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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"1756",leadTitle:null,fullTitle:"Carcinogen",title:"Carcinogen",subtitle:null,reviewType:"peer-reviewed",abstract:'During the last decades, cancer diseases have increased all over the world. 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Meta-analysis is used to synthesize the results of more than one study and overall effect size is considered to be valid only when some required assumptions are satisfied [1]. An increasing number of options for alternative medical treatment has given rise to the need for comparative effectiveness research [2, 3]. A randomized, controlled trials used to compare different treatment options are generally seen to be infeasible, there is a need for other methodological approaches. Since it makes it possible to combine data from many different studies so that a total estimate of treatment effect can be provided, a meta-analysis integrated into a systematic review is generally seen to be a useful statistical tool. On the other hand, there is an important limitation of standard meta-analysis; only two interventions can be compared at a time. When you have several treatment options to capitalize on, only partial information can be provided by a series of individual meta-analysis since only the questions about pairs of treatments can be answered in this way, which leads to difficulties in making optimal clinical decisions since each meta-analysis is just one constituent of the whole picture.
There is an increasing need for a method to be used to summarize evidence across many interventions [4]. In order to assess a number of interventions in terms of their relative effectiveness and to synthesize evidence from a set of randomized trials, network meta-analysis (or multiple treatments meta-analysis or mixed-treatment comparison) was created [5, 6, 7]. This method is built on the analysis of direct evidence (coming from research that directly randomizes treatments of interest) and indirect evidence (coming from research that compares treatments of interest with a common comparator) [8]. The benefits incurred by network analysis becoming increasingly popular have been reported in some applications and methodological articles [2, 9, 10]. Figure 1 shows the number of network meta-analysis (NMA) studies that have been published.
Number of network meta-analysis publications (search PubMed until January 2020).
Despite the fact that network meta-analysis shares many underlying assumptions with pairwise meta-analysis, it is not so much accepted as pairwise meta-analysis and thus criticized more [11].
The assumptions required by NMA about similarity, transitivity, and consistency [12, 13, 14, 15, 16, 17] are methodologically, logically, and statistically more strict [18, 19] because it should be examined whether each of these is satisfied or not [15, 20, 21].
For NMA, there are some methods to calculate the contribution of direct (and indirect) evidence of each comparison to its own NMA estimate, but how to define the contribution of each study to another estimate of treatment effect is an issue of greater ambiguity. There are a number of proposals made in the literature, each of which is based on a different approach but many of them are not without limitations and generally, there are contradictions between their results [20, 22, 23, 24]. There are some investigations having been conducted on the proportions of direct and indirect evidence in the past. One of these is the method of “back calculation” [21] introduced by Dias and some others have been proposed within a Bayesian framework [25]. There is even one proposed within a frequentist context [13]. In inverse variance method-based NMA, NMA estimates refer to linear combinations of treatment effect estimates from primary studies having coefficients that make up the rows of the hat matrix. It is easy to obtain the direct evidence proportion of a study or a comparison from the diagonal elements that the respective hat matrix has [13]. Dias and others proposed “node splitting” as an alternative. Node splitting refers to the estimation of the indirect evidence for comparison by modeling out all studies providing direct information for this comparison [25]. Additions were made to this method [26] and called “side splitting” by others [9]. There are different interpretations of the term “side” in the literature; for example, it was interpreted as an edge in the network graph by White [9] while it was interpreted as SIDE, an abbreviation of “Separating Indirect and Direct Evidence” by others [27, 28]. There is another way of quantifying the indirect evidence proposed by Noma and others, including the factorization of the total likelihood into separate component likelihoods [14]. Yet, none of these authors have attempted to make a definition or estimation of the contribution of each study to a given comparison in the network.
There are six basic steps that every NMA should follow, regardless of the analytic model chosen. These steps include
Understand network geometry,
Understand key concepts and assumptions,
Conduct analysis and present results,
Examine model assumptions through local and global tests,
Create a hierarchy of competing interventions (ranking),
Conduct heterogeneity and sensitivity analyses.
The network plot is fundamental to an NMA because it helps visualize the available studies and few of evidence across the multiple comparisons. In such a plot, each treatment/comparator identified in the review is represented by a node, and direct evidence comparing two interventions (i.e., studies which directly compared these two interventions) are represented via edges, connecting the respective nodes. The network plot of our example is presented in Figure 2.
A graph of the network generated by using the net graph function for the diabetes data.
In Figure 2, a network of treatments for type 2 diabetes is shown. The function served by the lines between the treatment nodes is to show which comparisons have been made in trials that are randomized. The absence of a line between two nodes means that there are no studies (that is, no direct evidence) comparing the two drugs. A network meta-analysis refers to an analysis of the data from all of these randomized trials at the same time. By means of a network meta-analysis, it is possible to estimate the relative effectiveness of two treatments even if they are not compared by any studies. For example, no comparison has been made between rosi and acar in any study but by using a common comparator (placebo), an indirect comparison can be made between them. After denoting rosi, acar, and placebo as treatments A, B, and C, respectively, it is possible to have an indirect comparison (AB) by subtracting the meta-analytic estimates of all studies of acar versus placebo (BC) from the estimate of all studies of rosi versus placebo (AC): AB indirect meta-analysis _ AC direct meta-analysis _ BC direct meta-analysis. If there is direct evidence (such as metf vs. sulf in (Figure 2), direct and indirect estimates can be combined by the network meta-analysis and mixed effect size can be calculated as the weighted average of the direct evidence (studies comparing metf and sulf directly) and the indirect evidence (for example, studies comparing metf and acar via placebo). The network constructed by studies of metf versus acar, metf versus placebo, and acar versus placebo is often named as a loop of evidence. By using indirect estimates, information can be provided on comparisons for which there are no trials. In this way, the accuracy of the direct estimate can be enhanced through the reduction of the width of the CIs in comparison with the direct evidence alone [9].
In a network meta-analysis, all the direct and indirect evidence can be utilized. Empirical studies have concluded that compared to a single direct or indirect estimate, it can produce more precise estimates of the intervention effects [2, 29]. Moreover, network meta-analysis has the potential of yielding data for comparisons made between pairs of interventions having never been evaluated within individual randomized trials. The comparison of all interventions of interest simultaneously in the same analysis makes it possible to estimate their ranking relatively for a given result. The purpose of this study is to show how analysis can be done with the network meta-analysis method using the R package program. Network meta-analysis as a functional method. It is to show that it can be done flexibly and easily with the R program to help researchers interested in this subject.
This chapter is organized as follows, In the next sections, we present a review of the methods for NMA as identified in our literature search. In Section 2, we present key concepts and the basic methodology for NMA. In Section 3 Diabetes treatments data is used as an example. The last section presents conclusions about our research and results found by network meta-analysis of diabetes data using the R program.
There may be different alternatives for the treatment of the same health condition and what makes NMA special is that through the synthesis of direct and indirect estimates for their relative effects, it allows the selection of the best treatment. Head-to-head studies can be conducted to directly compare two treatments A and B (AB studies). It is also possible to get an indirect estimate from studies in which these two treatments are compared with a common comparator treatment C, namely, AC and BC studies [9]. If we have both direct and indirect estimates, then we can combine them to estimate a mixed-treatment effect, as you can see in the left panel of Figure 3. In practice, there are numerous interventions for most health conditions that have been compared in various randomized trials and build a network of evidence. For the comparison of treatments within such a network, there may be direct and many different indirect estimates obtained through many different comparators, as illustrated in the example in the right panel of Figure 2.
Each circle represents an intervention, and lines represent direct comparisons.
Using NMA, all these different pieces of information can be compared so that an internally consistent overall estimate of the relative effects of all treatments can be produced. Researchers are still disputing about how valid it is to use indirect treatment comparisons (indirect evidence) while making decisions. There are strong arguments against using such evidence especially when there are direct treatment comparisons (direct evidence) [11, 30, 31, 32]. A focus of criticism is the nature of the evidence provided by NMA. Although patients in a randomized clinical trial (RCT) are randomly assigned to each of the treatments that are compared, it cannot be argued that the treatments are randomized across the included trials.
Thus, indirect comparisons can be defined as non-randomized comparisons and correspondingly they provide observational evidence rather than randomized evidence. Consequently, indirect treatment comparisons may be more susceptible to biased treatment effect estimates, due, for example, to confounding (for example, when randomized AB and AC studies are systematically different from BC; [2] and selection bias (e.g., when the selection of comparator in the study is based on the relative treatment effect [33].
Consider trial 1, a two-arm trial of the comparison “B–A”, and trial 2, a two-arm trial of the comparison “C–B”. If the estimated effect sizes in these trials are
Through indirect comparison, the benefits of randomization can be maintained in each trial, and differences across the trials are allowed (e.g.,, in baseline risk) if only the prognosis of the participants but not their response to treatment is affected by these differences (in whichever metric is chosen as a measure of effect size). However, the indirect comparison is based on the assumption that the treatment named as B is the same in both trials so that its effects are nullified when “B-A” and “C-B” are added together. It is not possible to test whether the difference between A and C is truly reflected by an indirect comparison without having further information. The comparison of the indirect comparison with a direct comparison would be allowed by a third trial of “C–A” (yielding result
Here
The existing research has widely investigated heterogeneity in meta-analysis, referring to the situation where multiple studies focused on the same research question have different underlying values regarding the effect measure that is being estimated. The way of understanding heterogeneity in the network meta-analysis scenario is to keep the treatment comparison constant while changing the study index. In particular, the existence of heterogeneity can be argued for comparison ‘B–A’ if
for pairwise comparison JK (taking values AB, AC, or BC in the running example) [34].
