|Year : 2020 | Volume
| Issue : 3 | Page : 191-215
Biomarkers in biological fluids in adults with periodontitis and/or obesity: A meta-analysis
Renata Scheeren Brum1, Poliana Mendes Duarte2, Graziela De Luca Canto3, Carlos Flores-Mir4, César Augusto Magalhães Benfatti1, André Luís Porporatti3, Gláucia Santos Zimmermann3
1 Department of Dentistry, Centre of Education and Research on Dental Implants (CEPID), Federal University of Santa Catarina, Florianópolis, Brazil
2 Department of Dentistry, University of Guarulhos, Guarulhos, Brazil; Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL, USA
3 Department of Dentistry, Brazilian Centre for Evidence-Based Research, Federal University of Santa Catarina, Florianópolis, Brazil
4 Department of Orthodontics, School of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
|Date of Submission||03-Oct-2019|
|Date of Decision||22-Feb-2020|
|Date of Acceptance||01-Mar-2020|
|Date of Web Publication||04-May-2020|
Renata Scheeren Brum
Department of Dentistry, Federal University of Santa Catarina, St. Delfino Conti, S/N, University Campus, Trindade, Florianópolis, Santa Catarina 88040-900
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Obesity and periodontal diseases have been investigated to be interconnected, but the molecular mechanism underlying this association is still not clear. The aim of this systematic review is to assess the association of serum, salivary and gingival crevicular fluid (GCF) inflammatory markers (IMs), obesity, and periodontitis. Studies that evaluated IM of adults according to obesity status (O) and periodontitis status (P) (O+P+; O-P+; O+P-) were screened on several electronic databases and grey literature up until February 2019. Risk of bias assessment and level of evidence were evaluated through Fowkes and Fulton scale and Grading of Recommendations Assessment, Development and Evaluation (GRADE). Meta-analyses were grouped according to the biological matrix studied (serum/GCF) and groups (O+P+ vs. O−P+/O+P+ vs. O+P−). Out of the 832 studies screened, 21 were considered in qualitative synthesis and 15 in quantitative synthesis (meta-analysis). Although included studies showed mostly “no” or “minor” problems during the quality assessment, GRADE assessment indicated very low to moderate level of evidence based on the question answered. O+P+ adults exhibited significantly higher serum levels of C-reactive protein (CRP), interleukin 6 (IL-6), leptin, and tumor necrosis factor-α (TNF-alpha) and higher resistin GCF levels than O−P+. O+P+ adults showed significantly higher serum levels of IL-6 and leptin and lower adiponectin serum levels than O+P−. Only qualitative information could be obtained of the IM vaspin, omentin-1, chemerin, IL-10, progranulin, MCP-4, IL-1β, and interferon-γ (IFN-γ). Obesity and periodontitis, together or separately, are associated with altered serum and GCF levels of CRP, IL-6, leptin, TNF-alpha, adiponectin, and resistin. It was not possible to evaluate the association between obesity and periodontitis at salivary levels. The role of recently investigated biomarkers as vaspin, omentin-1, chemerin, IL-10, progranulin, MCP-4, IL-1β, and IFN-γ, which can be key points underlying the association between obesity and periodontitis, remains to be further investigated.
Keywords: Cytokine, obesity, periodontal diseases, periodontitis, systematic review
|How to cite this article:|
Brum RS, Duarte PM, Canto GD, Flores-Mir C, Magalhães Benfatti CA, Porporatti AL, Zimmermann GS. Biomarkers in biological fluids in adults with periodontitis and/or obesity: A meta-analysis. J Indian Soc Periodontol 2020;24:191-215
|How to cite this URL:|
Brum RS, Duarte PM, Canto GD, Flores-Mir C, Magalhães Benfatti CA, Porporatti AL, Zimmermann GS. Biomarkers in biological fluids in adults with periodontitis and/or obesity: A meta-analysis. J Indian Soc Periodontol [serial online] 2020 [cited 2021 Sep 17];24:191-215. Available from: https://www.jisponline.com/text.asp?2020/24/3/191/283792
| Introduction|| |
The obesity global epidemy is a serious public health concern, because obesity is a risk factor to increased morbidity and mortality in cardiovascular diseases (CVDs), diabetes, cancers, and other chronic diseases. Gingivitis and periodontitis are infectious inflammatory diseases whose pathogenesis may be affected by environmental factors and systemic disorders, such as diabetes, smoking, and obesity.
