [68, 69], another work find that high salivary calcium content can be correlated with good dental health but not with periodontal bone destruction [70].
\nAccording to Patel et al. [69] study, phosphorus can be considered a biomarker for the diagnosis of sick and healthy periodontal tissues. The study concludes that as the severity of periodontal disease increases, it also increases total phosphorus levels.
\nAlkaline phosphatase has been evaluated in saliva as a possible biomarker for the detection of periodontitis. Dabra and Singh [16] first study 20 healthy subjects with gingivitis, and 20 with chronic periodontitis were included. This investigation showed a statistically significant increase in alkaline phosphatase activities in the saliva of patients with periodontal disease compared to the control group. A recent study of Patel et al. [69] included 150 healthy subjects, 50 patients with chronic generalized gingivitis, and 50 with periodontitis. In this study it was shown that alkaline phosphatase can be considered for the diagnosis of diseased and healthy periodontal tissues; since as the severity of periodontal disease increases, it also increases alkaline phosphatase levels.
\nThe pH of the saliva has been evaluated, and it has been found that there is a significant change in the pH depending on the severity of the periodontal condition, so the pH can be useful as a rapid diagnostic biomarker in the consultation. The study suggests that the pH becomes alkaline when patients have chronic gingivitis, but it becomes acidic when there is periodontitis [71].
\nA 2015 study found that the concentrations of ICTP were higher in the group with periodontitis and lower in the group with healthy patients; this study suggests that the level of ICTP in saliva increases as the patient presents with gingivitis and periodontitis, since the periodontitis samples had the maximum concentration of salivary ICTP. The authors suggest that more studies with a larger sample size be conducted to establish a correlation between the concentrations of ICTP and the individual clinical parameters [72].
\nIn the oral cavity, we find three fluids: the gingival crevicular fluid, the serum, and the total saliva. The gingival crevicular fluid is an exudate, and at present the quantification of its constituents is a current method to identify specific biomarkers with a reasonable sensitivity [73].
\nThe gingival crevicular fluid is an exudate secreted by the gums that can be found in the crevices located at the point where the gumline meets the teeth. The concentrations of this fluid are usually low but may increase when an inflammatory process occurs in the oral cavity [74].
\nIt is considered that due to the noninvasive and simple nature of its collection, the analysis crevicular fluid can be beneficial in determining the periodontal status [75].
\nRegarding the cytokines that have been evaluated, we can say that they are very similar to those that were evaluated in the saliva; besides that the results are also similar since it has been found that IL-β is the most important cytokine since diverse studies confirm high levels in periodontal disease compared to healthy [48, 76, 77].
\nIn the same way it happens with IL-2 and IL-6, where several studies conclude that both interleukins are important as biomarkers to identify patients with periodontal disease [48, 76, 78].
\nRegarding MCP-1, the levels of this biomarker were significantly higher in crevicular fluid than healthy subjects (p < 0.001) [54].
\nRegarding IFN-γ and TNF-α, both biomarkers were significantly higher in patients with aggressive periodontitis; this correlates with the findings in saliva where both biomarkers were elevated in sick patients [48].
\nWith respect to metalloproteinases, studies of biomarkers in crevicular fluid have shown that MMP-7 could be useful as a potential new biomarker for periodontitis [79]. Similar to that determined in saliva, MMP-8 is increased in patients with periodontitis and provides a good sensitive measure to establish differences between patients and healthy individuals [77]. It is also useful as a complementary tool in the periodontal diagnosis [67]. Another metalloproteinase that has proved useful is MMP-9. This metalloproteinase correlates with clinical measures and results in good sensitivity to predict the progression of periodontal disease [77].
\nA study was conducted to determine the usefulness of alkaline phosphatase as a biomarker, and this study showed a correlation with the clinical characteristics when mediated in crevicular fluid [80].
\nAccording to Mico et al. [81], epigenetic regulation by miRNAs has not yet been studied in periodontal disease using crevicular fluid. They analyzed the possible use as biomarkers of six miRNAs: miR-671, miR-122, miR-1306, miR-27a, miR-223, and miR-1226. Of the six miRNAs analyzed, only miR-1226 can be used as a promising biomarker for periodontal disease since it had statistically significant differences between the healthy group and patients with periodontitis.
\nAs previously mentioned, 8-OhdG is a marker of DNA damage and is considered a biomarker to detect oxidative stress [24], that is why it is not surprising that its usefulness as a biomarker of periodontitis was explored. This study was conducted in crevicular fluid, and it could be determined that evaluating this biomarker in crevicular fluid is more effective than in saliva and that it can be useful as a biomarker for determining periodontitis since according to the authors, the severity of the periodontal disease can be revealed [82].
\nTelopeptide has also been evaluated as a biomarker in periodontitis in the study by Aruna [83], which suggests that this biomarker could be useful as a specific marker of bone turnover in patients with periodontitis.
\nChondroitin sulfate is a biomarker that, due to its results in patients with chronic periodontitis, suggests that it is important in the diagnosis to evaluate the severity of alveolar destruction [80]. MUC4 protein was measured in crevicular fluid and according to this study can be considered as a new biomarker to rule out patients with periodontitis from healthy ones (p < 0.01) [79].
\nA final marker that we have considered for crevicular fluid is osteoprotegerin; this biomarker was studied by Kinney et al. [77]. They studied healthy patients, with gingivitis and periodontitis, finding that the biomarker OPG was elevated in patients with periodontal disease with a significant difference when compared with healthy patients, so they conclude that this biomarker has a good sensitivity to rule out periodontal disease of gingival health.
\nSerum in humans is a matrix commonly used in clinical and biological studies. Many authors recommend using the correct matrix. Both plasma and serum are derived from whole blood that has undergone different biochemical processes after blood extraction. The serum is obtained from the blood that has been clotted [84].
