Free radicals (FR) generated in biological systems.
\r\n\t- Image Classification – type or class of an object in an image prediction;
\r\n\t- Object Localization – the presence of objects in an image location and indication of their location with a bounding box;
\r\n\t- Object Detection – the presence of objects with a bounding box location and types or classes of the located objects in an image;
\r\n\t- Object Segmentation – recognized objects instances indication by highlighting the specific pixels of the object instead of a coarse bounding box.
\r\n\tThis book provides the reader with a balanced approach between the theory and practice of selected methods in these areas to make the book accessible to a range of researchers, engineers, developers and postgraduate students working in computer vision and related fields.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"e319d5ec22f712c84fad52564c2a0b3d",bookSignature:"Dr. George Melillos",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9968.jpg",keywords:"Detecting irregularities, Automatic visual inspection, Detecting unusual objects, Detection techniques, Object detection, Computer vision, Underground objects, Thermography, Digital photos, Pixels, Object localization, Geo location",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 15th 2019",dateEndSecondStepPublish:"March 18th 2020",dateEndThirdStepPublish:"May 17th 2020",dateEndFourthStepPublish:"August 5th 2020",dateEndFifthStepPublish:"October 4th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"292389",title:"Dr.",name:"George",middleName:null,surname:"Melillos",slug:"george-melillos",fullName:"George Melillos",profilePictureURL:"https://mts.intechopen.com/storage/users/292389/images/system/292389.jpg",biography:"Dr George Melillos is Postdoctoral Researcher at the Department of Civil Engineering and Geomatics, Cyprus University of Technology. He has over 20 years’ experience in IT and 15 years’ experience in GIS. He holds Diploma in Computer Programming/Programmer, Higher National Diploma (HND) in Software Engineering, a B.Sc. (Hons) in Computing, an M.A (Master of Arts) in ICT and Education and PhD in Remote Sensing, GIS and Space Technology at Cyprus University of Technology. He holds many professional certifications, including the Microsoft Certified Trainer (MCT), Microsoft Certified Application Developer (MCAD), Microsoft Certified Application Specialist (MCAS), Adobe Certified Associate (ACA) for Adobe Dreamweaver and Adobe Photoshop, ECDL Certified Trainer Professional (ECDL CTP) and ISO/IEC 27001 Lead Implementer. He is a member of the Cyprus Computer Society, member (MBCS) of the British Computer Society (BCS) - The Chartered Institute for IT, member of SPIE (Society of Photo-Optical Instrumentation Engineers), member of IEEE (Institute of Electrical and Electronics Engineers), member of IEEE Geoscience and Remote Sensing Society Resource Center, member of The Cyprus Remote Sensing Society and member of Engineering Council UK as Chartered Engineer (CEng). He is the author of two books: one for ECDL Web Editing – Using Adobe Dreamweaver and another one for ECDL Image Editing – Using Adobe Photoshop which have been approved by Ministry of Education of Cyprus, by Cyprus Computer Society and ECDL. These books are taught in schools (secondary education) in Cyprus. His research focuses on the detection of buried structures using space & GIS techniques for security & defense applications. He has publish scientific publications in high prestigious journals, edited books and conference proceedings as main author. He won an international recognition, attending as speaker in several conferences/workshops, and organizing international workshops.",institutionString:"Cyprus University of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Cyprus University of Technology",institutionURL:null,country:{name:"Cyprus"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247041",firstName:"Dolores",lastName:"Kuzelj",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247041/images/7108_n.jpg",email:"dolores@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"66259",title:"Antioxidant Compounds and Their Antioxidant Mechanism",doi:"10.5772/intechopen.85270",slug:"antioxidant-compounds-and-their-antioxidant-mechanism",body:'Oxidative stress in biological systems is a complex process that is characterized by an imbalance between the production of free radicals (FR) and the ability of the body to eliminate these reactive species through the use of endogenous and exogenous antioxidants. During the metabolic processes, a great variety of reactions take place, where the promoters are the reactive oxygen species (ROS), such as hydrogen peroxide (H2O2) and the superoxide radical anion (O2•−), among others. A biological system in the presence of an excess of ROS can present different pathologies, from cardiovascular diseases to the promotion of cancer. Biological systems have antioxidant mechanisms to control damage of enzymatic and nonenzymatic natures that allow ROS to be inactivated. The endogenous antioxidants are enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase, or non-enzymatic compounds, such as bilirubin and albumin. When an organism is exposed to a high concentration of ROS, the endogenous antioxidant system is compromised and, consequently, it fails to guarantee complete protection of the organism. To compensate this deficit of antioxidants, the body can use exogenous antioxidants supplied through food, nutritional supplements, or pharmaceuticals. Among the most important exogenous antioxidants are phenolic compounds carotenoids and vitamins C and some minerals such as selenium and zinc.
In the study of antioxidant compounds and the mechanisms involved, it is important to distinguish between the concepts of antioxidant activity and capacity. These terms are often used interchangeably. However, antioxidant activity refers to the rate constant of a reaction between an antioxidant and an oxidant. The antioxidant capacity is a measure of the amount of a certain free radical captured by an antioxidant sample [1]. Therefore, during the selection of a method, the response parameter must be considered to evaluate the antioxidant properties of a sample, which may be a function of the concentration of the substrate or concentration and the time required to inhibit a defined concentration of the ROS.
The reaction mechanisms of the antioxidant compounds are closely related to the reactivity and chemical structure of FR as well as the environment in which these reactive species are found. Therefore, it is very important to describe the ROS and, to a lesser degree, the reactive nitrogen species (RNS), which include both precursors and free radicals.
In the literature, there are many in vitro methods to evaluate the effectiveness of antioxidant compounds present in a variety of matrices (plant extracts, blood serum, etc.) using lipophilic, hydrophilic, and amphiphilic media (emulsions). The in vitro methods can be divided into two main groups: (1) hydrogen atom transfer (HAT) reactions and (2) transfer reactions of a single electron (SET). These methods are widely used because of their high speed and sensitivity. When carrying out a study related to the antioxidant properties of a sample, more than one method is usually used to evaluate the antioxidant capacity/activity [2]. This chapter describes the methods of in vitro antioxidant evaluation that are used frequently depending on the reaction mechanism of the antioxidant.
Oxygen is associated with aerobic life conditions [3], representing the driving force for the maintenance of cell metabolism and viability and at the same time involving a potential danger due to its paramagnetic characteristics. These characteristics promote the formation of partially oxidized intermediates with a high reactivity. These compounds are known as reactive oxygen species (ROS). ROS are free radicals (FR) or radical precursors. In stable neutral molecules, the electrons are paired in their respective molecular orbitals, known as maximum natural stability. Therefore, if there are unpaired electrons in an orbital, highly reactive, molecular species are generated that tend to trap an electron from any other molecule to compensate for its electron deficiency. The oxygen triplet is the main free radical, since it has two unpaired electrons. The reaction rate of triplet oxygen in biological systems is slow. However, it can become highly toxic because it metabolically transforms into one or more highly reactive intermediates that can react with cellular components. This metabolic activation is favored in biological systems, because the reduction of O2 to H2O in the electron transport chain occurs by the transfer of an electron to form FR or ROS [4].
Free radicals in a biological system can be produced by exogenous factors such as solar radiation, due to the presence of ultraviolet rays. Ultraviolet radiation causes the homolytic breakdown of bonds in molecules. FR also occur during the course of a disease. In a heart attack, for example, when the supply of oxygen and glucose to the heart muscle is suspended, many FR are produced. Another exogenous factor is chemical intoxication, which promotes the formation of FR. The organism, because it requires the conversion of toxic substances to less dangerous substances, promotes the release of FR. The toxicity of many drugs is actually due to their conversion into free radicals or their effect on the formation of FR. The presence of contaminants, additives, pesticides, etc., in food can also become a source of FR.
Inflammatory processes are due to endogenous factors that promote the presence of FR in the system. These FR, present inside the cleansing cells of the immune system, have the function of killing pathogenic microorganisms. Tissue damage is caused when FR are excessive during this process. Phagocytic cells (neutrophils, monocytes, or macrophages) use the NADPH oxidase system directly generating the superoxide ion (O2•−). O2•− is considered the primary ROS and when reacting with other molecules through enzymatic processes or catalyzed by metals generates secondary ROS. O2•− is protonated to produce H2O2 and HO2•. O2•− is produced from the irradiation of molecular oxygen with UV rays, photolysis of water, and by exposure of O2 to organic radicals formed in aerobic cells such as NAD•, FpH•, semiquinone radicals, cation radical pyridinium or by hemoproteins. Likewise, it is produced by phagocytic leukocytes as the initial product of the respiratory explosion when consuming O2. The radical O2•− does not react directly with polypeptides, sugars, or nucleic acids.
As a defense mechanism cells generate •NO by the action of nitric oxide-synthase on intracellular arginine. The combination of O2 with •NO results in the formation of ONOO•, which induces lipid peroxidation in lipoproteins. This happens in a very marked way in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, primary biliary cirrhosis, type 1 diabetes, celiac disease, Graves’ disease, Hashimoto’s disease, inflammatory bowel disease, scleroderma, multiple sclerosis, psoriasis, and vitiligo.
FR are necessarily present during metabolic processes because many of the chemical reactions involved require these chemical species. For example, the reactions of polymerization of amino acids to form proteins or the reactions of polymerization of glucose to form glycogen involve the participation of FR. FR are also involved in the catalytic activation of various enzymes of intermediary metabolism, such as hypoxanthine, xanthine oxidase, aldehyde oxidase, monoamine oxidase, cyclooxygenase, and lipoxygenase [5]. Generally, antioxidant enzymes efficiently control these radicals.
Another generating source of ROS is the structural alteration of essential macromolecules of the cell (DNA, protein, and lipids) by irreversible chemical reactions. These reactions generate derivatives, such as malonaldehyde and hydroperoxides that propagate oxidative damage.
Additionally, there are also RNS, such as nitric oxide (NO•), nitrogen dioxide (NO2•), as well as peroxynitrite (ONOO−), nitrosoperoxycarbonate (ONOOCO2−), and nitronium ions (NO2+), and the neutral species, peroxynitrous acid (ONOOH) and dinitrogen trioxide (N2O3). These species are generated in small amounts during normal cellular processes such as cell signaling, neurotransmission, muscle relaxation, peristalsis, platelet aggregation, blood pressure modulation, immune system control, phagocytosis, production of cellular energy, and regulation of cell growth [6]. Table 1 shows the most representative FR present during the process of energy production in aerobic biological systems.
Specie | Source | Function |
---|---|---|
O2•− | Enzymatic process, autoxidation reaction, and nonenzymatic electron transfer reactions | It can act as reducing agent of iron complexes such as cytochrome-c or oxidizing agent to oxidize ascorbic acid and α-tocopherol |
HO2• | Protonation of O2•− | HO2• initiates fatty acid peroxidation |
HO• | H2O2 generates HO• through the metal-catalyzed Fenton reaction | HO• reacts with both organic and inorganic molecules including DNA, proteins, lipids, and carbohydrates |
NO• | Action of nitric oxide-synthase using arginine as a substrate and NADPH as an electron source | NO• is an intracellular second messenger stimulates guanylate cyclase and protein kinases and helps in smooth muscle relaxation in blood vessels |
NO•2 | Protonation of ONOO− or homolytic fragmentation of ONOOCO2− | This radical acts on the antioxidative mechanism decreasing ascorbate and α-tocopherol in plasma |
ONOO• | Reaction of O2 with NO• | ONOO• is a strong oxidizing and nitrating species of methionine and tyrosine residues in proteins and oxidizes DNA to form nitroguanine |
CO3•− | The intermediate of reaction superoxide dismutase (SOD)-Cu2+-OH• react with bicarbonate to generates CO3•− | CO3•− oxidizes biomolecules such as proteins and nucleic acids |
ONOOCO2− | The peroxynytrite-CO2 adduct is obtained by reaction of ONOO− with CO2 | This anion promotes nitration of tyrosine fragments of the oxyhemoglobin via FR |
Free radicals (FR) generated in biological systems.
There are many ROS that act as biological oxidants, but the O2•− is the largest oxidant; the simple addition of a proton leads to the formation of HO2•, becoming a very active oxidizing agent. These transformations are summarized in Figure 1.
Reaction mechanism of superoxide radical.
Free radicals produce diverse actions on the metabolism of immediate principles, which can be the origin of cell damage [7]:
In the polyunsaturated lipids of membranes, producing loss of fluidity and cell lysis because of lipid peroxidation (Figure 2).
In the glycosides, altering cellular functions such as those associated with the activity of interleukins and the formation of prostaglandins, hormones, and neurotransmitters (Figure 3) [8].
In proteins, producing inactivation and denaturation (Figure 4) [9].
In nucleic acids, by modifying bases (Figure 5) [8], producing mutagenesis and carcinogenesis.
Reaction of hydroxyl radical with polyunsaturated fatty acids.
Reaction of hydroxyl radical with sugar [8].
Reaction of hydroxyl radical with α-aminoacids [9].
Reaction of hydroxyl radical with the basepair of DNA guanosine [8].
The human body responds to oxidative stress with antioxidant defense, but in certain cases, it may be insufficient, triggering different physiological and physiopathological processes. Currently, many processes are identified related to the production of free radicals. Among them are mutagenesis, cell transformation, cancer, arteriosclerosis, myocardial infarction, diabetes, inflammatory diseases, central nervous system disorders, and cell aging [10, 11].
Biological systems in oxygenated environments have developed defense mechanisms, both physiological and biochemical. Among them, at the physiological level, is a microvascular system with the function of maintaining the levels of O2 in the tissues, and at a biochemical level, the antioxidant defense can be enzymatic or nonenzymatic, as well as being a system for repairing molecules.
Aerobic organisms have developed antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and DT-diaphorase. SOD is responsible for the dismutation reaction of O2 to H2O2, which in subsequent reactions, catalyzed by catalase or by GPx, is converted into H2O and O2. SOD is the most important and most powerful detoxification enzyme in the cell. SOD is a metalloenzyme and, therefore, requires a metal as a cofactor for its activity. Depending on the type of metal ion required as a cofactor by SOD, there are several forms of the enzyme [12, 13]. CAT uses iron or manganese as a cofactor and catalyzes the degradation or reduction of hydrogen peroxide (H2O2) to produce water and molecular oxygen, thus completing the detoxification process initiated by SOD [14, 15]. CAT is highly efficient at breaking down millions of H2O2 molecules in a second. CAT is mainly found in peroxisomes, and its main function is to eliminate the H2O2 generated during the oxidation of fatty acids. GPx is an important intracellular enzyme that breaks down H2O2 in water and lipid peroxides in their corresponding alcohols; this happens mainly in the mitochondria and sometimes in the cytosol [16]. The activity of GPx depends on selenium. In humans, there are at least eight enzymes GPx, GPx1–GPx8 [17]. Among glutathione peroxidases, GPx1 is the most abundant selenoperoxidase and is present in virtually all cells. The enzyme plays an important role in inhibiting the process of lipid peroxidation and, therefore, protects cells from oxidative stress [18]. Low GPx activity leads to oxidative damage of the functional proteins and the fatty acids of the cell membrane. GPx, particularly GPx1, has been implicated in the development and prevention of many diseases, such as cancer and cardiovascular diseases [19]. DT-diaphorase catalyzes the reduction of quinone to quinol and participates in the reduction of drugs of quinone structure [20]. DNA regulates the production of these enzymes in cells.
This system of antioxidants consists of antioxidants that trap FR. They capture FR to avoid the radical initiation reaction. Neutralize the radicals or capture them by donating electrons, and during this process, the antioxidants become free radicals, but they are less reactive than the initial FR. FR from antioxidants are easily neutralized by other antioxidants in this group. The cells use a series of antioxidant compounds or free radical scavengers such as vitamin E, vitamin C, carotenes, ferritin, ceruloplasmin, selenium, reduced glutathione (GSH), manganese, ubiquinone, zinc, flavonoids, coenzyme Q , melatonin, bilirubin, taurine, and cysteine. The flavonoids that are extracted from certain foods interact directly with the reactive species to produce stable complexes or complexes with less reactivity, while in other foods, the flavonoids perform the function of co-substrate in the catalytic action of some enzymes.
Enzymes that repair or eliminate the biomolecules that have been damaged by ROS, such as lipids, proteins, and DNA, constitute the repair systems. Common examples include systems of DNA repair enzymes (polymerases, glycosylases, and nucleases) and proteolytic enzymes (proteinases, proteases, and peptidases) found in both the cytosol and the mitochondria of mammalian cells. Specific examples of these enzymes are GPx, glutathione reductase (GR), and methionine sulfoxide reductase (MSR). These enzymes act as intermediaries in the repair process of the oxidative damage caused by the attack of excess ROS. Any environmental factor that inhibits or modifies a regular biological activity becomes a condition that favors the appearance or reinforcement of oxidative stress.
