IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
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IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
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Designed to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
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After a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
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Our innovative Book Series format brings you:
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Topic Focused Publications - Each topic showcases high impact subject areas
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Renowned Editorial Expertise - Series Editors, Topic Editors, and a team of international Board Members that permanently support each Book Series
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Fast Publishing - quick turnaround which is unique for book publishing
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The benefit of ISSN and ISBN for increased citation and indexing possibilities
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IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\n
IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
We invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
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Note: Edited in October 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"8852",leadTitle:null,fullTitle:"Chemistry and Applications of Benzimidazole and its Derivatives",title:"Chemistry and Applications of Benzimidazole and its Derivatives",subtitle:null,reviewType:"peer-reviewed",abstract:"Finding new strategies for synthesizing benzimidazole derivatives and functionalizing the benzimidazole core has proved to be important due to the compound's various applications in medicine, chemistry, and other areas. The multitude of benzimidazole derivatives marketed as drugs has led to intensive research in the field for the discovery of new biologically active structures. The general applications of benzimidazole derivatives in materials chemistry, electronics, technology, dyes, pigments, and agriculture open up new research horizons. This book guides the rational design of benzimidazole derivatives synthesis with certain applications. Chapters cover such topics as therapeutic use of benzimidazole in conditions like diabetes, viruses, and parasitic diseases; X-ray crystal structure of selected benzimidazole derivatives; benzimidazole compounds for cancer therapy; and others.",isbn:"978-1-78984-553-2",printIsbn:"978-1-78984-552-5",pdfIsbn:"978-1-83962-241-0",doi:"10.5772/intechopen.81426",price:119,priceEur:129,priceUsd:155,slug:"chemistry-and-applications-of-benzimidazole-and-its-derivatives",numberOfPages:228,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"e95984a2b87df5a7ca051cb3345d5e7a",bookSignature:"Maria Marinescu",publishedDate:"October 2nd 2019",coverURL:"https://cdn.intechopen.com/books/images_new/8852.jpg",numberOfDownloads:12022,numberOfWosCitations:23,numberOfCrossrefCitations:16,numberOfCrossrefCitationsByBook:6,numberOfDimensionsCitations:31,numberOfDimensionsCitationsByBook:9,hasAltmetrics:1,numberOfTotalCitations:70,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 30th 2018",dateEndSecondStepPublish:"December 12th 2018",dateEndThirdStepPublish:"February 10th 2019",dateEndFourthStepPublish:"May 1st 2019",dateEndFifthStepPublish:"June 30th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"250975",title:"Ph.D.",name:"Maria",middleName:null,surname:"Marinescu",slug:"maria-marinescu",fullName:"Maria Marinescu",profilePictureURL:"https://mts.intechopen.com/storage/users/250975/images/system/250975.jpg",biography:"Maria Marinescu received her PhD in 2010 from the University of Bucharest, under the supervision of Prof. Mihaela Hillebrand, studying the chemistry and the electronic structure of the 1,2,3,4,5,6,7,8-octahydroacridine compounds, as a key structures for the new biomolecules and hydrogen-bonding receptors. Dr Maria Marinescu is currently an Assistant Professor at the University of Bucharest, Department of Organic Chemistry, Biochemistry and Catalysis and her current research interests are in organic synthesis of various heterocycles with applications in medicinal and materials chemistry, DFT studies in organic molecules related with their biological properties and applications of organic materials in art and archaeology.",institutionString:"University of Bucharest",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Bucharest",institutionURL:null,country:{name:"Romania"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"384",title:"Chemical Biology",slug:"chemical-biology"}],chapters:[{id:"67827",title:"Introductory Chapter: Short Insight in Synthesis and Applications of Benzimidazole and Its Derivatives",doi:"10.5772/intechopen.87174",slug:"introductory-chapter-short-insight-in-synthesis-and-applications-of-benzimidazole-and-its-derivative",totalDownloads:1010,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:null,signatures:"Maria Marinescu",downloadPdfUrl:"/chapter/pdf-download/67827",previewPdfUrl:"/chapter/pdf-preview/67827",authors:[{id:"250975",title:"Ph.D.",name:"Maria",surname:"Marinescu",slug:"maria-marinescu",fullName:"Maria Marinescu"}],corrections:null},{id:"67843",title:"Catalytic Intermolecular Functionalization of Benzimidazoles",doi:"10.5772/intechopen.87068",slug:"catalytic-intermolecular-functionalization-of-benzimidazoles",totalDownloads:949,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"This chapter describes contemporary strategies for selective catalytic intermolecular functionalization of the benzimidazole scaffold. Functionalization at nitrogen and position C-2 is well developed employing copper, palladium, rhodium, nickel, and cobalt catalysis. Direct CH activation is the predominant approach to C-2 functionalization. Nickel-based catalysts can activate C—O bonds in conjunction with C—H activation at benzimidazole which grants access to a very broad range of phenols and enols as convenient functionalization precursors in this chemistry. The remaining carbon positions of benzimidazoles are typically functionalized via a sequential halogenation/coupling strategy to ensure selectivity. A key success factor in enabling these chemistries has been the fine-tuning of catalyst-ligand combinations.",signatures:"Jørn H. Hansen and Richard Fjellaksel",downloadPdfUrl:"/chapter/pdf-download/67843",previewPdfUrl:"/chapter/pdf-preview/67843",authors:[{id:"286179",title:"Associate Prof.",name:"Jørn H.",surname:"Hansen",slug:"jorn-h.-hansen",fullName:"Jørn H. Hansen"},{id:"305734",title:"Dr.",name:"Richard",surname:"Fjellaksel",slug:"richard-fjellaksel",fullName:"Richard Fjellaksel"}],corrections:null},{id:"66327",title:"X-Ray Crystal Structure Analysis of Selected Benzimidazole Derivatives",doi:"10.5772/intechopen.85291",slug:"x-ray-crystal-structure-analysis-of-selected-benzimidazole-derivatives",totalDownloads:915,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"This chapter describes the X-ray crystal structure analysis of selected benzimidazole derivatives, viz. BIP: 2-(1H-benzimidazol-2-yl)phenol, MBMPBI: 1-(4-methylbenzyl)-2-(4-methylphenyl)-1H-benzimidazole, DPBI: 1,2-diphenyl-1H-benzimidazole, PBIP: 2-(1-phenyl-1H-benzimidazol-2-yl)phenol, FPPBI: 2-(4-fluorophenyl)-1-phenyl-1H-benzimidazole and NPBIBHS: 2-(naphthalen-1-yl)-1-phenyl-1H-benzimidazole benzene hemisolvate. The BIP molecule is planar, and in the crystal, it is arranged in parallel planes, stabilised by π-π interactions and the hydrogen bonds. In MBMPBI, benzimidazole cores of the two independent (A and B) molecules are planar. Two C▬H…N hydrogen bonds link B molecules only, forming centrosymmetric dimers with R22(8) ring motifs. In the DPBI molecule, the benzimidazole core is planar: one hydrogen-bond interaction (C▬H…N) and C▬H…π (three) interaction leading to the three-dimensional arrangement. In the PBIP molecule, the benzimidazole is nearly planar. The hydrogen bonds and a π-π stacking interaction are present in the crystal. In the FPPBI molecule, the benzimidazole unit is almost planar. The C▬H…F hydrogen bonds and weak C▬H…π interactions lead to a three-dimensional architecture in the crystal. In NPBIBHS, the naphthalene fragment lies out of the plane about the benzimidazole core unit. The C▬H…N hydrogen bonds and C▬H…π interactions lead to a three-dimensional architecture in the crystal.",signatures:"Aravazhi Amalan Thiruvalluvar, Gopalsamy Vasuki, Jayaraman Jayabharathi and Sivaraman Rosepriya",downloadPdfUrl:"/chapter/pdf-download/66327",previewPdfUrl:"/chapter/pdf-preview/66327",authors:[{id:"222223",title:"Prof.",name:"Jayabharathi",surname:"Jayaraman",slug:"jayabharathi-jayaraman",fullName:"Jayabharathi Jayaraman"},{id:"284920",title:"Dr.",name:"Aravazhi Amalan",surname:"Thiruvalluvar",slug:"aravazhi-amalan-thiruvalluvar",fullName:"Aravazhi Amalan Thiruvalluvar"},{id:"296645",title:"Dr.",name:"Sivaraman",surname:"Rosepriya",slug:"sivaraman-rosepriya",fullName:"Sivaraman Rosepriya"},{id:"297400",title:"Dr.",name:"Gopalsamy",surname:"Vasuki",slug:"gopalsamy-vasuki",fullName:"Gopalsamy Vasuki"}],corrections:null},{id:"66798",title:"Synthesis and Pharmacological Profile of Benzimidazoles",doi:"10.5772/intechopen.85229",slug:"synthesis-and-pharmacological-profile-of-benzimidazoles",totalDownloads:1729,totalCrossrefCites:6,totalDimensionsCites:7,hasAltmetrics:0,abstract:"Benzimidazoles are a class of heterocyclic, aromatic compounds which share a fundamental structural characteristic of six-membered benzene fused to five-membered imidazole moiety. Molecules having benzimidazole motifs showed promising application in biological and clinical studies. Nowadays it is a moiety of choice which possesses many pharmacological properties extensively explored with a potent inhibitor of various enzymes involved in a wide range of therapeutic uses which are antidiabetic, anticancer, antimicrobial, antiparasitic, analgesics, antiviral, and antihistamine, as well as used in cardiovascular disease, neurology, endocrinology, ophthalmology, and more. The increased interest for benzimidazole compounds has been due to their excellent properties, like increased stability, bioavailability, and significant biological activity. This book chapter mainly discussed recent synthetic methods developed for the benzimidazole derivatives and their pharmacological properties exemplified on several derivatives.",signatures:"Kantharaju Kamanna",downloadPdfUrl:"/chapter/pdf-download/66798",previewPdfUrl:"/chapter/pdf-preview/66798",authors:[{id:"284317",title:"Prof.",name:"Kantharaju",surname:"Kamanna",slug:"kantharaju-kamanna",fullName:"Kantharaju Kamanna"}],corrections:null},{id:"65847",title:"Antidiabetogenic Features of Benzimidazoles",doi:"10.5772/intechopen.84802",slug:"antidiabetogenic-features-of-benzimidazoles",totalDownloads:1064,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Literature