Consistency is the statistical manifestation of transitivity [12]. An additional way of making implicit inferences about the plausibility of the transitivity assumption is to check the network for consistency. What is meant by consistency is the statistical agreement between observed direct and (possibly many) indirect sources of evidence. A simple network can only contain treatments A, B, and C.
A consistency equation is generally used to express the relationship that is desirable between direct and indirect sources of evidence for a single comparison
where the mean effect size across all studies of comparison JK is represented by JK. (Under a fixed-effect meta-analysis model where the absence of heterogeneity is assumed, dJK represents a fixed (common) treatment effect for comparison JK). We refer to evidence that satisfies the consistency equation as showing consistency. We show this in Figure 4(a) as a three (non-touching) solid-edge relationship triangle in a network with only two-arm trials. Each edge represents one or more two-arm trials that compare two treatments identified at either end of the edge. Using the same line style (a solid line), we draw all three edges to describe the situation where there is no contradiction (inconsistency) between them, that is, Eq. (2) is valid [34].
Graphical representation of consistency, loop inconsistency and design inconsistency.
When studies focused on various treatment comparisons are highly different in such a way that their effect sizes are affected, the consistency Eq. (2) might not be valid; thus, the effect sizes are not “added up” around the loop in the figure. This is called loop inconsistency and is shown by drawing edges using different line styles (Figure 4(b)). Loop inconsistency may only result from when there are different comparisons made in at least three separate study groups (e.g., studies “B–A”, “C–A” and “C–B”). Equivalently, it can only occur when we have both indirect and direct estimates of effect size (e.g., when “C–B” is measured both directly and through “A” indirectly) [34]. Some examples showing the causes of loop consistency are given below:
Generally, some studies having more than two treatment arms are included in a network meta-analysis. In fact, about a quarter of randomized trials involve more than two arms [36], so it is important to select appropriate methods while dealing with the condition.
When there is the presence of multi-arm trials in an evidence network, the definition of loop inconsistency becomes more complicated. It is not possible to loop inconsistency in a multi-arm trial. As a result, consistency can occur for a network either structurally (because all studies include all treatments) or through observation (when assumptions about equality of direct and various indirect comparisons hold across studies), or by means of a combination of the two.
Also, loop inconsistency cannot be properly defined using Eq. (2) anymore, since average effect sizes,
The purpose of an NMA is to improve the decision-making process for making choices between alternative treatments for a specific health condition and a target population. Hence, the estimates intended to be estimated in an NMA are the mean relative treatment effect sizes among the treatments competing with each other as they are expected to be present in the target population. If unbiased estimates are yielded by studies involved in the dataset and if a representative sample of the population addressed is constituted by these studies, then estimates generated by an NMA model for these parameters will be unbiased and consistent. The same set of assumptions is adopted by NMA as a pairwise meta-analysis [37], but there is also another assumption adopted by it which can be difficult to assess [38] and is called transitivity [39], (also called similarity [40, 41], or exchangeability [42]). Transitivity means that information for comparison between treatments A and B can be attained through another treatment C using comparisons A to C and B to C. It is not possible to test his assumption statistically, but it is possible to evaluate its validity in a conceptual and epidemiological way [21].
What is meant by the transitivity assumption is that direct evidence from studies AC and BC can be combined to gain insights (indirectly) about AB comparison. However, this will be open to questioning if there are significant differences in the distribution of effect modifiers (variables or characteristics that alter the observed relative effects, e.g., the mean age of participants and treatment dose) across the AC and BC trials, which yield insights about the indirect comparison [24, 39]. An effect modifier might have different effects across studies of the same comparison (e.g., the mean age of participants may differ across AC trials), but if its distribution across comparisons (AC and BC) is similar, the assumption of transitivity may still hold [21]. As a consequence, how plausible the transitivity assumption is can be assessed by reviewing the collection of studies for significant differences in the distribution of effect modifiers. Assuming that the studies are similar, the assumption of transitivity may be realistic, on the condition that there aren’t any unknown modifiers of the relative treatment effect [43]. It is clear that such an assessment of transitivity may not be possible when the effect modifiers are not reported or when the number of studies per treatment comparison is low [12]. If there are significant differences identified and sufficient data is available, the transitivity of the network can be enhanced by using a network meta-regression. This might indicate, for example, that it is necessary for the common comparator treatment C to be similar in the AC and BC studies in terms of dose, modes of administration, duration, etc.
In an NMA of studies conducted to compare fluoride treatments administered to prevent dental caries, the definition of placebo differed between fluoride toothpaste studies and fluoride rinse studies [44], casting doubt on how plausible the transitivity assumption is and thus challenging the reliability of the NMA results. In another example, Julious and Wang [45] focused on how the use of placebo as an intermediate comparator can result in the distortion of the results of indirect comparisons due to changes in the population’s placebo response over the years; for instance, there might be a bias in the indirect estimate for A versus B when studies that compare treatment A versus placebo are older than studies that compare B versus placebo. Other ways used to formulate the transitivity assumption is to suppose that the true relative effect of A versus B is the same in the fixed-effects model or may vary across studies in the random-effects model, regardless of the treatments compared in each study [42, 46], that “missing” treatments in each trial are randomly missing [5] or, equivalently, that the choice of treatment comparisons in trials is not related directly or indirectly to the relative efficacy of the interventions. Finally, arguing that the patients included can be randomly distributed to any of the treatments in the network is an alternative way of postulating this assumption [21].
However, this does not mean that the assumption of transitivity will necessarily be valid. It should be stated that the absence of statistical inconsistency does not offer any evidence to prove the validity of the transitivity assumption that is essentially an assumption that cannot be tested as discussed in the previous section. Therefore, the conduct of an NMA should be preceded by a conceptual/theoretical evaluation of the transitivity assumption besides statistical tests for inconsistency [12] and the studies that are included in an NMA should always be reviewed for important differences that can be seen in patients, interventions, outcomes, study design, methodological characteristics, and reporting biases [2, 9, 14, 32, 43].
What is meant with the “design” of a study is a set of treatments that are compared within the study, recognizing that it is different from traditional interpretations made for the term. Then, differences in effect sizes among studies including different sets of treatments are referred to by design inconsistency. While allowing for this variation, it is implicitly assumed that different designs (i.e., different treatment sets included) can serve the function of a proxy for one or more important modifiers of effect [47]. Design inconsistency is depicted in Figure 4(e), in which different line styles represent possible contradictions between study designs. The AC effect size depicted with a solid line in the three-arm trial is different from the AC effect size in the two-arm trial depicted with a dashed line. It is possible to see design inconsistency as a special case of heterogeneity since study designs correspond to a study-level covariate that has the potential to change effect sizes in the study, as can occur in a standard meta-regression analysis. It should be noted that in a network of only two-arm studies, additional insights provided by loop inconsistency cannot be provided by the concept of design inconsistency. In the case of a multi-arm trial, loop inconsistency in two-arm trials means design inconsistency (Figure 4(f)). The reason for this is that the multi-arm trial must be self-consistent, so the effect sizes of the multi-arm trial should be different from those of at least one of the two-arm trials: our definition of design inconsistency. Nevertheless, what is implied by design inconsistency for loop inconsistency is less clear. Design consistency with one three-arm trial and two two-arm trials is shown in Figure 4(g). It is possible to create a loop by subtracting the pairwise BC comparison from the three-arm trial and then by comparing it to the two-arm trials. But, in this way, the existence of a consistent loop in the three-arm experiment is overlooked and thus it is unclear whether this network should be defined as exhibiting loop inconsistency. Also, it is seen in Figure 4(h) that the two-arm trials are consistent among themselves, but the effect sizes are different from the effect sizes of the multi-arm trial. Does this show design inconsistency without loop inconsistency? [34].
In order to make a comparison among the clinical trial studies used for analysis, it must be assumed that there is a similarity in the methodology used in the studies [12, 44]. The assessment of similarity is qualitatively performed on each of the selected articles from a methodological point of view and is not a hypothesis that can be tested statistically. The technique used to investigate similarity is the population, intervention, comparison, and outcome (PICO) technique [17]. Examination of similarity among the studies used for analysis is based on the following four items: clinical characteristics of study subjects, treatment interventions, comparison treatments, and outcome measures. In cases where the similarity assumption is not satisfied, the other two assumptions are also negatively affected [24] and moreover, there is also a need to check for the heterogeneity error [18, 21].
One way of graphically depicting the structure of a network of interventions is a network diagram [12]. Such a graph is comprised of nodes that represent the interventions in the network and lines that show the available direct comparisons between pairs of interventions. An example of a network diagram including four interventions is given in Figure 3. In this example, in order to show the presence of a three-arm study, distinct lines that form a closed triangular loop have been added. It should be noted that complex and useless network diagrams may be yielded by such presentation of multi-arm studies; in this case, a tabular format can be preferred to depict multi-arm studies (Figure 5).
Example of network diagram with four competing interventions and information on the presence of multi-arm randomized trials.
The estimation of the relative effects on HbA1c change, of adding different oral glucose-lowering agents to a baseline sulfonylurea therapy in patients with type 2 diabetes, was the aim of the network meta-analysis in Diabetes. Systemic literature research was carried out on all relevant articles that were published from January 1993 to June 2009 in Medline and Embase. The search strategy was restricted to “randomized controlled 170 Statistical Methods in Medical Research 22(2) trials”, “sulfonylurea or sulphonylurea” and “humans”. This initial search was confirmed by combining each of the Medical Subject Headings key words “chlopropamide”, “glibenclamide”, “glyburide”, “gliclazide”, “glimepiride”, “glipizide”, “gliquidone”, “tolbutamide” on the one hand and ‘RCT’ on the other hand. No language restriction was applied. R program was used to analyze the data (Figure 6).