\nIn a study conducted by Nile et al. [85], interleukin IL-17 was identified as a reliable biomarker in 40 patients with chronic periodontitis, later these subjects underwent periodontal therapy, and the values of this interleukin decreased; thus, they consider that IL-17 can be a valuable protein to monitor healing processes after a periodontal intervention.
\nAnother protein related to the immune response MCP-1 was studied by Boström et al. [86]. They studied healthy patients with periodontitis and detected that the MCP-1 protein was increased in the serum and inflamed connective tissue comparing it with healthy patients. In this way, they considered that MCP-1 can help identify patients with periodontitis.
\nWithin the metalloproteinases studied in serum, Lira et al. [65] reported that MMP-8 is elevated in patients with aggressive generalized periodontitis compared with the rest of the patients.
\nSreeram et al. [87] studied the transpeptidase biomarker (GGT) in healthy subjects and with periodontitis. This biomarker showed elevated levels in patients with periodontitis with respect to healthy. Among the conclusions found in this study was the GGT is useful, economic, and easy to use.
\nOnder et al [88] studied 4-hydroxynonenal (4-HNE) as a biomarker in serum, concluding that biomarker 4-HNE was at high levels in patients with periodontitis.
\nIn another serum study, other biomarkers of oxidative stress as total antioxidant capacity (TOS) and oxidative stress index (OSI) used in patients with periodontitis and healthy found high levels of TOS and OSI in patients with chronic periodontitis, this suggests that these biomarkers play important roles in periodontitis [89].
\nCalprotectin was studied by Lira et al. [65]; this biomarker was analyzed in patients with aggressive generalized periodontitis, found elevated levels in these patients compared with healthy and with gingivitis. In addition to the previous study, Nizam et al. [90] studied myeloperoxidase (MOP) and found that it increases in patients with generalized periodontitis compared to healthy ones; nevertheless Meschiari et al. [91] reported similar levels in patients with periodontitis and healthy. This discrepancy between both authors is possible due to the demographic variation and probably the anatomical site where the sample was extracted for analysis.
\nBlood can be a universal reflection of the state or phenotype. Its cellular components are erythrocytes, thrombocytes, and lymphocytes. The liquid portion is called plasma, when all the components are retained. The concentrations of various plasma components are routinely determined in clinical practice [92]. In this way, it is not surprising that biomarkers are sought in plasma.
\nAmong the cytokines evaluated in plasma, we can say that IL-8 and IL-10 were useful to discriminate patients with aggressive periodontitis from healthy ones, and we can add that they were interleukins different from those expressed in the crevicular fluid where IL-2 and IL-6 were relevant [78].
\nOn the other hand, IFN-γ is a biomarker that has been determined in plasma and was significantly high in patients with aggressive periodontitis, this correlates with the findings in crevicular fluid where this biomarker was elevated in sick patients [78].
\nRegarding MIP-1α, when it was determined in plasma, it was determined that it could be useful to discriminate patients with aggressive periodontitis from healthy ones, since it was found to be elevated [78].
\nPeriodontitis is one of the most prevalent illnesses in humans [93]. One of the main challenges faced by the periodontics field is to improve the methods for diagnostic and prognostic of periodontitis [94]. Biomarkers, previously described, can be useful in monitoring the current state of the disease, the effectiveness of the treatment, and possibly predict the progression. However, currently the single ideal biomarker displaying high specificity and sensitivity for discriminating and monitoring this disease has not been determined. Thus, the combination of different biomarkers could be more advantageous than single biomarkers [93]. This would provide a more accurate panorama of the state of periodontal disease.
\nClassic methods for periodontitis diagnosis as the inspection and the palpation by the specialist can be relatively inaccurate. Additionally, the use of periodontal probes, and radiography could only provide information about previous periodontal damage rather than the current state [93]. Thus, biomarkers have been proposed as complementary methods to defeat the mentioned limitations monitoring the clinical response to an intervention and future risk [95].
\nDesirable’s characteristics in test using biomarkers in periodontitis are easy to perform, rapid, and low cost, which could allow clinicians to perform early diagnosis and more effective personalized treatment.
\nDifferent factors are involved in the development of periodontitis, and a complex interaction between bacteria and immune system is observed. Additionally, periodontitis has been linked to at least 43 systemic diseases [96]. Thus, it is important to be careful when interpreting the results of biomarker tests because different factors could have a confounding impact on potential biomarkers [97]. Additionally, further large-scale studies are needed to prove specificity and sensitivity of the biomarkers analyzed in periodontitis and for utilization in routine clinical practice in the future.
\nCurrently, a number of biomarkers have been sought for the detection of periodontal disease, but so far an ideal biomarker has not been found that helps early detection of the disease; perhaps the combination of several is the most appropriate.
\nThe search for biomarkers continues, we suggest for further studies in search of new biomarkers, it should be consider having a larger sample size, a random source and keep a follow-up.
\nPeriodontal disease is already a very common problem in many countries; due to the above, the monitoring and reduction of the progress of periodontitis through surveillance and health promotion are part of the national health goal of countries like the United States [98].
\nDue to this, there has been an exhaustive search in recent years of biomarkers obtained from various sources, with saliva being the most used; however, we believe that new studies should include groups of patients with gingivitis on a daily basis, since this is considered an intermediate phase in which the patient can (if he/she carries out good dental hygiene and continues the treatment) stop the development of periodontitis [42], so that limit levels of these biomarkers may be detected.
\nIn addition to this, numerous studies have shown so far that among the best options for biomarkers are proteins such as IL-1β, MMP-8, and ICTP.
\nFrom our point of view, we should also include and explore molecules such as miRNAs and other noncoding RNAs such as lncRNA and circRNA, in addition to the classical molecules that are already known to directly participate in the development of inflammatory pathology, since the study of these molecules could yield new perspectives on the development and progression of periodontal disease, which at some point may have important applications as biomarkers with leading activity in the development and manifestation of periodontitis.