The relationship between obesity and periodontal diseases has been investigated in previous clinical studies and systematic reviews., Overall evidence has demonstrated positive consistent associations between parameters of obesity and clinical parameters of periodontitis – enough to postulate a pattern of increased risk of periodontitis in individuals with overweight or obesity. However, the underlying biological mechanisms linking both diseases are not fully understood so far.,
Obesity negatively affects the immune response by increasing the susceptibility to infections. Adipose tissue has emerged as an active participant in the regulation of several pathologic processes by means of the release of several cytokines that are involved in inflammatory processes. Based on these concepts, some mechanisms have been proposed to explain the association of obesity and periodontal diseases. Obesity was associated with increased levels and proportions of periodontal pathogens in subgingival biofilm of patients with periodontitis and periodontal health., Furthermore, increased body mass index (BMI) was related to altered levels of inflammatory mediators in gingival crevicular fluid (GCF) and serum of patients with periodontitis and periodontal health, whereas periodontitis per se seems to affect the circulatory levels of some adipose tissue-derived mediators.,,
A previous systematic review investigated the cytokine profile in the GCF of adults and adolescents with periodontitis with and without obesity. It was concluded that the periodontal inflammation seems to have a greater influence than obesity on the levels of biomarkers in GCF. However, a detailed analysis of the results from studies comparing the levels of inflammatory markers (IMs) in different biological fluids, such as GCF, serum, and saliva, in adults with obesity and periodontitis (O+P+), without obesity and with periodontitis (O−P+), and with obesity and without periodontitis (O+P−) has not been compiled so far. This distinction is important to better understand the underlying mechanisms between obesity and periodontitis. Therefore, the aim of this systematic review is to answer the following question: “Do adults with only obesity or only periodontitis or with both conditions differ in relation to the levels of IM in serum, saliva, or GCF?” The current investigation would provide an overview of the current status of the evidence on the impact of obesity and periodontitis on the IM underlying the pathogenesis of both diseases.
| Materials and Methods|| |
The present systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis checklist.
Protocol and registration
This systematic review is registered at PROSPERO (CRD42018101943).
The general review question was divided in two subquestions to better clarify which IM is affected by either or both conditions simultaneously:
Subquestion 1: Is obesity associated with altered levels of IMs in adults with periodontitis?
Evaluation of papers that compared the levels of IM between O+P+ and O−P+ adults.
Subquestion 2: Is periodontitis associated with altered levels of IMs in adults with obesity?
Evaluation of papers that compared the levels of IM between O+P+ and O+P− adults.
- Observational cross-sectional and longitudinal studies in adults that compared the levels of IM between O+P+ and O−P+ (Question 1) and between O+P+ and O+P− (Question 2) in serum, saliva, and/or GCF. Only baseline data of the longitudinal interventional studies were assessed and included
- Studies that clearly presented a definition of periodontitis and assessed clinical parameters such as marginal bleeding, bleeding on probing, suppuration, probing depth, and clinical attachment level, based on the standards of the International World Workshop for Classification of Periodontal Disease and Conditions
- Studies that clearly defined obesity ass BMI ≥ 30 and <40 kg/m2, based on anthropometric measurements, including weight (kg), height (m), by means of body mass index (BMI), according to World Health Organization.