The main characteristic of a compound or antioxidant system is the prevention or detection of a chain of oxidative propagation, by stabilizing the generated radical, thus helping to reduce oxidative damage in the human body [21]. Gordon [22] provided a classification of antioxidants, mentioning that characteristic. There are two main types of antioxidants, the primary (breaking the chain reaction, free radical scavengers) and the secondary or preventive. The secondary antioxidant mechanisms may include the deactivation of metals, inhibition of lipid hydroperoxides by interrupting the production of undesirable volatiles, the regeneration of primary antioxidants, and the elimination of singlet oxygen. Therefore, antioxidants can be defined as “those substances that, in low quantities, act by preventing or greatly retarding the oxidation of easily oxidizable materials such as fats” [23].
A compound that reduces in vitro radicals does not necessarily behave as an antioxidant in an in vivo system. This is because FR diffuse and spread easily. Some have extremely short life spans, on the order of nanoseconds, so it is difficult for the antioxidant to be present at the time and place where oxidative damage is being generated. Additionally, the reactions between antioxidants and FR are second order reactions. Therefore, they not only depend on the concentration of antioxidants and free radicals but are also dependent on factors related to the chemical structure of both reagents, the medium and the reaction conditions.
The phenolic compounds constitute a wide group of chemical substances, with diverse chemical structures and different biological activities, encompassing more than 8000 different compounds which are a significant part of the human and animal diet [24]. The phenolic compounds are important components in the mechanism of signaling and defense of plants. These compounds combat the stress brought about by pathogenic organisms and predators. The function of these compounds in plants is diverse: they are found as precursors of compounds of greater complexity or the intervention in the processes of regulation and control of plant growth, as well as the defensive medium of plants. Phenolic compounds have the capacity to act as hydrogen donors or to chelate metal ions such as iron and copper, by inhibiting the oxidation of low-density lipoproteins (LDL). These characteristics in the phenolic compounds are associated with a decrease in risks of neurodegenerative diseases, such as cardiovascular diseases [25], gastrointestinal cancers [26], colon [27], breast and ovarian cancers [28], and leukemia [29, 30, 31]. Phenolic compounds also have vasorelaxation and anti-allergenic activity [32]. The phenolic compounds inhibit the oxidation of in vitro LDL [33].
Phenolic compounds reduce or inhibit free radicals by transfer of a hydrogen atom, from its hydroxyl group. The reaction mechanism of a phenolic compound with a peroxyl radical (ROO•) involves a concerted transfer of the hydrogen cation from the phenol to the radical, forming a transition state of an H-O bond with one electron. The antioxidant capacity of the phenolic compounds is strongly reduced when the reaction medium consists of a solvent prone to the formation of hydrogen bonds with the phenolic compounds. For example, alcohols have a double effect on the reaction rate between the phenol and the peroxyl radical. On the one hand, the alcohols act as acceptors of hydrogen bonds. On the other hand, they favor the ionization of the phenols to anion phenoxides, which can react rapidly with the peroxyl radicals, through an electron transfer. The overall effect of the solvent on the antioxidant activity of the phenolic compounds depends to a great extent on the degree of ionization of the last compounds [34]. Leopoldini et al. [35] conducted a theoretical study to determine the dissociation energy of OH bonds and the adiabatic ionization potentials of phenolic compounds of varied structure and polarity, among them tyrosol, hydroxytyrosol, and gallic and caffeic acids. These studies were performed simulating solvated and vacuum conditions. The results showed a clear difference in the behavior of these phenolic compounds. The compounds most likely to undergo a HAT were tocopherol, followed by hydroxytyrosol, gallic acid, caffeic acid, and epicatechin (Figure 6), while the phenolic compounds, which were better able to SET, were kaempferol and resveratrol (Figure 7). This undoubtedly gives us an indication that phenolic compounds can suffer both HAT and SET and that this depends mainly on the chemical structure of the phenolic compounds.
Phenolic compounds with ability to HAT.
Phenolic compounds with ability to SET.
The method based on the Folin-Ciocalteu reagent is commonly used to determine and quantify total phenols. This method evaluates the ability of phenols to react with oxidizing agents. The Folin-Ciocalteu reagent contains sodium molybdate and tungstate, which react with any type of phenol [36]. The transfer of electrons at basic pH reduces the sodium molybdate and tungstate in oxides of tungsten (W8O23) and molybdenum (Mo8O23), which have a bright blue color in solution. This color intensity is proportional to the number of hydroxyl groups of the molecule [37].
Carotenoids are found in virtually all plants, animals, and microorganisms, and more than 700 carotenoids have been identified and characterized [38]. Most carotenoids have a characteristic symmetrical tetraterpene skeleton. The linear hydrocarbon skeleton is made up of 40 carbons and is susceptible to various structural modifications. These structural characteristics are related to degree of hydrogenation, cis-trans isomerization, presence of cycles at one or both ends of the linear skeleton, or the addition of side groups (which often contain oxygen) with their subsequent glycosylation. The most complex changes are related to the shortening or elongation of the resulting tetraterpene skeleton, to form carotenoids with chains of 50 carbons. It is also possible to find carotenoids with tetraterpene skeletons of 30 carbons, from the condensation of two units of farnesyl [39]. These compounds, in addition to conferring pigmentation on biological systems, fulfill other important functions. The most recent studies of these compounds are focused mainly on evaluating their function as antioxidants. The structural base fragment of the carotenoids is a conjugated polyunsaturated chain. This fragment is primarily responsible for the ability of these compounds to inhibit free radicals. Variations in the polyunsaturated chain from one carotenoid to another, together with the presence of hydroxyl groups, substantially modify the reactivity of the carotenoids. The reactivity of these compounds is also affected by the environmental conditions where they are found. For example, Edge and Truscott [40] found that carotenoids switch the antioxidant behavior to the prooxidant as a function of oxygen concentration. The study used a system that emulates a cell, to observe the protection effect induced by lycopene when exposing the system to high-energy radiation. Total protection is achieved in the absence of O2, but in the presence of 100% O2, protection is completely lost. Carotenoids are characterized as excellent peroxyl radical scavengers. The polyunsaturated chains that make up the base structure of carotenoids give these compounds a lipophilic character. Carotenoids play an important role in the protection of cell membranes and lipoproteins against peroxyl radicals.
The carotenoids react as antioxidant agents through three mechanisms: the first is the SET, the second from the formation of one adduct, and the third by HAT. In general, the antioxidant properties of carotenoids are related to their high capacity for electron donation. Everett et al. [41] found that β-carotene reacts with NO2• via SET. Carotenoid reactivity studies have also been carried out in the presence of the benzyl peroxyl radical, which has low reactivity, and it was concluded that in this case, the reaction mechanisms involved the formation of an adduct, while reactions by HAT are of little relevance [42].
Other studies have evaluated the effect of the chemical structure of carotenoids on the reactivity toward FR. One of these studies found that carotenoids substituted with electrons are more susceptible to oxidation than carotenoids with withdrawn electron groups. A study of carotenoid reactivity with phenoxy radicals shows the order of reactivity to be lycopene > β-carotene > zeaxanthin > lutein > echinenone > astaxanthin [43].
The effect of the solvent on the reactivity of carotenoids in the presence of FR has also been evaluated, and it was found that in nonpolar solvents, the reactions are promoted via adduct formation; while in polar solvents, the formation of adducts takes place first and then the SET [44].
Vitamin C refers to a group of ascorbic acid analogs that can be both synthetic and natural molecules. Ascorbic acid is a water-soluble ketolactone with two ionizable hydroxyl groups. Anion ascorbate is the dominant form at physiological pH (Figure 8). Ascorbate is a potent reducing agent and undergoes two subsequent losses of an electron, to form an ascorbate radical and dehydroascorbic acid. The ascorbate radical is relatively stable because the unpaired electron is delocalized by resonance. The ascorbate concentration in plasma of healthy humans is around 10 μg/mL. At these concentrations, the ascorbate is a co-antioxidant with vitamin E to protect LDL from peroxyl radicals [45]. The ascorbate radical is poorly reactive and can be reduced to ascorbate by reductase-dependent NADH and NADPH [46]. The ascorbate radical can alternatively undergo a disproportionation reaction that depends on pH, resulting in the formation of ascorbate and dehydroascorbic acid [47].
Chemical species related to vitamin C.
Vitamin C is chemically capable of reacting with most of the physiologically important ROS and acts as a hydrosoluble antioxidant. The antioxidant reaction mechanisms of vitamin C are based on the HAT to peroxyl radicals, the inactivation of singlet oxygen, and the elimination of molecular oxygen [48, 49]. For example, ascorbic acid can donate a hydrogen atom to a tocopheroxyl radical at the rate of 2 × 105 mol/s [50]. Also, it has been proven that ascorbate can produce reactions with oxidizing agents through SET [51] or a concerted transfer of electron/protons (SET/HAT) [52].
The antioxidant activity of a compound can be evaluated in vitro or in vivo by means of simple experiments, and at the same time, the possible prooxidant effect on different molecules can be evaluated. Antioxidant activity cannot be measured directly but is determined by the effects of the antioxidant to control the degree of oxidation. There are a variety of methods to evaluate antioxidant activity. Some methods involve a different oxidation step followed by the measurement of the response, which depends on the method used to evaluate the activity.
When the antioxidant activity of a sample is studied, it is necessary to consider the source of ROS as well as the target substrate. An antioxidant can protect lipids against oxidative damage, while, on the other hand, it can promote the oxidation of other biological molecules [53].
Most assays of antioxidant activity involve inducing accelerated oxidation in the presence of a promoter and controlling one or more variables in the test system, for example, temperature, antioxidant concentration, pH, etc. However, the oxidation mechanisms can change when modifications are carried out on some of these variables. Therefore, it is important to evaluate the intervals in which the quantification of the antioxidant activity is done to generate reliable results.
The methods to determine the antioxidant capacity are divided into two general groups. This division is based on the reaction mechanisms involved in the RF reduction process. The first group of methods is based on the SET and the second group is based on the HAT. The result is the same: the inactivation of free radicals; however, the kinetics and secondary reactions involved in the process are different. The methods based on SET detect the capacity of a potential antioxidant for the transmission of a chemical species, including metals, carbonyls, and radicals. SET is shown through a change in color as the oxidant is reduced by antioxidant [54]. The group of methods based on HAT measures the ability of an antioxidant to inactivate FR through the donation of a hydrogen atom. HAT reactions are theoretically independent of solvent nature and pH. These reactions are rapid and occur in no more than a few minutes. The presence of other reducing agents in samples, in addition to the antioxidants under study, makes HAT testing difficult and can lead to significant errors [55]. Table 2 shows the methods of evaluation of the antioxidant activity in vitro.
Method | Reaction mechanism | Characteristics | Reference |
---|---|---|---|
Total radical-trapping antioxidant parameter (TRAP) | HAT | TRAP assay involves the initiation of lipid peroxidation by generating water-soluble ROO• and is sensitive to all known chain-breaking antioxidants | [58] |
Total oxyradical scavenging capacity total assay (TOSCA) | HAT | Evaluates inhibition oxidation of α-keto-γ-methiolbutyric acid (KMBA) by ROS. The antioxidant activity is measured through ethylene concentration, generated during decomposition of KMBA, relative to a control reaction monitored by headspace gas chromatography (HS-GC) | [59] |
Crocin-bleaching assays (CBAs) | HAT | CBA is based on the abstraction of hydrogen atoms and/or addition of radical to the polyene structure of crocin and results in a disruption of the conjugated system accounting for crocin bleaching | [60] |
Oxygen radical absorbance capacity (ORAC) | HAT | ORAC assay is based upon the inhibition of peroxyl radical induced oxidation initiated by thermal decomposition of azo compounds such as AAPH | [61] |
Inhibition of 2,2-diphenyl-1-picrylhydracyl radical (DPPH•) | SET or HAT | Colorimetric method based on the measurement of the scavenging capacity of antioxidants towards DPPH• | [62] |
Inhibition of 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS•+) cation radical | SET or HAT | Colorimetric method to evaluate the decay of ABTS•+ in the presence of an antioxidant agent | [63] |
Total phenols assay by Folin-Ciocalteu reagent | SET | A mixture of phosphomolybdate and phosphotungstate in highly basic medium oxidized phenolic compounds | [64] |
Ferric-reducing antioxidant power (FRAP) | SET | Colorimetric method that evaluates the reduction of Fe3+-tripyridyltriazine complex (Fe3+-TPTZ) by turning it into a ferrous form (Fe2+-TPTZ) | [65] |
Total antioxidant capacity (TAC) | SET | This method is used to measure the peroxide level during the initial stage of lipid oxidation. Peroxides are formed during the linoleic acid oxidation, which reacts with Fe2+ to form Fe3+ and later these ions form a complex with thiocyanate | [66] |
Methods most commonly used to evaluate antioxidant capacity/activity in vitro.
The methods of evaluation of antioxidant activity must be fast, reproducible, and require small amounts of the chemical compounds to be analyzed, in addition to not being influenced by the physical properties of said compounds [56]. The results of in vitro assays can be used as a direct indicator of antioxidant activity in vivo; a compound that is ineffective in vitro will not be better in vivo [53]. These tests can also serve as warnings of possible harmful effects of chemical compounds. Because many factors can affect oxidation, including temperature, the concentration of oxygen in the reaction medium, and metal catalysts, the results may vary depending on the oxidation conditions employed. Tests that measure substrates or products can also give variable results depending on their specificity [57].
These methods are briefly described below.
The TRAP is used to determine the status of a secondary antioxidant in plasma. The results (TRAP value) are expressed as μmol of ROO• trapped per liter of plasma [58]. The test is based on the measurement of O2 uptake during a controlled peroxidation reaction, promoted by the thermal decomposition of 2,2′-azobis-(2-amidopropane) (ABAP), which produces ROO• at a constant rate (Figure 9). This starts with the addition of ABAP to human plasma; the parameter to be evaluated is the “delay time” of the O2 absorption in plasma induced by the antioxidant compounds present in the medium. The delay time is measured from the O2 concentration data in plasma diluted in a buffer solution monitored with an electrode. In addition to ABAP, other free radical initiators have been used, such as the ABTS [67], dichlorofluorescein diacetate [68], phycoerythrin [69], and luminol [70].
Formation of peroxyl radical from ABAP.
One of the main disadvantages of the TRAP method is the possibility of an error in the detection of the end point caused by the instability of the O2 electrode, because this point can take 2 h to reach. To minimize this problem, the electrochemical detection of O2 can be performed with a chemiluminescent detection based on the use of luminol and horseradish peroxidase [71].
This method is based on the evaluation of antioxidant activity in the gas phase, which consists of exposing α-keto-γ-methylthiobutyric acid (KMBA) to powerful oxidizing agents, such as •OH, ROO•, and ONOO− [59] (Figure 10). These oxidizing agents induce a transformation of KMBA to ethylene. To evaluate the effect of antioxidants, the ethylene formation is evaluated and compared to a control reaction by the use of headspace gas chromatography (HS-GC). The TOSCA assay is based on the inhibition of ethylene formation in the presence of antioxidant compounds that compete with KMBA for ROS.
Reaction between ROO• and KMBA.
The TOSCA method is not suitable for a high performance analysis because multiple injections of each sample are required to measure ethylene production [55]. The reaction kinetics of this method do not allow a linear relationship between the percentage of inhibition of KMBA oxidation and the concentration of antioxidants [72], which is a serious limitation.
The crocin bleaching test (CBA) is a method originally proposed to evaluate the inhibition of alkoxyl radicals produced photolytically. This is done by measuring the protective effect exerted by antioxidant compounds on crocin, a carotenoid that presents an intense red color, under the effect of alkoxyl radicals [60] (Figure 11). To achieve this, reaction kinetics are carried out in a UV-Vis spectrophotometer, measuring the absorbance at a wavelength of 440 nm to obtain the relative velocity constants. These constants present a good correlation with the known antioxidant activity of reference compounds. The absolute bleaching velocity of crocin depends strongly on the type of radical that attacks the polyene structure of crocin. Crocin exhibits a high selectivity toward the alkoxyl radicals produced during the photolysis of hydroperoxides, as well as peroxyl radicals produced after the thermolysis of azo initiators. Ordoudi and Tsimidou [73] carried out a detailed evaluation of the CBA, and among the factors, they considered the crocin probe, the antioxidant compound to be evaluated, the peroxyl radical generation conditions, and the monitoring of the reaction. As a result of this, they found that any commercial saffron could be used as a source of crocin for the preparation of the probe, because it is possible to eliminate interferences, such as tocopherols. They also found that the concentration of the working solution could be adjusted and that changes in the stock solution of the probe can occur during storage. Ordoudi and Tsimidou [74] also evaluated a group of 39 phenolic compounds of diverse structures, including hydroxybenzoic, hydroxyphenylacetic, hydroxyphenylpropanoic, and hydroxycinnamic acids. The results of that study showed that the activity depends strongly on the position of -COOH groups in relation to the position of the -OH groups. Therefore, the CBA allows evaluation of the effect of the position of functional groups that cause antioxidant activity in a chemical compound.
Chemical structure of crocin.