\nWe would like to appreciate the assistance of Ojeda Verdugo Einer Isaac, MD for providing technical editing and proofreading to improve the manuscript.
\nThe authors declare no conflict of interest, financial, or otherwise.
Aortic root dilation (AoD) is frequently an incidentally discovered, asymptomatic finding in that is seen on various imaging modalities [1]. The anatomy of the aortic root includes the annulus, sinuses of Valsalva, sinotubular junction and ascending aorta [1], with the size being a function of a patient’s biologic variables such as height, age, BSA, and gender [1, 2]. However, while natural variations in the size of the aortic root are well known, the identification of progression from normal to pathologic AoD is a key clinical diagnosis that carries significant cardiovascular risk including aortic dissection, rupture, valvular regurgitation and cardiac tamponade [1, 3, 4, 5]. The etiology of pathological AoD is varied, ranging from congenital, infectious, autoimmune, and idiopathic conditions; and influences the medical and surgical management [1, 5]. Due to the variety of clinical conditions that can result in AoD, and the risks associated with worsening AoD, a thorough understanding of the pathophysiology of AoD, noninvasive imaging modalities and pharmacologic therapies is critical. The aim of this chapter is to review the most common conditions associated with AoD, appropriate imaging modalities, and treatment strategies to manage AoD.
\nMultiple etiologies of AoD exist such as Marfan syndrome, bicuspid aortic valve, Loeys-Dietz and Ehler-Danlos syndromes, idiopathic conditions, hypertension, infections, and inflammatory disorders. In this chapter, we will discuss the various etiologies categorized into two standardized groups—genetically-mediated and nongenetically mediated AoD.
\nGenetically-mediated aortic root dilation or enlargement is the leading cause of thoracic aortic aneurysms. Marfan syndrome (MFS), the prototype condition for AoD, and bicuspid aortic valve has led to a greater understanding of AoD pathophysiology, pharmacologic treatment, timing of surgical intervention and optimal surveillance strategies with noninvasive imaging [6].
\nMFS is one of the most common hereditary disorders of connective tissues and is characterized by manifestations in cardiovascular, skeletal, and ocular systems [7]. MFS is the most common genetic cause of thoracic aortic aneurysms (TAAs). Its inheritance is almost exclusively autosomal dominant and mostly involves a mutation of the fibrillin-1 (FBN1) gene encoding the connective tissue structural protein fibrillin-1 [8]. The widely accepted incidence of Marfan syndrome is ~1 in 5000 individuals [9].
\nAlthough the inheritance pattern is predominantly autosomal dominant, rare cases of autosomal recessive FBN1 gene mutations has been described [10]. While patients with Marfan phenotypes usually have an affected family member, 25% of the cases are sporadic due to de novo mutations [9]. In addition, in <10% of Marfan cases, no mutation of FBN1 was determined [11]. Since it was first identified as the main cause of Marfan syndrome, FBN1 mutations, depending on how it is mutated, were linked to a variety of syndromes and phenotypes [12]. Animal studies investigating the pathophysiology of the disease demonstrated over-expression of TGF-β in the mitral valve preceding prolapse, the aorta associated with dilatation, skeletal muscle associated with myopathy, and the dura leading to ectasia [12]. Later, mutations in TGF-beta receptor 2 (TGFBR2) and TGFBR1 genes were identified in some patients with Marfan phenotypes and subsequently implicated in the disease process in FBN1 mutation negative individuals [13, 14, 15]. These genes were also linked to another condition later, namely Loeys-Dietz syndrome (LDS) [14].
\nThe diagnosis of Marfan syndrome is established by using a combination of clinical manifestations, family history, and the presence of FBN1 mutation. In order to facilitate accurate recognition of the syndrome and improve patient management and counseling, a set of defined clinical criteria, called the Ghent nosology was developed [16] and later revised [17] (Table 1). Apart from the genetic testing for FBN1 mutation, Ghent nosology uses a systemic score calculation using clinical manifestations of Marfan and an aortic root dilatation Z-score (see noninvasive imaging below).
\nPatients with family history of Marfan disease | \n
\n
| \n
\n
| \n
\n
| \n
Patients without family history of Marfan disease | \n
\n
| \n
\n
| \n
\n
| \n
\n
| \n
Revised Ghent nosology.
One of the major causes of mortality and clinical hallmark of Marfan syndrome is aortic root dilation and related complications such as dissection, rupture and/or aortic valvular regurgitation. Aortic root dilation is typically first identified on echocardiography in 60–80% of Marfan patients [18]. Therefore, surveillance echocardiography has been routinely used to serially monitor aortic dimensions. If the aortic root diameter is above 4.5 cm in adults, aortic dilation rates are above 0.5 cm/year, and/or significant aortic insufficiency is already present, more frequent monitoring is recommended [6] (see Diagnosis and Surveillance of Aortic Root Dilation below for more detailed guidelines).
\nBicuspid aortic valve is one of the most frequent congenital heart anomalies in adults, affecting 0.9–2% of the population [19]. Most cases of bicuspid aortic valve are familial and studies show that heritability of the disease is ~90% making it an autosomal dominant pattern with incomplete penetrance [20]. Bicuspid aortic valve can occur alone or with other congenital cardiovascular disorders such as coarctation of the aorta, supravalvular or subvalvular aortic stenosis, and ventricular septal defect [21].
\nThe diagnosis is often established by transthoracic echocardiogram (TTE), which has high sensitivity (~92%) and specificity (~96%) [22]. TTE is also useful for surveillance of potential complications of bicuspid aorta such as aortic stenosis, aortic dilation, aortic regurgitation, and infective endocarditis [23]. Given the risk of inheritance, first degree relatives are also recommended to be screened with TTE [21].