Diabetes example and view the data.
An original dataset offered by Senn [48] will be used in our first network meta-analysis. In this dataset, there are effect size data obtained from randomized controlled trials that compare different medications for diabetes. The effect size obtained for all comparisons represents the mean difference (MD) of diabetic patients’ HbA1c value in the posttest. What is represented by this value is the concentration of glucose found in the blood, which is aimed to be decreased with diabetic medication. As can be seen, there are 28 rows that represent the treatment comparisons and seven columns in the data. In the first column, TE, there is the effect size of each comparison, and the respective standard error is contained in se TE. In case effect size data that have already been calculated for each comparison might not be possessed.
The two treatments that are compared are represented by treat1. long, treat2. long, treat1, and treat2. As a shortened name of the original treatment name is contained in the variables treat1 and treat2, they are redundant.
We can now move forward by fitting our initial network meta-analysis model using the net metafunction. Now, we can look at the results of our first model, for now assuming a fixed-effects model.
As we have created our network meta-analysis model, we can go ahead and draw our network graph (Figure 2).
Several types of information are conveyed by this network graph.
First, there is the overall structure of comparisons in our network, which makes it possible for us to understand which treatments were compared with each other in the original data.
Second, there are the edges having a different thickness, indicating how often this specific comparison can be found in our network. We see that there are many trials comparing Rosiglitazone with Placebo.
There is also one multiarm trial in our network, represented by the triangle shown in blue in our network.
As a next step, our attention can be shifted towards the direct and indirect evidence in our network by looking at the rate of direct and indirect contribution to each comparison. A function has been prepared to this end with the name of direct.evidence.plot.
As can be seen in Figure 7, there are many estimates included in our network model that needed to be inferred by indirect evidence only. We are also provided with two additional metrics by the plot: The Minimal Parallelism and the Mean Path Length of each comparison. It is noted by König [49] that lower values of minimal parallelism and Mean Path Length >2 means that care should be taken while interpreting results for specific comparison.
Direct evidence proportion for each network estimate.
Then we can look at our network’s estimates for all possible combinations of treatments. In order to be able to do this, result matrices stored in our net meta results object under the fixed effects model can be used. Through a few preprocessing steps, the matrix can be made easier to read. First, the matrix is extracted from our data and the numbers in the matrix are rounded to three digits.
When the fact that a “triangle” in our matrix includes too much redundant information is considered, it seems to be possible to replace the lower triangle with an empty value.
The net league() function offers an extremely convenient way of exporting all estimated effect sizes. A matrix similar to the one given above can be generated by this function. Yet, in the matrix created by this function, only the pooled effect sizes belonging to the direct comparisons available in our network will be shown by the upper triangle, like the ones to be attained if a conventional meta-analysis had been conducted for each comparison. As there is no direct evidence for all comparisons, we will see some fields in the upper triangle empty. In this case, the network meta-analysis effect sizes for each comparison are contained by the lower triangle. The biggest advantage of this function is that it allows effect size estimates and confidence intervals to be shown together in each cell; the only thing that we need to tell the function is how the brackets for the confidence intervals should look like and how many digits we want our estimates to have behind the comma.
In a network meta-analysis, the most interesting question desired to be answered is: which intervention works the best? Such an ordering of treatments from most to least useful can be performed by the net rank() function implemented in net meta. The net rank() function is also built on a method of frequentist treatment ranking that uses P-scores. With these P-scores, the certainty that one treatment is better than another treatment is measured. It has been shown that this P-score is equivalent to the SUCRA score [50]. Our net meta object is needed as input by the function. Moreover, the small values parameter used to define whether smaller effect sizes in comparison are an indicator of a beneficial (“good”) or harmful (“bad”) effect should be specified. Now we will look at the output for our example:
As can be seen, the Rosiglitazone treatment has the highest P-score, which indicates that this treatment may be particularly helpful. Contrarily, the P-score of Placebo is zero, supporting our intuition that placebo may not be the best treatment decision. It should be noted, however, that treatment should never be automatically concluded to be the best just because it has the highest score [51]. One of the good ways to be used to visualize the uncertainty in our network is to generate network forest plots with the “weakest” treatment as a comparison. The forest plot can also be used to do this. The reference group for the forest plot can be specified by using the reference group argument (Figures 8 and 9).
Forest plot for fixed effect model with placebo as reference.
Forest plot for random-effects model with placebo as reference.
Now it can be seen that the results are more ambiguous than they seemed before; it is seen that several high-performing treatments having overlapping confidence intervals are available. This means we cannot make a firm judgment about which treatment is actually the best, but rather we see that there are a number of treatments that are more effective compared to placebo.
It is possible to decompose the Q total statistic (of the “whole network”) into a Q statistic to assess heterogeneity between studies having the same design (“within designs”) and a Q statistic to assess design inconsistency (“between designs”). The subsets of treatments that are compared with each other in a study are used to define designs.
For this analysis, the fixed-effect model has been used and it is seen that there is considerable heterogeneity/inconsistency within as well as between designs. The total within-design heterogeneity can be further decomposed into the contribution from each design.
As can be seen, the network meta-analysis includes 26 studies and these 26 studies use 15 different designs. Because only five designs for which more than one study exist, the remaining Q statistics specific to design are equal to zero and do not have any degrees of freedom. Except for design metf:rosi (p value = 0.67), heterogeneity is higher than would be expected between the contributing studies for all the other four designs; in the case of metf:plac a substantial amount more (
Now the net heat plot, put forward by Krahn, König, and Binder [49] will be introduced. This is a graphical presentation where two types of information are shown in a single plot. These are:
For each network estimate, the contribution of each design to this estimate, and
For each network estimate, the extent of inconsistency due to each design.
Net heat plot is very useful in terms of evaluating the inconsistency in our network model, and what contributes to it (Figure 10).
Net heat plot of the Senn data example based on a fixed-effect model.
A quadratic matrix is produced by the function so that each element in a row can be compared to all other elements in the columns. It should be noted here that rows and columns do not refer to all treatment comparisons in our network rather to specific designs. Thus, we also have rows and columns for the multiarm study, which had a design that compares “Plac”, “Metf” and Acar. Comparison of treatments with only one type of evidence (i.e., indirect or indirect evidence) is not included in this chart, as we are dealing with cases of inconsistency between direct and indirect evidence. Moreover, the net heat plot has also two important properties: 1. Gray boxes. The Gray boxes for each design comparison show the extent to which one treatment comparison is important in terms of estimating another treatment comparison. The increasing size of the box indicates the increasing importance of comparison. This can be easily analyzed by going through the rows of the plot one after another, and then by checking for each row in which columns the gray boxes are the largest. In rows where the row comparison and the column comparison intersect, the boxes are large, which is a common finding and means that direct evidence was employed. For instance, it is possible to see a big gray box at the point where the “Plac vs Rosi2” row and the “Plac vc Rosi” column intersect [52].
The colored backgrounds which range from blue to red indicate the inconsistency of the comparison in a row, which can be attributed to the design in a column. Inconsistent fields are shown in the upper-left corner in red. For instance, it is seen that the entry in column “Metf vs. Sulf” is shown with red in the row for “Rosi vs. Sulf”. This indicates that the evidence that “Metf vs. Sulf” provides for the “Metf vs. Sulf” estimation is not consistent with the other evidence. We can now remember that the fixed effects model that we initially used for our network analysis forms the basis of these results. On the basis of the things we have seen so far, we can reach the conclusion that due to too much unexpected heterogeneity, justification is not provided for the fixed effects model. How the net heat graph changes when a random-effects model is assumed can be controlled by changing the random argument of the net heat function to TRUE. It is seen that this results in a significant reduction of inconsistency in our network (Figure 11).
Net heat plot of the Senn data example from a random-effects model.
Net splitting, also known as node splitting, is another method for checking consistency in our network. With this method, our network estimates are split into the contribution of direct and indirect evidence and in this way, we can control for inconsistency in specific comparisons in our network. To generate a net split and compare the results.
Here, the important information is found in the p-value column. Any value that is
Net split plot of the Senn data example from a fixed-effect model.
For the estimation and comparison of treatment effects in a particular area, network meta-analysis can be used as a potentially powerful tool for using all the evidence. This approach has been depicted through an example from diabetes [48], which shows how to graph the network and explore a range of analyses. The results of our first model (fixed-effect model) Q value of DeFronzo1995 is highest with
Looking at the forest network plot, we see that there are several high-performance treatments with overlapping confidence intervals. From here, we looked at the net heat plot as we could not make a definitive decision.
The extent of the information obtained in a given treatment comparison by means of indirect evidence and the extent of heterogeneity can be defined as two important aspects of network meta-analysis. The net heat graph communicates information about both of these and the software allows for the decomposition of heterogeneity within and between designs. If there is clinically relevant heterogeneity, it is worth being explored further. Looking at Figure 10, a particularly large gray box is seen where the “Plac vs. Rosi2 row and the “Plac vs. Rosi” column intersect. Using the.random-effects model in Figure 11, we see that the inconsistency is significantly reduced.
Since it is not possible to conduct covariate adjustment at present with the software, one approach is to conduct study-specific (ideally individual participant data) analyses with appropriate covariate adjustment before the software presented here is used to perform network meta-analysis.