data on the insulinogenic effect of 2-aminobenzimidazole prompted us to investigate its novel derivatives, particularly those containing an additional fused cycle in C1,2-α position, including imidazole, dihydroimidazole, or tetrahydropyrimidine ring. Consensus analysis of the hypoglycemic effect of these compounds performed with IT Microcosm and PASS system revealed that activity is mostly characteristic for N9-2,3-dihydroimidazo[1,2-a]benzimidazole derivatives. Substructural analysis of hypoglycemic activity identified substituents that determine the greatest pharmacological effect. According to the in silico assessment of the ADME properties, RU-254 was nominated as a lead compound due to the most optimal calculated and experimental activity and pharmacokinetic parameters. Preclinical studies have shown that identified compound has a pronounced insulinogenic effect and hypoglycemic effect, both in intact animals and in animals with experimental diabetes mellitus. RU-254 also reduces the level of glycated hemoglobin upon chronic administration, slightly decreases the activity of DPP-4, and increases the average number of Langerhans islets in the pancreas. Pharmaceutical drug formulation of RU-254 was developed and investigated for pharmacokinetic, pharmacodynamic, and toxicological properties. The dosage form of the drug under the name limiglidol (compound RU-254, diabenol) was evaluated in the full cycle of clinical studies that confirmed the safety, tolerability, and prominent antidiabetic properties of the drug.",signatures:"Alexander A. Spasov, Pavel M. Vassiliev, Vera A. Anisimova and Olga N. Zhukovskaya",downloadPdfUrl:"/chapter/pdf-download/65847",previewPdfUrl:"/chapter/pdf-preview/65847",authors:[{id:"286012",title:"Prof.",name:"Pavel",surname:"Vassiliev",slug:"pavel-vassiliev",fullName:"Pavel Vassiliev"},{id:"286027",title:"Prof.",name:"Alexander",surname:"Spasov",slug:"alexander-spasov",fullName:"Alexander Spasov"},{id:"286031",title:"Prof.",name:"Olga N.",surname:"Zhukovskaya",slug:"olga-n.-zhukovskaya",fullName:"Olga N. Zhukovskaya"},{id:"286074",title:"Prof.",name:"Vera A.",surname:"Anisimova",slug:"vera-a.-anisimova",fullName:"Vera A. Anisimova"}],corrections:null},{id:"67500",title:"Development of Benzimidazole Compounds for Cancer Therapy",doi:"10.5772/intechopen.86691",slug:"development-of-benzimidazole-compounds-for-cancer-therapy",totalDownloads:1101,totalCrossrefCites:6,totalDimensionsCites:11,hasAltmetrics:0,abstract:"A fact that is largely unknown in the lay press and even the scientific community is that today cancer kills more people worldwide than tuberculosis (TB), malaria, and human immunodeficiency virus (HIV) combined. Benzimidazole is a heterocyclic aromatic organic compound considered to be a useful pharmacophore in a variety of impactful drugs. The purpose of this review is to highlight the benzimidazole-containing agents that are currently in clinical use or in clinical development as anticancer drugs. It is hoped that this review would function as comprehensive working reference of research accomplishment in the field of discovery and development of benzimidazole-based anticancer drugs.",signatures:"Puranik Purushottamachar, Senthilmurugan Ramalingam and Vincent C.O. Njar",downloadPdfUrl:"/chapter/pdf-download/67500",previewPdfUrl:"/chapter/pdf-preview/67500",authors:[{id:"287305",title:"Prof.",name:"Vincent",surname:"Njar",slug:"vincent-njar",fullName:"Vincent Njar"},{id:"299412",title:"Dr.",name:"Puranik",surname:"Purushottamachar",slug:"puranik-purushottamachar",fullName:"Puranik Purushottamachar"},{id:"299413",title:"Dr.",name:"Senthilmurugan",surname:"Ramalingam",slug:"senthilmurugan-ramalingam",fullName:"Senthilmurugan Ramalingam"}],corrections:null},{id:"67074",title:"Benzimidazoles: From Antiproliferative to Multitargeted Anticancer Agents",doi:"10.5772/intechopen.86249",slug:"benzimidazoles-from-antiproliferative-to-multitargeted-anticancer-agents",totalDownloads:1084,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Benzimidazole derivatives are known to act against a range of biological targets and thus gained clinical applications in a wide spectrum of diseases. Few examples of multitargeted benzimidazole derivatives that were reported during the last decade will be described in this chapter. Multitargeting agents for serving the polypharmacology approach to combat shortcomings of the main one-drug-one target main dogma will be briefly explored. In that context, the multitargeting benzimidazole derivatives gain a special attention. This includes discovery (hit-to-lead), structure-activity relationship (SAR), and binding mode of at least one lead (or hit) in each group. Special attention will be given to two structures dovitinib and AT9283 that are reported to exhibit potent in vitro and in vivo activities against a group of kinases and non-kinase target (as shown recently for dovitinib).",signatures:"Yousef Najajreh",downloadPdfUrl:"/chapter/pdf-download/67074",previewPdfUrl:"/chapter/pdf-preview/67074",authors:[{id:"285330",title:"Dr.",name:"Yousef",surname:"Najajreh",slug:"yousef-najajreh",fullName:"Yousef Najajreh"}],corrections:null},{id:"66268",title:"Bisbenzimidazoles: Anticancer Vacuolar (H+)-ATPase Inhibitors",doi:"10.5772/intechopen.85231",slug:"bisbenzimidazoles-anticancer-vacuolar-h-sup-sup-atpase-inhibitors",totalDownloads:1123,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Small molecule chemotherapeutic agents such as Imatinib, Gefitinib, and Erlotinib have played a significant role in the treatment of cancer. Although the unprecedented progress has been achieved in cancer treatment with these targeted agents, there is a strong demand for the development of selective and highly efficacious cancer drugs. V-ATPases are emerging as important target for the identification of novel therapeutic agents for cancer. Our screening and drug discovery processes have identified the bisbenzimidazole derivative (RP-15) as a potent anticancer V-ATPase inhibitor. In the present study, bisbenzimidazoles (compound-25, RP-11 and RP-15) have been tested for proton-pump inhibition activity in human hepatoma cell line (Huh7.5). RP-15 displayed comparable proton-pump inhibition activity to the standard Bafilomycin A1. We examined the antiproliferative activity of these analogs in two highly invasive and metastatic inflammatory breast cancer (IBC) cell lines (SUM 149PT and SUM190PT) along with Huh7.5. The compound-25 (SUM190PT: IC50 = 0.43±0.11 μM) and its structural analog RP-11 (SUM190PT: IC50 = 0.49±0.09 μM) have shown significant inhibition toward IBC cell lines. Additionally, RP-11 and RP-15 have demonstrated very good cytotoxicity toward the majority of cancer cell lines in the NCI 60 cell line panel.",signatures:"Renukadevi Patil, Olivia Powrozek, Binod Kumar, William Seibel, Kenneth Beaman, Gulam Waris, Neelam Sharma-Walia and Shivaputra Patil",downloadPdfUrl:"/chapter/pdf-download/66268",previewPdfUrl:"/chapter/pdf-preview/66268",authors:[{id:"237361",title:"Dr.",name:"Gulam",surname:"Waris",slug:"gulam-waris",fullName:"Gulam Waris"},{id:"243940",title:"Dr.",name:"Binod",surname:"Kumar",slug:"binod-kumar",fullName:"Binod Kumar"},{id:"289504",title:"Dr.",name:"Shivaputra",surname:"Patil",slug:"shivaputra-patil",fullName:"Shivaputra Patil"},{id:"289506",title:"Dr.",name:"Renukadevi",surname:"Patil",slug:"renukadevi-patil",fullName:"Renukadevi Patil"},{id:"289690",title:"Dr.",name:"Olivia",surname:"Powrozek",slug:"olivia-powrozek",fullName:"Olivia Powrozek"},{id:"289691",title:"Dr.",name:"William",surname:"Seibel",slug:"william-seibel",fullName:"William Seibel"},{id:"289692",title:"Dr.",name:"Kenneth",surname:"Beaman",slug:"kenneth-beaman",fullName:"Kenneth Beaman"},{id:"289693",title:"Dr.",name:"Neelam",surname:"Sharma-Walia",slug:"neelam-sharma-walia",fullName:"Neelam Sharma-Walia"}],corrections:null},{id:"66526",title:"Optical Sensing (Nano)Materials Based on Benzimidazole Derivatives",doi:"10.5772/intechopen.85643",slug:"optical-sensing-nano-materials-based-on-benzimidazole-derivatives",totalDownloads:1240,totalCrossrefCites:1,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Benzimidazole derivatives are well-known biologically active substances, and therefore, they are mostly synthesised for therapeutic purposes. However, such heteroaromatic molecular systems own structure-related properties that enable a variety of applications, especially in optical science. Multifunctionality of the benzimidazole unit, such as electron accepting ability, π-bridging, chromogenic pH sensitivity/switching and metal-ion chelating properties, makes it an exceptional structural candidate for the design of optical chemical sensors and functional materials. Development of smart molecular sensors and novel (nano)materials is the emerging trend observed in materials and optical sensing science in general, in which the benzimidazole molecular systems strongly contribute and participate. In this chapter, we summarised recent advances in optical sensing (nano)materials that incorporate the benzimidazole structural moiety. Solid-state optical sensing systems, including self-assembled molecular materials based on benzimidazoles, are reviewed and discussed. In addition, immobilisation of benzimidazole derivatives onto or into various substrates and matrices, such as organic and inorganic polymers, bulk membranes and nanoparticles, utilising different chemical and physical methods, is presented and analysed.",signatures:"Ema Horak, Robert Vianello and Ivana Murković Steinberg",downloadPdfUrl:"/chapter/pdf-download/66526",previewPdfUrl:"/chapter/pdf-preview/66526",authors:[{id:"288132",title:"Ph.D.",name:"Ema",surname:"Horak",slug:"ema-horak",fullName:"Ema Horak"},{id:"295983",title:"Dr.",name:"Robert",surname:"Vianello",slug:"robert-vianello",fullName:"Robert Vianello"},{id:"295984",title:"Dr.",name:"Ivana",surname:"Murković Steinberg",slug:"ivana-murkovic-steinberg",fullName:"Ivana Murković Steinberg"}],corrections:null},{id:"66558",title:"Benzimidazole as Solid Electrolyte Material for Fuel Cells",doi:"10.5772/intechopen.85430",slug:"benzimidazole-as-solid-electrolyte-material-for-fuel-cells",totalDownloads:978,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"This chapter is focused in the application of benzimidazole, mainly in the form of poly[2,2′-(m-phenylene)-5,5′-bisbenzimidazole] (PBI) and poly(2,5-benzimidazole) (ABPBI), in the fuel cell technology. A short introduction is given of the fuel cell principles, explaining both the theory and the high importance of this technology. PBI and ABPBI are used in a certain type of fuel cells: the polymer electrolyte fuel cells and are key materials in the composition of some of the electrolyte membranes used. Commercially available membranes composed of PBI are indicated in order