- Studies in children or adolescents
- Studies that included subjects with known systemic diseases (diabetes mellitus, cancer, hypertension, and hypothyroidism, among others) and recent history of antibiotic and anti-inflammatory therapy or periodontal treatment and studies that included pregnant or lactating women and smokers
- In vitro and animal studies
- Reviews, case reports, letters, and personal opinions
- Studies without at least two of the three investigated groups (O+P+, O−P+, or O+P−).
Literature search was performed up to February 6, 2019. Electronic databases consulted were the following: the Cochrane, Lilacs, PubMed (including MedLine), Scopus, and gray literature (OpenGrey, Google Scholar, and ProQuest).
Full strategy search according to each database is shown in [Appendix 1]. No date and language restrictions were applied. EndNote Web (Clarivate Analytics, USA) was used to identify and eliminate duplicate studies.
Titles and abstracts of potential articles were screened independently by two reviewers (RSB and GSZ). Lists of selected studies were compared, and when necessary, a third reviewer was consulted (PMD) to make the final decision. After the initial search and selection phase, assessment of the full articles was performed. The reviewers also performed a hand-search in the reference list of all included studies. Potential full copies of articles to be included in this review were thereafter independently inspected by the same reviewers. No language restriction was applied.
One author (RSB) collected the necessary information from the selected articles using predefined data collection worksheets. The second author (GSZ) cross-checked all obtained information and confirmed its accuracy. When needed, the authors of the included studies were contacted.
Risk of bias in individual studies
Quality assessment and risk of bias control were performed according to the guidelines described by Fowkes and Fulton. It allows the classification of cross-sectional, cohort, controlled trial, and case–control studies. Questions were applied by two reviewers (RSB and GSZ). When evaluating criteria for each question, the importance of failures or missing information in relation to their expected effect on the results was scored as “major” (++) problem, “minor” (+) problem, “no problem” (0), or not applicable “NA.”
The levels of IM in serum, saliva, and GCF were considered the main outcomes. Comparable outcomes were standardized to the same measurement unit previously to meta-analysis procedures, when necessary.
Synthesis of the results
Results were separated according to the type of IM, type of biological fluids, and subquestions (subquestion 1/subquestion 2). Random effects meta-analysis was performed using Comprehensive Meta-Analysis V3 software (Biostat, USA). Statistical heterogeneity was calculated by inconsistency indexes (I2) and a value >90% was considered an indicator of substantial heterogeneity between studies. The significance level was set at 5.0%.
Risk of bias across studies
The level of evidence (certainty) was assessed employing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) for results included in meta-analyses. Risk of bias, inconsistency, directness, and imprecision were factors considered.
| Results|| |
From an initial amount of 832 articles, 571 were considered for abstract reading after eliminating duplicates and 5 papers were identified through hand-search. A total of 44 articles were screened thereafter for full-text review. Of the 44 articles evaluated, 23 studies did not fulfill the inclusion criteria and were later excluded [reasons for exclusion in [Appendix 2]. Hence, 21 studies were included in the qualitative synthesis. All 21 included studies answered the subquestion 1 [Table 1], whereas only 10 papers answered the subquestion 2 [Table 2]. Of the 21 studies that answered subquestion 1, 15 were included in meta-analysis, whereas of the 10 studies that answered subquestion 2, only 7 were included in meta-analysis. Concerning the quantitative synthesis, only studies including serum and GCF showed comparable results to be included in meta-analysis for both questions. Data about salivary levels of IM were not comparable between studies (e.g., different IM analyzed) and therefore salivary levels of IM were not included in meta-analysis. Flow diagram is shown in [Figure 1].
|Table 1: Main characteristics and outcomes of included studies that answered the Subquestion 1 (comparison of serum, saliva, and/or gingival crevicular fluid levels of inflammatory markers between subjects with obesity and periodontitis O+P+ and subjects without obesity with periodontitis O-P+)|
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|Table 2: Main characteristics and outcomes of included studies that answered the Subquestion 2 (comparison of serum, saliva and/or gingival crevicular fluid levels of adipokines between subjects with obesity and periodontitis O+P+ and subjects with obesity without periodontitis O+P- patients)|
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Study characteristics are summarized in [Table 1] and [Table 2].