Rapidly progressing myelopathy can result from a thoracic or upper lumbar disc herniation compressing the anterior spinal cord. With a prevalence of approximately 6.5%, thoracic disc herniation (TDH) is not routinely diagnosed [1]. This low incidence contributes to the lack of familiarity with treatment methods and several factors contribute to a reticence for treating TDH. The calcified or ossified nature of the pathology, the difficulty to safely access and decompress the anterior spinal cord without causing worsening myelopathy and the complications associated with thoracic or thoracolumbar spinal approaches make this condition challenging for the spine surgeon.
The anterior thoracotomy approach has been traditionally considered as a treatment of choice to treat thoracic disc pathology. Compared to the posterior approaches, such as the costotransversectomy, anterior approaches can offer increased visualization and access to safely decompress midline thoracic lesions. To minimize pain and pulmonary complications associated with thoracotomy, thoracoscopic [2] and more recently the lateral mini-open technique have been reported to treat thoracic disc pathology [3, 4, 5, 6, 7, 8, 9]. Although considered a lateral approach, this technique offer direct access to the anterior spinal canal without requiring retraction of the dural sac. Another significant advantage of the lateral mini-open approach is it can be performed without depending on a thoracic access surgeon.
Under general anesthesia and without dual-lumen intubation, patients are positioned on lateral decubitus (Figure 1). Motor and sensory evoked potentials are monitored intraoperatively. A left or right side approach is chosen to access the same side of the disc protrusion if lateralized. Careful preoperative review of thoracic spine computed tomography (CT) and/or magnetic resonance imaging (MRI) helped localize the large vessels. Pre-operative hook-wire localization can be performed to accurately localize the pathology [4]. For midline anterior lesions, the senior author prefers a right-sided approach to avoid the descending aorta from T5–6 to T8–9. The location of the descending aorta on the left side of the vertebral body from T5 to T8 needs to be taken into account if the contralateral annulus needs to be released during the interbody arthrodesis. Breaking the table is usually not performed.
The lateral decubitus position was used for the thoracic mini-open lateral approach in a patient with T10–11 myelopathy. Note that the tape used to secure the upper body should be positioned closer to the shoulders in the case of a more rostral thoracic spinal level.
Under fluoroscopic localization, the anterior and posterior limit of the vertebral bodies above and below the pathological level are delineated. A 3–5 cm incision must span the entire anteroposterior distance of the disc space and is extended posteriorly over or between the underlying ribs. After blunt dissection of the intercostal muscles the rib is partially resected using Leksell and/or Kerrisons rongeurs. The bone is kept as autograft or can be replaced using rib reconstruction techniques to reduce intercostal wound pain. The retropleural space is then dissected bluntly by retracting the parietal pleura from the thoracic wall using sponge sticks or endoscopic kittners. Further rib resection posteriorly may help the dissection if needed. The rib head is then palpated in the retropleural space. Serial dilators are inserted and the retractor blade length is chosen. Using fluoroscopy in lateral projection the table-mounted 3 blade retractors are centered at the junction of the posterior disc and the canal (Figure 2). The middle blade is oriented anteriorly toward the lung to retract the parietal pleura. This leaves a space between the caudal and cranial blades where instruments can be freely manipulated (Figure 3). In the case where the parietal pleural is inadvertently torn and the lung is visualized, the approach becomes transthoracic and a placement of a laparotomy compress between the lung and the middle blade aids with exposure as well as protects the visceral pleura.
Intraoperative fluoroscopic image showing positioning of the retractor. The working space is centered over the posterior disc space and the anterior spinal canal junction.
Left-sided approach. The surgeon is facing the back of the patient. The patient head is to the right side of the picture. The orthostatic retractor is positioned with the middle blade retracting the parietal pleural and lung away from the surgeon. Instruments are manipulated between the caudal and rostral blades.
Using the operating microscope or loupes with a headlight, the parietal pleura over the rib head and disc space is divided using a long tip cautery tool. Careful attention is aimed at preserving the exiting nerve root. When identified, the exiting nerve root can be retracted and protected with the cranial blade of the retractor. Using a high-speed drill with 16-cm minimally invasive curve attachments (Stryker, Kalamazoo, MI), the rib head is drilled and bony struts are created in the vertebral bodies on each side of the posterior disc space to create a partial corpectomy space where disc fragments can be dislodged without retracting the dural sac. Drilling of the superior pedicle of the inferior vertebral body helps to expose the spinal canal. The posterior disc is removed with pituitary rongeurs. Ossified disc herniations are drilled laterally just anterior to the dural sac until they become completely freed from the vertebral bodies and disc space. Then the remaining osteophytes can be gently dissected from the posterior longitudinal ligament (PLL) and dura in the partial corpectomy space without excessive manipulation of the spinal cord (Figure 4). Resection of the PLL helps to visualize the dura to assess the decompression. Once the dural sac is fully decompressed anteriorly, an interbody arthrodesis can be accomplished by mobilizing the retractor in the center of the disc space in the anteroposterior plane. The discectomy can then be completed with serial shavers. The contralateral annulus can be released with a Cobb elevator in order to place an interbody cage which spans the full apophyseal ring of the vertebral bodies. An expandable stand-alone cage (Rise-L, Globus Medical, Audubon, PA, USA) filled with autograft and allograft is then positioned. A Jackson-Pratt or Hemovac drain is left in the retropleural or intrapleural cavity. In the event of a visceral pleura laceration, placement of a chest tube is preferred (Figures 5–7).
Intraoperative images under microscopic visualization.
Preoperative sagittal
Preoperative sagittal
This technique has been preferred by the author to treat one or two levels thoracic myelopathy. A total of 15 consecutive cases, 73% males and 27% females, who underwent a thoracic or thoracolumbar lateral mini-open approach to decompress the anterior spinal canal were included (Table 1). Mean age at surgery was 55.8 years (range, 38–76) and mean body mass index was 33.8 kg/m2 (range, 22.8–50.9). Fourteen patients presented with myelopathy symptoms while only six patients presented with radicular thoracic pain. A calcified disc was found in two patients. The most frequent level affected was T10–11. Two patients had two consecutive levels treated. Mean estimated blood loss was 400 mL (range, 50–2150) and mean operative time was 188 minutes (range, 113–328). Mean length of stay was 8 days (range, 2–23). No positive correlation was found between BMI and ORT,
Case no. | Age | Sex | Smoker | BMI | Myel. | Rad. | Cal. | Level (s) | Trans. | Arthro. | EBL (ml) | ORT (min) | LOS (days) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 72 | Female | No | 31.7 | Yes | No | Yes | T7–8 | No | No | 2150 | 233 | 3 |
2 | 51 | Male | No | 29.0 | Yes | Yes | No | T12-L1 | No | Yes | 200 | 263 | 4 |
3 | 43 | Male | No | 50.9 | Yes | No | No | T10–11 | No | Yes | 750 | 328 | 11 |
4 | 53 | Male | No | 40.0 | Yes | No | No | T11–12 | No | Yes | 350 | 134 | 12 |
5 | 71 | Male | No | 29.0 | Yes | No | No | T10–11 | Yes | Yes | 100 | 182 | 9 |
6 | 39 | Male | Yes | 24.0 | Yes | Yes | No | T9–10 | Yes | Yes | 250 | 163 | 2 |
7 | 57 | Male | No | 31.1 | Yes | No | No | T11–12 | No | Yes | 75 | 195 | 2 |
8 | 50 | Female | No | 35.8 | Yes | No | Yes | T9–10 | No | Yes | 50 | 156 | 3 |
9 | 41 | Male | No | 43.0 | Yes | Yes | No | T10–11 | No | Yes | 250 | 165 | 13 |
10 | 66 | Male | No | 40.7 | Yes | No | No | T10–11, T11–12 | No | Yes | 1000 | 214 | 14 |
11 | 59 | Male | No | 32.9 | Yes | Yes | No | T10–11 | No | Yes | 75 | 113 | 3 |
12 | 51 | Female | No | 29.5 | No | Yes | No | T10–11 | No | Yes | 200 | 146 | 4 |
13 | 70 | Male | Yes | 22.8 | Yes | No | No | T11–12 | No | Yes | 100 | 129 | 23 |
14 | 38 | Male | No | 32.9 | Yes | No | No | T5–6 | No | Yes | 300 | 192 | 15 |
15 | 76 | Female | No | 33.6 | Yes | Yes | No | T11–12, T12-L1 | No | Yes | 150 | 226 | 7 |
Cases demographic, clinical and surgical data.
Abbreviations: Arthro., interbody arthrodesis; BMI, body mass index; Cal., calcified disc; EBL, estimated blood loss; LOS, total length of stay; Myel., myelopathy; ORT, operative time; Rad., radicular pain; Trans., transpleural.
Case no. | Preoperative | Postoperative |
---|---|---|
1 | 3 | 3 |
2 | 2 | 3 |
3 | 3 | 7 |
4 | 3 | 3 |
5 | 3 | 4 |
6 | 3 | 3 |
7 | 4 | 5 |
8 | 6 | 7 |
9 | 2 | 3 |
10 | 3 | 6 |
11 | 5 | 7 |
12 | N/A | N/A |
13 | 2 | 3 |
14 | 2 | 3 |
15 | 2 | 2 |
Motor dysfunction score of the lower extremities by the modified Japanese Orthopedic association scale.
N/A, not applicable because the patient had radiculopathy without myelopathy.
The mini-open direct lateral approach has gained popularity to perform indirect decompression and interbody fusion in the lumbar spine [10] (Tables 3 and 4). Below the L2–3 level, the direct lateral approach is usually not performed to directly decompress the spinal canal because placement of the retractor more dorsally can result in direct nerve injury due to the proximity of the lumbar plexus [9]. Above L1–2, the mini-open lateral approach can be safely performed to remove midline anterior lesions and directly decompress the spinal cord and ipsilateral exiting nerve root (Table 5). At L1–2 and L2–3, the author experience has shown this approach to be useful in decompressing the anterior spinal canal but special care needs to be taken to identify and protect the exiting nerve root.