to give an overview of their potential performance. The synthesis of the polymers is explained. Moreover, the preparation of the different kinds of membranes, both in proton exchange membrane fuel cells (PEMFCs) and anion exchange membrane fuel cells (AEMFCs) is studied. A deep description is given about the properties that make this family of compounds so interesting for the fuel cell technology as well as an how these polymers have been characterized with the corresponding analysis. The comparison with other ion exchange membranes is also discussed. Special attention will be given to the state of the art of different kinds of PBI/ABPBI fuel cell electrolyte membranes, in which our group and others are working nowadays.",signatures:"Daniel Herranz and Pilar Ocón",downloadPdfUrl:"/chapter/pdf-download/66558",previewPdfUrl:"/chapter/pdf-preview/66558",authors:[{id:"289174",title:"Prof.",name:"Pilar",surname:"Ocon",slug:"pilar-ocon",fullName:"Pilar Ocon"},{id:"289175",title:"MSc.",name:"Daniel",surname:"Herranz",slug:"daniel-herranz",fullName:"Daniel Herranz"}],corrections:null},{id:"66205",title:"Supramolecular Assembly of Benzimidazole Derivatives and Applications",doi:"10.5772/intechopen.85333",slug:"supramolecular-assembly-of-benzimidazole-derivatives-and-applications",totalDownloads:829,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Herein, we focus on the chemical and physical properties of benzimidazole and its derivatives used for the synthesis of supramolecular materials. The design and modification of benzimidazole opens the scope of the diversity of structures (different sizes and morphologies) that can be built. The synthesized materials include not only small coordination complexes but also isolated crystals, metal-organic frameworks, metal-coordination polymers, smart nanocontainers, and more advanced macrostructures such as microflowers and nanowires. These supramolecular structures are based on noncovalent interactions, mostly on metal coordination chemistry and π-π stacking interactions. Moreover, the same molecule, due to its chemical structure, can undergo both sorts of interactions in order to induce the self-assembly into supramolecular materials. In this process, as it is shown in this chapter, the conditions used for the assembly determine the final structure and morphology of the fabricated macromolecule. Finally, we show most recent applications of these materials in the field of sensing, photoluminescence, fuel cell, and fabrication of new nanostructures.",signatures:"Ana Beloqui",downloadPdfUrl:"/chapter/pdf-download/66205",previewPdfUrl:"/chapter/pdf-preview/66205",authors:[{id:"289147",title:"Dr.",name:"Ana",surname:"Beloqui",slug:"ana-beloqui",fullName:"Ana Beloqui"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"2553",title:"Lipid Peroxidation",subtitle:null,isOpenForSubmission:!1,hash:"b39734aa940b2d63ae5e8773d3dd5280",slug:"lipid-peroxidation",bookSignature:"Angel Catala",coverURL:"https://cdn.intechopen.com/books/images_new/2553.jpg",editedByType:"Edited by",editors:[{id:"196544",title:"Prof.",name:"Angel",surname:"Catala",slug:"angel-catala",fullName:"Angel Catala"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2323",title:"Carbohydrates",subtitle:"Comprehensive Studies on Glycobiology and Glycotechnology",isOpenForSubmission:!1,hash:"f7c2e6a3566eee14c9884ad0820a6416",slug:"carbohydrates-comprehensive-studies-on-glycobiology-and-glycotechnology",bookSignature:"Chuan-Fa Chang",coverURL:"https://cdn.intechopen.com/books/images_new/2323.jpg",editedByType:"Edited by",editors:[{id:"145728",title:"Prof.",name:"Chuan-Fa",surname:"Chang",slug:"chuan-fa-chang",fullName:"Chuan-Fa Chang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"372",title:"Aflatoxins",subtitle:"Biochemistry and Molecular Biology",isOpenForSubmission:!1,hash:"b7f7359995dc5ee04e12df282495f77e",slug:"aflatoxins-biochemistry-and-molecular-biology",bookSignature:"Ramón Gerardo Guevara-González",coverURL:"https://cdn.intechopen.com/books/images_new/372.jpg",editedByType:"Edited by",editors:[{id:"62559",title:"Dr.",name:"Ramon G.",surname:"Guevara-Gonzalez",slug:"ramon-g.-guevara-gonzalez",fullName:"Ramon G. 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1. Introduction
In June 2006, Cisco released a virtual network index (VNI) forecast that projects global IP traffic over the next 5 years [1]. According to Cisco’s paper, there has been quantitative evidence that proliferation of global IP traffic will exchange data to reach the order of zettabyte (ZB) by 2021. This massive amount of data will be driven mainly by the number of connected devices to IP networks, such as smart phones, tablets, sensors and machine-to-machine (M2M) applications that are estimated to be more than three times the global population. Hence, in this era, just about every physical object we see (e.g. health-care monitoring apparatus, machinery, appliances, autonomous cars and intelligent transportation, etc.) will be connected, forming the Internet of Things (IoT) [2]. In order to handle the countless number and various types of devices as well as linking the existing radio-access technologies, a new architecture that will increase data rate, lower end-to-end latency and improve the coverage is urgently required. Therefore, to meet with this demand, a new standard on the fifth-generation (5G) networks is currently under consideration [3].
Health and medical care are considered as one of the most fascinating applications that can fully benefit from IoT deployment. The IoT that employs various sensor and smart medical devices may serve in, for example, tele-auscultation, remote health monitoring, remote diagnostics and possibly treatment as well as elderly care [4, 5, 6]. Such Internet of Medical Things (IMedT) is expected to reduce consultation and transportation cost and to shrink the gap for those who live in the isolated/remote areas where the presence of doctors is void. Nevertheless, transmitting medical data to health-care providers through the public networks require high data security as public networks are somehow vulnerable to spoof attack. In this chapter, two anonymisation techniques based on wavelet decomposition and wavelet packet (WP) transform for securing ECG signals will be discussed.
2. Motivations
An electrocardiogram (ECG) signal contains important health information of a patient. It is used to detect abnormal heart rhythms by measuring the electrical activity generated by the heart as it contracts. Recent studies show that an ECG signal can be used as a biometric method for robust human identification and authentication [7, 8, 9]. The ECG signal was found to be unique for each individual over a long period of time [10, 11]. An ECG biometric system consists of feature extraction and classifiers to identify and recognise a person. The selection of appropriate features is crucial for successful individual identification. In [12], ECG-based biometric features were grouped as fiducial based, non-fiducial based or hybrid.
An unsecure ECG signal can be subjected to man in the middle attack where fraudsters can use the spoofed recorded ECG data to gain access to a secured service [13, 14, 15]. A scenario where a man in the middle attack can be a real threat for health information transmission is presented in Figure 1. The figure illustrates possible attack points that include (1) wireless links between sensor nodes that collect health information data from wireless body area networks (WBAN) and gateways, (2) wire/wireless links between the gateway and the edge router, (3) wire/wireless links between the other side of the edge router and health-care provider router and (4) repository in the data centre/public server or health-care provider. In order to minimise such security threat to a system, a health-care provider needs to comply with certain widely accepted standards to protect medical records safely. For example, US government passed the Health Insurance Portability and Accountability Act (HIPAA) in 1996 for protecting medical privacy users [16], the European Union adopted the Directive on Data Protection in 1995 [17], the Health Information Privacy Code was passed by New Zealand government in 1994, which sets specific rules for agencies in the health sector to ensure protection of individual privacy [18] and the personally controlled electronic health record (PCEHR) eHealth system was launched by Australian government in 2012 [19].
Figure 1.
Possible attack points for unsecure ECG signals subjected to man in the middle attack.
There have been several proposed security techniques including image [20] and ECG steganography [21, 22, 23, 24] to secure confidential patient information. In the steganography techniques, sensitive patient information is concealed inside public host data without incurring huge computational overhead or any increase in the size of the host data [21]. ECG data is used as the host signal to embed secret patient information and physiological readings. This may create watermarked ECG signals that is then transferred to a remote hospital server for further diagnosis. The effectiveness of ECG watermarking is dependent on the difference between the original host data and the watermarked data, that is, greater differences point to an ineffective steganography process. Unfortunately, all steganography methods bear some degree of information loss. This severe loss of information contributes to smeared/incorrect signal features and in some cases can lead to the failure of reconstructing the original ECG signal from the watermarked ECG signal [22]. However, even effective ECG watermarking can result in the delectability of ECG fiducial and non-fiducial features, which may allow for patient identification according to research in [7, 8, 9]. Therefore, a method combining the advantages of steganography with a technique that hides ECG fiducial and non-fiducial features is required. In this chapter, a review between two ECG anonymisation methods based on wavelet decomposition and wavelet packet transform (WPT) is presented.
Recent ECG anonymisation approaches based on wavelet decomposition were proposed in [13, 14]. During the wavelet decomposition process, filters of different cut-off frequencies were used to analyse the ECG signal at different scales (frequencies). It can be done by passing the ECG signal through a series of high-pass filters (i.e. the detail coefficients) for examining the high-frequency bands. The ECG signal was also passed through a series of low-pass filters (i.e. the approximation coefficients) to evaluate the low-frequency bands. Wavelet decomposition at level 3 was used during signal evaluation in the chapter [13]. Moreover, in the order to construct a complete evaluation, two individual methods were studied during the experimentation [13]. Block diagram for the wavelet decomposition can be seen in Figure 2.