The ORAC method is based on the inhibition of oxidation induced by peroxyl radicals and simultaneously evaluates the time effect and the inhibition degree. The ORAC test is based on hydrogen atom transfer (HAT) and uses a reaction mechanism that competes between antioxidants and a fluorescence probe (fluorescein) for a radical [61]. The test begins with the thermal decomposition of azo compounds, such as [2,2′-azobis-(2-amidino-propane)dihydrochloride (AAPH)], which is the source of free radicals that promotes the degradation of fluorescein. The antioxidant to be evaluated promotes the elimination of the peroxyl radicals, protecting the fluorescein from degradation. The decay in fluorescence due to the attack of the radicals and the protection by the antioxidants results in a curve. The antioxidant capacity is calculated from the area under the fluorescence decrease curve (AUC). This assay uses trolox as a standard; therefore, generally the antioxidant activity in this assay is expressed in terms of trolox equivalents. The ORAC method has been widely used to measure the antioxidant capacity of beverages [75], supplements [55], and vegetables and fruits [55, 76].
There are modifications to this assay that include the use of fluorescein as a probe, adaptation to a high performance format, and the ability to measure the lipophilic, hydrophilic, and total antioxidant capacity of a substance.
The ORAC assay is carried out at pH 7.4, adjusted with a phosphate buffer, in the presence of the antioxidant, AAPH, and fluorescein at a constant temperature of 37°C. Fluorescence is monitored at 1 min intervals for 35 min at an excitation wavelength of 485 nm and an emission wavelength of 520 nm [77].
The ORAC method can also be used for the detection of •OH and other radicals by modifying the initiators. In addition, the method has been modified for the detection of lipophilic antioxidants, encapsulating these compounds in β-cyclodextrins [78].
The 1,1-diphenyl-2-picrylhydrazyl radical (DPPH•) (Figure 12) is characterized as a stable free radical because pi electrons of the aromatic systems present in the molecule can compensate for the lack of an electron. DPPH• does not dimerize, as most other free radicals do. The delocalization of the electron also gives rise to a deep violet color, characterized by absorption in solution at around 517 nm. Brand-Williams et al. [62] evaluated the activity of specific compounds or extracts using DPPH• in solution. When a solution of DPPH• is in contact with a substance that can donate a hydrogen atom or with another radical (R•), the reduced form DPPH-H or DPPH-R is produced with the consequent loss of color and therefore the decrease or loss of absorbance (Figure 8). Consequently, the reduction of DPPH• provides an index to estimate the ability of the test compound to trap radicals. The alcoholic solutions of 0.5 mM are densely colored, and in this concentration, the law of Lambert-Beer is fulfilled in the useful absorption interval [79].
DPPH• reduction by an antioxidant.
ArOH is an antioxidant that acts by donating hydrogen atoms, to obtain radicals with stable molecular structures that will stop the chain reaction. The new radical (ArO•) can interact with another radical to form stable molecules (DPPH-OAr, ArO-OAr). The reaction between DPPH• and an antioxidant compound depends on the structural conformation of the same, so quantitative comparisons are not always appropriate.
The basis of this methodology is focused on measuring the reduction of free radicals by antioxidant compounds. Different concentrations and the time of the reaction are measured (30 min or until the steady state is reached). So far, there are no reports about the existence of a mathematical kinetic model that helps to understand the behavior of antioxidants [80].
The experimental models use the percentage of DPPH• remaining to obtain the necessary quantities that are required to reduce the initial concentration to 50% (EC50). In addition, kinetics is performed to determine the amount of time needed for the steady state to reach EC50 from the curves. EC50 and effective concentration 50 (TEC50) are used to calculate antiradical efficiency (AE). Low values of EC50 and TEC50 show a high antioxidant strength, and a rapid decrease in absorption is observed during the reaction [81]. The antiradical efficiency can be estimated based on the scale contained in Table 3.
Range | Antiradical efficiency classification |
---|---|
AE = 1 × 10−3 | Low |
1 × 10−3 < AE = 5 × 10−3 | Medium |
5 × 10−3 < AE = 10 × 10−3 | High |
AE ≫ 10 × 10−3 | Very high |
Scale of antiradical efficiency (AE) against DPPH• [81].
It is a fast, simple, inexpensive, and widely used method to measure the ability of compounds to act as free radical scavengers or hydrogen donors. It can also be used to quantify antioxidants in complex biological systems, for solid or liquid samples. The method is applied to measure the overall antioxidant capacity [82] and the activity of eliminating free radicals from fruit and vegetable juices [83]. It has been successfully used to investigate the antioxidant properties of wheat grain and bran, vegetables, oils, and flours in various solvents, including ethanol, aqueous acetone, methanol, and benzene [84, 85, 86, 87].
The radical scavenging DPPH• method allows for a reaction with almost any type of antioxidant due to the stability of DPPH•. This means there is sufficient time for even weak antioxidants to react with DPPH• [82]. This method can be used with both polar and nonpolar organic solvents to evaluate hydrophilic and lipophilic antioxidants [55].
The method has some disadvantages, among which is that DPPH• can react with other radicals and consequently the time to reach the stable state is not linear to the concentration ratio of the antioxidant/DPPH• [62, 80]. The stability of DPPH• can be affected by solvents with properties of a Lewis base, as well as the presence of dissolved oxygen [88]. The absorbance of DPPH• in methanol and acetone is lower than with other solvents [89].
Because the radical scavenging DPPH• method is quite simple and used in various fields of chemistry, automated assays combined with analytical techniques have been developed (Table 4).
Automation | Characteristics | References |
---|---|---|
Flow injection analysis (FIA) by high performance liquid chromatography (HPLC) | Bioassay-guided fractionation of natural products or food samples | [90] |
PC-controlled sequential injection analysis (SIA) | SIA is a FIA technique modified by using a pump to continuously draw sample and reagent solutions into different lines of tubing | [91] |
Electrochemical selective determination of antioxidant activity based on DPPH•/DPPH | Current intensity is proportional to the residual concentration of DPPH• after reaction with the antioxidant | [92] |
Relative DPPH radical scavenging capacity (RDSC) | The RDSC uses the area under the curve, expressed as trolox equivalents. These approaches take into account both the kinetic and the thermodynamic measurements of the radical-antioxidant reactions | [93] |
High performance thin layer chromatography (TLC)-DPPH• | Post-chromatographic derivatization is carried out with DPPH•. The plates are scanned before DPPH• and 30 min after DPPH derivatization in absorption-reflection mode at optimized wavelengths | [94] |
Hyphenated high speed counter current chromatography (HSCCC)-DPPH• | After the HSCCC separation, the effluent is split into two streams by use of an adjustable high-pressure stream splitter. One portion is sent through the detector and the fraction collector, while the second portion is sent to a secondary coil for on-line radical-scavenging detection | [95] |
Automated modes to evaluate radical scavenging capacity DPPH•.
The FRAP analysis was introduced by [65, 96] to measure total antioxidant activity and is based on the ability of samples to reduce ferric ion Fe3+ to ferrous ion Fe2+, forming a blue complex. A high absorption at a wavelength of 700 nm indicates a high reduction power of the chemical compound or extract [66]. The value of FRAP has been used to determine the antioxidant activity of red wines [97]. The work of Schleisier et al. [98] was designed to determine the antioxidant activity in tea extracts and juices expressed in Fe2+ equivalents. The absolute initial index of the reduction of ferrylmyoglobin determined by spectroscopy in the visible region has been suggested to characterize the antioxidant activity of individual flavonoids [99]. There are several trials to evaluate FRAP; one of them is to evaluate the power of a compound or extract to reduce the complex of 2,4,6-tripyridyl-s-triazine-Fe2+ (TPTZ-Fe2+). An antioxidant reduces the ferric ion (Fe3+) to ferrous ion (Fe2+) in the TPTZ complex; the latter forms a blue complex (Fe2+/TPTZ), which absorbs at a wavelength of 590 nm (Figure 13). The reaction must be carried out under acidic conditions (pH 3.6) to preserve the solubility of Fe. The reducing power is related to the degree of hydroxylation and the conjugation in the phenols [55].
Reaction mechanism for the FRAP assay in the presence of an antioxidant [55].
The FRAP assay has an incubation time of 4 min at 37°C for the antioxidant activity of most samples. This is done because the redox reactions, involved in the assay, occur within the incubation period. However, it has been shown that FRAP values can vary significantly, depending on the time scale of analysis [55, 96].
ABTS is a target molecule used to evaluate the reactivity of antioxidant samples in the presence of peroxides. The ABTS initially is subjected to an oxidation reaction with potassium permanganate, potassium persulfate or 2,2′-azo-bis (2-amidinopropane), producing the radical cation of the ABTS (ABTS•+) with a blue greenish color that absorbs at wavelengths of 415, 645, 734, and 815 nm [100, 101, 102]. The ABTS•+ is stable for several minutes. The ABTS•+ is subjected to the antioxidant sample causing the reduction of ABTS•+ and consequently the discoloration of the reaction mixture (Figure 14). Therefore, the degree of discoloration can be expressed as the inhibition percentage of ABTS•+, which is determined as a function of antioxidant concentration and time. This method can be used at different pH and is useful to study the effect of pH on antioxidant activity. ABTS is soluble in both aqueous and organic solvents and consequently is useful for evaluating the antioxidant activity of samples in different media and is commonly used in solutions that simulate an ionic serum (pH 7.4) based on a phosphate buffer (PBS) containing 150 mM NaCl. When a medium of PBS is used, the samples react in a time interval of approximately 30 min, while in alcohol, they require longer reaction times [103]. The level of peroxide is determined by the absorbance at some of the above-mentioned wavelengths. The IC50 is calculated by plotting the percentage of inhibition against different concentrations of the antioxidant sample [104]. The IC50 values indicate the sample concentration required to eliminate 50% of the ABTS•+. Low IC50 values indicate high radical uptake activity. The antioxidant activity against ABTS•+ can also be evaluated through the unit of antioxidant activity (TAA), which expresses the equivalents of trolox in μmol with respect to each gram of sample extract in dry base.
Reaction of ABTS•+ with antioxidant compounds.
The inhibition of ABTS•+ activity in an antioxidant sample has a strong correlation with the radical scavenging capacity DPPH• because both radicals have the capacity to accept electrons and H• from the antioxidant compounds present in the samples [105, 106].
TAC is defined as the ability of a compound to inhibit the oxidative degradation of lipids [66]. Lipid peroxidation involves the oxidative deterioration of lipids with unsaturation. This peroxidation, called the initiation process, begins with the formation of conjugated dienes and trienes, known as primary oxidation products due to the abstraction of a hydrogen atom. Subsequently, a propagation process is carried out that consists of the reaction of the deprotonated species derived from the lipids with O2, leading to the formation of peroxyl radicals (ROO•). The high energy of free radicals promotes the abstraction of hydrogen atoms from neighboring fatty acids. This leads to the formation of hydroperoxides that promotes the formation of new R• radicals. The latter radicals react with each other to produce stable molecules of the R-R and ROOR type [107]. To encourage the antioxidant activity of a chemical compound, it is necessary to inhibit the peroxidation of a fatty acid emulsion; linoleic acid is generally used as a model. The hydroperoxides derived from linoleic acid subsequently react with Fe2+, causing the oxidation of this ion to produce Fe3+. The Fe3+ ions form a complex with thiocyanate (SCN−), and this complex has a maximum absorbance at 500 nm [108]. This complex is used to measure the peroxide value.
The ferric thiocyanate method is used to measure the peroxide value in edible oils. To avoid errors in the determination of the peroxide value, it is important to avoid the presence of oxygen in the reaction medium and this can be achieved by bubbling nitrogen [109]. These authors found that the results of the thiocyanate assay also depend on the solvent, reducing agent and type of hydroperoxides present in the sample.
The reaction mechanisms involved in the antioxidant activity/capacity of different groups of compounds depend on several factors. Among these factors are the chemical structure of these compounds, the nature of the solvent, the temperature and pH, as well as the reactivity and chemical structure of free radicals. All these factors can also influence the reaction rate. Consequently, it is very important that, for studies of antioxidant properties, at least three evaluation methods are selected: one to exclusively evaluate the HAT, another the SET, and a combined method, HAT/SET. Also, it is important to perform reaction kinetics. In addition to this, it is essential to consider that in mixtures of antioxidant compounds, possible synergistic effects are present and can enhance the activity/capacity or even modify their reaction mechanisms.
The authors thank Carol Ann Hayenga for her English assistance in the preparation of this manuscript. Support was provided by the Technological University of the Mixteca.
The authors have no conflict of interest to declare and are responsible for the content and writing of the manuscript.
This chapter does not contain any studies with human participants or animals performed by any of the authors.
VA is an essential component of the life-sustaining therapy in end stage kidney disease patients relying on a sustained extracorporeal circulation for haemodialysis (HD) or haemodiafiltration (HDF) [1, 2]. Indeed, VA is often referred to as the lifeline or Achilles heel for a dialysis-dependent patient [3]. VA performance is a key factor to drive success or failure in all forms of extracorporeal renal replacement treatment [4]. Furthermore, VA dysfunction or complication is the major cause of morbidity requiring interventional procedures (angioplasty and revision) or hospitalisation [4, 5, 6]. Furthermore, VA morbidity represents a tremendous burden both for patient and health care system [7, 8]. VA management in chronic kidney disease patient is of tremendous importance in quality care of dialysis patients, since it represents a daily duty for care givers in the nephrology area to ensure success of renal replacement therapy, to improve patient outcome and to reduce burden of VA morbidity [1, 9].
\nVA for HD belongs to three main categories: (1) arteriovenous fistula (AVF) made of native or autologous vessel (aAVF) or heterologous vessel (hAVF) [10]; (2) arteriovenous graft (AVG) made of synthetic polymer or bioprosthesis; and (3) venous–venous access consisting mainly in tunnelled central venous catheter (tCVC) inserted preferably in the superior vena cava system [11]. A schematic representation of various VA types is in Figures 1 and 2. aAVF is still the preferred VA strongly recommended by best practice guidelines due to its long-term patency superiority, higher performances and fewer complications in majority of patients [11, 12, 13].
\nAutologous AV fistula.
Heterologous AV graft.
Several autologous AVF types have been developed to fit with patient anatomic and physiologic characteristics. Briefly, according to their location on the upper arms, they are categorised either as distal (wrist) or proximal (elbow or upper arm); according to the type of anastomosis, they are categorised as side to side anastomosis or artery side to vein end anastomosis [14, 15] or vein transposition [16].
\nIf the end-stage kidney disease (ESKD) patient is not a suitable candidate for an AVF, the AVG is the second VA option. Compared to the AVF, the AVG has better mechanical strength, earlier use, decreased primary failure rates, development of graft stenosis, a fivefold increase in infection risk, a poorer long-term patency, higher levels of complications and more interventions than AVF [17]. AVG should be preferred over a CVC because of fewer complications and better survival rates [18]. AVG access is made usually of synthetic material (e.g., PTFE) or biomaterial and realise a conduit between artery and vein [17]. Recently, a new biologic human acellular vessel, as a potential solution to AVG disadvantages, has been evaluated with promising evidence [19]. Human acellular vessels were implanted into 60 patients. The vessels had no dilatation and rarely had post-cannulation bleeding. At 12 months, 28% had primary patency, 38% had primary assisted patency and 89% had secondary patency [19]. AVG may be constructed either on the forearm as straight conduit (radial artery to cephalic vein), or as looped conduit (brachial artery to cephalic vein), or on the upper arm as straight conduit (brachial artery to axillary vein) or looped conduit (axillary artery to axillary vein). Less commonly AVG looped is created on the lower extremity (femoral artery to axillary vein) or as transthoracic conduit (axillary artery to contralateral axillary vein).
\nAlthough AVF is the preferred vascular access, double-lumen non-tunnelled catheter is the VA of choice when urgent or emergency HD is requested or when AVF/AVG becomes dysfunctional. Tunnelled dialysis catheters can be safely used as vascular access till the maturation of fistula and may be an alternative to arteriovenous fistula or graft for long-term VA if indicated. tCVC can be considered as permanent VA vein, in patients with recurrent access thrombosis, low blood pressure (cardiomyopathy), severe vascular disease (“steal” syndrome), trypanophobia (fear of needles), in case of premature exhaustion of veins needed for AVF creation and reduced life expectancy. Catheters are available in a variety of materials, configurations and tip designs, with the aim to maximise the blood flow, reducing recirculation preventing the catheter tip obstruction. There are well-established guidelines for selection of an insertion site for CVCs. The preferred site is the right internal jugular vein. In case, for different reasons, it is not possible to utilise the above vascular approach, and the second option is the left internal jugular vein. Other options are the subclavian veins keeping in mind the higher risk of subsequent stenosis or venous occlusion. The femoral vein for long-term CVC access should be avoided in patients waiting for kidney transplantation due the iliac vein risk stenosis.
\nInterestingly, percentage of various VA types varies tremendously among HD population worldwide. Several factors contribute to heterogeneity of VA prevalent use and distribution that include dialysis vintage (incident vs. prevalent), age (young vs. old), gender (male vs. female), ethnicity, comorbidities (high vs. low risk), dialysis modality (HD vs. HDF) or dialysis setting (in centre vs. home or self-care).
\nFurthermore, it is of utmost importance noting that practice patterns have likely a strong impact on VA choice and prevalent use [20]. In other words, VA choice is not only driven by patient conditions or treatment modalities but also depends strongly on local or regional practice patterns including referral time to nephrologist, CKD patient management, care access, VA expertise and commitment, also patient choice. As an example, prevalence of AVFs in incident patients (<6 months) may vary from 20 to 80% from one country to another considering comparable patient profile, while the use of CVCs may vary from less than 5–80% in the same condition [20, 21]. Comparing VA repartition in prevalent patients, the same heterogeneous distribution holds true, with prevalence of 30% to over 90% of AVFs from one country to another with comparable patient profile [22, 23].