No. | Sex (% female) | Age | BMI | Myel. (%) | Rad. (%) | Cal. (%) | EBL (ml) | ORT (min) | LOS (days) | Trans. (%) | Chest tube (%) | Myel. stable or improved (%) | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Present study | 15 | 27 | 55.8 | 33.8 | 93.3 | 40 | 13.3 | 400 | 188 | 8 | 13 | 0 | 100 |
Bartels et al. [3] | 21 | 57 | 58.8 | N/A | 100 | 4.7 | 100 | 732 | 222 | N/A | 100 | 100 | 100 |
Deviren et al. [4] | 12 | 67 | 53 | N/A | 66.7 | 0 | N/A | 440 | 210 | 5 | 100 | 100 | 100 |
Kasliwal and Deutsch [5] | 7 | 42.9 | 52 | N/A | 100 | 57.1 | N/A | 180 | N/A | 2.6 | 0 | 0 | 42.8 |
Malham et al. [6] | 3 | 33 | 61.7 | 28.6 | 33.3 | 33.3 | 0 | <50 | N/A | 5 | 66 | 33 | 100 |
Nacar et al. [7] | 33 | 54 | 52.9 | 31 | 69.7 | 93.9 | 57.5 | 300 | 174 | 5 | 76 | 76 | 91 |
Uribe et al. [9] | 60 | 47 | 57.9 | 31 | 70 | 51.6 | 33 | 290 | 182 | 5 | 75 | 22 | 83.3 |
Literature review on mini-open lateral approach for symptomatic thoracic or upper lumbar disc disease: Demographic, clinical and surgical data.
Age, BMI, EBL, ORT, LOS values are means. Abbreviations: BMI, body mass index; Cal., calcified disc; EBL, estimated blood loss; LOS, length of stay; Myel., myelopathy; No., number of cases; N/A, not available; ORT, operative time; Rad., radicular pain; Trans., transpleural.
Static cage (%) | Expandable cage (%) | Autograft only (%) | Allograft only (%) | Autograft and allograft (%) | rhBMP-2 (%) | Sup. anterior inst. (%) | Sup. posterior decom. and inst. (%) | Sup. posterior decom. Only (%) | |
---|---|---|---|---|---|---|---|---|---|
Present study | 0 | 93 | 13 | 0 | 80 | 0 | 7 | 0 | 0 |
Bartels et al. [3] | 0 | 0 | 0 | 0 | 0 | 0 | 14 | 0 | 0 |
Deviren et al. [4] | 100 | 0 | 100 | 0 | 0 | 3 | 100 | 8 | 8 |
Kasliwal and Deutsch [5] | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Malham et al. [6] | 100 | 0 | 0 | 100 | 0 | 100 | 0 | 0 | 0 |
Nacar et al. [7] | 100 | 0 | N/A | N/A | N/A | N/A | 100 | 3 | 9 |
Uribe et al. [9] | 90 | 0 | 57 | 0 | 40 | 3 | 33 | 10 | 3 |
Literature review on mini-open lateral approach for symptomatic thoracic or upper lumbar disc disease: Interbody arthrodesis and supplemental surgical data.
Abbreviations: Decom. = Decompression, Inst. = Instrumentation, N/A = not available, Sup. = Supplemental
Level | Present study | Bartels et al. [3] | Deviren et al. [4] | Kasliwal and Deutsch [5] | Malham et al. [6] | Nacar et al. [7] | Uribe et al. [9] | |
---|---|---|---|---|---|---|---|---|
T4–5 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | |
T5–6 | 1 | 1 | 0 | 0 | 0 | 2 | 1 | |
T6–7 | 0 | 3 | 1 | 1 | 1 | 3 | 8 | |
T7–8 | 1 | 2 | 1 | 2 | 0 | 8 | 12 | |
T8–9 | 0 | 1 | 1 | 2 | 0 | 3 | 12 | |
T9–10 | 2 | 3 | 0 | 2 | 1 | 2 | 8 | |
T10–11 | 6 | 4 | 1 | 1 | 0 | 5 | 9 | |
T11–12 | 4 | 8 | 4 | 0 | 0 | 8 | 14 | |
T12-L1 | 2 | 0 | 4 | 0 | 1 | 6 | 7 | |
L1–2 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | |
L2–3 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Literature review on mini-open lateral approach for symptomatic thoracic or upper lumbar disc disease: Spinal levels treated.
Present study | Bartels et al. [3] | Deviren et al. [4] | Kasliwal and Deutsch [5] | Malham et al. [6] | Nacar et al. [7] | Uribe et al. [9] | |
---|---|---|---|---|---|---|---|
Intra-operative CSF leak | 1 | 2 | 0 | 0 | 0 | 2 | 7 |
New lower extremity weakness | 0 | 1 | 0 | 0 | 0 | 0 | 1 |
Neuropathic pain at incision | 2 | 0 | 1 | 0 | 1 | 1 | 1 |
Pleural effusion | 6 | N/A | 1 | 0 | N/A | 2 | 1 |
Pneumothorax | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Post-op chest tube | 2 | N/A | 1 | 0 | N/A | 2 | 1 |
Reoperation | 1 | 0 | 0 | 0 | 0 | 0 | 3 |
Cage subsidence | 2 | N/A | N/A | N/A | N/A | N/A | N/A |
Pseudoarthorosis | 1 | N/A | N/A | N/A | N/A | 0 | 0 |
Literature review on mini-open lateral approach for symptomatic thoracic or upper lumbar disc disease: Complications.
Abbreviation: CSF, cerebrospinal fluid; N/A, not available.
Obesity is a risk factor for lumbar spondylosis [11, 12] and prior studies suggest that class I obesity is frequently found in patients with symptomatic thoracic or thoracolumbar spondylosis [7, 9]. The mini-open lateral approach was found to be ideal in treating morbid obese patients as the amount of adipose tissue did not interfere with the approach (Figure 8). The working length is increased in obese patients, mandating usage of longer retractor blades, but the body mass index is not associated with increased surgical time.
Preoperative sagittal
Delayed deformity following thoracic discectomy without instrumented fusion has been reported as low as <3% [13]. In the case of rapidly worsening myelopathy caused by extrusion of a soft or partially calcified thoracic disc, concomitant arthrodesis is often performed as the condition is thought to result from chronic instability [13, 14]. The extent of the decompression by removing the posterior longitudinal ligament (PLL), the ipsilateral inferior pedicle and/or the lateral facet complex can also potentially increase segmental instability. However the natural history and pathophysiology of TDH presenting with myelopathy is still poorly understood and large thoracoscopic series has been performed without arthrodesis with successful long-term outcomes [15, 16].
Expandable lateral interbody cages have been shown to provide immediate stability, limiting flexion, extension, lateral bending and axial rotation comparable to static cages [17]. The main advantage is considered to be the small cage height (7 mm) at implantation, which is thought to minimize vertebral endplate disruption thus potentially decreasing later implant subsidence. The use of BMP-2 for interbody arthrodesis or adding supplemental anterior or posterior instrumentation should be considered when pre-existing factors that can lead to pseudoarthosis are present.
The author prefers using expendable spacer to decrease the risk of device migration during insertion. Because the PLL is frequently divided during the decompression procedure, a larger static cage could accidentally slip posteriorly during placement in the kyphotic thoracic spine, resulting in cord compression. This risk is similar to anterior cage migration during implantation of static cages when anterior longitudinal ligament release is performed for deformity correction in the lumbar spine [18].
The most frequent reported complication in the literature was intra-operative cerebrospinal fluid leak (Table 6). This complication was associated with calcified disc herniations and could be successfully repaired [7, 9]. Case no. 1 who had a calcified thoracic disc herniation had a small intraoperative cerebrospinal fluid leak repaired with onlay allograft and DuraSeal® (Covidien, Waltham, MA, USA). Other postoperative complications included 6 pleural effusions, two of which required interventional radiology placement of chest tube. Costovertebral neuralgia is usually treated with neuropathic pain medication such as gabapentin or pregabalin. Topical lidocaine can also be used.
The results of this study need to be interpreted with caution because of its retrospective nature and the limited number of cases reported. Although the outcomes were consistent with the literature, long-term follow-up would be necessary to better assess the risk of pseudoarthrosis and the persistence of resolution of symptoms.
A larger number of case series have reported successful treatment of symptomatic TDH using the mini-open lateral technique. With a short length of stay for elective cases, a relatively low complication rate and improvement of motor function in the majority of patients, the mini-open lateral approach can be considered a safe and effective procedure for symptomatic TDH. Arthrodesis using expandable cages without additional anterior instrumentation can provide satisfactory short-term outcomes. However supplemental anterior or posterior fixation should also be considered when significant pre-existing instability is suspected, when multiple contiguous levels are treated or when significant cage subsidence is noted during cage expansion.
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\\n\\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
\\n\\nCONFLICT OF INTEREST – ACADEMIC EDITOR
\\n\\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
\\n\\nAvoidance Measures for Academic Editors of Conflicts of Interest:
\\n\\nFor manuscripts submitted by the Academic Editor (or a scientific advisor), an appropriate person will be appointed to handle and evaluate the manuscript. The appointed handling Editor's identity will not be disclosed to the Author in order to maintain impartiality and anonymity of the review.