Figure 2.
ECG anonymisation using wavelet decomposition.
3.1. Method 1: discrete wavelet base anonymisation
In the first method, approximation (cA3) and detail (cD3) coefficients were removed after level 3 decomposition. Subsequently these nodes were encrypted using the well-known RSA symmetric cryptography. On the other hand, the remaining nodes, that is, cD1 and cD2, were compressed and transmitted to the ECG repository. Figure 3 shows that without knowledge of nodes cA3 and cD3, the newly constructed signal in the repository completely hides P wave and T wave of the original ECG. It can be concluded that the first method hides most of the features required to reconcile the identity of a patient [7]. On the contrary, this method is not able to provide complete obfuscation of the cardiovascular conditions. This is mainly because the RR interval and certain types of arrhythmias are visible [25] as obvious in Figure 3. However, this method only required minimal selection of coefficient (approximately 25%) for encryption and key distribution. This is the main advantage of the first method. This method will perform well when faster distribution of key is priority and strong security is not deemed necessary. The removed coefficients are shown in Figure 4.
Figure 3.
Normal ECG signal (top) and reconstructed annonymised ECG signal without nodes cA3 and cD3.
Figure 4.
Removed (Selected for Encryption) Coefficients for Method 1.
3.2. Method 2: discrete wavelet base anonymisation
In the second method, nodes cA3, cD3 and cD2 were selected for encryption, while the remaining coefficients cD1 were transmitted to the ECG repository. In contrast to the previous method, Figure 5 shows that the reconstructed ECG from the coefficients that are extracted from the repository is completely able to obfuscate features related to cardiovascular condition and person identification.
Figure 5.
Normal ECG signal (top) and reconstructed annonymised ECG signal without nodes cA3, cD3 and cD2.
Therefore, this method provides higher ECG security by compromising larger key size (approximately 50%) as can be seen in Figure 6. Figure 5 shows that the reconstructed ECG signal does not contain any ECG features.
Figure 6.
Removed (selected for encryption) coefficients for method 2.
Both methods described above suffer from long key size and lack of complete obfuscation to the ECG data. The long key size requires wider bandwidth during transmission process of the key to the ECG repository. On the other hand, lack of complete obfuscation results in trivial interpretation of the anonymised ECG signal. Therefore, due to these two main reasons, other methods based on the wavelet packet were proposed and developed.
Wavelet packet transform has been used in many applications of biomedical signal processing, for example, feature extraction, noise reduction, data compression and QRS detection. Furthermore, wavelet packet transform has long been used for ECG signal analysis. A wavelet packet function [18] is defined as
φj,knt=212φn2jt−m,E1
where j and m are the scale (frequency) and the translation (time) parameters, respectively, and n=0,1,3,… is the oscillation parameter. The structure of wavelet packet (WP) decomposition is described as a binary tree structure E; each node is described as jn, where j is a node’s scale level and n is a node’s number on the corresponded level. The root node 00 of the WP tree corresponds to the entire frequency range, 0fs2, where fs is the ECG sampling frequency of the ECG signal. Each internal node of the WP tree jn∈E is called a parent node that is divided into two child nodes: the first and the second nodes are associated with low-pass hm and high-pass gm filters. These nodes forms a quadrature mirror filter (QMF) pair [19].
The scaling function ωt and the mother wavelet φt for the wavelet packet when n=0,1 and j=m=0 are given by
φ0t=ωt,φ1t=ψt.E2
The other wavelet packet functions for n=2,3,… and j=1 are shown as follows:
where the low-pass filter gives hm=12ωtω2t−m, and the high-pass filter gives gm=12ψtψ2t−m. The operator .. stands for the inner product. The wavelet packet coefficients of the ECG signal, xt, are expressed as follows:
Qjnm=xψj,mn=∫−∞∞xtψj,mntdtE7
Each coefficient measures a specific sub-band frequency content, controlled by the scaling parameter, j, and the oscillation parameter, n. The ECG signal, xt, can be decomposed into a different time-frequency space with Eq. (6) and Eq. (7). By computing the full wavelet packet decomposition on the ECG signal, for the jth level of decomposition, we have 2j sets of sub-band coefficients of length N2j, where N is the ECG signal length [20]. Each sub-band coefficient, node, has a frequency range in the interval n2j+1n+12j+1,n=0,1,…,2j−1. This is how wavelet packet decomposes the original ECG signal into two or more coefficients.
4.2. The generalised framework for the ECG anonymisation method
In this section, a generalised framework for the ECG anonymisation using wavelet packet transform (WPT) will be introduced. The proposed framework for ECG anonymisation can be seen in Figure 7, while its pseudo-code is listed in Algorithm 1. This framework comprises the following steps:
Figure 7.
Wavelet packet-based ECG anonymisation process.
Step 1: Perform wavelet packet decomposition of the ECG signal, xt, at level j. The signal coefficients at this level are given by
C=cjn:n=01…2j−1E8
where cjn represents the coefficients of the nth node at level j.
Step 2: Exclude the first node, cj0, from C in Eq. (8) to get
C¯=cjn:n=12…2j−1.E9
The excluded node is set to
k=cj0E10
where k is an unencrypted and uncompressed key that includes the low-frequency components of the ECG signal, xt.
Step 3: Modify each node in C¯, Eq. (9), using a reversible function/operation such as logarithm or division. In this chapter each node in C¯ is divided by Γ. Γ is a reversible function driven from the key coefficients. Hence, the modified coefficients in C¯ are given by
C¯̂=C¯Γ=cjnΓ:n=12…2j−1,E11
where Γ=k+offset, offset=mink+η, η is a constant and . is the absolute operator. The offset term in Γ is used to prevent division by zero.
Step 4: Securely distribute the key, K, and the offset value to medical personnel. The key security will be achieved by compressing and encrypting the first node, k, and the offset as follows:
K=EΔkoffset=EΔcj0offset,E12
where Δ. is the compression operator and E. is the encryption operator [9]. Compression and encryption are beyond the scope of this chapter.
Step 5: Perform wavelet packet reconstruction to the modified terminal nodes’ coefficient, C¯̂, to get the anonymised ECG, yt.
Step 6: Upload the anonymised ECG, yt, to the repository.
4.3. The ECG reconstruction method
The proposed reconstruction process for the anonymised ECG signal is shown in Figure 8, while the pseudocode is shown in Algorithm 2. The authorised personnel receives the secure key, K, and the anonymised ECG, yt, and performs the reconstruction process by the following steps:
Figure 8.
Wavelet packet-based reconstruction process for the anonymised ECG.
Step 1: Perform decryption and decompression to the key, K, to get Γ
Γ=ΛDK,E13
where Λ. and D. are the decryption and decompression operators, respectively. Decryption and decompression are beyond the scope of this chapter.
Step 2: Perform wavelet packet decomposition of the ECG signal, yt, at level j to get C¯̂=C¯Γ as in Eq. (11).
Step 3: Multiply each node at C¯̂ by the factor Γ to get
C¯=f−1C¯̂=C¯̂×Γ=cjn:n=12…2j−1E14
Algorithm 1: Wavelet packet-based ECG anonymisation process
Algorithm 2: Wavelet packet-based reconstruction process
1: Begin 2: xt←ECG_signal 3: C←wpacket_decompositionxtj 4: k←cj0 // exclude the first node as a key 5: C¯←cjn 6: offset←mink+η 7: Γ←k+offset 8: C¯̂←C¯Γ 9: K←EΔkoffset //compression and encryption 10: Send K to healthcare providers or doctors as a key 11: yt←wpacket_reconstructionC¯̂j 12: Upload yt to public server 13: Save yt with unique ID for a particular individual 14: End
1: Begin 2: k←ΛDKoffset // decryption and decompression 3: yt←Anonymised_ECG_signal 4: C¯̂←wpacket_decompositionytj 5: C¯←C¯̂×Γ 6: cjn←C¯ 7: k←Γ−offset 8: cj0←k 9: C←add_first_nodecj0cjn 10: xt←wpacket_reconstructionCj 11: End
Step 4: Add the first node, cj0=Γ−offset, to the WPT vector C¯ at Eq. (14) to get the WPT vector coefficients, C, of the original ECG signal, xt.
Step 5: Perform wavelet packet reconstruction of the coefficients vector, C, at level j to recover the original unanonymised ECG signal, xt.
5. Algorithm validation
Two types of electrocardiogram (ECG) signals were used to validate and investigate the performance and the effectiveness of the generalised ECG anonymisation framework. These signals are
normal ECG signal for a healthy subject, and
abnormal ECG signals for a patient with supraventricular arrhythmia and a patient with ventricular tachyarrhythmia.
The normal and abnormal ECG signals with different sampling frequencies were used in this chapter to study the robustness of the proposed anonymisation approach in concealing and smearing the ECG’s fiducial and non-fiducial features. The normal and abnormal ECG data were obtained from the PTB ECG database [26] and the MIT-BIH arrhythmia database [27], respectively. These databases are publically available [26, 27].
In the evaluation process in the latter sub-section, bior5.5 wavelet was used. Besides this type of mother wavelet resembling the shape of an ECG signal, it is widely used for speech, video and biomedical signals providing that bior5.5 inherited linear phase. Nevertheless, it should be noted that for ECG anonymisation in this chapter, mother wavelet will not impact the anonymisation result since the ECG signal will be constructed back to its original at the receiver side.
The security of the proposed scheme depends on the following parameters that are required at the receiver side:
the encrypted security key which should be shared secretly,
the reversible function that should be used to reconstruct the original ECG information from the anonymised ECG, and
the type of transformation and the level of decomposition (wavelet packet transform at level 2 is used in this study).
An attacker with stolen key (i.e. able to decrypt the secure key) using brute force or any other method will require the knowledge of the reversible function and the level of decomposition. This information will be stored inside a patient/medical personnel PC and will not be transmitted under any circumstance. In this case, brute force attack is infeasible for the attack.
In the following sections, performance analysis using cross-correlation of normal and anonymised ECG signals, power spectral density of anonymised ECG signal and percentage residual difference (PRD) methods will be examined.