Risk of bias within studies
[Table 3] presents the results of the risk of bias assessment in the individual studies.
|Table 3: Results of individual studies according to Fowkes and Fulton checklist|
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Results of individual studies
Qualitative results for individual studies are presented in [Table 1] and [Table 2].
Subquestion 1 meta-analysis results
Serum C-reactive protein, interleukin-6, leptin, tumor necrosis factor-α, adiponectin, and resistin in O+P+ and O−P+ groups
While serum adiponectin and resistin levels did not differ significantly between O+P+ and O−P+ groups (P > 0.05), serum C-reactive protein (CRP), interleukin 6 (IL-6), leptin, and tumor necrosis factor-α (TNF-alpha) levels were higher in the O+P+ than in the O−P+ group (P< 0.05) [Figure 2], [Figure 3], [Figure 4].
|Figure 2: Quantitative results of serum adiponectin and C-reactive protein (O+P+ vs. O-P+)|
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|Figure 3: Quantitative results of serum interleukin-6 and leptin (O+P+ vs. O-P+)|
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|Figure 4: Quantitative results of serum resistin and tumor necrosis factor-a (O+P+ vs. O-P+)|
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Gingival crevicular fluid C-reactive protein, tumor necrosis factor-α, adiponectin, resistin, interleukin-6, and leptin in O+P+ and O−P+ - groups
The GCF levels of most of the IM did not differ between O+P+ and O−P+ groups, including adiponectin, CRP, leptin, TNF-α, and IL-6 (P > 0.05). GCF levels of resistin were higher in the O+P+ than in the O−P+ group (P< 0.05) [Figure 5], [Figure 6], [Figure 7].
|Figure 5: Quantitative results of gingival crevicular fluid adiponectin and C-reactive protein (O+P+ vs. O-P+)|
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|Figure 6: Quantitative results of gingival crevicular fluid leptin and resistin (O+P+ vs. O-P+)|
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|Figure 7: Quantitative results of gingival crevicular fluid tumor necrosis factor-a and IL-6 (O+P+ vs. O-P+)|
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Subquestion 2 meta-analysis results
Serum C-reactive protein, interleukin-6, tumor necrosis factor-α, leptin, and adiponectin in O+P+ and O+P− groups
Serum TNF-α and CRP did not differ between O+P+ and O+P− groups (P > 0.05). Serum IL-6 and leptin levels were higher, whereas serum adiponectin levels were lower in the O+P+ when compared to the O+P− group (P< 0.05) [Figure 8], [Figure 9], [Figure 10].
|Figure 8: Quantitative results of serum adiponectin and C-reactive protein (O+P+ vs. O+P-)|
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|Figure 10: Quantitative results of serum tumor necrosis factor-a and leptin (O+P+ vs. O+P-)|
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Gingival crevicular fluid C-reactive protein, resistin, and leptin in O+P+ and O+P− groups
GCF levels of CRP, leptin, and resistin did not differ between O+P+ and O+P− groups (P > 0.05) [Figure 11] and [Figure 12].
|Figure 11: Quantitative results of gingival crevicular fluid C-reactive protein and leptin (O+P+ vs. O+P-)|
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|Figure 12: Quantitative results of gingival crevicular fluid resistin (O+P+ vs. O+P-)|
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Confidence in cumulative evidence
GRADE results for subquestion 1 (serum and GCF samples) are presented in [Table 4] and [Table 5], respectively, whereas for subquestion 2 (serum and GCF samples) are presented in [Table 6] and [Table 7], respectively, which were included as Supporting Material. Overall quality of evidence varied between “very low” to “moderate.”