\nVA creation strategy planning is important to ensure best outcome to dialysis patients. It is now well established that careful clinical assessment and non-invasive vascular network mapping (US Doppler) facilitate VA construction and increase success rate [24, 25, 26]. Best practices emphasise and recommend such an approach to reduce failure rate and optimise VA creation, maturation and management [11, 12].
\nEarly referral of advanced chronic kidney disease patient to nephrologist and to expert vascular surgeon may facilitate decision for VA choice and creation [27]. VA nurse coordinator has been shown to facilitate management of ESKD patients, to reduce CVCs use and to improve VA outcome in incident patients [28, 29, 30].
\nFew general rules for VA creation are recommended from best clinical practice guidelines: first, start with native AVF distal position at the non-dominant wrist and move proximally to the elbow in case of failure, second, favour artery side to vein-end anastomosis with reduced and fixed anastomosis diameter, third, consider using synthetic graft conduct in case of multiple failed attempts and fourth, tCVC might be a suitable option, in case of repeated VA attempt failures, in elderly patients, in patients with limited life time expectancy or as mid or long-term bridging solution to facilitate creation and maturation of AVF or AVG [12].
\nVA construction should be ideally performed within expert centres adequately staffed, imaging capacities and providing full clinical service to correct immediate or short-term VA dysfunction [31, 32].
\nVA performance is crucial to ensure delivery of adequate renal replacement therapy. It relies on four main indicators: access flow, recirculation, pressure changes, and dialysis dose delivery. VA performance is more critical with short dialysis than in long or more frequent dialysis treatment schemes.
\nVA flow is the main parameter that drives dialysis session efficiency [4, 33]. Ideally, access flow with AVF or AVG should be higher than 500–600 ml/min to ensure extracorporeal blood flow of 350–400 ml/min. Choice of dual lumen tCVC should aim to achieve 350–400 ml/min blood flow on a regular basis [34].
\nIn case of dialysis efficiency reduction due to VA dysfunction, that will be expressed by a Kt/V decline trend over time [35] (better if evaluated with online automated system and in continuous mode [36, 37]) and an increasing of serum potassium, phosphate, urea and creatinine levels. Dynamic pressure changes in vascular access either from venous or arterial side are reflecting VA dysfunction and suggesting a stenosis either on the distal vein or the proximal artery and impeding access flow reduction [38]. VA recirculation is usually very low and less than 1% with well-functioning AVF and AVG [39]. High recirculation (>10%) reflects VA dysfunction (e.g., stenosis of distal vein or proximal artery) and requires further investigation and intervention on VA if needed. It is important noting that tCVCs have by design and functional characteristics, higher recirculation than AVF or AVG. A well-functioning CVC has a recirculation closed to 10%, and higher recirculation is a strong signal of CVC dysfunction [34]. Recirculation is usually measured by dilution methods that sense either changes in US velocity (Transonic) [33], electrical impedance, optical (CritLine), ionic dialysance change [40] or thermal changes (BTM) [41] with relative good concordance [42]. Fresenius Medical Care (FMC), Europe Middle East Africa (EMEA) and NephroCare (NC) clinics commonly apply the thermodilution measurements [43]. The thermodilution method makes it possible to determine the total blood recirculation with a non-invasive temperature bolus technique, and thus detect vascular problems that could reduce the efficacy of dialysis. This method can be used to assess both grafts/fistula and cardiopulmonary recirculation. In case the VA recirculation is confirmed the colour, Doppler US can provide an accurate anatomical and haemodynamic information, also measuring the access flow. This examination can be performed as part of a routine surveillance program, to detect early VA problems, or suspected dysfunction. However, limitations for its use are lack of staff and/or knowledge in the HD unit. Imaging techniques as the angiography and magnetic resonance flow measurements can allow a better definition of blood flow and stenosis visualising inside the vessel lumens.
\nIn brief, reduced access flow, increased recirculation, low Kt/V and significant pressure changes are all indicating VA dysfunction that needs to be confirmed, explored and treated adequately [44].
\nA dedicated quality assurance program to VA monitoring and management is strongly recommended in dialysis facilities, as part of best clinical practices, to improve dialysis patient outcome [45] (see Section 4). VA outcome is usually best summarised by three hard clinical endpoints: functionality (e.g., maturation and access flow), technical survival (e.g. primary patency and secondary patency) and VA-related morbidity (e.g., dysfunction, infection and intervention) [46]. In brief, VA outcome depends on three groups of factors: first, patient medical profile (e.g., age, gender, comorbidity, diabetes and vascular calcification); second, VA type (e.g., autologous AVF and synthetic graft); third, practice patterns (e.g., creation skills, monitoring and maintenance) [47]. It is not our intent to review factors implicated in these outcomes but only to provide some brief trends and facts. Autologous AVFs have better survival than synthetic AVGs considering both primary and secondary-assisted patency [48, 49, 50]. Median technical survival with AVFs ranges between 3 and 10 years compared to AVGs which range between 1 and 4 years. Substantial loss of AVFs (10–30%) occurs shortly after creation due to thrombosis or poor maturation. Late stenosis or aneurysm may be observed with AVFs in long-term run depending on cannulation technique. Loss of AVGs occurs later due to stenosis in relation with myointimal hyperplasia in almost 90% of cases. Patency of AVGs requires tight monitoring and frequent restoring and maintaining procedural interventions (e.g., percutaneous angioplasty and stenting) [51]. Infection risk is about three times higher with AVGs. Intervention rate (e.g., angioplasty) to keep VA patency is 3–10 times higher with AVGs than AVFs in long run.
\nVA-related morbidity represents a tremendous burden for patient (pain, anxiety and depression) and healthcare system (hospitalisation, technical procedures and interventions and cost). VA-related problems represent a common cause of hospitalisation in dialysis patients accounting for 10–15% of cases [5].
\nVA complications vary according to VA type [52]. Arteriovenous accesses (AVF and AVG) are associated with less complications and risks as compared to tCVC [53]. AVF is still the “standard” for VA presenting significant less complications and longer survival patency than AVG [54].
\nMost common complications of recently created AVFs and AVGs are inadequate flow, failure to mature and thrombosis [55]. This aspect is further developed in the next section.
\nVA dysfunction in mature access requires further exploration and imaging (e.g., Doppler US, contrast media phlebography or arteriography and digital VA imaging) to identify the cause of poor flow or insufficient development. Based on the root cause analysis of the VA dysfunction, specific interventional procedures may be proposed. Usually they consist in percutaneous angioplasty with or without stenting. In the worst cases, surgical VA revision or new VA creation might be preferred.
\nThrombosis occurs rarely as an unexpected event but usually follows and/or complicates an underlying stenosis of the distal or proximal vein or proximal artery [56]. This well-established fact reinforces the need for regular VA monitoring to correct pre-emptively this causal factor. Treatment of thrombosis requires urgent action by VA interventional expert consisting usually in a combination of thrombolytics and thrombectomy techniques [57, 58, 59]. After successful declotting, it is important to treat underlying stenosis by percutaneous balloon angioplasty to prevent thrombosis recurrence [60].
\nAneurysms or more frequently false aneurysms may have developed on the vein segment of the VA either with AVFs or AVGs [61]. They result from repeated cannulation in the same area and high venous pressure. False aneurysms should be resected since they are exposed to further complications (e.g., infection and bleeding), and cause of high venous pressure (e.g., stenosis) should also be treated by balloon angioplasty.
\nSteal syndrome is a rare but painful and severe condition that needs to be treated adequately [62]. Steal syndrome results from retrograde blood flow after AV access creation, and a condition that diverts blood flow to proximal segment creates functional ischaemia in distal arm segment. It is more likely to be observed in severely arteriopathic and vascular calcified patients. Severity of steal syndrome is graded from minor (pale, blue and cold hand) to major (ischaemic pain, ulceration and necrosis of digits or hand). Treatment of steal syndrome consists usually in venous banding (high flow steal syndrome) or distal revascularisation and interval ligation (DRIL procedure) (normal flow steal syndrome). In worst cases, closing AVF or AVG would be considered as a safer option.
\nInfection of VA is not common in AVFs but more common in AVGs (2–3 times) and much more common (5–7 times) with tCVCs [63]. Infection results from specific risk of VA and chronic dialysis patient profile, but more likely from VA handling practices and hygienic rules of the dialysis facility [64].
\nComplications are associated with CVC placement (puncture of the associated artery, bleeding, major venous laceration, atrial perforation, pneumothorax and air embolism) and use (malfunction and limitation of dialysis performances, central vein stenosis or thrombosis and catheter infection) [65, 66, 67]. For patients who are treated with HD, the risks of major cardiovascular events, fatal and non-fatal infections and overall mortality are far greater with catheters than with AVF.
\nThe NKF/DOQI guidelines define CVC dysfunction as the failure to attain a sufficient extracorporeal blood flow rate of ≥300 ml/min with a pre-pump arterial pressure lower than −250 mmHg [68]. Catheter dysfunction can lead to catheter thrombosis in the extreme. Early CVC dysfunction is defined as a catheter that never functioned adequately after placement and is mainly consequent to technical problems. Later, CVC dysfunction is related to partial or total catheter occlusions induced by intrinsic thrombus within the CVC, external fibrin sheath or extrinsic thrombus around the catheter in the vein leading to catheter adherence to the vessel wall or to the cardiac atrium. The majority of thrombi associated with CVC are asymptomatic. If the dialysis staff notices a decreasing Kt/V, an increasing level of serum potassium, phosphate, urea and creatinine and an increase of both negative arterial pressure and positive venous pressure during consecutive dialysis sessions, a CVC dysfunction could be suspected. If thrombosis involves the catheter tip, it may not be possible to withdraw blood and/or to infuse fluids and there may be leaking at the access site. In general, symptoms vary from local tenderness or pain at the site of entry to obstructive symptoms with swelling of the ipsilateral extremity, neck or face. Atrial thrombi may become symptomatic, with pulmonary or systemic (paradoxical) embolism or catheter dysfunction, or may be incidentally found as an atrial mass. In the experience of the authors of various studies, many patients who undergo an echocardiogram bring equivocal reports describing valve vegetation vs. tip catheters thrombi [69, 70, 71].
\nWhenever a native AVF can be created and is able to mature in no more than 12 weeks, it is considered the first and best choice as a VA [72]. Higher long-term longevity, less thrombotic or infectious morbidity, needs less procedure for maintenance. Overall a native AVF is big life and money saver.
\nThe optimal VA is one that enables an adequate dialysis treatment, for as long as needed, keeping in mind that ultimately the natural history of a VA is failure. Its characteristics are a good blood inflow through the feeding artery, and an access flow (Qa) > 600 ml/min, without recirculation. It must be superficial (<0.6 cm skin deep), have a thick wall, a long straight segment to allow two needle punctures 2.5 cm away, a diameter > 0.6 cm, a good venous outflow, without causing distal ischemia in that limb.
\nThat perception lead health authorities, some agencies and big provider chains to influence access choice through incentives and performance indicators, as if it was a black & white issue. In fact, AVF should not be always first and CVC are not always last. VA type comprises two of the nine quality metrics in the US CMS’s five star rating of dialysis facilities a Quality Incentives Program (QIP) that rewards high AVF prevalence and penalises CVCs, without regard to patient case-mix.
\nThere has never been a RCT comparing different VA choices regarding mortality or other hard outcomes. All large observational trials compared accesses achieved as opposed to the accesses that were intended (as in intention to treat). As 30–60% of all AVFs created either fail or need several procedures to mature and the CVC group in most studies were people in whom AVF failed, or CVC was chosen because of a predictable bad prognosis (old age, congestive heart failure, short life expectancy…), then we really cannot answer the question on which VA is the best or correlate it with hard outcomes [73]. If we exclude patients that begin HD urgently, mortality between AVF and CVC patients become identical [73].
\nVA is only one example of the paradox between patient-centred care and the tyranny of quality metrics based on population studies. Reconciling this paradox is what clinical judgement is all about and why physicians cannot be replaced by algorithms, care paths or protocol-driven medicine [74].
\nThe native AVF comes with its own set of disadvantages. There is a higher risk of primary failure (non-maturation), up to 60% failing prior to ever being cannulated, angiographic procedures frequently required to assist maturation. Attempt to maximise fistula use by increasing creation rates has led to the unintended consequence of higher primary failure rate and longer dependency on catheters [75, 76].
\nStudies have shown that the primary failure rate is two times greater for fistulas (40%) than AVG (19%), with similar cumulative patency, in addition, the number of catheter days before AV access use was more than double in those having a fistula (81 days) compared with AVGs (38 days). However, grafts require more angioplasties (1.4 vs. 3.2 events) and thrombolysis (0.05 vs. 0.98 events) interventions per 1000 patient-days [76, 77]. The risk of primary fistula failure is much higher for lower arm fistula (28%) than with upper arm fistula (20%) [75].
\nAccording to the EDTA Registry, there is a trend for decreasing AVF in incident patients from 42% in 2005 to 32% in 2009, while there was an increment in CVCs from 58 to 68% (80% in the USA), with large international variation. In prevalent patients, AVFs went from 66 to 62% and CVCs from 28 to 32% [23, 78]. In a recent meta-analysis, CVCs (compared with AVF) have a higher risk of all-cause mortality (RR 1.53), fatal infection (RR 2.1), and cardiovascular events (RR 1.48) [18]. Grafts need twice as many angioplasties (1.4 vs. 3.2 events/1000 acc. days) than AVF, more thrombolysis (0.06 vs. 0.98 events/1000 acc. days). Although they need more procedures, their cumulative patency is the same when primary AVF failure is factored in [79].
\nApplying a proportional hazard model to examine mortality in incident HD pts aged 65–90 years old in association with the type of VA, but accounting for case-mix and health status, the RR of AVF is 1.0, graft 1.18, CVC transformed in AVF 1.2, CVC transformed in a Graft 1.38 and CVC permanently 1.54 (both adjustments reduce RR in CVCs of 44%) [80].
\nUsing a decision analysis model (fed with data extracted from DOPPS 2, the REDUCE FTM study, the DAC study and CMS data) of the best option for patients initiating HD with a CVC, an AVF attempt strategy is associated with better survival and lower annual cost, but that advantage is progressively lost in patients above 60 years or diabetics [81]. The advantages of an AVF attempt strategy lessened considerably among older patients, particularly women with diabetes, reflecting the lower fistula success rates and lower life expectancy.
\nAlthough upper-arm fistulas have a greater chance of maturation, the loss of multiple lower-arm possibilities will sooner exhaust VA sites. Also, the upper-arm option exposes patients to higher frequency of steal syndrome, potential adverse long-term complications of high-flow AVF on cardiac function and an incidence of cephalic arch stenosis that is dramatically higher when compared with the forearm choice [82].
\nAccording to data from CMS, the first year cost in the common scenario of patients initiating haemodialysis with a CVC, the annual cost of access-related procedures and complications is higher in patients who initially receive an AVF vs. an AVG. In their first year, the average annual cost of an AVF is $10,642 vs. $6810 in an AVG. The CVC group had the highest median annual access-related cost of $28,709 largely attributed to high frequency hospitalisations due to bacteraemia, repeated use of thrombolytics, and frequent catheter replacement [83].
\nIt is consensual that once established, a native AVF is the preferred HD access, and all guidelines recommend placement of an AV access before dialysis initiation; however, that desideratum is achieved only in less than one third of all incident patients [84]. If we create it too early, the access may need extra procedures to keep its patency until dialysis initiation and many more CKD stages 4 and 5 patients will die of cardiovascular events than those who will progress to end-stage renal failure needing dialysis, and on the other hand, if we do it too late more than 60% of all patients will begin their treatment through CVC, without time for full maturation of their AV access [85].
\nHod examined the optimal timing of incident fistula placement in a population of elderly patients above 66 years old, showing that the odds ratio for successful fistula use was maximised when surgery was performed 6–9 months before dialysis was needed, with worst results in obese females, in diabetics and patients with congestive heart failure [86]. Unfortunately, even when a patient is being monitored in clinic by a nephrologist, the rate of progression of CKD to ESRF is not constant, the need for dialysis can be precipitated by random, unexpected clinical events and the correlation between measurements of renal function and uraemic clinical symptoms are poor; therefore, it may be quite difficult to plan the best timing. The best strategy would be to develop techniques that speed fistula maturation below 2 months’ time after surgical creation, what would make planning much easier and accurate [87]. Despite the tremendous heterogeneity in the decline of kidney function in stage 5 CKD patients, factoring in the presence of diabetes, the degree of proteinuria and the eGFR trajectory in the preceding year, significantly improved our prediction capability of dialysis commencement [88].
\nAccess malfunction is a source of tremendous emotional and physical suffering, dialysis treatments loss, low treatment adequacy, urgent need for a central catheter as a substitution access and referral for new angiography or surgical procedures.