5.1. Performance evaluation over normal electrocardiogram
An electrocardiogram (ECG) signal has a well-defined P, QRS and T signature that is represented with each heartbeat. The P-wave arises from the depolarisation of the atrium. The QRS complex arises from depolarisation of the ventricles and T-wave arises from repolarisation of the ventricle muscles. The duration, shape and amplitude of these waves are considered as major features in time-domain analysis. Sometimes the time morphologies of these waves are similar.
The normal ECG was obtained from the PTB database (patient247, signal s0479). The sampling frequency, fs, for this signal was 1 kHz. A total of 10 s of this signal was transformed by wavelet packet decomposition at level 2, j=2. Decomposition level, j, depends on the ECG sampling frequency. Higher sampling frequency requires a low value of j to conceal all features in the anonymised signal. Node c20 of size N4 (N = 10,000 samples) was removed from the wavelet packet coefficients of the normal ECG signal. This node was used to generate the key, K, which was distributed securely to medical personnel. The anonymised ECG is reconstructed from the rest nodes, three nodes, using the anonymisation algorithm in Section II (B) and transmitted confidently over the public internet, since the anonymised ECG does not impose any threat to privacy.
Figure 9 (a) and (b) shows the time-domain representation of the 10-s normal ECG signal (patient247, signal s0479) and its anonymisation version, respectively. The frequency range for the anonymised ECG after node c20 removal is 125 and 500 Hz. From the time-domain representation of the ECG signal and its anonymisation in Figure 9 (a) and (b), the proposed anonymisation algorithm conceals all fiducial features from the reconstructed ECG signal (Figure 9(b)). Figure 10 (a) and (b) shows the frequency representation of the 10-s normal ECG signal (Figure 9 (a)) and its anonymisation version, respectively. The non-fiducial features were also concealed as shown in the frequency-domain representation of the anonymised version of the normal ECG signal.
Figure 9.
Time-domain representation of 10-s normal ECG signal, (a) unanonymised ECG signal and (b) anonymised ECG signal. The sampling frequency was fs = 1 kHz.
Figure 10.
Power spectral density of 10-s normal ECG signal, (a) unanonymised ECG signal and (b) anonymised ECG signal. The sampling frequency was fs = 1 kHz, the power spectral method was Welch periodogram.
Figure 11 shows the time-domain representation of the coefficients c20 which was used to create the secure key, K. The frequency range for c20 in this data is between 0 and 125 Hz. This node preserves all fiducial features in the original ECG signal. Figure 12 (a) and (b) shows the reconstructed ECG signal at the medical personnel side and its cross-correlation with the original ECG signal at the patient side, respectively. From Figure 12 (b), both signals are highly correlated, which guarantees a lossless reconstruction.
Figure 11.
Time-domain representation of the first node c20 coefficients for the 10-s normal ECG signal in Figure 9(a). This node was used to create the secure key.
Figure 12.
Ten seconds reconstructed ECG signal, (a) time domain representation of the reconstructed ECG signal, (b) cross correlation between the normal ECG signal in Figure 9(a) and its reconstructed version.
5.2. Performance evaluation over abnormal electrocardiogram
An arrhythmia is an abnormality in the heart’s rhythm or heartbeat pattern. The heartbeat can be too slow, too fast, have extra beats or otherwise beat irregularly [28]. The types of abnormal ECG signals investigated in this study were supraventricular arrhythmia and ventricular tachyarrhythmia. Supraventricular arrhythmia occurs in the upper areas of the heart and is less serious than ventricular arrhythmia. It has irregular shapes of QRS complexes [28]. These arrhythmia data—supraventricular arrhythmia and ventricular tachyarrhythmia—were obtained from the MIT-BIH arrhythmia database [26].
5.2.1. Supraventricular arrhythmia
The sampling frequency, fs, for this signal was 128 Hz. A total of 10 s of this signal was transformed by wavelet packet decomposition at level 2, j=2.
Node c20 of size N4 (N = 1280 samples) was removed from the wavelet packet coefficients of the supraventricular arrhythmia signal. This node was used to generate the key, K, which was distributed securely to medical personnel. The frequency range for c20 in this data is between 0 and 16 Hz. The other nodes at level 2 with the frequency range between 16 and 64 were used to construct the anonymised signal.
Figure 13 (a) and (b) shows the time-domain representation of the 10-s ECG signal of a patient with supraventricular arrhythmia and its anonymisation version, respectively. The frequency-domain representation for both signals is shown in Figure 14 (a) and (b). The fiducial and non-fiducial features were concealed in the time-domain and frequency-domain representation of the anonymised supraventricular arrhythmia signal.
Figure 13.
Time-domain representation of 10-s ECG signal of a patient with supraventricular arrhythmia, (a) unanonymised ECG and (b) anonymised CG. The sampling frequency was fs = 128 Hz.
Figure 14.
Power spectral density of ten seconds normal ECG signal of a patient with supraventricular arrhythmia, (a) unanonymised ECG and (b) anonymised ECG. The sampling frequency was fs = 128 Hz, and the power spectral method was Welch periodogram.
Figure 15 shows the time-domain representation of the coefficients c20, which was used to create the secure key, K. This node preserves all fiducial features in the original supraventricular arrhythmia signal.
Figure 15.
Time-domain representation of the first node c20 coefficients for the 10-s abnormal ECG signal in Figure 7 (a). This node was used to create the secure key.
5.2.2. Ventricular tachyarrhythmia
The sampling frequency, fs, for this signal was 250 Hz. A total of 10 s of this signal was transformed by wavelet packet decomposition at level 2. Node c20 of size N4 (N = 2500 samples) was removed from the wavelet packet coefficients of the ventricular tachyarrhythmia signal. This node was used to generate the key K, which was distributed securely to medical personnel. The other nodes were used to reconstruct the anonymised ventricular tachyarrhythmia signal.
Figure 16 (a) and (b) shows the time-domain representation of the 10-s ECG signal of a patient with ventricular tachyarrhythmia and its anonymisation version, respectively. The frequency-domain representation for both signals is shown in Figure 17 (a) and (b). The fiducial and non-fiducial features were concealed in the time-domain and frequency-domain representation of the anonymised supraventricular arrhythmia signal.
Figure 16.
Time-domain representation of 10-s ECG signal of a patient with ventricular tachyarrhythmia, (a) unanonymised ECG and (b) anonymised ECG. The sampling frequency was fs = 250 Hz.
Figure 17.
Power spectral density of 10-s ECG signal of a patient with supraventricular arrhythmia, (a) unanonymised ECG and (b) anonymised ECG. The sampling frequency was fs = 250 Hz, the power spectral method was Welch periodogram.
Figure 18 shows the time-domain representation of the coefficients c20 which was used to create the secure key, K. This node preserves all fiducial features in the original supraventricular arrhythmia signal.
Figure 18.
Time-domain representation of the first node c20 coefficients for the 10-s abnormal ECG signal in Figure 10 (a). This node was used to create the secure key.
5.3. Performance evaluation with the PRD metric
The percentage residual difference (PRD) is used to measure the difference between the original ECG signal and the anonymised ECG signal using the following equation.
PRD=∑i=1Nxi−yi2∑i=1Nxi2E15
where xi is the original ECG signal, yi is the anonymised ECG signal and i=1…N, where N is the total number of the sample.
Performance of the proposed anonymisation algorithm using PRD metric is shown in Table 1. It can be seen from the table that the minimum and the maximum PRD measured were 14.8 and 70.6%, respectively. The PRD value depends on the ECG frequency bandwidth and its sampling frequency.
ECG type
Sampling frequency fs, Hz
PRD %
Normal ECG
1000
70.6
Supraventricular arrhythmia
128
29.6
Ventricular tachyarrhythmia
250
14.8
Table 1.
PRD performance results of normal and abnormal ECG signal for the proposed algorithm.
Comparing with ECG steganography methods, ECG steganography has a low PRD value between original and watermarked ECG signal. For example, in [14], the maximum PRD measured was 0.6%. Low PRD is essential in ECG steganography to guarantee correct diagnosis of the ECG watermarked signal. However, the lower value of PRD makes the ECG vulnerable to attack [1, 2, 3, 9].
6. Conclusions
A generalised wavelet packet-based ECG anonymisation framework has been presented in this chapter. This proposed anonymisation technique was used to conceal fiducial and non-fiducial features from normal and abnormal ECG signal for secure transmission over the public internet. Normal and abnormal ECG signals with different sampling frequencies have been investigated by the proposed method. Signal transformations other than wavelet packet transform can be used in this framework. Such transformations should have inverse property.
The performance analysis revealed that the proposed method is able to conceal both fiducial and non-fiducial features in normal and abnormal ECG signals under examination. Moreover, the analysis showed that the reconstructed ECG is highly correlated with the original ECG signal. It achieved a lossless reconstruction of the ECG data and proved the robustness of the proposed method. The security measures taken to secure the key and other information such as the level of decomposition and the knowledge of the reversible function make attacks using methods such as brute force is infeasible.