\nPrevalence of aortic dilation in patients with bicuspid aortic valve disease ranges from 20 to 84% depending on the criteria used in different studies [24]. The risk of aortic dilation increases with age and the risk of dissection increases as the aortic diameter increases [25, 26]. When the aortic root diameter is above 4.5 cm, there is a family history of aortic dissection, or aortic diameter change is rapid it is recommended to perform echocardiogram annually [21]. More frequent surveillance is recommended for patients with aortic root diameters approaching surgical thresholds (see Surgical Interventions section below).
\nLoeys-Dietz syndrome (LDS) is a rare congenital syndrome characterized by hypertelorism (widely spaced eyes), a split uvula or cleft palate, tortuous arteries and aortic aneurysms. LDS shares many features with Marfan syndrome [14]. Most of the LDS cases are sporadic or show an autosomal dominant pattern of inheritance [14].
\nThe incidence and prevalence of the disease is still not well established.
\nLoeys-Dietz syndrome was initially classified into two subtypes based on the severity of the cutaneous and craniofacial features but later was divided into six subtypes stratified by genotypes [27]. These subtypes are labeled 1–6 and associated with mutations in TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3, SMAD2, respectively [27]. Type 1 and type 2 are the most commonly seen subtypes with frequencies of 20 and 55% among all subtypes, respectively [28].
\nAortic root dilation is a hallmark feature of this disease entity and is frequently seen in patients (~80%) [29]. Another vascular manifestation is aneurysms throughout the arterial tree. This is a concerning clinical manifestations of the disease and can cause aggressive arteriopathy; therefore, early operative intervention at ascending aortic diameters of ≥42 mm is recommended [30].
\nEhlers-Danlos syndromes (EDS) are a heterogeneous and relatively rare group of connective tissue disorders characterized by skin hyperextensibility, joint hypermobility, and tissue fragility [31]. Ehler-Danlos syndrome can present with a variety of clinical manifestations and can be caused by different kinds of genetic mutations. Overall prevalence of EDS is ~1 in 5000 and EDS hypermobile (hEDS) is the most common type [31].
\nVascular complications can be seen with different types of EDS; however, it is most commonly seen in type IV (vascular or arterial ecchymotic type; vESD), characterized by an autosomal dominant mutation in COL3A1 (collagen, type III, α-1 gene) encoding type III procollagen [32]. Up to 80% with vESD patients suffer from vascular complications by the age 40 years [32]. Therefore EDS patients, especially vEDS, patients should be routinely evaluated for aortic root disease. These patients are recommended to undergo elective operation at smaller diameters (4.0–5.0 cm) to avoid acute dissection or rupture. Patients with a growth rate of more than 0.5 cm/year in an aorta that is <5.5 cm in diameter are recommended to be considered for operation [33].
\nAortic root dilation is an established phenomenon that has shown strong correlations to key pathobiological factors such as age, body surface area (BSA), height and gender. The correlation of aortic root size with age and BSA were initially described in the development of screening nomograms using M-mode echocardiograms [34]. Follow up studies with 2D echocardiography further validated these correlations, allowing for the development of nomograms for normal patient populations or adjusted for patients with underlying congenital disorders (i.e., Marfan syndrome) [2, 35]. These studies evaluating AoD by echocardiograms are further supported by reviews of autopsy data that show clear correlations to key pathobiological factors such as increased age and height with AoD [36].
\nDespite the validation of age as being correlated strongly with AoD, the mechanism of age on the development of AoD still remains an area of active research. One of the predominant hypotheses is based on the idea of cyclic stress, and how the aorta degrades through gradual mechanical decline of elastin proteins [37]. Elastic arteries, namely the aorta, are estimated to dilate by 10% with each beat [38]. It is hypothesized that the shear stress over a normal lifetime results in the degradation of elastic lamella, resulting in arterial dilation and stiffening [38]. This is corroborated by histologic data demonstrating damage to medial elastin of the proximal aorta [38]. Furthermore, there is evidence to suggest that in the absence of risk factors such as hypertension or atherosclerosis, the aortic wall undergoes age-associated reprograming that is proinflammatory promotes progression of arterial disease [39]. Wang et al. demonstrated in pathologic samples of aortas that age correlated with increased smooth muscle cell invasion, and increased production of downstream angiotensin II mediators [39].
\nIn addition to age and BSA, gender is another key factor which can increase the risk and progression of AoD [40]. In the Framingham study of 1849 men and 2152 women, not currently diagnosed with cardiac disease or having a cardiac history, aortic root was 2.4 mm smaller in women than men with m-mode echocardiography [40]. A systematic review in 2014 of 10,741 patients with hypertension revealed men had a significantly higher incidence of AoD relative to women [41].
\nIn conclusion, a series of biological variables are correlated with AoD, and it is important to take these into account as they are potential confounders or contributors in the evaluation of patients with pathologic AoD. Even exercise capacity has been correlated with AoD, with a recent meta-analysis showing that athletes defined by participation in National Collegiate Athletic Association (NCAA) or international equivalent had an aortic root diameter that was larger than nonathletic controls [42], and a statistically significant increase by measurement of sinuses of Valsalva and aortic root annulus [42]. It is important to understand the significance of biological variables such as age, height, BSA, or gender to fully evaluate pathologic AoD without the influence of known confounders.
\nHypertension is a well-known risk factor for aortic dissection, and in some studies, it is estimated to factor into roughly half of the overall risk for aortic dissection [43]. A recent prospective cohort study of 30,447 patients, 86% of patients who developed aortic dissection had hypertension [4]. However the relationship between hypertension and AoD is not as clearly established. In a Framingham study of 3195 patients, there was no relationship between the development of AoD with hypertension [44]. A subsequent follow up study of Framingham participants evaluating aortic root diameter was positively correlated with mean arterial pressure, but negatively associated with pulse pressure, indicating that the mechanism behind AoD is more complicated [45]. Moreover, investigations have shown that in patients with other comorbidities for AoD, such as, Turner syndrome, hypertension is significantly associated with increased prevalence of AoD [45]. This has led to interesting insights into the cyclic stress hypothesis of the development of AoD [43]. If AoD develops due to chronic shear stress, then it would be expected that AoD is correlated with higher pulse pressure (PP), which would presumably lead to greater stress and aortic dilation [43]. However, studies have reported an inverse relationship between AoD and PP [43]. Additionally a systematic review in 2014 showed that in a population of 10,791 hypertensive patients, 9.1% had AoD with a significant gender skew toward men [41]. However there was no significant correlation of mean arterial pressure or pulse pressure values and AoD [41]. While hypertensive patients have a higher incidence of AoD, the mechanism remains to be further investigated. Moreover, these unclear correlations between MAP, PP, and AoD suggest that the aorta is not static, but a dynamic structure whose response to stress, such as hypertension, is still being elucidated [43].