\\n\\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\\n\\nCONFLICT OF INTEREST - REVIEWER
\\n\\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\\n\\nEXAMPLES OF CONFLICTS OF INTEREST:
\\n\\nFINANCIAL AND MATERIAL
\\n\\nNON-FINANCIAL
\\n\\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\\n\\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\\n\\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\\n\\nEXAMPLES:
\\n\\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\\n\\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\\n\\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\\n\\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\\n\\nPolicy last updated: 2016-06-09
\\n"}]'},components:[{type:"htmlEditorComponent",content:"In each instance of a possible Conflict of Interest, IntechOpen aims to disclose the situation in as transparent a way as possible in order to allow readers to judge whether a particular potential Conflict of Interest has influenced the Work of any individual Author, Editor, or Reviewer. IntechOpen takes all possible Conflicts of Interest into account during the review process and ensures maximum transparency in implementing its policies.
\n\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
\n\nA Conflict of Interest can be identified at different phases of the publishing process.
\n\nIntechOpen requires:
\n\nCONFLICT OF INTEREST - AUTHOR
\n\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
\n\nCONFLICT OF INTEREST – ACADEMIC EDITOR
\n\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
\n\nAvoidance Measures for Academic Editors of Conflicts of Interest:
\n\nFor manuscripts submitted by the Academic Editor (or a scientific advisor), an appropriate person will be appointed to handle and evaluate the manuscript. The appointed handling Editor's identity will not be disclosed to the Author in order to maintain impartiality and anonymity of the review.
\n\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\n\nCONFLICT OF INTEREST - REVIEWER
\n\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\n\nEXAMPLES OF CONFLICTS OF INTEREST:
\n\nFINANCIAL AND MATERIAL
\n\nNON-FINANCIAL
\n\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\n\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\n\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\n\nEXAMPLES:
\n\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\n\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\n\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\n\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\n\nPolicy last updated: 2016-06-09
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Javaid",coverURL:"https://cdn.intechopen.com/books/images_new/8378.jpg",editedByType:"Edited by",editors:[{id:"208759",title:"Dr.",name:"Muhammad Salik",middleName:null,surname:"Javaid",slug:"muhammad-salik-javaid",fullName:"Muhammad Salik Javaid"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6056",title:"Engineering and Mathematical Topics in Rainfall",subtitle:null,isOpenForSubmission:!1,hash:"76855b91984ffabc0aa220cc9d845957",slug:"engineering-and-mathematical-topics-in-rainfall",bookSignature:"Theodore V Hromadka II and Prasada Rao",coverURL:"https://cdn.intechopen.com/books/images_new/6056.jpg",editedByType:"Edited by",editors:[{id:"181008",title:"Dr.",name:"Theodore V.",middleName:"V.",surname:"Hromadka II",slug:"theodore-v.-hromadka-ii",fullName:"Theodore V. 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Quinn",coverURL:"https://cdn.intechopen.com/books/images_new/1269.jpg",editedByType:"Edited by",editors:[{id:"138347",title:"Dr.",name:"Nigel W.T.",middleName:null,surname:"Quinn",slug:"nigel-w.t.-quinn",fullName:"Nigel W.T. Quinn"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2503",title:"Water Treatment",subtitle:null,isOpenForSubmission:!1,hash:"296eb93cd4d7425db9a1f7c0d57032fe",slug:"water-treatment",bookSignature:"Walid Elshorbagy and Rezaul Kabir Chowdhury",coverURL:"https://cdn.intechopen.com/books/images_new/2503.jpg",editedByType:"Edited by",editors:[{id:"137631",title:"Dr.",name:"Walid",middleName:null,surname:"Elshorbagy",slug:"walid-elshorbagy",fullName:"Walid Elshorbagy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:25,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"41947",doi:"10.5772/50738",title:"Natural Zeolites in Water Treatment – How Effective is Their Use",slug:"natural-zeolites-in-water-treatment-how-effective-is-their-use",totalDownloads:16538,totalCrossrefCites:66,totalDimensionsCites:148,abstract:null,book:{id:"2503",slug:"water-treatment",title:"Water Treatment",fullTitle:"Water Treatment"},signatures:"Karmen Margeta, Nataša Zabukovec Logar, Mario Šiljeg and Anamarija Farkas",authors:[{id:"139658",title:"Dr.",name:"Karmen",middleName:null,surname:"Margeta",slug:"karmen-margeta",fullName:"Karmen Margeta"}]},{id:"49024",doi:"10.5772/61250",title:"Biological and Chemical Wastewater Treatment Processes",slug:"biological-and-chemical-wastewater-treatment-processes",totalDownloads:27850,totalCrossrefCites:57,totalDimensionsCites:105,abstract:"This chapter elucidates the technologies of biological and chemical wastewater treatment processes. The presented biological wastewater treatment processes include: (1) bioremediation of wastewater that includes aerobic treatment (oxidation ponds, aeration lagoons, aerobic bioreactors, activated sludge, percolating or trickling filters, biological filters, rotating biological contactors, biological removal of nutrients) and anaerobic treatment (anaerobic bioreactors, anaerobic lagoons); (2) phytoremediation of wastewater that includes constructed wetlands, rhizofiltration, rhizodegradation, phytodegradation, phytoaccumulation, phytotransformation, and hyperaccumulators; and (3) mycoremediation of wastewater. The discussed chemical wastewater treatment processes include chemical precipitation (coagulation, flocculation), ion exchange, neutralization, adsorption, and disinfection (chlorination/dechlorination, ozone, UV light). Additionally, this chapter elucidates and illustrates the wastewater treatment plants in terms of plant sizing, plant layout, plant design, and plant location.",book:{id:"4619",slug:"wastewater-treatment-engineering",title:"Wastewater Treatment Engineering",fullTitle:"Wastewater Treatment Engineering"},signatures:"Mohamed Samer",authors:[{id:"175050",title:"Prof.",name:"Mohamed",middleName:null,surname:"Samer",slug:"mohamed-samer",fullName:"Mohamed Samer"}]},{id:"48803",doi:"10.5772/60770",title:"Bioremediation of Polluted Waters Using Microorganisms",slug:"bioremediation-of-polluted-waters-using-microorganisms",totalDownloads:11431,totalCrossrefCites:37,totalDimensionsCites:85,abstract:"Water pollution is an issue of great concern worldwide, and it can be broadly divided into three main categories, that is, contamination by organic compounds, inorganic compounds (e.g., heavy metals), and microorganisms. In recent years, the number of research studies concerning the use of efficient processes to clean up and minimize the pollution of water bodies has been increasing. In this context, the use of bioremediation processes for the removal of toxic metals from aqueous solutions is gaining considerable attention. Bioremediation can be defined as the ability of certain biomolecules or types of biomass to bind and concentrate selected ions or other molecules present in aqueous solutions. Bioremediation using microorganisms shows great potential for future development due to its environmental compatibility and possible cost-effectiveness. A wide range of microorganisms, including bacteria, fungi, yeasts, and algae, can act as biologically active methylators, which are able to at least modify toxic species. Many microbial detoxification processes involve the efflux or exclusion of metal ions from the cell, which in some cases can result in high local concentrations of metals at the cell surface, where they can react with biogenic ligands and precipitate. Although microorganisms cannot destroy metals, they can alter their chemical properties via a surprising array of mechanisms. The main purpose of this chapter is to provide an update on the recent literature concerning the strategies available for the remediation of metal-contaminated water bodies using microorganisms and to critically discuss their main advantages and weaknesses. The focus is on the heavy metals associated with environmental contamination, for instance, lead (Pb), cadmium (Cd), and chromium (Cr), which are potentially hazardous to ecosystems. The types of microorganisms that are used in bioremediation processes due to their natural capacity to biosorb toxic heavy metal ions are discussed in detail. This chapter summarizes existing knowledge on various aspects of the fundamentals and applications of bioremediation and critically reviews the obstacles to its commercial success and future perspectives.",book:{id:"4602",slug:"advances-in-bioremediation-of-wastewater-and-polluted-soil",title:"Advances in Bioremediation of Wastewater and Polluted Soil",fullTitle:"Advances in Bioremediation of Wastewater and Polluted Soil"},signatures:"Luciene M. Coelho, Helen C. Rezende, Luciana M. Coelho, Priscila\nA.R. de Sousa, Danielle F.O. Melo and Nívia M.M. Coelho",authors:[{id:"163731",title:"Prof.",name:"Nivia",middleName:null,surname:"Coelho",slug:"nivia-coelho",fullName:"Nivia Coelho"},{id:"177651",title:"Dr.",name:"Luciana",middleName:null,surname:"Coelho",slug:"luciana-coelho",fullName:"Luciana Coelho"},{id:"177741",title:"Dr.",name:"Luciene M.",middleName:null,surname:"Coelho",slug:"luciene-m.-coelho",fullName:"Luciene M. Coelho"},{id:"177742",title:"Dr.",name:"Helen C.",middleName:null,surname:"Rezende",slug:"helen-c.-rezende",fullName:"Helen C. Rezende"},{id:"177743",title:"Dr.",name:"Priscila A.R.",middleName:null,surname:"de Sousa",slug:"priscila-a.r.-de-sousa",fullName:"Priscila A.R. de Sousa"},{id:"177744",title:"Dr.",name:"Danielle F.O.",middleName:null,surname:"Melo",slug:"danielle-f.o.