\n',keywords:"anonymisation, biometric, electrocardiogram, encryption, steganography, wavelet analysis",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/60705.pdf",chapterXML:"https://mts.intechopen.com/source/xml/60705.xml",downloadPdfUrl:"/chapter/pdf-download/60705",previewPdfUrl:"/chapter/pdf-preview/60705",totalDownloads:996,totalViews:161,totalCrossrefCites:1,totalDimensionsCites:1,totalAltmetricsMentions:0,introChapter:null,impactScore:0,impactScorePercentile:34,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"October 5th 2017",dateReviewed:"January 26th 2018",datePrePublished:null,datePublished:"October 3rd 2018",dateFinished:"April 13th 2018",readingETA:"0",abstract:"Wavelet packet transform has been used in many applications of biomedical signal processing, for example, feature extraction, noise reduction, data compression, electrocardiogram (ECG) anonymisation and QRS detection. The wavelet analysis methods, in these applications, represent the temporal characteristics of a biological signal by its spectral components in the frequency domain. Furthermore, it has been shown in many works that the ECG signal can be used as a biometric method for robust human identification and authentication. In this case, it is necessary to anonymise the ECG data during the distribution and storage of the signal in a public repository. A neglectful system leads to an eavesdropper recording the ECG data and uses it as recognition data to gain access via an ECG biometric system. This chapter discusses and reviews recent researches on ECG anonymisation wavelets-based techniques. These techniques use discrete wavelet transform and wavelet packet transform. A comparative study between the wavelets-based methods will be presented.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/60705",risUrl:"/chapter/ris/60705",book:{id:"6547",slug:"wavelet-theory-and-its-applications"},signatures:"Seedahmed S. Mahmoud and Jusak Jusak",authors:[{id:"224971",title:"Ph.D.",name:"Seedahmed",middleName:null,surname:"Mahmoud",fullName:"Seedahmed Mahmoud",slug:"seedahmed-mahmoud",email:"seedahmed.sharif@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"240139",title:"Dr.",name:"Jusak",middleName:null,surname:"Jusak",fullName:"Jusak Jusak",slug:"jusak-jusak",email:"jusak@stikom.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Motivations",level:"1"},{id:"sec_3",title:"3. Wavelet decomposition-based ECG anonymisation approach",level:"1"},{id:"sec_3_2",title:"3.1. Method 1: discrete wavelet base anonymisation",level:"2"},{id:"sec_4_2",title:"3.2. Method 2: discrete wavelet base anonymisation",level:"2"},{id:"sec_6",title:"4. Wavelet packet-based ECG anonymisation approach",level:"1"},{id:"sec_6_2",title:"4.1. Overview of wavelet packet transform",level:"2"},{id:"sec_7_2",title:"4.2. The generalised framework for the ECG anonymisation method",level:"2"},{id:"sec_8_2",title:"4.3. The ECG reconstruction method",level:"2"},{id:"sec_10",title:"5. Algorithm validation",level:"1"},{id:"sec_10_2",title:"5.1. Performance evaluation over normal electrocardiogram",level:"2"},{id:"sec_11_2",title:"5.2. Performance evaluation over abnormal electrocardiogram",level:"2"},{id:"sec_11_3",title:"5.2.1. Supraventricular arrhythmia",level:"3"},{id:"sec_12_3",title:"5.2.2. Ventricular tachyarrhythmia",level:"3"},{id:"sec_14_2",title:"5.3. 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IEEE Transactions on Instrumentation and Measurement. 2008;57(2):248-253'},{id:"B11",body:'Wubbeler G, Stavridis M, Kreiseler D, Bousseljot R-D, Elster C. Verification of humans using the electrocardiogram. Pattern Recognition Letters. 2007;28:1172-1175'},{id:"B12",body:'Odinaka I, Lai P, Kaplan AD, O’Sullivan JA, Sirevaag EJ, Rohrbaugh JW. ECG biometric recognition: A comparative analysis. IEEE Transactions on Information Forensics and Security. 2012;7(6):1812-1824'},{id:"B13",body:'Sufi F, Mahmoud SS, Khalil I. A Wavelet Based Secured ECG Distribution Technique for Patient Centric Approach. In: The Proceedings of 5th International Workshop on Wearable and Implantable Body Sensor Networks, Hong Kong, China; 2008'},{id:"B14",body:'Fahim KS, Mahmoud SS, Khalil I. A novel wavelet packet-based anti-spoofing technique to secure ECG data. International Journal of Biometrics. 2008;1(2):191-208'},{id:"B15",body:'Reinsmidth E, Schwab D, Yang L. Securing a connected mobile system for healthcare. IEEE 17th International Symposium on High Assurance Systems Engineering (HASE), Orlando, FL, USA. Jan. 2016. pp. 19-22'},{id:"B16",body:'Department of Health & Human Services USA. Security 101 for covered entities. HIPAA Security Series. 2007;2:1-11'},{id:"B17",body:'European Parliament and of the Council. Directive 95/46/EC on the protection of individuals with regard to the processing of personal data and on the free movement of such data. Official Journal of the European Communities. 1995;1:281/31-281/50'},{id:"B18",body:'Privacy Commisioner. Health Information Privacy Code 1994. Ed. 2008. Auckland, New Zealand: KB Printed Ltd; 2008'},{id:"B19",body:'Pearce C, Bainbridge M. A personally controlled electronic health record for Australia. Journal of the American Medical Informatics Association. 2014;21(4):707-713'},{id:"B20",body:'Özkaynak F, Yavuz S. Analysis and improvement of a novel image fusion encryption algorithm based on DNA sequence operation and hyper-chaotic system. Nonlinear Dynamics. 2014;78(2):1311-1320'},{id:"B21",body:'Ibaida A, Khalil I. Wavelet-based ECG steganography for protecting patient confidential information in point-of-care systems. IEEE Transactions on Biomedical Engineering. 2013;60(12):3322-3331'},{id:"B22",body:'Tseng K, He X, Kung W, Chen S, Liao M, Huang H. Wavelet-based watermarking and compression for ECG signals with verification evaluation. Sensors. 2014;14(2):3721-3736'},{id:"B23",body:'Liji CA, Indiradevi KP, Babu A. Integer-to-integer wavelet transform based ECG steganography for securing patient confidential information. Procedia Technology. 2016;24:1039-1047'},{id:"B24",body:'Chen C-K et al. Personalized information encryption using ECG signals with chaotic functions. Information Sciences. 2012;193:125-140'},{id:"B25",body:'Bartolo A, Clymer BD, Bugess RC, Turnbull JP, Golish JA, Perry MC. An arrhythmia detector and heart rate estimator for overnight polysomnography studies. IEEE Transactions on Biomedical Engineering. 2001;48(5):513-521'},{id:"B26",body:'The PTB Diagnostic ECG Database, http://www.physionet.org/physiobank/database/ptbdb (viewed Dec. 2015)'},{id:"B27",body:'MIT-BIH Arrhythmia Database, http://physionet.org/physiobank/database/svdb/ (viewed Dec. 2015)'},{id:"B28",body:'Hebbar AK, Hueston WJ. Management of Common Arrhythmias: Part I. Supraventricular arrhythmias. Journal of American Family Physician. 2002;65(12):2479-2486'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Seedahmed S. Mahmoud",address:"seedahmed.sharif@gmail.com",affiliation:'
Department of Electrical and Electronic Technology, Applied Engineering College, Lincoln College International, Kingdom of Saudi Arabia
Department of Computer Engineering, Institut Bisnis dan Informatika Stikom Surabaya, Indonesia
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1. Introduction
Diarrhea is one of the most common symptoms in the gastroenterologist clinical practice. It is defined as an increase in the average number of bowel movements, stool output and/or weight, or a reduced stool consistency, and according to duration, can be acute if it lasts less than 7 days, persistent acute (>7 days and < 14 days), sub-acute (>14 days and < 28 days), or chronic (>4 weeks) [1, 2, 3, 4, 5, 6]. Most episodes of acute diarrhea occur as a result of infectious agents or dietary transgression. Acute persistent and subacute diarrhea may be caused by unidentified microorganisms or might be secondary to medications [1]. Chronic diarrhea is one of those conditions with the broadest differential diagnosis, that includes anatomical and/or physiologic abnormalities of the gastrointestinal (GI) tract, inflammatory or neoplastic conditions, malabsorptive disorders, drug side effects, dysbiosis, functional as well as post-infectious syndromes such as small intestine bowel overgrowth (SIBO), functional diarrhea or post-infectious irritable bowel syndrome (Pi-IBS) [2, 3, 4, 5, 6]. One of the most common, albeit rarely unconsidered causes, is drug-side effect [7, 8]. A large number of at least 700 drugs have been implicated as cause of chronic diarrhea through a number of different, and sometimes overlapped pathophysiologic mechanisms [9]. Although initial therapy is drug withdrawal, in several cases treatment directed at pathophysiologic mechanism is needed to revert damage and improve symptoms.
2. Mechanisms of enteral damage
Enteral damage and consequent symptoms such as diarrhea, bloating, flatulence and pain may be mediated through different mechanisms falling into two main categories: (1) Functional damage: it can be caused by abnormalities in any of the mechanisms involving digestion (maldigestion) and/or absorption (malabsorption), GI motility disturbances, alterations in the water and electrolyte absorption and/or secretion mechanisms, and altered microbiota and/or microbiome (dysbiosis), and (2) Microscopic or overt mucosal damage: this can be caused by direct contact of the drug, ischemic-related damage, systemic inflammatory or autoimmune mechanisms, and may affect different portions of the small intestine, colon, or both (Figure 1, [9]). According to the involved mechanism, main symptoms may predominate diarrhea, malabsorptive complaints such as steatorrhea, weight loss and anemia, or abdominal pain, and in severe cases, occult or overt bleeding.
Figure 1.
Pathophysiologic mechanisms of enteropathy according to drug type.
3. Maldigestion and malabsorption
Small intestine is involved in both digestive and absorptive processes of all major nutrients, fatty acids and multiple ions, occurring across the entire intestinal wall at different levels. Normal functional anatomy includes a full bowel length, normal intestinal villi and absorptive capacity, conserved neuroendocrine regulatory systems, and a normal motility activity, particularly the major motor complex (MMC) [10]. Several drugs may interfere with one or multiple mechanisms associated with either digestion processes or mechanisms associated with intestinal absorption. Alpha-glucosidase inhibitors such as acarbose decrease carbohydrate digestion, lipase-inhibitors such as orlistat and cetilistat affect fat absorption, bile acid binding resins such as cholestyramine or colestipol affects not only bile acid absorption but also that of vitamin B12 and lipid-soluble vitamins, but as they are used in bile-acid diarrhea as main therapeutic indication, they can be associated with constipation instead of diarrhea. Different drugs may induce calcium precipitation, such as aluminum or tetracycline, with further changes in bowel habit. Structural damage leading to villous inflammation and/or atrophy is described in the mucosal damage section [11].
3.1 Drugs associated with interference in digestion and/or malabsorption processes
A number of drugs used to treat metabolic conditions such as diabetes mellitus and obesity have intrinsic malabsorptive mechanisms as their main mode of action, and may lead to diarrhea and other related symptoms due to those mechanisms.
Acarbose is a pseudo-tetrasaccharide that selectively inhibits alpha-glucosidase activity in the brush border membrane of the small intestine, an essential enzyme for digestion of starch, maltose and sucrose, delaying glucose absorption from carbohydrate food and thus improving glycemic control among patients with either glucose intolerance or diabetes mellitus [12]. Among common side effects, mainly intrinsic to its mode of action, include flatulence, bloating and diarrhea [13].