\nSince the first mass production of penicillin in 1945, the modern era of antibiotics has resulted in a decrease in the prevalence of mycotic aneurysms due to bacterial infections in developed countries [46, 47]. However they can still be found in developing countries, and are rare but well described causes of mycotic aneurysms [46]. Most common pathogens include Salmonella, Staphylococcus and Streptococcus pneumonia, and while rare have been in the pathogenesis of mycotic aneurysms of the aortic root [46, 48, 49]. Other common bacteria include Mycobacterium tuberculosis and Treponema pallidum, which will be discussed below, and more rare causes include Listeria, Bacteroides, Clostridium septicum, and Campylobacter jejuni [46]. With the majority of bacterial aortitis, aneurysm development is generally saccular, and Salmonella has been reported in case studies to predominantly affect the abdominal aorta than the thoracic [46, 48]. Infections with Staphylococcal species generally are related to underlying aortic valve infections, but have been reported to progress into aneurysms of the aortic root [46, 49].
\n\nTreponema pallidum, a sexually transmitted spirochete which is the causative organism of syphilis, is a well characterized cause of aortitis [46, 50, 51]. Cardiovascular involvement is limited to late stage, or tertiary syphilis, and generally occurs 5 to upwards of 40 years after primary infection [50, 51]. Aortitis, and aneurysm development is due to invasion of the vasa vasorum, resulting in obliterative endarteritis that leads to degradation of the aortic media [50, 51]. The chronic inflammation results in fibrosis of the intima, a phenomenon known as “tree-barking” that ultimately progresses to aneurysm development. In an autopsy study in 1960 of 51 aortic aneurysms secondary to syphilitic aortitis, 7.8% were found at the sinuses of Valsalva and 29.4% involved the ascending aorta, representing a majority of the sample [52]. This predominance to the ascending thoracic aorta have been further corroborated in later studies, however the detailed echocardiographic analysis of syphilitic aortitis, specifically in relation to AoD is limited due to the rarity of the disease presentation [46, 50].
\nTuberculosis is a relatively common infection especially in developing countries [53]. Mycobacterium tuberculosis, the causative pathogen, is a known cause of mycotic aortic aneurysms [46, 50]. Pathogenesis of tuberculous mycotic aneurysm is believed to be due to lymphatic spread or hematogenous seeding, and mortality rates are reported as high as 60% in patients who develop this complication [50]. While more commonly affecting the distal aortic arch and descending aorta, there are case reports detailing aortic root aneurysms due to tuberculosis [50, 54].
\nThere have been case reports proposing an association between aortic aneurysms and HIV [50]. In a variety of these cases the causes are generally multifactorial, as the majority of cases have reported coinfections (Q fever and leishmaniasis) or comorbid autoimmune conditions (giant cell arteritis) [55, 56]. It is still an area of investigation as to whether there is a true association, and there is sparse data showing a relationship with AoD.
\nAnkylosing spondylitis, a seronegative spondyloarthropathy, is a chronic, progressive rheumatologic disorder, and was one of the first found to be associated with aortitis [50, 57]. The proposed mechanism of AoD in ankylosing spondylitis is fibrous growth development along the intima, which leads to subsequent weakening [57]. Prior TEE studies further evaluated the prevalence of AoD in ankylosing spondylitis, and 82% of patients with ankylosing spondylitis had aortic root abnormalities [58]. Specifically, 61% of patients had aortic root thickening and 25% of patients had AoD [58]. AoD in these populations is a relatively common phenomenon and is associated with significant cardiac morbidity [45, 57].
\nRelapsing polychondritis is another autoimmune disorder, which is a multisystem inflammatory disorder that primarily affects the cartilaginous structures of the body [59]. Cardiovascular involvement is common, estimated to be the second most frequent cause of death and can result in aneurysm development in 5% of cases of both thoracic and abdominal aorta [50, 59]. AoD has been known to occur, albeit rare, with cases of requiring surgical revision after the development of aortic regurgitation [60, 61].
\nTakayasu arteritis is a chronic granulomatous large vessel vasculitis, predominantly found in pediatric populations [50, 62]. A rare disorder, the pathogenesis is characterized by granulomatous panarteritis that can affect the entirety of the aorta and major branches, however predominantly affects the common carotid and subclavian artery [62]. While rare, there are reports of AoD from Takayasu arteritis resulting in aortic regurgitation [63, 64].
\nGiant cell arteritis is a large vessel vasculitis that is characterized by chronic granulomatous inflammation [50]. While commonly affecting carotid, temporal and vertebral arteries, it has been known to affect the ascending aorta, at times resulting in dissection or aortic valve insufficiency [50]. The development of AoD from GCA may be influenced by other comorbid conditions such as HIV; however, this association is currently only supported with case reports [55].
\nAdditionally left ventricular hypertrophy is reported to be positively correlated with AoD. Early retrospective reviews of echocardiographic studies have shown a positive relationship between LVH and AoD, and this has been further supported in subsequent systematic reviews [41, 65]. Patients with AoD with concomitant left ventricular hypertrophy are shown to have an increased risk of adjusted cardiovascular events [66]. However as with previous studies, the exact mechanism between LVH and AoD is still being determined.