\nThe most common first VA complications include haemorrhage, usually at the sutures level, infection, revealed in the first 15 days, local pain/inflammation, failure to mature producing poor dialysis adequacy and early thrombosis. Non-maturation and thrombosis, both have as an underlying mechanism the development of early stenosis along the arterial inflow, in the VA itself or in the access outflow.
\nStenosis is necessary for thrombosis, but it is not enough. Only 30% of stenosis above 50% of lumen compromise will cause thrombosis in the next 6 months, we just do not know which ones [89], and on the other hand, stenosis treatment based on morphology, percutaneous angioplasty, induces accelerated neointimal hyperplasia with recurrent stenosis [90]. In 20% of all cases, recurrent stenosis occurs in 1-week post-procedure and 40% in 1 month [51].
\nWe define VA maturation by our capability to cannulate it with two needles and deliver a minimum blood flow to the extracorporeal circuit of 350 ml/min for the whole dialysis, 4 months after its creation, for a minimum of eight dialysis in 1 month [91].
\nImmediately after fistula creation, the blood flow increases from an average of approximately 20 ml/min in the radial artery to as much as 300 ml/min in a radio-cephalic fistula, 1 week later the mean blood flow rate increases further to an average of 540 ml/min and the mean shear stress from 5 to 10 dyne/cm2 to 24.5 dyne/cm2. Ultimately, the increase in flow in a well-developed fistula can reach 600–1200 ml/min [2].
\nThe functional ability of the artery and vein to dilate and achieve a rapid increase in blood flow are the most important determinants of fistula maturation [92] and declared that success correlated much better with Qa one day after surgery than with preoperative vessel diameter [91]. Increased shear stress sensed by the endothelium, related directly with flow rate and inversely with vessel radius, initiates the vascular response and secretion of vasodilators and anti-inflammatory mediators, to reduce neointimal hyperplasia and lower shear stress back toward baseline levels.
\nAt the pathogenic level, the stenosis seems to be caused by a combination of neointimal hyperplasia and an inadequate outward or positive remodelling [93]. The abundant presence of myofibroblasts within the neointima is consistent with a role for the adventitia as a source of cells for neointimal proliferation. New biologic interventions, delivered periadventitial during surgery may old promise in preventing fistula maturation failure [92, 94].
\nThe process of care to maximise AVF includes: (a) early referral to a nephrologist; (b) patient and hospital staff education to save peripheral veins, avoiding peripheral as well as central I.V. lines (in our experience, 75% of all patients in a renal ward have an I.V. line in the cephalic vein), as well as transvenous implantation of pace-makers to be substituted by epicardial leads; and (c) timely referral to the right surgeon (well trained and experienced in obtaining VAs), that will probably order, or preferably will do it himself a pre-operative vascular mapping. Remind him to avoid grafts, but, if no other choice, do not save in their length and that an AVF do not always have to be distal [95].
\nPreoperative physical examination provides essential information in patients needing AVF construction but is rarely sufficient nowadays because an increasing proportion of HD patients has a compromised vasculature, the result of age, diabetes, many years of dialysis therapy and prior HD catheters. Non-invasive assessment by duplex sonography is very helpful in locating veins that are not clinically visible and also provides information about their functional characteristics, including venous outflow. Duplex sonography is the method of choice for evaluation of arteries. A calcified artery with a small lumen and thickened wall will never provide adequate fistula function [96].
\nVascular mapping (Figure 3) is a technique that leads to information on patient’s inflow and outflow anatomy as they relate to arteriovenous access creation. It can be done by using US evaluation, or angiographic mapping, both have pros and cons, the choice depends on local expertise and availability.
\nVascular network mapping: arterial map and venous map.
The US scanner should allow examination with B-mode and Doppler mode, using linear array probes with a frequency of 7 MHz for B-mode and 5 MHz for Doppler. Patients more likely to benefit from pre-operative US evaluation are those with: (a) difficult clinical examination (obese, absent pulses and multiple previous access surgery); (b) possible arterial disease (older age, diabetics and cardiovascular disease); and (c) venous disease (previous cannulation) [97]. Doppler US has a distinct advantage of being a non-invasive modality that can evaluate both structural and functional aspects of vessels that play a key role in access maturation [98].
\nPreoperative mapping in some settings leads to marked increase in placement of AVF and a reduction in the use of catheters [24, 99]. Comparing pre-op US Doppler with physical examination, there was a dramatic increase in AVF creation 64 vs. 34% [24], reduction in graft placement from 62 to 30% and in tunnelled catheters insertion 24–7% [99]. Those were not universal findings, though.
\nThe success rate of fistula formation does not correlate with vessel diameter but with flow, mainly in the day after [92], and in some series, a preoperative Doppler US achieved 80% successful constructed AVFs. Average parameters in this success cases: artery internal diameter 2.6 mm (vs. 1.6), Qa 54.5 ml/min (vs. 24.1), and resistive index 0.5 (vs. 0.7). Risk of primary failure is much higher for lower arm fistula, and long-term patency is not better, increase in vein ID after compression 59% (vs. 12.4) and Qa increased to 300 ml/min in 1 week (vs. 4–8 weeks) [100].
\nThere is no systematic evidence that preoperative US mapping will induce an increase in the proportion of fistulas ultimately used for dialysis or a reduction in catheter use. It appears that the results from vessel mapping only influenced the decision as to the type or location of the AV access in surgeons with less than 15 years of experience [101]. In patients with pre-operative vascular mapping, on multiple variable logistic regression, factors associated with failure to mature were female gender, age > 65 years and forearm location (up to 78% if the three criteria were met), and the extracted mapping hemodynamic measurements could not differentiate patients with mature or immature forearm fistulas [102].
\nThere is clearly more to maturation than vessel diameter, non-anatomic factors likely to contribute to maturation failure include the underlying vascular pathology and impaired endothelial function associated with CKD, vein trauma from surgical manipulation and the haemodynamic stresses resulting from the creation of an AV anastomosis [94]. Preoperative duplex US scanning and venography increased first fistula creation rate from 66 to 83%, but maturation rates actually declined from 73 to 57%, probably due to basing decision mostly on the vessels diameter [103].
\nDialysis VA outcome relies on three main components: support of a referent vascular access centre (VAC) providing expertise and service 24/7/365 per year; implementation of a quality assurance process optimising use of VA; commitment and skills of trained nursing staff ensuring best use and management of VA. This last part will be addressed more specifically in the nurse perspective section.
\nA VAC is a dedicated department specifically designed and equipped to deal with VA dysfunction. Its goals are to provide easy access in less than 24 hours to an experienced VA surgeon or interventional nephrologist, to increase the prevalent number of patients dialysed through native arteriovenous fistulas (AV fistulas) and above all to reduce the number of patients requiring a catheter as a transient or permanent VA. Place and role of VAC are summarised in Figure 4.
\n(A) Place of VAC in clinic network organisation; (B) role of VAC in coordinating VA care.
The structure of a VAC is very similar to an ambulatory surgical unit, with continuous service from 9:00 am to 9:00 pm, 5 days a week, with a standard operating room and angiography suit functioning side by side, staffed by VA expert surgeons and interventional nephrologists. The perfect setup for a multidisciplinary approach to VA care is in a constant dialogue between surgeons and nephrologists.
\nThe equipment should include a portable C-arm with capability for digital subtraction and road mapping, US equipment for central vein access localisation and puncture, pre-procedure patients´ triage and procedure planning, sterilisation facilities and a common recovery room for both disciplines. Supplies are tailored to operator preferences, within economic considerations [31, 32]. The VAC must be licenced by the health authorities, and their physicians credentialed to perform the needed techniques.
\nIn our network, we manage around 5000 HD patients, treated in 37 dialysis units evenly covering the whole country, serviced by two freestanding ambulatory VACs and connected by a paperless dedicated software (VAonline©), a computerised database that handles dialysis unit referrals, reporting from the VAC back to the units and a permanent registry of our clinical activity used for research and administrative purposes. It connects and extracts data from the main network database (EuCliD).
\nReferrals to the VA are decided at the discretion of the attending nephrologist in the dialysis unit, and on arrival to the VAC patients are assessed to confirm referral correctness. Referral indications to the surgical pole of our VAC include: (a) construction and revision of AV fistulas or grafts; (b) exudative infection of the VA; (c) distal ischaemia of the access limb; (d) actively growing aneurysms; (e) haemorrhage or rupture of the VA; and (f) native AF thrombosis.
\nReferral indications to the angiography suite include: (a) graft thrombosis; (b) growing oedema of the access limb; (c) pain in the access limb during treatment; (d) unexplained reduction of dialysis adequacy (Kt/V) and/or VA flow (Qa drop < 600 ml/min in a graft, or < 400 ml/min in a native AV fistula confirmed in a second measurement); (e) SVC syndrome; and (f) native AV fistula non-maturation. Local bylaws require that all central venous catheters be implanted in hospitals.
\nTechniques performed in the operating room include: (a) construction or revision of native AV fistulas and grafts; (b) basilic vein transposition; (c) surgical treatment of VA infection; and (d) surgical treatment of ischemia or aneurysms of the VA limb. Techniques performed in the angiography suite include: (a) diagnostic angiography (mapping not achieved with ultrasound); (b) stenosis A=angioplasty; (c) pharmacomechanic thrombolysis; and (d) VA stenting.
\nIn our series, with around 3000 interventions per year in both VACs, the most common referral cause is by far a drop in Qa in 61.2% of all causes, meaning that a VA surveillance program like ours, using daily physical examination by trained dialysis nurses and monthly measurement of Qa in the dialysis unit, although of controversial benefit, will have a major impact in the workload of the VAC and in the costs of the whole operation.
\nThe most common site of stenosis, requiring intervention, was in the access itself in 31% of all cases, graft venous anastomosis in 29%, in the cephalic arch with 9.9% and the swing segment of the native AV fistula (the proximal segment immediately after the AV anastomosis) in 9.1%.
\nThe most common procedures in the angiography suite were isolated balloon angioplasty in 67.5% of all cases, thrombolysis + angioplasty in 14.3% (depending on the graft prevalence in each region) and 10.1% did not need any endovascular intervention (false positive referrals). We decrease the implantation of stents, extremely expensive and not suitable for reintervention once suffering a stenosis recurrence, to less than 0.5% of all procedures, substituted in the same indications by drug eluting balloons. We were not successful accomplishing needed endovascular treatment in 7.1% of all cases.
\nLike the experience of others [104], in our centres, the procedures profile changed in the last years from a majority of interventions in grafts (angioplasties and thrombectomies) to one characterised primarily by angioplasties performed on AV fistulas. The number of interventional procedures did not decrease, and it was just the referral pattern and the percutaneous intervention required that changed in parallel with the increasing AV fistulas utilisation in prevalent patients.
\nA VAC needs a quality assurance program, to continuously monitor its performance. In our network, we use: (a) in first accesses an AVF construction in 80% of all cases; (b) in subsequent VAs 60% of AVF; (c) primary AVF failure at 3 months in less than 40% of all cases; (d) percentage of function VAs 7 days post-thrombolysis > 75% and at 3 months > 50%; and (e) absence of VA infection 15 days post-intervention. We also monitor the dialysis unit, requiring less than 1 referral to the VAC per patient year. We closely follow our success and complication rate according to international standards [105, 106].
\nIn our experience, the major achievements of a VAC in our network are a substantial reduction in the waiting time for urgent procedures (28% of all referrals) to the same day response (elective referrals 4–6 days), the clear improvement of training and education of physicians and nurses in the dialysis units, now generating 0.3 surgeries/pt.Year, 0.37 angiographies/pt.Year, a precipitously drop of prevalent patients being dialysed through a tunnelled catheter from 24 to 14% and the total disappearance from our units of transient catheters. VA-related hospital admissions went from 1.3 to 0.6 episodes/pt.Year and they were 20% of all admissions and are now less than 10%. Our numbers compare favourably with the experience of others [107].
\nSo, the question is, do we need a VAC for our dialysis patients? It depends on how good and how prompt is VA care offered in your region, if you are working in a capitated system, as in our case, is VA management included in the care bundle, are you mainly serving your own patients, raising the quality and coordination of care they previously received, or is there a market for you to sell a service outside your network. Do dialysis units in your area implemented a VA surveillance program, and in that case, do we intend to act pre-emptively to correct apparent malfunction?
\nTo turn it into a success, it is important to monitor and influence the process of care delivered in our VAC, avoiding futile procedures such as AV fistulas that will never mature, diagnostic angiographies not needing therapeutic intervention (false positive referrals), useless angioplasties that will only accelerate more severe recurrences, or short-lived thrombolysis. It is imperative that we reach a consensus on how to define success and reward it (is it Δ Qa, Kt/V improvement, recurrence rate?). It is also of utmost importance to establish an accredited program for training young surgeons and nephrologists in VA care to guarantee future expertise in this field [108].
\nIf we manage to be responsible for the full cycle of VA care, without sharing responsibilities with other providers, we may expect to keep costs control below the reimbursement rate, reduce the hospitalisation rate due to VA morbidity and limit the number of dialysis treatments lost. Reducing the number of patients with catheters we will avoid morbidity due inadequate dialysis, and the extra costs of supplies for in-treatment catheter handling as well the cost of thrombolytics to treat recurrent catheter obstruction and antibiotics to treat frequent catheter infections.
\nIn the U.S. to break even a VAC in their current reimbursement environment, requires at least 800 patients, I suspect we would need a larger patient base in Europe; however, the feasibility of a VAC is quite variable and depends on unique payment structure in different geographic locations, specific needs of the patient population being covered and the availability of trained operators.
\nPatients with ESKD are fragile and vulnerable. For those who depend on HD, the ongoing success requires access to blood vessels capable of providing high volume extracorporeal blood flow to execute efficient HD treatments. Indeed, a properly functioning and reliable VA is one of the key successes of the HD adequacy. Unfortunately, the vascular access for HD continues to be referred to as the “Achilles Heel” of the HD procedure. Complications have a negative effect on the quality of life and continue to be a leading cause for morbidity and mortality of ESKD patients, with dysfunction being a major cause of morbidity and mortality in HD patients [109, 110].
\nVA options for HD include the placement of endogenous AVF, AVG and tCVC. The AVF is the preferred choice for chronic HD VA, rather than AVG and CVC, due the better outcomes (morbidity and mortality) and lower need for interventions and complications that could reduce both efficiency and efficacy of HD treatments which also increase the overall HD costs [111, 112, 113, 114]. The selection of access should be individualised based on life expectancy and comorbidities and in consultation with a vascular surgeon with experience in the creation of HD VA. However, AVF is not always the ideal VA choice for certain ESKD patient categories such as the elderly: for those patients, the selection of VA should be individualised based on life expectancy and comorbidities. AVF, AVG and CVC are all used in older patients for permanent VA.
\nThe HD VA long patency depends on several factors and minimises its complications, and failure has high priority in dialysis therapy and is a significant challenge for nephrologist, nurse and surgeon. The multidisciplinary team approach with agreement on a common set of targets [115], the surgeon experience [116] and adopting specific prevention measures such as, time referral for surgery with preliminary vascular mapping, specific VA surveillance strategies, AVF and AVG cannulation techniques with specific hygiene procedures are mandatory measures to prevent the VA both early and late failure or complications such as stenosis, thrombosis and infection.
\nThe first challenge is the time referral to the vascular surgeon allowing to the AVF to mature adequately (1–6 months) and to be used for HD, remaining useable for many years with minimal intervention. Early referral of patients with CKD is strongly recommended. This approach helps to preserve access sites and provides adequate time for planning the creation and allowing maturation of the VA [68]. The most experienced surgeon of the HD vascular access team should be responsible, or supervise the AVF creation. Fassiadis [117] demonstrated that the primary success and primary and secondary patency rates of a series of consecutive radio-cephalic fistulae were affected by the experience of the surgeon. The risk of AVF primary failure related to ESKD patient increasing age, gender (female) and comorbidities (cardiac disease, pulmonary disease, peripheral arterial disease, diabetes and obesity) should be improved by careful patient evaluation and vascular mapping prior AVF creation. Patient evaluation (medical history and physical examination) and preoperative mapping of arm vessels allow a higher percentage AVF placements as well as an increased fistula success rate [24, 118]. Physical and US examination are intended to evaluate both the arterial and the venous system: vascular lesions, classified as inflow or outflow problems, should be identified allowing the surgeon the best AVF option protecting as much possible the arm vessel paucity for native AVF. The goals of the arterial evaluation are to find an artery capable of delivering the blood flow at rate to allow the HD treatment correctly. The axillary, brachial, radial and ulnar pulses should be examined as well as the blood pressure between the two arms to assure that the vessels are patent. By modified duplex Allen test is evaluated the hand arterial blood circulation if the radial or the ulnar arteries will be utilised in the AVF creation. The artery used must be of sufficient size (diameter > 2 mm) [119]. A forearm cephalic vein AVF (radial artery–cephalic vein) (brachial artery–cephalic vein) is preferred. The entire extent of the vein, its drainage, the diameter, depth and assessment of the ability to dilate should be assessed. The upper arm cephalic vein AVF (brachial artery–cephalic vein) is evaluated in case no suitable vein is found in the forearm. The non-dominant forearm is preferable for dialysis access placement, and the first choice used is the radio-cephalic AVF [111]. In case the first choice is not available, the other options from the most to least desirable are the following [113]: (a) dominant forearm radio-cephalic AVF; (b) non-dominant, or dominant upper arm brachiocephalic AVF; (c) non-dominant or dominant upper arm Brachiobasilic vein transposition AVF; (d) forearm loop graft rate; (e) upper arm straight graft; and (f) upper arm loop graft (axillary artery to axillary vein).