Orlistat is a reversible inhibitor of gastric and pancreatic lipoprotein lipases, resulting in inhibition of up to 30% of dietary fat absorption, decreasing fat mass, as well as levels of the regulatory hormone leptin as patients lose weight [14]. Most common adverse events, also intrinsic to its mechanism of action, are diarrhea, steatorrhea, flatulence, bloating and abdominal pain [15]. Recently a second lipase inhibitor, cetilistat, has shown similar efficacy with fewer side effects when compared to orlistat, however prevalence of diarrhea may be as high as 25% of users [16].
Metformin, a dimethyl-biguanide, is an oral glucose-lowering agent absorbed in the small intestine, that has several modes of action: it reduces hepatic glucose production by inhibition of hepatic gluconeogenesis, it increases insulin sensitization by increasing plasma glucagon-like-protein (GLP) type 1 concentrations, with a smaller effect on dipeptidyl-peptidase 4 (DPP-4), resulting in increased glucose uptake in the small intestine [17]. It may also induce alterations in enteral microbiome, particularly increased abundance of Akkermansia muciniphila, a bacterium reported to improve glucose tolerance by increasing endocannabinoids, reducing inflammation, and increasing gut mucous barrier thickness [18]. Despite these beneficial effects, metformin is frequently associated with GI side effects such as flatulence, bloating, dyspepsia, and diarrhea. A number of potential mechanisms of GI intolerance have been described, including altered transport of serotonin, histamine or both, increased enterocyte lactate concentration, dysbiosis, increased bile acid pool in the distal ileum, bile acid receptor activation, and increased conversion from primary to secondary bile acids, which are pro-secretory, leading to increased water and electrolyte luminal secretion. Most of these side effects are dose-related and decrease with time, or after probiotic use, but may persist or even develop after withdrawal [19].
4. Alterations in motility and water absorption/secretion
As previously mentioned, small intestine is both an absorptive and secretory organ, and most of the water and electrolyte handling in the GI tract is regulated at this level by autonomic nerve system as well as by neuromuscular signal pathways [10]. A number of drugs may alter one or several of the mechanisms associated with normal GI motility and/or water and electrolyte secretion including laxatives, motilin analog antibiotics, enterokinetic drugs, secretagogues, colchicine, and prostaglandin analogs.
4.1 Drugs associated with diarrhea due to dysmotility and/or alterations in water absorption and/or secretion
Several antibiotics, particularly the macrolides (e.g., azithromycin, clarithromycin, erythromycin), act as motilin analogues. Motilin is a hormone that induces MMC activity though four distinct phases: first one is a period of near quiescence, second is characterized by irregular small-amplitude waves, phase III induces high-amplitude propulsive contractions all along the small intestine, and during phase IV, motor activity declines to basal values [20]. Although macrolides have a predominant gastroduodenal site-of-action, they may also induce diarrhea by similar MMC-related mechanisms in the small bowel, and are fully reversible after stopping the drug [21].
Laxatives are drugs used to treat different types of constipation, and may cause diarrhea through a number of mechanisms according to pharmacologic type. Osmotic agents extract through osmosis fluid into the intestinal lumen to soften stools an accelerate colon transit time, examples are non-absorbable carbohydrates (e.g., lactulose), polyethylene glycol, as well as citrate, sodium or phosphate-based products. Stimulant agents induce high-amplitude propagated contractions (HAPC) and alter intestinal and colonic absorption as well as secretion mechanisms, examples include the anthraquinones senna and cascara sagrada, bisacodyl and sodium picosulfate. Newer enterokinetic drugs such as tegaserod and prucalopride are agonists of serotonin 5-HT4 receptors throughout the GI tract, they also induce increased MMC and HAPC activity and accelerate enteric transit time. Secretagogue agents such as linaclotide, plecanatide, lubiprostone and tenapanor increase intestinal secretion by one of three different mechanisms: activation of intestinal guanylate cyclase C receptors, increasing intraluminal fluid secretion (e.g., linaclotide, plecanatide), type 2 chloride channel activation in the apical membrane of epithelial cells resulting in increased fluid and chloride secretion (e.g., lubiprostone), and inhibition of gastrointestinal sodium-hydrogen exchanger-3 (e.g., tenapanor). All these drugs are used for treating chronic constipation, and IBS with predominant constipation, and diarrhea is the most common side effect. Colchicine is a cytotoxin used to treat acute attacks of gout, and is frequently associated with diarrhea as enhances intestinal water secretion. Misoprostol, a prostaglandin analogue used in the past for drug-associated peptic ulcer disease or in the obstetric practice, is associated frequently with diarrhea induced by an increased smooth-muscle GI activity [22].
5. Dysbiosis
Dysbiosis is a term used to describe any quantitative and/or qualitative imbalance, dysfunction or disturbance of the gut microbiota and microbiome as an indicator of disease or poor health status [23], and may be caused by a number of risk factors, including medications. Drugs and microbiota have a two-way relationship: drugs exert a significant impact on organs and tissues through their effect on gut microbiota, but in the other hand, microbiota metabolic capacity may affect stability, metabolite production, availability, absorption and thus, increase or decrease efficacy and/or toxicity of different medications [24, 25, 26]. A number of drugs have been described to alter the composition of the gut microbiota, including antibiotics, proton-pump inhibitors (PPI), nonsteroidal anti-inflammatory drugs (NSAID), opioids, metformin, statins, psychotropics, particularly atypical anti-psychotics, levothyroxine, anticoagulants, antiarrhythmics, and several oncologic medications including chemotherapeutic agents, and targeted therapy [18, 27, 28, 29, 30, 31, 32, 33]. A recent study evaluated more than 1000 marketed drugs and found that 24% of them induced significant microbiota composition [30].
5.1 Drugs associated with diarrhea due to dysbiosis
Between 5 and 49% of antibiotic users develop diarrhea during or after treatment. Prevalence is highly variable and can be influenced by reporting country, age, and hospital setting. For instance, antibiotic-associated diarrhea (AAD) represent between 3.2–29% of all causes of diarrhea, with a mean prevalence of 9.6%, in the emergency department this figure raises to 18.6%, and in the intensive care units range from 13.9 to 21.5% [34, 35, 36]. Risk factors for AAD are: increasing age, therapy with more than 1 antibiotic, clindamycin use, long-term antibiotic use, and concomitant PPI use. In most cases, withdrawal of antibiotic may stop diarrhea. However, longer use may predispose to enteral and colonic damage, dysbiosis, and increases risk of developing infections by patobionts (microorganisms that usually interact with host in a symbiotic way, but have the potential of acting as pathogens under certain circumstances). Most common microorganisms associated with DAA are Clostridioides difficile (formerly known as Clostridium difficile), Klebsiella pneumoniae, Clostridium perfringens, and Staphylococcus aureus [37]. Mechanisms associated with DAA can be divided into two main categories: alteration of microbiota/microbiome, and direct effect over intestinal mucosa and motility. Current vision of DAA pathophysiology suggests that antibiotics induce bacterial diversity depletion by at least 30%, with selection of intrinsically resistant micro-organisms, they also may generate gen transfer and de novo mutations conferring resistance to antibiotics. On the other hand, they alter genetic expression, protein activity and cell metabolism, induce under-expression of immunoglobulins, decrease neutrophil and natural killer cell activity, and alter T-cell balance by increasing cytotoxic cells, causing an increased inflammatory tone, that may have a deleterious effect over intestinal permeability [27, 28, 29]. Clostridioides difficile infection (CDI) is a severe form of DAA with a mixed pathophysiologic model including altered host immune factors, bacterial virulence factors, altered intestinal microbiome and metabolic environment [38]. It has been described a decreased microbial diversity, a direct effect over intestinal permeability, a positive effect on toll-like receptor expression and activation, immune system dysregulation, an altered short-chain fatty acid synthesis, as well as an effect on biliary salts increasing bacterial sporulation/germination capacity [25]. Multiple antibiotics have been linked to ICD, particularly clindamycin, which increase odds ratio almost up to 47 times, but different groups of antibiotics such as amoxicillin/clavulanic acid, aztreonam, cefalosporins, ampicillin, fluoroquinolones, macrolides and even tetracycline may increase risk of ICD [39]. During the last 2 years since the beginning of the SARS-COV-2 pandemics, an increasing incidence of ICD has been reported as widespread antibiotic use and abuse [40, 41, 42]. Infection with SARS-COV-2 is associated with two patterns of diarrhea: an early stage, mainly associated to infection itself, apparently caused by direct functional damage of columnar epithelium, and mediated by angiotensin-converting enzyme 2 (ACE-2) receptor interference [40, 42], and a mid to late stage, occurring weeks thereafter, mainly associated with antibiotic use and is related to secondary dysbiosis. A cohort of infected patients that developed diarrhea during the weeks and months following the infection were evaluated, and an AAD prevalence of 16.7% was reported during the follow-up time, with 70% of those developing ICD. In that study, medications associated with increased risk of CDI were amoxicillin (OR 2.2), clarithromycin (OR 3.7), as well as prolonged systemic steroid use (OR 4.4), a drug known for decreasing systemic inflammatory response and immunity [41].
Proton pump inhibitors (PPI) inhibit gastric acid secretion through irreversible blockage of the hydrogen-potassium pump in the parietal cell, and are used for a number of conditions associated with acid exposure such as gastroesophageal reflux disease, peptic-ulcer disease and associated bleeding, and certain types of dyspepsia, and are one of the most common used drugs worldwide [43]. Chronic associated hypochloridria may induce significant changes in microbiota composition throughout the whole gastrointestinal tract. At small intestine long-term PPI use is associated with increasing abundance of Streptococcaceae, Staphylococcaceae, Enterobacteriaceae, Clostridiaceae, and decreased abundance of Bifidobacteriaceae, and an increased risk for small intestine bacterial overgrowth (SIBO), a condition defined by the presence of more than 10 [5] bacteria per ml of duodenal aspirate and characterized by chronic malabsorptive diarrhea has been reported [31, 44, 45]. In the large bowel, prolonged PPI use also reduces microbial diversity, increasing abundance of Proteobacteria, and may also increase risk of CDI (OR 2.3), apparently as a result of a combined pro-inflammatory environment and altered bile-acid homeostasis [45, 46].