\nAortic root dilation is typically a silent disease, with most cases being diagnosed incidentally on imaging. AoD can become symptomatic as the aneurysm enlarges. Aortic root aneurysms grow at an average of 1–4 mm/year [5], with a faster rate of growth noted in patients with bicuspid aortic valves, Marfan syndrome, ESRD, male gender, and smokers [5, 67]. When the aneurysm enlarges to the point of compressing surrounding structures the patient may begin to observe symptoms—the most common of which is chest pain, seen in up to 75% of patients [5, 68]. Other nonspecific symptoms can include back pain, abdominal pain and fatigue (though only present in 5% of patients).
\nAdditionally, patients may present with symptoms secondary to complications of a dilated aortic root such as aortic insufficiency and congestive heart failure. Thus, patients can develop dyspnea as the presenting symptom of aortic root dilation up to 40% of the time [68]. Other presenting symptoms may be related to the complications noted in Table 2 [69, 70, 71, 72, 73, 74].
\nComplication of aortic root aneurysm | \nPresenting symptom | \n
---|---|
Aortic insufficiency, aortic regurgitation | \nDyspnea, diastolic murmur, congestive heart failure symptoms | \n
Aortic dissection | \nSharp chest pain, may radiate to the back | \n
Thromboembolism | \nSymptoms of stroke | \n
Compression of tracheal or bronchus | \nHemoptysis, cough, recurrent pneumonitis | \n
Compression of left recurrent laryngeal nerve | \nHoarseness | \n
Compression of superior vena cava | \nSigns of superior vena cava syndrome | \n
Compression of esophagus | \nDysphagia | \n
Complications and presenting symptoms of aortic root dilation.
Acute aortic emergencies that occur secondary to aortic root dilation include dissection, rupture, and aortic insufficiency. As the aortic root diameter increases, the risk for aortic dissection and rupture rises [75]. Aortic dissections are the most common acute aortic emergencies [76], and can be classified depending on the segment of the aorta affected: type A dissections involve the ascending aorta (seen in aortic root dilation), while type B dissections are those that occur distal to the left subclavian artery.
\nAortic dissection most commonly presents with acute onset chest pain that may radiate to the back. The character of the pain has traditionally been described as ripping or tearing in nature, however over half of patients may instead complain of sharp pain [77]. In addition, geriatric populations are less likely to have an acute onset of pain [78]. Physical exam findings that may be present include unequal blood pressures in the upper extremities, a new diastolic murmur indicative of acute aortic regurgitation, or muffled heart sounds secondary to tamponade (with proximal extension of the dissection). Imaging may be notable for widening of the mediastinum on CXR [77]. In order to aid in the diagnosis of a dissection, an aortic dissection detection risk score (ADD-RS) has been developed. The score is comprised of three categories: the presence of high risk conditions such as Marfan syndrome, the presence of typical symptoms (such as abrupt onset chest pain), and the presence of physical exam findings such as unequal blood pressure readings in the upper extremities. Each group is given a score of 1 if a feature is present, and the total score helps pave the next steps of workup—a score of 0 can be followed by diagnostic workup of other pathologies, while scores of 2–3 should be followed by expedited workup and immediate surgical consultation for possible aortic dissection [79].
\nAortic rupture is also an acute and life-threatening complication of aortic root dilation. It can present similarly to aortic dissection with regards to chest pain, however rupture can lead to severe and abrupt hypotension. Moreover, contingent with the site of rupture the patient may have symptoms such as hemoptysis [80] (if there is rupture into the lung), hematemesis [81] (if there is rupture into the esophagus), or cardiogenic shock [82] (if there is rupture into the pericardial cavity with resultant tamponade physiology).
\nAortic root dilation may also lead to aortic insufficiency. Roughly 30% of aortic insufficiency is now recognized as being caused by aortic root dilation, surpassing the incidence of any valvular cause [83]. The pathophysiology is related to stretching of the aortic valve annulus secondary to aortic root dilation, which results in incomplete closure of the aortic leaflets during diastole. Unfortunately, at the onset of aortic regurgitation, patients may be asymptomatic; therefore, congestive heart failure can develop when the regurgitant valve goes unnoticed.
\nWhile aortic root aneurysms are known to grow at an average of 1–4 mm/year [5], it is difficult to ascertain how fast an individual’s aortic root aneurysm will grow, therefore necessitating surveillance imaging. The frequency of surveillance imaging recommended is dependent on the etiology of the aortic root dilatation as well as its size, with genetically mediated aortic disease having a lower threshold for more frequent (biannual) imaging [84]. At the very least however patients are recommended to have annual imaging for aortic root dilation to closely monitor the aortic diameter. The impact that frequent imaging (CT, MR angiography or echocardiography) has on public health is likely significant, with cumulative costs. In addition, any patient with a bicuspid aortic valve should be screened for a thoracic aortic aneurysm, as well as screening all first-degree family members of a patient with genetic conditions such as Marfan syndrome [85].
\nThe aortic root is the most proximal segment of the aorta. It extends from the annulus of the aortic valve to the sinotubular junction (STJ). It is composed of the left, right, and non coronary sinuses of Valsalva. The diameter of the aorta decreases as it moves distally. The aortic root is assessed using multimodality imaging techniques. These include transthoracic echocardiogram (TTE), cardiac magnetic resonance imaging (cMRI), and cardiac computed tomography angiography (cCTA).
\nTTE is widely used for the detection and monitoring of aortic root pathology. Early studies established age- and sex-specific nomograms for aortic root measurements [86]. These studies used the motion mode (M-mode) of TTE, in which the amplitude of the ultrasound pulses amplitudes is converted to corresponding level on gray-scale imaging [86]. Using the M-mode, the American Society of Echocardiography (ASE) has recommended using the leading-edge to leading-edge approach for measuring the aortic root [87]. Later studies used 2D TTE and obtained reference measurements of the aortic root. This is now preferred over M-mode images, which may be off-axis and are subject to aortic motion that may produce erroneous measurements.