|Table 4: GRADE working group grades of evidence for serum inflammatory markers levels subjects with obesity and periodontitis O+P + and subjects without obesity with periodontitis O-P+ (Subquestion 1)|
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|Table 5: GRADE working group grades of evidence for gingival crevicular fluid inflammatory markers levels of subjects with obesity and periodontitis O+P+ and subjects without obesity with periodontitis O-P+ (Subquestion 1)|
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|Table 6: GRADE working group grades of evidence for serum inflammatory markers levels of subjects with obesity and periodontitis O+P+ and subjects with obesity without periodontitis O+P- patients (Subquestion 2)|
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|Table 7: GRADE working group grades of evidence for gingival crevicular fluid adipokine levels of subjects with obesity and periodontitis O+P+ and subjects with obesity without periodontitis O+P - patients (Subquestion 2)|
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| Discussion|| |
Although the underlying mechanisms on the link between obesity and periodontitis remain to be completely elucidated, it is suggested that a critical role of inflammatory mediators including adipokines, cytokines, and chemokines can be facilitated by increased adipose and inflamed periodontal tissues., The current systematic review compiled data of 21 studies evaluating the serum, GCF, and salivary levels of IM in subjects presenting either obesity or periodontitis or both simultaneously. Comparisons were made in obese subjects without periodontitis and nonobese subjects with periodontitis. Classical IM, including CRP, IL-6, and TNF-α, were the most investigated biomarkers, whereas several newly discovered IM (e.g., IL-34, omentin, vaspin, and chemerin) were poorly explored, precluding a more thorough evaluation by means of meta-analysis. Serum and GCF were the most studied biological matrices, whereas only two studies analyzed the IM in saliva., Probably, the low quantity of studies evaluating salivary levels of biomarkers underlying the association among periodontitis and obesity is justified because saliva is a contaminated and less trustworthy source. Overall qualitative findings and meta-analysis demonstrated significant higher circulatory and local levels of pro-IMs in subjects with both obesity and periodontitis (O+P+ group), when compared to subjects presenting periodontitis only or obesity only. Together, these findings suggest that both conditions may act as cofactors of the inflammatory process, favoring a pro-inflammatory profile.
The subquestion 1 [Table 1] focused on the comparison of IM levels between adults affected by periodontitis differing by the status of obesity. According to meta-analysis, four IMs with pro-inflammatory biological activities (CRP, IL-6, TNF-α, and leptin) were significantly elevated in serum of O+P+ compared to O−P+ adults. It supports the classical concept that obesity may induce a shift toward a systemic pro-inflammatory profile, resulting in the development of a chronic, low-grade inflammatory state, which can contribute to the pathogenesis of several comorbidities and complications. In GCF, the levels of resistin were significant higher in O+P+ than in O−P+ subjects. Resistin is an adipocyte- and monocyte-derived cytokine associated with insulin resistance, which plays important roles in amplifying the inflammatory state related to several diseases, including metabolic syndrome, Type 2 diabetes mellitus, and CVDs. Previous investigations have shown higher levels of resistin in patients with periodontitis when compared to periodontally healthy controls, suggesting resistin as a possible marker of periodontal diseases., Herein, we noticed that periodontal resistin levels are even more increased in the presence of obesity, being a possible pathway of exacerbation of periodontal breakdown in those patients. It seems that obesity yields negative impact at systemic and periodontal levels by increasing the levels of some pro-inflammatory IMs.