\nAfter AVF creation immediate thrombosis, failing to mature, or early fistula failure, may develop [120], and after the maturation late failure and other complications can occur [120]. VA monitoring and surveillance are crucial to ensure best outcome of VA and success to renal replacement program [121, 122, 123]. The AVF monitoring and the early identification of complications contribute to maintain the long-term patency of the AVF. Once the HD treatment is started, skilled nurses should evaluate the VA at each dialysis session. VA monitoring is performed on a regular basis synchronised with dialysis sessions to detect early dysfunction or complication. A routinely weekly physical examination of mature AVF is recommended by 2006 National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines and 2008 Society for Vascular Surgery [68, 119]. The nurse should inform the nephrologist in case of abnormal noise intensity [12], oedema, redness, swelling, bruising, haematoma, rash or break in skin, bleeding, other exudate, aneurysm or pseudo-aneurysm. The AVF blood flow is in the range of 800–2000 mL, and the thrill is associated with a blood flow >450 ml/min: in case the patient notices that the pulse or the thrill is reduced or it cannot be felt he/she should immediately inform the clinical staff. Patients should be instructed to keep the access extremity clean and to avoid wearing any cloths or wristwatches that restrict flow.
\nVA surveillance is intended to assess objectively and to follow over time VA performance and dialysis treatment delivery efficacy. It requires specific non-invasive tests and special instruments. Three main key parameter indicators are usually monitored: effective dialysis dose delivered, recirculation of VA [124, 125] and VA flow.
\nTime trend behaviour monitoring of VA performance based on selected indicators is crucial to detect early VA dysfunction (e.g., stenosis). Pre-emptive intervention has been shown very effective in correcting stenosis (percutaneous angioplasty) and preventing further risk of thrombosis and dysfunction. Precise knowledge of individual VA performances, threshold values (e.g., access flow 500–600 ml/min) and time trend analyses are required to optimise and personalise VA maintenance strategy [126, 127].
\nTime of first use or first cannulation varies according to VA type, maturation degree and local expertise: native AVF may be cannulated within 4–8 weeks after creation; AVG may be cannulated earlier 2–6 weeks; tunnelled CVC may be used immediately after insertion. Timing of VA cannulation (early <2 weeks or late >3–4 weeks) does not seem to impact VA outcome, and this is a particular feature of dialysis policy units [128].
\nThe correct cannulation technique is mandatory for preventing AVF injury that might cause infiltration/haematoma or intimal damage with subsequent stenosis that might lead AVF thrombosis. Recommendations for the AVF cannulation procedures are few and mainly focused on needle size, angle of needle insertion and direction of needle bevel. Experienced dialysis staff only should be allowed to cannulate a newly created fistula. For first cannulations, local anaesthesia performed with topic anaesthetic cream or patch (Emla) is recommended [129].
\nIn FMC EMEA NC clinics, the following cannulation procedures are applied [43]. The arterial needle should be placed in the direction of the blood flow and bevel down, but in case of anatomical restrictions, the needle is placed against blood flow and bevel up. The venous needle is always placed in the direction of the blood flow. The needle should be inserted at an angle of 20–35°, and when flashback is observed, the needle should be lowered and advanced into the centre of the vessel. Sites on the AVF which display evidence of aneurysm formation should be avoided. In mature AVF, 15- or 14-G needles are needed to support a blood flow rate of >350 ml/min needed for high efficiency dialysis or convective treatments. In 2006, NKF KDOQI guidelines recommended the use of arterial needles with a back-eye, to reduce the need for flipping or twisting the needle [68]. Parisotto showed in a cohort of 7058 patients from nine countries, that area cannulation technique (repeated cannulations concentrated over a small vessel area (2–3 cm)) was associated with a significantly higher risk of access failure than rope-ladder or buttonhole. Retrograde direction of the arterial needle with bevel down was also associated with an increased failure risk [130]. Moreover, patient application of pressure during cannulation appeared more favourable for VA longevity than not applying pressure or using a tourniquet [130].
\nThe buttonhole needling is postulated to be associated with a reduction in haematoma and might increase long-term survival of AVF with less complication. The buttonhole technique is a cannulation method where the AVF is cannulated in the exact same spot, at the same angle and depth of penetration every time [131, 132, 133, 134]. By using the exact same spot, a scar tissue tunnel track will be created. The procedure should be performed by the same cannulator until the track tunnel has been created. After track creation, this technique should always be performed by highly experienced staff. Using a sharp needle, it takes approximately 6–12 cannulations (depending on the individual patient) to create a track at a given site. The creation of a scar tissue tunnel track allows the use of a blunt needle [43].
\nThe needle removal procedure is as important as the cannulation. Needle withdrawal must be done carefully in order to prevent tearing of the vessel, to minimise access trauma and to achieve optimal haemostasis. Each needle should be withdrawn slowly, keeping the same angle as that of insertion, until the entire needle has been removed. Digital pressure should be applied only after the needle is completely removed to prevent damage to the vessel wall and should be sufficient to stop bleeding but not so great as to stop the flow of blood through the VA [43, 135].
\nCannulation and needle removal techniques are similar in patients with either AVF or AVG with the exception of the buttonhole technique that cannot be utilised to cannulate the AVG. It is suggested to avoid “flip” or rotate the bevel of the needle 180°. Flipping can lead to stretching of the needle insertion site, which can cause bleeding from the needle site and oozing, during dialysis treatment and can damage the graft [135].
\nSome medications, including statins, antiplatelet agents, anticoagulants, and dipyridamole have been reported to potentially affect VA outcome. Saran evaluated the association between VA failure and the use of specific drugs [136]. Calcium channel blockers improved the primary graft patency (relative risk [RR] for failure, 0.86; P = 0.034). Aspirin therapy was associated with better secondary graft patency (RR, 0.70; P < 0.001). Treatment with angiotensin-converting enzyme inhibitors was associated with significantly better secondary fistula patency (RR, 0.56; P = 0.010). Patients administered warfarin showed worse primary graft patency (RR, 1.33; P = 0.037). Statin treatment could be associated with reduced neointimal proliferation, vascular inflammation, and improved AVF dysfunction [137, 138, 139]. A Cochrane review reported that antiplatelet treatment can improve the 1-month patency rates of AVFs and AVGs [140]. Dipyridamole demonstrated to reduce ePTFE graft occlusion reducing the vascular smooth muscle proliferation and the neointimal hyperplasia [141].
\nInfection is the second most common cause of AVF-AVG loss after stenosis/thrombosis [9]. An effective hygiene and infection control policy is essential, and healthcare staff must be trained appropriately. Standard precautions prevent healthcare-associated transmission of infectious agents among patients and healthcare workers, and they must be applied to all patients. Appropriate sterile technique should be used [43]. The patient’s skin must be disinfected with an appropriate solution (before needle insertion for approximately 30–60s) starting at the chosen cannulation site and moving outward in a circular rubbing motion. If the skin is touched by the patient or staff after the skin prep has been applied but the cannulation has not been completed, repeat the preparation.
\nThe CVC exit-site infection can be defined as a culture-positive inflammation external to the cuff of the catheter and localised to the exit site and not extending beyond the cuff. It is characterised by local redness, crusting and a variable amount of exudate. In most of these cases, the patients respond well with local measures, like topical antibiotic application (without fever). The CVC tunnel infection is defined as a culture-positive inflammation within the catheter tunnel but beyond the catheter cuff, with negative blood culture. Usually it is characterised by erythema, tenderness and induration in tissues overlying the catheter and > 2 cm from the exit site. CVC-related bloodstream infection (CRBSI) is defined as the presence of bacteraemia originating from an intravenous catheter. The diagnosis of CRBSI is often suspected clinically in a patient using a CVC who presents fever or chills, unexplained hypotension, and no other local sign. Severe sepsis and metastatic infectious complications, such as infective endocarditis, septic arthritis, osteomyelitis, spinal epidural abscess and septic emboli, can prolong the course of CRBSI and should be considered in patients who do not respond appropriately to treatment. Specific connection and disconnection procedures to prevent the CVC infections are applied in FMC EMEA NC [69].
\nPatient information and education are powerful means for keeping VA functional and safe and to guarantee successful dialysis therapy. These needs extend to patient’s family and relatives. Awareness and learning processes should start as soon as the patient is diagnosed with chronic kidney disease. VA creation is a significant milestone in the life cycle of CKD patient that marks almost the final step of kidney disease progression and announce the start of replacement therapy. VA planning and creation are usually associated with a severe psychological trauma in renal patient that needs to be adequately prepared. Therefore, regarding VA education, it is important to differentiate in the life cycle of CKD patient two stages: before and after VA construction.
\nPreservation of vessels is an essential message and task that should be given to any CKD patients and relatives [11]. It is of utmost importance that CKD patients are aware of how they can preserve their vessels in both arms. They need to realise very early that vessels are essential for VA creation as a line to life-sustaining therapy and superficial vein resources are not endless. Patient education should include information to avoid and/or to refrain using major vessels located in the forearm for blood sampling, intravenous (IV) injections and infusions or invasive arterial procedures and to avoid the use of upper arms veins for catheterisation (e.g., angiography) or radio-logical procedures (e.g., contrast media imaging). Such message should be repeated at each hospital or clinical admission. Instead the use of superficial veins of the hand and minor vessels of upper arm should be preferred for exploration or imaging.
\nPatient education means more than providing information, CKD patients will benefit from counselling to actively participate in the choice of their treatment modality, to act on their own care and in successfully self-managing certain tasks needed by their treatment [11]. Patient education is needed to increase patients’ skills and confidence in managing their own disease. Education should be part of CKD management program during outpatient clinic consultation as a continuous training process. Long-term follow-up of renal patient gives caregivers and patient a better understanding of the choice regarding the type of renal replacement therapy and VA option. Obviously, patient education does not mean simply handing over information. Appropriate materials and personalised education (e.g., adapted to age, educational level, cultural and language barriers), that consist both in providing written documents, pictures, movies, social media and discussions, but also in regular checking of patient understanding and knowledge. This regular interaction between patient and care giver is one of the most efficient components of the educational and training process.
\nWhen the creation of VA is planned or performed, the patient must be informed about and what to be expected after the surgery. Also, he must be asked to report immediately to the VA reference centre if side effects or important changes occur. Important and practical advices after VA surgery include for example: to keep the arm warm and dry; to monitor the surgical wound for changes; to elevate the arm slightly to prevent swelling; to use the other hand to feel VA thrill; to avoid sleeping on the fistula arm, wearing tight sleeve, carrying heavy weights, violent sports or activity that may cause a trauma to the AVF; to avoid blood pressure measurements, blood sampling and IV injections on the VA; to ask dialysis nurse to check AV patency if patient is already on dialysis via a CVC.
\nMaturation of AV access is an important period for long-term VA outcome corresponding to the non-use of the VA. This time may last 4–8 weeks dependent on the VA type, medical patient profile and vascular network characteristics. After wound healing, patient needs to start appropriate exercise program for enhancing flow in the VA arm (e.g., open and close hand, squeeze soft ball and touch fingertips with thumb) that will foster VA maturation. Long-term monitoring of VA is needed for dialysis patient. In the patient’s life, VA patency and local skin aspect should be checked at least daily. The easiest way is to put their hand or fingers on the fistula to feel a buzzing sensation (thrill) and to detect abnormal pain or temperature.
\nPatients with a dysfunctioning VA may require at some points imaging and/or interventional procedures. It is necessary to explain planned procedures or examinations to the patient. Patients should be informed about the contrast media use for the examination and be aware of allergy or other potential side effects. Expected results of investigation and potential required intervention should be carefully explained to the patient.
\nHygienic rules should be applied any time on the VA arm to prevent skin colonisation and migration of bacteria from the skin to the blood circulation system at the time of needling (e.g., AVF or AVG) or VA connection (e.g., CVC). General recommendations consist in washing access arm with water and soap every day, before and after each dialysis session, avoid coughing or sneezing on the VA, keep the haemostatic and adhesive dressing for up to 3–4 hours after VA disconnection. Teach patients of the importance of preserving VA from special risky practices (e.g., sauna and steam bath, swimming, extreme sport and gardening with gloves).
\nPain and discomfort caused by VA cannulation and needling are of major concern for dialysis patient. Pain assessment is a primary task and responsibility of nursing staff when caring dialysis patient [142]. Dialysis patients are exposed to pain with VA cannulation more than 300 times per year. Such repetitive exposure to pain and discomfort causes anxiety and depression, reduces quality of life, and interferes with daily life enjoyment.
\nPain is an unpleasant emotional and sensory experience due to an actual or potential tissue injury that is tremendously enhanced by anxiety. This is a quite stressful condition that can lead to severe and uncontrollable fear of needles known as “needle phobia” or “trypanophobia” leading eventually to “dialysis phobia.” In this sense, the pain control during VA cannulation by nursing staff should be considered as a top priority in dialysis units. Pain intensity during VA cannulation may benefit from regular monitoring relying either on subjective assessment (nurse feeling) or better and more objective assessment using visual analogue scale (VAS).
\nTo prevent fear of needles and pain caused by the VA cannulation, dialysis nursing team should be adequately trained in pain management. Effective pain control improves patient satisfaction with dialysis nursing care, helps patient to accept haemodialysis and enhances their quality of life. Effective and personalised plans are needed to manage VA needling pain in dialysis patients. There are different pharmacological and non-pharmacological pain management strategies for VA needling. General approaches include topical heat or cold therapy, rhythmic breathing, distraction, transcutaneous electrical nerve stimulation, aromatherapy, acupressure, massage, active listening and music therapy. Topical treatment approaches aiming to reduce pain via local anaesthesia that include Emla (cream or patch) and lidocaine (cream or intradermic injection) or local analgesia such as Arnica topical cream or diclofenac sodium topical gel are now more frequently proposed. Other approaches may be advised such as hypnosis or gas anaesthesia with inhalation of nitrous oxide depending on the psychological component and on the local setting.
\nVA cannulation method is still an “art” and procedure that reflects local unit practices and personal nursing skills [130]. Interestingly, despite the impact needling has on VA survival and patient outcome, there is no universal or standardised method proposed for proper cannulation [143].
\nThere are three cannulation methods used by nursing staff: rope-ladder, area cannulation and buttonhole [144]. The rope-ladder (site-rotation) method appears to be the most used worldwide being considered as the safest one. It consists of alternating puncture sites at a defined distance from the previous one along the VA vessel as an attempt to prevent aneurysm formation, stenosis and repeated trauma by multiple punctures. The area (one-site-itis) puncture is the insertion of the needles in the same general area of 2–3 cm, session after session [145]. This method exposes to weakness VA wall with progressive dilation leading to false aneurysm. The buttonhole (constant-site) method is less used in centre but seems of great interest for patient self-cannulating their own VA. It consists in creating a track by cannulating repeatedly the same spot and angle with sharp needle over 6–9 weeks. Once the track is formed, then a blunt needle can be used for subsequent cannulation. Buttonhole cannulation appears to be less painful and create less anxiety than rope-ladder but exposes to a more risk of infection. Nursing vascular access procedures are detailed in a separate document accessible and downloadable from the website:
Despite strong recommendations from best clinical practice guidelines, the use of tCVC is very common and tends to increase over time in almost all countries either in incident (10–80%) and prevalent (2–48%) dialysis patients [20]. Such trend most likely reflects change in medical profile of dialysis patients (e.g., advanced age, comorbidities, short life expectancy and repeated failures of VA creation), change in medical practices (e.g., easy access to CVC and shortage of motivated vascular surgeon) and poor or fragmented management of CKD patients (e.g., late referral). Interestingly, prevalence of tCVC in prevalent patients varies from 20 to 40% in Europe.
\nNurses play a crucial role in the management of all VAs. VA assessment, cannulation and care are mandatory skills for dialysis nurses: failure to correctly perform this operation may result in serious complications for the patients [145].
\nA highly-skilled dialysis nurse is required to ensure that each cannulation/connection procedure is carried out with minimal or no complications. At every dialysis session, and before each cannulation/connection, ensure that the patient’s VA is functional and has no problems in obtaining the optimal blood flow ensuring an adequate dialysis [43]. The competencies and responsibilities to achieve this are as follows:
The nurses should have competence in:
AVF/AVG and CVC assessment
AVF/AVG cannulation techniques and care
CVC connection and care
Management of complications
Patient education related to VA care
The nurses should have responsibility for:
Ensuring patient comfort and safety
Reporting and documenting all complications relating to VA
Liaising with the dialysis medical team to early identify and manage complications
Before starting the cannulation procedure for AVF/AVG or the connection of the CVC, the Registered Nurse (RN) must assure the preparation of the environment, material and patient following strictly the hygienic rules.
\nThe impact of health care-associated infections implies prolonged hospital stay, long-term disability, increased resistance of microorganisms to antimicrobials, massive additional financial burden, high costs for patients and their families and excess deaths [146]. In accordance with the WHO hand hygiene should routinely be performed.