\nOn echocardiogram, the aortic root diameter is typically measured in the parasternal long-axis view from the right coronary sinus to the opposite sinus of Valsalva. When unable to obtain the long axis view, the parasternal short axis view may provide more accurate measurements. However, universal landmarks to measure the root in this view have not been established. Some suggest measuring the diameter from the right coronary sinus to the opposite commissure. These measurements are typically performed at end diastole, as this represents the resting aortic diameter [88]. In adults, these measurements correlate with age and body size. In addition, the aorta is about 2 mm larger in men compared to women due to differences in body size [89]. Normal values stratified by body surface area and age have been published by the ASE [87].
\nImportantly, TTE is limited by its two-dimensional images and thus does not give a complete depiction of the aortic root. It is also limited by patient factors that limit the visualization windows and thus aortic root measurement. Since the aorta is not a straight tube, it can be imaged obliquely leading to over-estimation of its true diameter. Newer modalities, such cMRI and cCTA, can provide three-dimensional images.
\nDespite ECG-gated CT being the most accurate modality for evaluating the thoracic aorta, it is limited by the radiation and contrast exposure. This is particularly important in younger patients with connective tissue disorders that require serial follow up imaging. Cardiac MRI provides an alternative approach for imaging the thoracic aorta including the aortic root and is considered the preferred modality in select groups. It can be performed with ECG gating to provide motion-free evaluation of the aorta. In addition, young patients, in whom this is more commonly used, can hold their breath for longer periods, allowing acquisition of images with high spatial resolution.
\nCardiac MRI evaluation of the aorta does not require contrast use. MRI sequences used include balanced steady-state free precession (SSFP) sequences, fast imaging employing steady-state acquisition (FIESTA), true fast imaging with steady-state precession (FISP), and balanced fast-field echo (FFE) sequences. These sequences provide a high signal-to-noise ratio and adequate contrast between vessel wall and blood pool [90]. When used with ECG gating and contrast enhanced MRA, images tend to have less artifact, higher resolution, and overall short imaging time. Another approach is to use ECG gating 2D balanced SSFP sequence that is oriented perpendicular to the aortic root in two planes to assess the aortic valve and root throughout the cardiac cycle. In addition, prospective ECG gating and respiratory navigation with three-dimensional balanced SSFP sequences can provide 3D aortic imaging without contrast administration [91, 92].
\nIt is important to note that different methods of aortic measurement have been described and guidelines are less well defined. Aortic root measurements can be challenging given different approaches. Burman et al. found in the Framingham Heart Study that cusp-commissure dimensions better corresponded with reference echocardiographic aortic root measurements [89, 93]. This best correlated with study measurements after averaging the three end-diastolic cusp-commissure measurements [93]. In addition, there is a lack of consensus with regard to measurements used (inner lumen only versus lumen and wall) and whether measurements should be adjusted to body surface area, sex, and age.
\nAlthough TTE is widely used for the imaging and surveillance of aortic root, cardiac computed tomography angiography (cCTA) is currently the most commonly used technique for the study of the thoracic aorta. Main advantages of cCTA are fast scanning times, low artifact sensibility, and wide availability including emergency rooms operating 24 h [94].
\nThe new generation CT scanners acquire high-resolution 3D datasets of the thoracic aorta, showing sensitivities up to 100% and specificities of 98–99% [95]. ECG synchronization is vital for detailed assessment of the aortic root anatomy since it allows suppression of pulsation artifacts [96]. ECG gating also allows viewing images in a particular phase of the cardiac cycle. Unfortunately, the ECG-gated technique can increase the acquisition time and required breath-hold time. In order to minimize the increased acquisition times, employment of a 64 or wider ECG-gated row detector system is suggested [95, 97].
\nModern CT scanners can be used to employ several different cardiac synchronization methods such as prospective ECG triggering where images are only acquired during a specified portion of the cardiac cycle, starting at a predetermined delay from the R wave; retrospective ECG gating where the desired cardiac phase is selected retrospectively from the raw data [95, 97]. The details of each technique will not be discussed in this chapter; however, it is important to determine the advantages and disadvantages of different techniques. The main limitations of CT are related to the radiation exposure and the use of iodinated contrast media and different techniques come at a higher cost of each limitation.
\nFor the surveillance of aortic root, any technique can be used and be useful; therefore, the technique with the least amount of radiation exposure should be selected such as prospective sequential triggering without padding, retrospective gating with tube-current modulation optimized for diastolic-phase datasets only, or a prospectively triggered high-pitch helical acquisition [95, 97]. Retrospective ECG gating acquires redundant helical CT data which allows the reconstruction of images at different cardiac phases and providing detailed images which can be useful in complicated cases and pre-/post-operative imaging since pseudoaneurysm or small leaks which are some of the most common complications of aortic root surgery can only be detected during a specific phase of the cardiac cycle. Iodinated contrast-media is another risk related to CT imaging given the risk of contrast induced nephropathy and allergic reactions of various severity. Surveillance CT data for the dimensions of aortic root can be acquired without contrast injection; however, a complete endoluminal evaluation can only be achieved by the injection of contrast-medium [97].
\nIt is standard of care to monitor the size of aortic aneurysms that are below surgical threshold, <5.5 cm for nongenetic aneurysms and <5.0 cm for genetically-mediated aneurysms [98]. In general, physicians should be conscientious about patient cumulative radiation exposure as there is evidence that it can increase cancer incidence and cancer mortality [99]. One study estimated that ionizing radiation exposure results in 0.7% of total expected baseline cancer incidence and 1% of total cancer mortality. These rates increase with greater cumulative exposure [99]. Therefore, physicians should opt to perform serial CT imaging with longer intervals in the most appropriate patients. A study investigating patients with moderate-risk thoracic aortic aneurysms (defined as size <5.0 cm) showed that patients with aneurysms below 4.3 cm had overall lower risk of significant aneurysm growth or size reaching surgical threshold. Thus, the authors suggested that these subset of patients undergo surveillance CT scans less frequently.