-melo",fullName:"Danielle F.O. Melo"}]},{id:"41953",doi:"10.5772/52665",title:"Treatment Technologies for Organic Wastewater",slug:"treatment-technologies-for-organic-wastewater",totalDownloads:10725,totalCrossrefCites:25,totalDimensionsCites:76,abstract:null,book:{id:"2503",slug:"water-treatment",title:"Water Treatment",fullTitle:"Water Treatment"},signatures:"Chunli Zheng, Ling Zhao, Xiaobai Zhou, Zhimin Fu and An Li",authors:[{id:"141286",title:"Dr",name:"An",middleName:null,surname:"Li",slug:"an-li",fullName:"An Li"},{id:"155298",title:"Dr.",name:"Chunli",middleName:null,surname:"Zheng",slug:"chunli-zheng",fullName:"Chunli Zheng"},{id:"155299",title:"Dr.",name:"Ling",middleName:null,surname:"Zhao",slug:"ling-zhao",fullName:"Ling Zhao"},{id:"155300",title:"Dr.",name:"Xiaobai",middleName:null,surname:"Zhou",slug:"xiaobai-zhou",fullName:"Xiaobai Zhou"},{id:"155301",title:"Dr.",name:"Zhimin",middleName:null,surname:"Fu",slug:"zhimin-fu",fullName:"Zhimin Fu"}]},{id:"30860",doi:"10.5772/36310",title:"Use of Agro-Industrial Wastes in Solid-State Fermentation Processes",slug:"use-of-agro-industrial-wastes-in-solid-state-fermentation-processes",totalDownloads:4186,totalCrossrefCites:9,totalDimensionsCites:66,abstract:null,book:{id:"1868",slug:"industrial-waste",title:"Industrial Waste",fullTitle:"Industrial Waste"},signatures:"Solange I. Mussatto, Lina F. Ballesteros, Silvia Martins and José A. Teixeira",authors:[{id:"107810",title:"Dr.",name:"Solange I.",middleName:null,surname:"Mussatto",slug:"solange-i.-mussatto",fullName:"Solange I. Mussatto"},{id:"109520",title:"MSc.",name:"Lina F.",middleName:null,surname:"Ballesteros",slug:"lina-f.-ballesteros",fullName:"Lina F. Ballesteros"},{id:"109522",title:"MSc.",name:"Silvia",middleName:null,surname:"Martins",slug:"silvia-martins",fullName:"Silvia Martins"},{id:"109523",title:"Prof.",name:"José António",middleName:null,surname:"Teixeira",slug:"jose-antonio-teixeira",fullName:"José António Teixeira"}]}],mostDownloadedChaptersLast30Days:[{id:"49024",title:"Biological and Chemical Wastewater Treatment Processes",slug:"biological-and-chemical-wastewater-treatment-processes",totalDownloads:27848,totalCrossrefCites:57,totalDimensionsCites:105,abstract:"This chapter elucidates the technologies of biological and chemical wastewater treatment processes. The presented biological wastewater treatment processes include: (1) bioremediation of wastewater that includes aerobic treatment (oxidation ponds, aeration lagoons, aerobic bioreactors, activated sludge, percolating or trickling filters, biological filters, rotating biological contactors, biological removal of nutrients) and anaerobic treatment (anaerobic bioreactors, anaerobic lagoons); (2) phytoremediation of wastewater that includes constructed wetlands, rhizofiltration, rhizodegradation, phytodegradation, phytoaccumulation, phytotransformation, and hyperaccumulators; and (3) mycoremediation of wastewater. The discussed chemical wastewater treatment processes include chemical precipitation (coagulation, flocculation), ion exchange, neutralization, adsorption, and disinfection (chlorination/dechlorination, ozone, UV light). Additionally, this chapter elucidates and illustrates the wastewater treatment plants in terms of plant sizing, plant layout, plant design, and plant location.",book:{id:"4619",slug:"wastewater-treatment-engineering",title:"Wastewater Treatment Engineering",fullTitle:"Wastewater Treatment Engineering"},signatures:"Mohamed Samer",authors:[{id:"175050",title:"Prof.",name:"Mohamed",middleName:null,surname:"Samer",slug:"mohamed-samer",fullName:"Mohamed Samer"}]},{id:"52474",title:"Slaughterhouse Wastewater: Treatment, Management and Resource Recovery",slug:"slaughterhouse-wastewater-treatment-management-and-resource-recovery",totalDownloads:6816,totalCrossrefCites:18,totalDimensionsCites:53,abstract:"The meat processing industry is one of the largest consumers of total freshwater used in the agricultural and livestock industry worldwide. Meat processing plants (MPPs) produce large amounts of slaughterhouse wastewater (SWW) because of the slaughtering process and cleaning of facilities. SWWs need significant treatment for a sustainable and safe discharge to the environment due to the high content of organics and nutrients. Therefore, the treatment and final disposal of SWW are a public health necessity. In this chapter, the regulatory frameworks relevant to the SWW management, environmental impacts, health effects, and treatment methods are discussed. Although physical, chemical, and biological treatment can be used for SWW degradation, each treatment process has different advantages and drawbacks depending on the SWW characteristics, best available technology, jurisdictions, and regulations. SWWs are typically assessed using bulk parameters because of the various pollutant loads derived from the type and the number of animals slaughtered that fluctuate amid the meat industry. Thus, an on-site treatment using combined processes would be the best option to treat and disinfect the slaughterhouse effluents to be safely discharged into receiving waters.",book:{id:"6050",slug:"physico-chemical-wastewater-treatment-and-resource-recovery",title:"Physico-Chemical Wastewater Treatment and Resource Recovery",fullTitle:"Physico-Chemical Wastewater Treatment and Resource Recovery"},signatures:"Ciro Bustillo-Lecompte and Mehrab Mehrvar",authors:[{id:"66753",title:"Prof.",name:"Mehrab",middleName:null,surname:"Mehrvar",slug:"mehrab-mehrvar",fullName:"Mehrab Mehrvar"},{id:"189304",title:"Dr.",name:"Ciro",middleName:"Fernando",surname:"Bustillo-Lecompte",slug:"ciro-bustillo-lecompte",fullName:"Ciro Bustillo-Lecompte"}]},{id:"48946",title:"Cogeneration Power-Desalting Plants Using Gas Turbine Combined Cycle",slug:"cogeneration-power-desalting-plants-using-gas-turbine-combined-cycle",totalDownloads:4659,totalCrossrefCites:8,totalDimensionsCites:10,abstract:"The gas-steam turbine combined cycle (GTCC) is the preferred power plant type because of its high efficiency and its use of cheap and clean natural gas as fuel. It is also the preferred type in the Arab Gulf countries where it is used as cogeneration power-desalting plant (CPDP). In this chapter, descriptions and analysis of the GTCC components are presented, namely, the gas turbine cycle (compressor, combustor, gas turbine), heat recovery steam generator, and steam turbine. Combinations of the GTCC with thermally driven desalination units to present CPDP are presented. A parametric study to show the effect of using GTCC on several operating parameters on the CPDP is also presented, as well as cost allocation methods of fuel between the two product utilities (electric power and desalted seawater are also presented).",book:{id:"4613",slug:"desalination-updates",title:"Desalination Updates",fullTitle:"Desalination Updates"},signatures:"M.A. Darwish, H.K. Abdulrahim, A.A. Mabrouk and A.S. Hassan",authors:[{id:"173364",title:"Prof.",name:"Mohamed",middleName:null,surname:"Darwish",slug:"mohamed-darwish",fullName:"Mohamed Darwish"},{id:"173603",title:"Dr.",name:"Hassan",middleName:null,surname:"Abdulrahim",slug:"hassan-abdulrahim",fullName:"Hassan Abdulrahim"},{id:"173774",title:"Dr.",name:"Abdel Nasser",middleName:null,surname:"Mabrouk",slug:"abdel-nasser-mabrouk",fullName:"Abdel Nasser Mabrouk"},{id:"175519",title:"Dr.",name:"Ashraf",middleName:null,surname:"Hassan",slug:"ashraf-hassan",fullName:"Ashraf Hassan"}]},{id:"54201",title:"Pulp Mill Wastewater: Characteristics and Treatment",slug:"pulp-mill-wastewater-characteristics-and-treatment",totalDownloads:4914,totalCrossrefCites:8,totalDimensionsCites:23,abstract:"The production of chemical pulp in recent times is 180 million tons per year; while the production of eucalyptus pulp has increased intensively, especially in the southern hemisphere. The pulp and paper industry has long been considered a large consumer of natural resources (wood and water) and one of the largest sources of pollution to the environment (air, water courses and soil). Important efforts are being made to reduce the pollutant levels and water consumption of the industry. The wastewater composition, and therefore, the efficiency of effluent treatments and characteristics of the discharges to water are strongly dependent on the applied technology and raw materials. Despite a large body of literature on softwood-based wastewater, few studies have examined the characteristics of kraft eucalyptus bleaching effluents and their behaviour in the different biological treatments. The largest secondary treatment systems today use the activated sludge process. Sixty to seventy-five per cent of all the biological effluent treatment plants within the pulp and paper industry use this kind of treatment system. This chapter reviews the current pulping technologies at mills and compares the chemical composition and biological treatment of wastewater between softwood and hardwood bleached pulps.",book:{id:"5417",slug:"biological-wastewater-treatment-and-resource-recovery",title:"Biological Wastewater Treatment and Resource Recovery",fullTitle:"Biological Wastewater Treatment and Resource Recovery"},signatures:"María Noel Cabrera",authors:[{id:"187931",title:"Dr.",name:"María Noel",middleName:null,surname:"Cabrera",slug:"maria-noel-cabrera",fullName:"María Noel Cabrera"}]},{id:"54320",title:"Phosphorus Recovery by Struvite Crystallization from Livestock Wastewater and Reuse as Fertilizer: A Review",slug:"phosphorus-recovery-by-struvite-crystallization-from-livestock-wastewater-and-reuse-as-fertilizer-a-",totalDownloads:2566,totalCrossrefCites:7,totalDimensionsCites:15,abstract:"In China, the intensive livestock farming produces massive livestock wastewater with high concentration of phosphorus. Discharge of these compounds to surface water not only causes water eutrophication but also wastes phosphorus resources for plant growth. Therefore, it’s necessary combining the removal of phosphorus from livestock wastewater with its recovery and reuse as fertilizer. As a valuable slow-release mineral fertilizer, struvite crystallization has become a focus in phosphorus recovery. In this chapter, struvite crystallization mechanism, reaction factors, crystallizers, and the applications of struvite as fertilizer are discussed. Two steps of nucleation and crystal growth for struvite crystallization from generation to growth are introduced. The reaction factors, including molar ratio of magnesium and phosphate, solution pH, coexisting substances, and seeding assist, of struvite crystallization are summarized. Several innovate types of crystallizer, which relate to the shape and size of harvest struvite to realize the phosphorus recycling, are demonstrated. Due to the influence of toxic or harmful impurities in struvite on its reuse as fertilizer, the environmental risk evaluation of struvite application is introduced. 