When taking into account subquestion 2 [Table 2], the focus was the impact of periodontitis on the levels of IMs in subjects with or without obesity. This subject was less explored than Question 1, given the more limited number of papers included on this topic. Of the five serum IMs assessed in meta-analysis, serum levels of the pro-IMs IL-6 and leptin were significantly higher, whereas adiponectin, an anti-inflammatory adipokine, was lower in O+P+ than in O+P− subjects. Those findings support the notion that periodontitis might intensify the systemic pro-inflammatory state of subjects with obesity, further increasing the risk systemic diseases. Noteworthy, it was shown that the levels of IL-6 and leptin seem to be significantly higher in serum of subjects with periodontitis and obesity when compared to those with obesity or periodontitis alone. IL-6 is a cytokine enrolled in chronic and acute inflammatory states, as well as in maturation of B-cells and in vascular damage. It is also associated with increased susceptibility of diseases such as diabetes mellitus and rheumatoid arthritis., Leptin plays a dual role as a hormone and as a cytokine, affecting endocrine functions, bone metabolism, energy homeostasis, and of inflammatory responses. Therefore, it appears that the interaction of obesity and periodontitis increases the levels of some IM to a greater extent than when these conditions act separately, suggesting that obese patients with periodontitis may be at an even increased risk for systemic complication related to systemic inflammatory burden.
The current systematic review indicated from “very low” to “moderate” certainty levels of evidence through GRADE evaluation.,, This is attributed to confounders that were also evaluated through Fowkes and Fulton checklist, such as, mismatching of age and sex, different brands of kits employed, and lack of blindness during biological fluid collection or laboratory analysis. Another confounder factor that should be mentioned is the lack of standardization on the time of body fluid collection, because some biomarkers might be influenced by circadian variation in several conditions.
It is important to highlight that just cross-sectional data were analyzed, which provides only evidence of association on the impact of obesity and/or periodontitis on IM levels. Longitudinal data could not be included in the present analysis because it is unethical to expose individuals to obesity and/or periodontitis. Therefore, randomized clinical trials evaluating this relationship focus on the evaluation of periodontal treatment impact on IM levels of individuals with obesity,, which was not analyzed by this systematic review. Cohort studies were not found.
Another important consideration is that only qualitative analysis could be performed for some biomarkers (i.e., vaspin, omentin-1, chemerin, IL-10, progranulin, MCP-4, IL-1β, and interferon-γ [IFN-γ]) that have been pointed as key adipokines related to obesity and/or to the pathogenesis of periodontal diseases. The actual role of these most recently identified markers on the association between obesity and periodontitis needs to be further evaluated.
Scientific evidence indicates that obesity alters the serum levels of IMs such as CRP, IL-6, leptin, TNF-alpha, adiponectin, and resistin in subjects with periodontitis, whereas periodontitis alters the levels of IMs in subjects with obesity, both favoring a pro-inflammatory profile. In individuals having both conditions, the systemic inflammatory profile appears to be increased. The current evidence also indicates that resistin concentration is increased in the GCF periodontal sites of obese subjects with periodontitis than in those of nonobese subjects. Additional studies are necessary to estimate the impact of obesity and/or periodontitis on salivary IM levels. The identified certainty levels ranged from “very low” to “moderate,” implying that future-related research might significantly change the direction and strength of the identified differences.
Thus, the following recommendations are listed for future research:
- Inclusion of a greater number of patients, because the longitudinal studies cannot be performed
- Inclusion of a greater number of biomarkers, which can be key points on the association among periodontitis and obesity, such as vaspin, omentin-1, chemerin, IL-10, progranulin, MCP-4, IL-1β, and IFN-γ, in such a way that the inflammatory cascade of both diseases can be extensively understood
- Standardization of body fluid collection time
- Employment of international recognized classification for both conditions, that is, obesity and periodontitis.
| Conclusion|| |
Obesity alters the serum levels of specific IMs in subjects with periodontitis, while periodontitis alters the levels of IMs in subjects with obesity, both favoring a pro-inflammatory profile. In individuals having both conditions the systemic inflammatory profile appears to be increased. The identified certainty levels ranged from “very low” to “moderate” and future research might change the direction and strength of identified differences.
The authors acknowledge the contribution of the following author for providing data and important comments: Dr. Cem A. Gürdan, Ramanarayana Boyapati, Sigrun Eick. The review authors also thank Wagner S. Brum for their comments on the English version of this article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]