\nManagement focuses on slowing the rate of growth and the complications of aortic root dilation. The line of management that is chosen for a patient depends on symptoms and size of the aneurysm. For patients who are asymptomatic and have root dilation <55 mm, medical management is advised. In patients with Marfan syndrome or a bicuspid aortic valve, the cut off of ≤50 mm is used for medical management [1, 100].
\nThe use of beta blockers has shown a survival benefit in patients with aortic root dilation secondary to Marfan syndrome [101]. While data on survival benefits for patients with bicuspid aortic valves is sparse, the common practice is to also prescribe beta blockers given that both conditions share a similar pathology and therefore both are likely to benefit from beta blockade. The mechanism by which beta blockers slow the progression of aortic root dilation is through their negative inotropic and chronotropic effects, reducing the peak left ventricular ejection rate and therefore decreasing shear stress and the rate of aortic dilation [102].
\nThe goal blood pressure for patients with thoracic aortic aneurysms is <130/80 mmHg. In patients who cannot tolerate beta blockers, calcium channel blockers (CCB) are an alternative group of medications available. While less studied as compared to beta blockers, CCB have also been found to reduce the rate of aortic root dilation [103]. Other agents that can be used for additional blood pressure control include ACE-inhibitors and ARBs.
\nIn order to reduce the risk for complications such as aortic dissection, patients should be counseled on smoking cessation, and cessation of drugs that increase aortic wall stress such as cocaine or other stimulants. In addition patients should have dyslipidemia well controlled, which can be achieved through the use of atorvastatin 40–80 mg daily in individuals with aortic root aneurysms [104, 105].
\nPatients should be counseled on avoiding high intensity and collision sports, such as boxing and cycling. Instead patients should take part in low dynamic sports, such as, golf [5, 106]. Pregnancy should be avoided in patients with Marfan syndrome with an aortic diameter >40 mm, if a patient does chose to become pregnant however there must be close follow up with surveillance imaging of the aortic diameter [5, 101].
\nEmergent surgical interventions are indicated for management of an aortic dissection or rupture, or a symptomatic aneurysm. In addition, surgical repair can be performed electively in high risk patients to prevent propagation of an aneurysm (Table 3). Indications for elective surgical intervention include the absolute size of the aneurysm—if the diameter is over 55 mm, or over 50 mm in patients with Marfan syndrome or bicuspid valves. Other indications for elective surgery include if the rate of growth of an aneurysm surpasses 10 mm/year, and if there is concurrent aortic insufficiency [1, 100]. In addition, patients who undergo aortic insufficiency repair who have concurrent aortic root dilation should be considered for aortic replacement at the time of their surgery—that is since 25% of patients with aortic root diameters >40 mm will eventually also require intervention for their aortic aneurysm [107].
\nEmergent surgical repair | \nElective surgical repair | \n
---|---|
\n
| \n\n
| \n
Indications for emergent and elective surgical repair of aortic root dilation.
As opposed to supravalvular aortic aneurysms, aortic root aneurysms involve the coronary ostia as well as the aortic valve, which have implications on the type of surgical procedure available for patients. There are two approaches for a surgical intervention: radical and conservative. In a radial surgical intervention the patient’s aortic valve and root are replaced (commonly referred to as the Bentall procedure), whereas in conservative interventions only the aortic root is replaced [108].
\nThe Bentall procedure involves replacing the aortic valve with a prosthetic valve, and thus has the caveat of requiring indefinite anticoagulation [5]. If patients have a high bleeding risk it may therefore be worthwhile investigating replacement of the aortic root while preserving the valve. In addition, it is important to note that a large number of patients with aortic root dilation are young (secondary to its association with Marfan syndrome), and therefore lifelong anticoagulation in cases such as these confers a cumulative bleeding risk. Preserving the aortic valve while surgically treating the aortic root dilatation is made possible by the development of two surgical procedures: the first is removing the aortic root while keeping the valve intact. The second method is through re-implantation of the aortic valve [5]. Both the Bentall procedure as well as aortic valve-preserving procedures have been shown to have comparable short and long-term outcomes with regards to the risk of death and valve associated complications. The main difference however is that patients undergoing valve sparing operations were significantly more likely to develop moderate to severe aortic regurgitation later [108].
\nIn patients with both severe aortic stenosis and ascending aortic aneurysm, undergoing surgical aortic valve replacement (sAVR) and concomitant surgical intervention for aortic aneurysms above 4.5 cm is recommended by the American College of Cardiology (ACC) foundation guidelines [84]. However, in high-risk surgical patients, undergoing a transcatheter aortic valve replacement (TAVR) has become an alternative approach that obviates the need for parallel surgical aortic aneurysm intervention. This raises the concern for the safety of TAVR catheter-based delivery system in patients with aortic aneurysms since intraoperative rupture or dissection risk potentially increases. However, a clinical study showed that TAVR does not increase intraoperative aortic dissection/rupture risk or mortality with a median follow-up of 14 months [109]. Therefore, there are no recommendations against performing TAVR in patients with ascending aortic aneurysms.
\nNone.
IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Chapters",metaDescription:"IN TECH aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.\n\nWhen submitting a manuscript the Corresponding Author is required to accept the terms and conditions set forth in our Publication Agreement as follows:",metaKeywords:null,canonicalURL:"/page/publication-agreement-chapters",contentRaw:'[{"type":"htmlEditorComponent","content":"The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\\n\\n1. DEFINITIONS
\\n\\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
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\\n\\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\\n\\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
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\\n\\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
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\\n\\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
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\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
\\n\\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\\n\\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\\n\\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
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\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. 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