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She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. 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She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. 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He is also Member of the Laboratory of genetic, animal and feed resource and member of Animal science Department of INAT. He graduated from Higher School of Agriculture of Mateur, University of Carthage, in 2002 and completed his masters in 2006. Dr. M’HAMDI completed his PhD thesis in Genetic welfare indicators of dairy cattle at Higher Institute of Agronomy of Chott-Meriem, University of Sousse, in 2011. 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Then take a masters degree in science in Germany (Animal breeding). Take a doctorate in animal science at the UANL.",institutionString:null,institution:{name:"Universidad Autónoma de Nuevo León",country:{name:"Mexico"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",slug:"miguel-quaresma",fullName:"Miguel Quaresma",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309250/images/9059_n.jpg",biography:"Miguel Nuno Pinheiro Quaresma was born on May 26, 1974 in Dili, Timor Island. He is married with two children: a boy and a girl, and he is a resident in Vila Real, Portugal. He graduated in Veterinary Medicine in August 1998 and obtained his Ph.D. degree in Veterinary Sciences -Clinical Area in February 2015, both from the University of Trás-os-Montes e Alto Douro. He is currently enrolled in the Alternative Residency of the European College of Animal Reproduction. 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After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón Poggi",slug:"juan-carlos-gardon-poggi",fullName:"Juan Carlos Gardón Poggi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:null,institution:{name:"Valencia Catholic University Saint Vincent Martyr",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",country:{name:"United Kingdom"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",biography:"Samir El-Gendy is a Professor of anatomy and embryology at the faculty of veterinary medicine, Alexandria University, Egypt. Samir obtained his PhD in veterinary science in 2007 from the faculty of veterinary medicine, Alexandria University and has been a professor since 2017. Samir is an author on 24 articles at Scopus and 12 articles within local journals and 2 books/book chapters. His research focuses on applied anatomy, imaging techniques and computed tomography. Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",biography:"Dr. Fonseca-Alves earned his DVM from Federal University of Goias – UFG in 2008. He completed an internship in small animal internal medicine at UPIS university in 2011, earned his MSc in 2013 and PhD in 2015 both in Veterinary Medicine at Sao Paulo State University – UNESP. Dr. Fonseca-Alves currently serves as an Assistant Professor at Paulista University – UNIP teaching small animal internal medicine.",institutionString:null,institution:{name:"Universidade Paulista",country:{name:"Brazil"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",biography:"María de la Luz García Pardo is an agricultural engineer from Universitat Politècnica de València, Spain. She has a Ph.D. in Animal Genetics. Currently, she is a lecturer at the Agrofood Technology Department of Miguel Hernández University, Spain. Her research is focused on genetics and reproduction in rabbits. The major goal of her research is the genetics of litter size through novel methods such as selection by the environmental sensibility of litter size, with forays into the field of animal welfare by analysing the impact on the susceptibility to diseases and stress of the does. Details of her publications can be found at https://orcid.org/0000-0001-9504-8290.",institutionString:null,institution:{name:"Miguel Hernandez University",country:{name:"Spain"}}},{id:"350704",title:"M.Sc.",name:"Camila",middleName:"Silva Costa",surname:"Ferreira",slug:"camila-ferreira",fullName:"Camila Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/350704/images/17280_n.jpg",biography:"Graduated in Veterinary Medicine at the Fluminense Federal University, specialist in Equine Reproduction at the Brazilian Veterinary Institute (IBVET) and Master in Clinical Veterinary Medicine and Animal Reproduction at the Fluminense Federal University. She has experience in analyzing zootechnical indices in dairy cattle and organizing events related to Veterinary Medicine through extension grants. I have experience in the field of diagnostic imaging and animal reproduction in veterinary medicine through monitoring and scientific initiation scholarships. I worked at the Equus Central Reproduction Equine located in Santo Antônio de Jesus – BA in the 2016/2017 breeding season. I am currently a doctoral student with a scholarship from CAPES of the Postgraduate Program in Veterinary Medicine (Pathology and Clinical Sciences) at the Federal Rural University of Rio de Janeiro (UFRRJ) with a research project with an emphasis on equine endometritis.",institutionString:null,institution:null},{id:"41319",title:"Prof.",name:"Lung-Kwang",middleName:null,surname:"Pan",slug:"lung-kwang-pan",fullName:"Lung-Kwang Pan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41319/images/84_n.jpg",biography:null,institutionString:null,institution:null},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain.Dr. Satué is accredited as a Private University Doctor Professor, Doctor Assistant, and Contracted Doctor by AVAP (Agència Valenciana d'Avaluació i Prospectiva) and currently, as a full professor by ANECA (since January 2022). To date, Katy has taught 22 years in the Department of Animal Medicine and Surgery at the CEU-Cardenal Herrera University in undergraduate courses in Veterinary Medicine (General Pathology, integrated into the Applied Basis of Veterinary Medicine module of the 2nd year, Clinical Equine I of 3rd year, and Equine Clinic II of 4th year). Dr. Satué research activity is in the field of Endocrinology, Hematology, Biochemistry, and Immunology in the Spanish Purebred mare. She has directed 5 Doctoral Theses and 5 Diplomas of Advanced Studies, and participated in 11 research projects as a collaborating researcher. She has written 2 books and 14 book chapters in international publishers related to the area, and 68 scientific publications in international journals. Dr. Satué has attended 63 congresses, participating with 132 communications in international congresses and 19 in national congresses related to the area. Dr. Satué is a scientific reviewer for various prestigious international journals such as Animals, American Journal of Obstetrics and Gynecology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology, among others. Since 2014 she has been responsible for the Clinical Analysis Laboratory of the CEU-Cardenal Herrera University Veterinary Clinical Hospital.",institutionString:null,institution:null},{id:"201721",title:"Dr.",name:"Beatrice",middleName:null,surname:"Funiciello",slug:"beatrice-funiciello",fullName:"Beatrice Funiciello",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201721/images/11089_n.jpg",biography:"Graduated from the University of Milan in 2011, my post-graduate education included CertAVP modules mainly on equines (dermatology and internal medicine) and a few on small animal (dermatology and anaesthesia) at the University of Liverpool. After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". Master\\\'s degree in Ecology and Biodiversity Conservation at Federal University of Mato Grosso with a scholarship by CAPES/REUNI program: Project \\"Reproductive biology of Melanorivulus punctatus\\". PhD\\\'s degree in Science (Cell and Tissue Biology Area) \n at University of Sao Paulo with scholarship granted by FAPESP; Project \\"Development of morphofunctional changes in ovary of Astyanax altiparanae Garutti & Britski, 2000 (Teleostei, Characidae)\\". She has experience in Reproduction of vertebrates and Morphology, with emphasis in Cellular Biology and Histology. She is currently a teacher in the medium / technical level courses at IFMT-Alta Floresta, as well as in the Bachelor\\\'s degree in Animal Science and in the Bachelor\\\'s degree in Business.',institutionString:null,institution:null},{id:"442807",title:"Dr.",name:"Busani",middleName:null,surname:"Moyo",slug:"busani-moyo",fullName:"Busani Moyo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Gwanda State University",country:{name:"Zimbabwe"}}},{id:"439435",title:"Dr.",name:"Feda S.",middleName:null,surname:"Aljaser",slug:"feda-s.-aljaser",fullName:"Feda S. Aljaser",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"423023",title:"Dr.",name:"Yosra",middleName:null,surname:"Soltan",slug:"yosra-soltan",fullName:"Yosra Soltan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"349788",title:"Dr.",name:"Florencia Nery",middleName:null,surname:"Sompie",slug:"florencia-nery-sompie",fullName:"Florencia Nery Sompie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sam Ratulangi University",country:{name:"Indonesia"}}},{id:"428600",title:"MSc.",name:"Adriana",middleName:null,surname:"García-Alarcón",slug:"adriana-garcia-alarcon",fullName:"Adriana García-Alarcón",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428599",title:"MSc.",name:"Gabino",middleName:null,surname:"De La Rosa-Cruz",slug:"gabino-de-la-rosa-cruz",fullName:"Gabino De La Rosa-Cruz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428601",title:"MSc.",name:"Juan Carlos",middleName:null,surname:"Campuzano-Caballero",slug:"juan-carlos-campuzano-caballero",fullName:"Juan Carlos Campuzano-Caballero",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}}]}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular Economy, Contingency Planning and Response to Disasters, Ecosystem Services, Integrated Urban Water Management, Nature-based Solutions, Sustainable Urban Development, Urban Green Spaces",scope:"