\nPPE (hand and face protection, aprons and gowns) serves to protect HCW from hazards and preventable injuries in the workplace. Some PPE items, such as gloves and masks, protect HCWs and patients.
\nUniforms are not considered as PPE. Nonetheless they provide the HCW with professional attire that supports the HCW in carrying out her or his work in the dialysis unit, while at the same time preventing cross-contamination between the workplace and the home.
\nPrior to any HD treatment, assessment of patient’s general condition to identify potential problems that may arise during the treatment should be performed: temperature (as a routine, only for CVC), diet, loss of appetite, vomiting, diarrhoea and any other intercurrences between treatments like cramps, bleeding or some other signs or symptoms of complications.
\nThe nurse needs to weigh the patient and compare the value with the last post dialysis weight and to the prescribed dry weight. Blood pressure and pulse must be evaluated and all treatment parameters should be validated. When using a CVC, the catheter exit site must be examined thoroughly for the presence of any signs of infection. A physical assessment of the VA must be carried out before every treatment.
\nUsing the eyes, ears and fingertips, AVF/AVG are assessed for complications. Inspection (observe and look for):
Signs and symptoms of inflammation/infection: redness, drainage, abscess, warmth, oedema and rash over the fistula.
Infiltration/haematoma: needle infiltration of new AVF is a relatively frequent complication, and haematoma can develop easily in patients on chronic anticoagulation therapy.
Pseudo-aneurysms are frequently seen on the fistula arm: pseudo-aneurysms develop because of trauma from cannulating the same site or due to a significant proximal stenosis in the outflow tract.
Skin colour: changes in the skin colour could point to stenosis of infection, discoloured or cyanotic fingers could be an early sign of steal syndrome.
Palpation (touch and feel):
Thrill: normally a very prominent thrill is present at the anastomosis and the fistula is soft and easily compressible, the thrill diminishes evenly along access length.
Skin temperature: warmth could be a sign of infection; cold could be a sign of decreased blood supply (possible steal syndrome).
Auscultation (listen to the fistula):
Listen for bruit: listen to entire access every treatment and note changes in sound characteristics.
AVF/AVG physical examination is crucial to evaluate the proper function and to detect possible signs of complications. If any sign of complication is present, the VA should not be used and the patients should be evaluated by the nephrologist [43].
\nCVC, despite being considered the worst HD VA, is used in a considerable number of patients, up to 80%, either due to the need to start HD following emergency catheter placement or due to lack of native vessel to create an AVF or place an AVG. The goal of performing a HD treatment via a CVC should be the achievement of the best patient outcome as possible, while keeping all possible complications under control. For this purpose, it is fundamental that all team members are familiar with the principles of CVC care, which include assessment, usage, surveillance and maintenance.
\nThe exit site of the CVC must always be inspected at each HD treatment for any signs of irritation, infection or development of allergy to dress or disinfectant solution, including tenderness, skin peeling, rash, swelling, exudate and redness. European Renal Best Practice (ERBP) recommends to always ensure the area being cleansed around the exit site is slightly larger than the final dressing and include the section of the catheter that will be underneath the dressing [147].
\nThere is a wide variety of different types of products for dressing and securing CVCs, but the superiority of one over another has not yet been demonstrated. According to ERBP, for long-term catheters sterile gauze is preferable, for enabling maximal natural airing of the exit site.
\nBefore starting the HD treatment, the patency of the catheter should be evaluated. The locking solution use in the previous treatment should be removed by withdrawing 3–5 ml, locking solution mixed with blood. Using a 10 ml syringe filled with 0.9% NaCl, a small amount of blood should be aspirate into the syringe and observed for clots containment. If yes, flush should not be done. If unable to flush the physician should be alerted to assess and, if necessary, provide intervention.
\nBefore needle insertion in an AVF/AVG, proper needle-site preparation should be done to reduce infection rates. Site selection should be done prior to the final skin preparation.
\nThe most important procedure is the cannulation of an AVF/AVG, and over the course of a day, it is carried out on numerous occasions by the dialysis nurse. Choice of the correct cannulation site and technique are fundamental factors for an optimal dialysis session (more information at Section 6.1).
\nTape the needle in place on completion of insertion, secure it using a minimum of three strips of tape: one to fix the wings, a second on top of it to secure the needle and a third one to secure the needle tubing.
\nThe procedure of needle removal by the nurse is as important as the cannulation of the AVF. Needle withdrawal must be done carefully to prevent tearing of the vessel, to minimise access trauma and to achieve optimal HS. The needle should be removed using the same inclination as the insertion angle. Appropriate pressure should be applied after complete needle removal (thrill should be felt above and below the site of pressure). The pressure must be hold for 8–12 min without checking.
\nHS of the first cannulation must always be performed by skilled nursing staff, since the vessel wall is fragile and there is an increased risk of haematoma formation. Manual compression applied by the nurse, health care assistant, or patient is the standard of care following withdrawal of HD needles. For the patients who cannot or are unwilling to hold pressure for sufficient time for HS the use of a HS clamp or band is required.
\nOne of the most important responsibilities of the nurses is patient education. To achieve shared decision making, improve understanding and adherence, motivate, and encourage self-management, effective patient education is crucial [20] (more information at Section 5).
\nA good knowledge on VA management is necessary to enable the nurse to assess, plan, implement and evaluate the care given to patients before, during and after cannulation (AVF/AVG) or connection (CVC) and to deal with complications. The first use of a VA is an important opportunity for the expert nurse to demonstrate and transfer her/his knowledge and expertise to novice HD nurse. This will ensure the continuing education of healthcare staff engaged in patient care within the HD unit.
\nAs stated in the background section, VA is an essential component of a life-sustaining therapy in ESKD patients with a significant effect on both patient outcomes and associated costs [3, 8]. Therefore, taking a value-based approach and identifying opportunities for VA that would provide the right balance between optimal patient outcomes and total spending would be the ultimate goal [148].
\nThe clinical/medical evidence basis clearly shows from a value-based perspective that it is obvious that native arteriovenous fistula is still the best VA option providing the highest survival expectation and the lowest complication risk [149]. However, patient profiles have become more complex including an increase of co-morbidities that affect the success rates of AVF [150]. Therefore, several attempts have been made to substitute failing native AVF by new VA devices including vascular graft (synthetic and biomaterial), implantable devices (graft, venous catheter and port catheter) or hybrid system (graft port or venous port catheter) with limited success [151, 152].
\nWhat are the new VA perspectives to improve outcome and/or to expand VA possibilities in difficult cases. Several opportunities are currently under clinical investigation:
\nFirst, better management and use of existing VA from installation (VA network mapping) to maintenance permitted by use of non-invasive imaging (US-based) including monitoring technologies (online monitoring HD) [149, 153, 154] or connected technologies offering 24/7 continuous monitoring of VA patency [155]. The idea behind is to facilitate maturation of newly created AVF and/or to intervene earlier on failing VA to permit percutaneous interventional procedures for restoring patency [156].
\nSecond, make better use and improve outcome of tCVC or implanted venous access port devices by implementing strict rules of handling and generalisation of catheter locking solutions [157].
\nThird, assess clinical value of minimally invasive procedures such as percutaneous creation of VA [158, 159].
\nFourth, use medication either with systemic or local action to prevent thrombosis, to reduce neointimal proliferation leading to stenosis [160, 161, 162].
\nFifth, evaluate performance and outcome of bioengineered VA conduit based on vascular matrix formation and autologous cell seeding as part of regenerative medicine [19, 163].
\nNext to the medical future outlook, the economic perspective should also be considered, reviewing the bottom part of the value-based healthcare equation where value “is defined as the health outcomes achieved per dollar spent” [148]. Two systematic reviews (one focused on VA creation and the other on VA maintenance) identified a total of ~15 economic evaluations and/or cost and resource use analyses. As from a medical perspective, AVF is concluded to be the most cost-effective VA type for HD patients [164]. Nevertheless, the number of studies identified, and the level of evidence currently available shows a clear gap in knowledge to come to a solid conclusion from a health economic point of view. Especially, the total patient life cycle with regards to costs is not clearly mapped including the identification of: downstream costs, costs of adverse events, associated costs of patency rates and long-term consequences in effectiveness of the HD treatment.
\nFinally, there is one additional component that would need to be tackled which is the health system set up in general around transition management for CKD patients including VA placement and maintenance. According to Porter, healthcare needs to be structured based on meaningful outcomes to patients to maximise the value that is delivered in the end [165]. As part of this structure, episodic treatment should be transferred to bundling therapies under the responsibility of one provider [165]. Translating this to renal care would entail to include VA placement and management in the dialysis reimbursement bundle, which is already the case in, for example, USA, Portugal and Spain.
\nThe reason for this reorganisation is especially needed as currently approximately 32–73% of the CKD patient population experiences an unplanned start of dialysis [166, 167, 168, 169]. This unplanned start leads to the use of the least optimal VA type (CVC) rather than AVF as this requires a 6-month maturity phase. This suboptimal start is caused by a lack of screening and diagnosis of CKD patients in time, as these patients are first seen by a general practitioner (GP) rather than a nephrologist [170]. Hence, awareness/educational measures toward GPs could also be one of the future outlooks from a health policy perspective to improve VA practice and consequently the lifecycle of HD patients.
\nIn conclusion, the outlook for the future for VA practice is promising and has potential to improve significantly from multiple perspectives (medical, economic, health system, etc.). A collaboration and partnership between these disciplines would create an understanding and clear roadmap for next steps to put these into practice.
\nVA is an essential component of renal replacement therapy in ESKD patients. VA is currently referred to the life line of dialysis-dependent patient. Dialysis access relies on two main options: arteriovenous shunt (autologous AVF and AV graft); veno-venous access (tunnelled catheter and venous port device). AVFs are still the preferred VA option associated with best outcomes, higher performances and lower morbidity. Various innovative and quite interesting options, including minimally invasive percutaneous creation of AVFs and implantation of bioengineered vascular conduit deserve further clinical studies to enter in the VA armamentarium. VA performance is a key factor to drive success of extracorporeal renal replacement treatment. Furthermore, VA dysfunction and/or morbidity (stenosis, thrombosis and infection) are a source of frequent hospitalisation and corrective procedures. VA management in CKD patient is of tremendous importance in the overall quality care of dialysis patients. VA care and outcome are greatly improved in a large dialysis care provider network by means of a referent VAC and continuous quality improvement program [171].
\nWe thank Jörg Rammo for conceptualising, designing the project and providing editorial assistance on the manuscript, Iain Morris for carefully reviewing the manuscript. All authors participated in critically revising the manuscript for important intellectual content and approved the final manuscript to be published.
\nAll authors are employees of Fresenius Medical Care.
You have been successfully unsubscribed.
",metaTitle:"Unsubscribe Successful",metaDescription:"You have been successfully unsubscribed.",metaKeywords:null,canonicalURL:"/page/unsubscribe-successful",contentRaw:'[{"type":"htmlEditorComponent","content":""}]'},components:[{type:"htmlEditorComponent",content:""}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5774},{group:"region",caption:"Middle and South America",value:2,count:5239},{group:"region",caption:"Africa",value:3,count:1721},{group:"region",caption:"Asia",value:4,count:10411},{group:"region",caption:"Australia and Oceania",value:5,count:897},{group:"region",caption:"Europe",value:6,count:15810}],offset:12,limit:12,total:118377},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{},books:[{type:"book",id:"8969",title:"Deserts and Desertification",subtitle:null,isOpenForSubmission:!0,hash:"4df95c7f295de7f6003e635d9a309fe9",slug:null,bookSignature:"Dr. Yajuan Zhu, Dr. Qinghong Luo and Dr. Yuguo Liu",coverURL:"https://cdn.intechopen.com/books/images_new/8969.jpg",editedByType:null,editors:[{id:"180427",title:"Dr.",name:"Yajuan",surname:"Zhu",slug:"yajuan-zhu",fullName:"Yajuan Zhu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8977",title:"Protein Kinase - New Opportunities, Challenges and Future Perspectives",subtitle:null,isOpenForSubmission:!0,hash:"6d200cc031706a565b554fdb1c478901",slug:null,bookSignature:"Dr. Rajesh Kumar Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8977.jpg",editedByType:null,editors:[{id:"329385",title:"Dr.",name:"Rajesh",surname:"Singh",slug:"rajesh-singh",fullName:"Rajesh Singh"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9659",title:"Fibroblasts - Advances in Cancer, Autoimmunity and Inflammation",subtitle:null,isOpenForSubmission:!0,hash:"926fa6446f6befbd363fc74971a56de2",slug:null,bookSignature:"Ph.D. Mojca Frank Bertoncelj and Ms. Katja Lakota",coverURL:"https://cdn.intechopen.com/books/images_new/9659.jpg",editedByType:null,editors:[{id:"328755",title:"Ph.D.",name:"Mojca",surname:"Frank Bertoncelj",slug:"mojca-frank-bertoncelj",fullName:"Mojca Frank Bertoncelj"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9662",title:"Vegetation Index and Dynamics",subtitle:null,isOpenForSubmission:!0,hash:"0abf2a59ee63fc1ba4fb64d77c9b1be7",slug:null,bookSignature:"Dr. Eusebio Cano Carmona, Dr. Ricardo Quinto Canas, Dr. Ana Cano Ortiz and Dr. Carmelo Maria Musarella",coverURL:"https://cdn.intechopen.com/books/images_new/9662.jpg",editedByType:null,editors:[{id:"87846",title:"Dr.",name:"Eusebio",surname:"Cano Carmona",slug:"eusebio-cano-carmona",fullName:"Eusebio Cano Carmona"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9667",title:"Neuroimmunology",subtitle:null,isOpenForSubmission:!0,hash:"9cf0e8203ce088c0b84add014fd8d382",slug:null,bookSignature:"Prof. Robert Weissert",coverURL:"https://cdn.intechopen.com/books/images_new/9667.jpg",editedByType:null,editors:[{id:"79343",title:"Prof.",name:"Robert",surname:"Weissert",slug:"robert-weissert",fullName:"Robert Weissert"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9816",title:"Idiopathic Pulmonary Fibrosis",subtitle:null,isOpenForSubmission:!0,hash:"365bb9762ba33db2d07e677690af1772",slug:null,bookSignature:"Dr. Salim Surani and Dr. Venkat Rajasurya",coverURL:"https://cdn.intechopen.com/books/images_new/9816.jpg",editedByType:null,editors:[{id:"15654",title:"Dr.",name:"Salim",surname:"Surani",slug:"salim-surani",fullName:"Salim Surani"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10218",title:"Flagellar Motility in Cells",subtitle:null,isOpenForSubmission:!0,hash:"5fcc15570365a82d9f2c4816f4e0ee2e",slug:null,bookSignature:"Prof. Yusuf Bozkurt",coverURL:"https://cdn.intechopen.com/books/images_new/10218.jpg",editedByType:null,editors:[{id:"90846",title:"Prof.",name:"Yusuf",surname:"Bozkurt",slug:"yusuf-bozkurt",fullName:"Yusuf Bozkurt"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10231",title:"Proton Therapy",subtitle:null,isOpenForSubmission:!0,hash:"f4a9009287953c8d1d89f0fa9b7597b0",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10231.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10343",title:"Ocular Hypertension",subtitle:null,isOpenForSubmission:!0,hash:"0ff71cc7e0d9f394f41162c0c825588a",slug:null,bookSignature:"Prof. Michele Lanza",coverURL:"https://cdn.intechopen.com/books/images_new/10343.jpg",editedByType:null,editors:[{id:"240088",title:"Prof.",name:"Michele",surname:"Lanza",slug:"michele-lanza",fullName:"Michele Lanza"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10370",title:"Advances in Fundamental and Applied Research on Spatial Audio",subtitle:null,isOpenForSubmission:!0,hash:"f16232a481c08a05cc191ac64cf2c69e",slug:null,bookSignature:"Dr. Brian FG Katz and Dr. Piotr Majdak",coverURL:"https://cdn.intechopen.com/books/images_new/10370.jpg",editedByType:null,editors:[{id:"278731",title:"Dr.",name:"Brian FG",surname:"Katz",slug:"brian-fg-katz",fullName:"Brian FG Katz"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10504",title:"Crystallization",subtitle:null,isOpenForSubmission:!0,hash:"3478d05926950f475f4ad2825d340963",slug:null,bookSignature:"Dr. Youssef Ben Smida and Dr. Riadh Marzouki",coverURL:"https://cdn.intechopen.com/books/images_new/10504.jpg",editedByType:null,editors:[{id:"311698",title:"Dr.",name:"Youssef",surname:"Ben Smida",slug:"youssef-ben-smida",fullName:"Youssef Ben Smida"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:18},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:5},{group:"topic",caption:"Business, Management and Economics",value:7,count:2},{group:"topic",caption:"Chemistry",value:8,count:8},{group:"topic",caption:"Computer and Information Science",value:9,count:6},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:7},{group:"topic",caption:"Engineering",value:11,count:20},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:4},{group:"topic",caption:"Materials Science",value:14,count:5},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:25},{group:"topic",caption:"Neuroscience",value:18,count:2},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:3},{group:"topic",caption:"Physics",value:20,count:3},{group:"topic",caption:"Psychology",value:21,count:4},{group:"topic",caption:"Robotics",value:22,count:1},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:1}],offset:12,limit:12,total:202},popularBooks:{featuredBooks:[{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5249},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editedByType:"Edited by",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editedByType:"Edited by",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editedByType:"Edited by",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editedByType:"Edited by",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9669",title:"Recent Advances in Rice Research",subtitle:null,isOpenForSubmission:!1,hash:"12b06cc73e89af1e104399321cc16a75",slug:"recent-advances-in-rice-research",bookSignature:"Mahmood-ur- Rahman Ansari",coverURL:"https://cdn.intechopen.com/books/images_new/9669.jpg",editedByType:"Edited by",editors:[{id:"185476",title:"Dr.",name:"Mahmood-Ur-",middleName:null,surname:"Rahman Ansari",slug:"mahmood-ur-rahman-ansari",fullName:"Mahmood-Ur- Rahman Ansari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editedByType:"Edited by",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editedByType:"Edited by",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editedByType:"Edited by",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9313",title:"Clay Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6fa7e70396ff10620e032bb6cfa6fb72",slug:"clay-science-and-technology",bookSignature:"Gustavo Morari Do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/9313.jpg",editedByType:"Edited by",editors:[{id:"7153",title:"Prof.",name:"Gustavo",middleName:null,surname:"Morari Do Nascimento",slug:"gustavo-morari-do-nascimento",fullName:"Gustavo Morari Do Nascimento"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",isOpenForSubmission:!1,hash:"c2c8773e586f62155ab8221ebb72a849",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",editedByType:"Edited by",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"3",title:"Health Sciences",slug:"health-sciences",parent:null,numberOfBooks:1619,numberOfAuthorsAndEditors:41913,numberOfWosCitations:24429,numberOfCrossrefCitations:12914,numberOfDimensionsCitations:32771,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"health-sciences",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editedByType:"Edited by",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editedByType:"Edited by",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9406",title:"Clinical Implementation of Bone Regeneration and Maintenance",subtitle:null,isOpenForSubmission:!1,hash:"875a140c01518fa7a9bceebd688b0147",slug:"clinical-implementation-of-bone-regeneration-and-maintenance",bookSignature:"Mike Barbeck, Nahum Rosenberg, Patrick Rider, Željka Perić Kačarević and Ole Jung",coverURL:"https://cdn.intechopen.com/books/images_new/9406.jpg",editedByType:"Edited by",editors:[{id:"204918",title:"Dr.",name:"Mike",middleName:null,surname:"Barbeck",slug:"mike-barbeck",fullName:"Mike Barbeck"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9122",title:"Cosmetic Surgery",subtitle:null,isOpenForSubmission:!1,hash:"207026ca4a4125e17038e770d00ee152",slug:"cosmetic-surgery",bookSignature:"Yueh-Bih Tang",coverURL:"https://cdn.intechopen.com/books/images_new/9122.jpg",editedByType:"Edited by",editors:[{id:"202122",title:"Prof.",name:"Yueh-Bih",middleName:null,surname:"Tang",slug:"yueh-bih-tang",fullName:"Yueh-Bih Tang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9134",title:"Recent Advances in Digital System Diagnosis and Management of Healthcare",subtitle:null,isOpenForSubmission:!1,hash:"ff00a5718f23cb880b7337b1c36b5434",slug:"recent-advances-in-digital-system-diagnosis-and-management-of-healthcare",bookSignature:"Kamran Sartipi and Thierry Edoh",coverURL:"https://cdn.intechopen.com/books/images_new/9134.jpg",editedByType:"Edited by",editors:[{id:"29601",title:"Dr.",name:"Kamran",middleName:null,surname:"Sartipi",slug:"kamran-sartipi",fullName:"Kamran Sartipi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editedByType:"Edited by",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9569",title:"Methods in Molecular Medicine",subtitle:null,isOpenForSubmission:!1,hash:"691d3f3c4ac25a8093414e9b270d2843",slug:"methods-in-molecular-medicine",bookSignature:"Yusuf Tutar",coverURL:"https://cdn.intechopen.com/books/images_new/9569.jpg",editedByType:"Edited by",editors:[{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9157",title:"Neurodegenerative Diseases",subtitle:"Molecular Mechanisms and Current Therapeutic Approaches",isOpenForSubmission:!1,hash:"bc8be577966ef88735677d7e1e92ed28",slug:"neurodegenerative-diseases-molecular-mechanisms-and-current-therapeutic-approaches",bookSignature:"Nagehan Ersoy Tunalı",coverURL:"https://cdn.intechopen.com/books/images_new/9157.jpg",editedByType:"Edited by",editors:[{id:"82778",title:"Ph.D.",name:"Nagehan",middleName:null,surname:"Ersoy Tunalı",slug:"nagehan-ersoy-tunali",fullName:"Nagehan Ersoy Tunalı"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9839",title:"Outdoor Recreation",subtitle:"Physiological and Psychological Effects on Health",isOpenForSubmission:!1,hash:"5f5a0d64267e32567daffa5b0c6a6972",slug:"outdoor-recreation-physiological-and-psychological-effects-on-health",bookSignature:"Hilde G. Nielsen",coverURL:"https://cdn.intechopen.com/books/images_new/9839.jpg",editedByType:"Edited by",editors:[{id:"158692",title:"Ph.D.",name:"Hilde G.",middleName:null,surname:"Nielsen",slug:"hilde-g.-nielsen",fullName:"Hilde G. Nielsen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,isOpenForSubmission:!1,hash:"13aaddf5fdbbc78387e77a7da2388bf6",slug:"animal-reproduction-in-veterinary-medicine",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",editedByType:"Edited by",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editedByType:"Edited by",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editedByType:"Edited by",editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1619,mostCitedChapters:[{id:"19013",doi:"10.5772/21983",title:"Cell Responses to Surface and Architecture of Tissue Engineering Scaffolds",slug:"cell-responses-to-surface-and-architecture-of-tissue-engineering-scaffolds",totalDownloads:9697,totalCrossrefCites:109,totalDimensionsCites:230,book:{slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",title:"Regenerative Medicine and Tissue Engineering",fullTitle:"Regenerative Medicine and Tissue Engineering - Cells and Biomaterials"},signatures:"Hsin-I Chang and Yiwei Wang",authors:[{id:"45747",title:"Dr.",name:"Hsin-I",middleName:null,surname:"Chang",slug:"hsin-i-chang",fullName:"Hsin-I Chang"},{id:"53659",title:"Ms.",name:"Yiwei",middleName:null,surname:"Wang",slug:"yiwei-wang",fullName:"Yiwei Wang"}]},{id:"46479",doi:"10.5772/57353",title:"Floating Drug Delivery Systems for Eradication of Helicobacter pylori in Treatment of Peptic Ulcer Disease",slug:"floating-drug-delivery-systems-for-eradication-of-helicobacter-pylori-in-treatment-of-peptic-ulcer-d",totalDownloads:1995,totalCrossrefCites:79,totalDimensionsCites:180,book:{slug:"trends-in-helicobacter-pylori-infection",title:"Trends in Helicobacter pylori Infection",fullTitle:"Trends in Helicobacter pylori Infection"},signatures:"Yousef Javadzadeh and Sanaz Hamedeyazdan",authors:[{id:"94276",title:"Prof.",name:"Yousef",middleName:null,surname:"Javadzadeh",slug:"yousef-javadzadeh",fullName:"Yousef Javadzadeh"},{id:"98229",title:"Dr.",name:"Sanaz",middleName:null,surname:"Hamedeyazdan",slug:"sanaz-hamedeyazdan",fullName:"Sanaz Hamedeyazdan"}]},{id:"25512",doi:"10.5772/30872",title:"Epidemiology of Psychological Distress",slug:"epidemiology-of-psychological-distress",totalDownloads:8066,totalCrossrefCites:57,totalDimensionsCites:145,book:{slug:"mental-illnesses-understanding-prediction-and-control",title:"Mental Illnesses",fullTitle:"Mental Illnesses - Understanding, Prediction and Control"},signatures:"Aline Drapeau, Alain Marchand and Dominic Beaulieu-Prévost",authors:[{id:"84582",title:"Dr.",name:"Aline",middleName:null,surname:"Drapeau",slug:"aline-drapeau",fullName:"Aline Drapeau"},{id:"84605",title:"Dr.",name:"Alain",middleName:null,surname:"Marchand",slug:"alain-marchand",fullName:"Alain Marchand"},{id:"84606",title:"Dr.",name:"Dominic",middleName:null,surname:"Beaulieu-Prévost",slug:"dominic-beaulieu-prevost",fullName:"Dominic Beaulieu-Prévost"}]}],mostDownloadedChaptersLast30Days:[{id:"43758",title:"Anxiety Disorders in Pregnancy and the Postpartum Period",slug:"anxiety-disorders-in-pregnancy-and-the-postpartum-period",totalDownloads:39763,totalCrossrefCites:11,totalDimensionsCites:20,book:{slug:"new-insights-into-anxiety-disorders",title:"New Insights into Anxiety Disorders",fullTitle:"New Insights into Anxiety Disorders"},signatures:"Roberta Anniverno, Alessandra Bramante, Claudio Mencacci and Federico Durbano",authors:[{id:"157077",title:"Dr.",name:"Federico",middleName:null,surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano"},{id:"166382",title:"Dr.",name:"Roberta",middleName:null,surname:"Anniverno",slug:"roberta-anniverno",fullName:"Roberta Anniverno"}]},{id:"70711",title:"Fetal Growth Restriction",slug:"fetal-growth-restriction",totalDownloads:1706,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"growth-disorders-and-acromegaly",title:"Growth Disorders and Acromegaly",fullTitle:"Growth Disorders and Acromegaly"},signatures:"Edurne Mazarico Gallego, Ariadna Torrecillas Pujol, Alex Joan Cahuana Bartra and Maria Dolores Gómez Roig",authors:[{id:"202446",title:"Ph.D.",name:"Maria Dolores",middleName:null,surname:"Gómez Roig",slug:"maria-dolores-gomez-roig",fullName:"Maria Dolores Gómez Roig"},{id:"311835",title:"Dr.",name:"Edurne",middleName:null,surname:"Mazarico",slug:"edurne-mazarico",fullName:"Edurne Mazarico"}]},{id:"70405",title:"Hemostasis in Cardiac Surgery: How We Do it with Limited Resources",slug:"hemostasis-in-cardiac-surgery-how-we-do-it-with-limited-resources",totalDownloads:2694,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:null,title:"Contemporary Applications of Biologic Hemostatic Agents across Surgical Specialties - Volume 1",fullTitle:"Contemporary Applications of Biologic Hemostatic Agents across Surgical Specialties - Volume 1"},signatures:"Fevzi Sarper Türker",authors:null},{id:"64851",title:"Herbal Medicines in African Traditional Medicine",slug:"herbal-medicines-in-african-traditional-medicine",totalDownloads:9954,totalCrossrefCites:10,totalDimensionsCites:17,book:{slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Ezekwesili-Ofili Josephine Ozioma and Okaka Antoinette Nwamaka\nChinwe",authors:[{id:"191264",title:"Prof.",name:"Josephine",middleName:"Ozioma",surname:"Ezekwesili-Ofili",slug:"josephine-ezekwesili-ofili",fullName:"Josephine Ezekwesili-Ofili"},{id:"211585",title:"Prof.",name:"Antoinette",middleName:null,surname:"Okaka",slug:"antoinette-okaka",fullName:"Antoinette Okaka"}]},{id:"59779",title:"Effective Communication in Nursing",slug:"effective-communication-in-nursing",totalDownloads:6504,totalCrossrefCites:2,totalDimensionsCites:4,book:{slug:"nursing",title:"Nursing",fullTitle:"Nursing"},signatures:"Maureen Nokuthula Sibiya",authors:[{id:"73330",title:"Dr.",name:"Nokuthula",middleName:null,surname:"Sibiya",slug:"nokuthula-sibiya",fullName:"Nokuthula Sibiya"}]},{id:"64762",title:"Mechanism and Health Effects of Heavy Metal Toxicity in Humans",slug:"mechanism-and-health-effects-of-heavy-metal-toxicity-in-humans",totalDownloads:6302,totalCrossrefCites:32,totalDimensionsCites:64,book:{slug:"poisoning-in-the-modern-world-new-tricks-for-an-old-dog-",title:"Poisoning in the Modern World",fullTitle:"Poisoning in the Modern World - New Tricks for an Old Dog?"},signatures:"Godwill Azeh Engwa, Paschaline Udoka Ferdinand, Friday Nweke Nwalo and Marian N. Unachukwu",authors:[{id:"241837",title:"Mr.",name:"Godwill Azeh",middleName:null,surname:"Engwa",slug:"godwill-azeh-engwa",fullName:"Godwill Azeh Engwa"},{id:"274194",title:"BSc.",name:"Paschaline Ferdinand",middleName:null,surname:"Okeke",slug:"paschaline-ferdinand-okeke",fullName:"Paschaline Ferdinand Okeke"},{id:"286975",title:"Dr.",name:"Friday",middleName:null,surname:"Nweke Nwalo",slug:"friday-nweke-nwalo",fullName:"Friday Nweke Nwalo"},{id:"286976",title:"Dr.",name:"Marian",middleName:null,surname:"Unachukwu",slug:"marian-unachukwu",fullName:"Marian Unachukwu"}]},{id:"64858",title:"The Neurobiology of Anorexia Nervosa",slug:"the-neurobiology-of-anorexia-nervosa",totalDownloads:892,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"anorexia-and-bulimia-nervosa",title:"Anorexia and Bulimia Nervosa",fullTitle:"Anorexia and Bulimia Nervosa"},signatures:"Ashley Higgins",authors:null},{id:"57717",title:"In Vitro Cytotoxicity and Cell Viability Assays: Principles, Advantages, and Disadvantages",slug:"in-vitro-cytotoxicity-and-cell-viability-assays-principles-advantages-and-disadvantages",totalDownloads:12581,totalCrossrefCites:32,totalDimensionsCites:63,book:{slug:"genotoxicity-a-predictable-risk-to-our-actual-world",title:"Genotoxicity",fullTitle:"Genotoxicity - A Predictable Risk to Our Actual World"},signatures:"Özlem Sultan Aslantürk",authors:[{id:"211212",title:"Dr.",name:"Özlem Sultan",middleName:null,surname:"Aslantürk",slug:"ozlem-sultan-aslanturk",fullName:"Özlem Sultan Aslantürk"}]},{id:"63771",title:"The Role of Catheter Reshaping at the Angiographic Success",slug:"the-role-of-catheter-reshaping-at-the-angiographic-success",totalDownloads:536,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"angiography",title:"Angiography",fullTitle:"Angiography"},signatures:"Yakup Balaban",authors:[{id:"252647",title:"Associate Prof.",name:"Yakup",middleName:null,surname:"Balaban",slug:"yakup-balaban",fullName:"Yakup Balaban"}]},{id:"61866",title:"Plants Secondary Metabolites: The Key Drivers of the Pharmacological Actions of Medicinal Plants",slug:"plants-secondary-metabolites-the-key-drivers-of-the-pharmacological-actions-of-medicinal-plants",totalDownloads:5564,totalCrossrefCites:13,totalDimensionsCites:32,book:{slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Rehab A. Hussein and Amira A. El-Anssary",authors:[{id:"212117",title:"Dr.",name:"Rehab",middleName:null,surname:"Hussein",slug:"rehab-hussein",fullName:"Rehab Hussein"},{id:"221140",title:"Dr.",name:"Amira",middleName:null,surname:"El-Anssary",slug:"amira-el-anssary",fullName:"Amira El-Anssary"}]}],onlineFirstChaptersFilter:{topicSlug:"health-sciences",limit:3,offset:0},onlineFirstChaptersCollection:[{id:"75579",title:"Thoracic Organ Procurement during Multi-Organ Retrieval",slug:"thoracic-organ-procurement-during-multi-organ-retrieval",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.95793",book:{title:"Organ Donation and Transplantation"},signatures:"Suresh Keshavamurthy, Vipin Dulam, Eros Leotta, Mohammed A. Kashem and Yoshiya Toyoda"},{id:"75361",title:"Management of Patients with Refractory Coeliac Disease",slug:"management-of-patients-with-refractory-coeliac-disease",totalDownloads:4,totalDimensionsCites:0,doi:"10.5772/intechopen.96231",book:{title:"Celiac Disease"},signatures:"Paul J. Ciclitira and Alastair Forbes"},{id:"75570",title:"Chronic Obstructive Pulmonary Disease Related to Wood and Other Biomass Smoke: A Different Phenotype or Specific Diseases?",slug:"chronic-obstructive-pulmonary-disease-related-to-wood-and-other-biomass-smoke-a-different-phenotype-",totalDownloads:7,totalDimensionsCites:0,doi:"10.5772/intechopen.96485",book:{title:"Chronic Obstructive Pulmonary Disease - A Current Conspectus"},signatures:"Carlos A. Torres-Duque, Felipe Severiche-Bueno and Mauricio González-García"}],onlineFirstChaptersTotal:662},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/159402/david-eaton",hash:"",query:{},params:{id:"159402",slug:"david-eaton"},fullPath:"/profiles/159402/david-eaton",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()