A number of different drugs such as atypical anti-psychotics, antidepressants and other mood stabilizers, statins, antiarrhythmics, and anticoagulants are associated with changes in microbiome composition, but its role as a cause of diarrhea is unclear [30, 47, 48]. In several cases, in statins for instance, microbiome changes may be associated with improved outcomes, such as better lipid control [47], in others, as with psychotropics, resulting dysbiosis is associated with anti-commensal activity and drug metabolism alterations, resulting in minor GI symptomatology [30, 48]. Finally, NSAID and immunotherapy are drugs involved in enteropathy by different mechanisms, including dysbiosis, but as mucosal damage is their main pathophysiologic mechanism, are discussed below.
6. Mucosal damage
Drug-associated gastrointestinal damage may affect any part of the GI tract, and small intestine and colon enteropathy accounts for 20–40% of all GI side effects [10]. Mechanisms include direct cytotoxic damage on the intestinal mucosa resulting in several degrees of inflammation, including mucositis, erosions and/or ulcers, hemorrhagic enteritis, alterations in permeability, protein-loss associated enteropathy, and ischemic damage, either caused by long-standing vasoconstriction and/or thrombosis [11]. In some cases, as with chemotherapeutic agents, bone marrow damage and neutropenia may lead to intestinal bacterial translocation, secondary infections with pathogens such as Pseudomonas and fungi, resulting in neutropenic enteritis [49]. Another group of inflammatory conditions characterized by microscopic changes only, without endoscopic abnormalities, may affect any part of the GI tract. When small intestine is the affected organ, the condition is called microscopic enteritis, it is manifested usually by chronic diarrhea, anemia and micronutrient deficiencies, and may present with a variety of histological findings with different inflammatory infiltrates –eosinophilic, lymphocytic, or both, collagen deposits, and in some cases, mucosal atrophy. A number of drugs can be associated with this type of microscopic inflammation, affecting small intestine (i.e., angiotensin inhibitors), colon (PPI, selective serotonin release inhibitor antidepressants (SSRI)), or both (aspirin, NSAID) [50, 51].
6.1 Drugs associated with diarrhea due to macroscopic enteral mucosal damage
Non-steroidal anti-inflammatory drugs (NSAID) are prescribed for a variety of pain and inflammation-associated conditions such as rheumatologic and orthopedic disorders, migraine as well as post-surgical states, and exert their effects through cyclooxygenase (COX) inhibition with resultant decrease of prostaglandin synthesis. NSAID are associated both with upper and lower GI symptoms, as well as mucosal injury at any part of the GI tract, and symptoms vary widely from dyspepsia and heartburn to diarrhea, bloating and overt GI bleeding [7, 8, 11, 52, 53, 54, 55]. Despite gastroduodenal damage is the most common clinical presentation in most NSAID long-term users, up to 70% may develop different degrees of mucosal breaks, including erosions, ulcerations, mucosal hemorrhage or even stenosis in distal portions of the small intestine such as jejunum or ileum, as determined by studies using video capsule endoscopy [56, 57]. Pathophysiology of NSAID-induced enteropathy is a complex one, and includes different mechanisms such as COX inhibition and topical effect, interactions with bacteria and bile acids, as well as overexpression of pro-inflammatory cytokines. Inhibition of COX-1 is associated with decreased mucosal blood flow, mucus production, and intestinal motility, which are predominant, but not critical factors for damage. Topical effect, a COX-independent action requiring mucosal contact of the drug from the luminal side, is considered the triggering event in most cases [53, 54]. Once NSAID is absorbed into the cell, induces mitochondrial injury by producing vacuolation and swelling, and alters oxidative phosphorylation and electron transport, considered one of the earliest intracellular changes after NSAID administration. As a result, intestinal permeability is increased, allowing luminal factors to disrupt the intestinal barrier function [54]. A second mechanism is associated with interactions between microbiota, bile acids and further activation of innate immunity after being exposed to NSAID. Animal models have shown that germ-free rats treated with NSAID do not develop intestinal ulcers unless bacteria are introduced. NSAID induce an increase in Gram-negative bacterial abundance, Clostridium spp. and Enterobacterococci. It is well known that Gram-negative bacterial lipopolysaccharides either activate or inhibit toll-like receptors (TLR), leading to inflammatory cascade activation. It has been suggested that antibiotics against Gram-negative bacteria may be effective in reducing NSAID-induced enteral damage [58]. Some bile acids have shown to induce a pro-inflammatory state associated with interleukin-8 (IL-8) and nuclear factor-kβ activation (NF-κβ) activation [54]. Degree of enteral damage varies according to NSAID type and their effect over COX isoforms: non-selective NSAID such as diclofenac, naproxen, meloxicam, or indomethacin inhibits both COX-1 (a constitutive enzyme involved in mucosal integrity), and COX-2 (an isoform primarily inducible related to inflammation), and therefore exert effects through several mechanisms, including topical and systemic effect, as well as dysbiosis. Naproxen have been associated with increased enteral permeability, while indomethacin induces overexpression of the pro-inflammatory tumor necrosis factor-α (TNF-α). NSAID enterohepatic circulation also plays a role in enteral damage, as many are carboxylic acids conjugated in the liver and excreted to bile, cleaved by beta-glucoronidases in the small bowel lumen, and lately reabsorbed. Acetylsalicylic acid (e.g., aspirin), even at low doses, may induce small bowel mucosal breaks after 2 weeks of therapy, mainly due to direct contact damage. On the other part, selective COX-2 inhibitors (ICOX-2) such as celecoxib and etoricoxib have their effect only over the inflammatory isoform, sparing COX-2 and thus, reducing significantly the risk of mucosal damage, unless they are given for prolonged periods of time, after which may have similar risk to that seen with conventional NSAID [7, 11, 53, 54, 58, 59]. Several approaches may diminish the risk of NSAID-induced enteropathy, including withdrawal of drugs, use of selective ICOX-2, or NSAID at the lower therapeutic dose and for short periods of time, or combination with probiotics such as Lactobacillus casei, VSL#3, and S. boulardii, as well as misoprostol, a prostaglandin analog. PPI are not indicated for either prophylaxis nor therapy, and may indeed increase the risk of intestinal injury, apparently associated with changes in microbiota composition [60]. Novel intestinal-sparing NSAID known as co-drugs, consist of two portions: the “NSAID portion” and a gaseous mediator portion (based on nitric oxide or hydrogen sulfide) that exerts mucosal protective effect while sparing therapeutic effect [53]. Further studies are needed to prove their long-term safety in the GI tract.
In addition to NSAID, several drugs may induce small intestine mucosal disease secondary to vasoconstriction and ischemia, including potassium supplements, oral contraceptive pills, and a number of cytotoxic drugs such as methotrexate and chemotherapeutic agents that are associated with different degrees of mucositis [11], and are discussed below.
Among patients receiving oncologic therapy, those treated with cytotoxic drugs, radiotherapy, targeted therapy, and immunotherapy, particularly with the so-called check-point inhibitors have increased risk of developing various degrees of enteropathy and diarrhea. Between 40 and 100% of cancer patients treated with chemotherapeutic agents develop gut toxicity at some point during their treatment, a term called “chemotherapy-induced intestinal mucositis” (CIM). Prevalence and severity depend on drug and dosing regimen, intensity, route of delivery, and patient predisposing conditions. CIM pathophysiology involves mainly mechanisms related to cell growth inhibition, immunological reactions, and dysbiosis [61]. Cytotoxic agents such as methotrexate, doxorubicin, 5-fluorouracil, capecitabin and irinotecan target enteral tissue by interrupting DNA synthesis by direct injury or by generation of reactive oxygen species, leading to release of active signaling factors (i.e., caspases, β-catenin, and NF-κβ), and eventually to mucosal damage and apoptosis, most of which wipe out the intestinal crypt stem cell pool [61, 62]. A five-stage model for CIM has been proposed, that includes: 1) initiation, 2) signal activation and primary damage response, 3) pathway amplification, 4) tissue inflammation (e.g., erosions, ulcerations, apoptosis), and 5) healing. Clinical picture varies widely, and ranges from short periods of diarrhea and abdominal pain, to severe degrees of enterocolitis. When bone marrow-targeted chemotherapeutic agents are also given, increased risk of neutropenic enterocolitis, abdominal sepsis, and even death may occur. Treatment options, beside adjusting dose or even withdrawal of the drug may include antibiotics and probiotics in order to restore normal gut microbiota and reduce pathogenic intestinal bacteria, octreotide to decrease peptide-associated intestinal secretions, antioxidants such as amifostine, a drug that detoxifies reactive metabolites and scavenges free radicals, steroid anti-inflammatory agents to reduce inflammatory response, and possibly incretins and anti-apoptotic agents, most of which are under investigation [11, 61, 62].
Radiation therapy plays an important role as sole curative therapy for 25% of all cancers, and as adjuvant with chemotherapy in many other cases. During radiotherapy of abdominal and/or pelvic tumors, either the small intestine, colon or both are included in the treatment field and may be prone to toxicity. Risk factors for gut damage include those related to therapy itself such as radiation dose, time-dose-fractionation parameters, volume, and concomitant chemotherapy, and patient-related factors such as advanced age, previous abdominal surgeries, as well as vascular and metabolic comorbidities. Radiation enteropathy is classified as early or delayed when occurs prior or after 3 months after treatment. Early symptoms are nausea and abdominal pain, while diarrhea occurs usually after 2 or 3 weeks of treatment onset, and may persist for longer periods of time. Mechanisms of damage are multifactorial and include increased production of reactive oxygen species, mitotic cell death, mucosal atrophy, endothelitis, microvascular sclerosis, as well as fibrosis of the entire bowel wall. As radiation affects predominantly rapidly proliferating intestinal cells, villus epithelium turnover is insufficient to keep normal absorptive mechanisms. Long-term side-effects may include nutrient malabsorption, anemia, stenosis, and in most severe cases, intestinal obstruction. Management is largely symptomatic, with anti-diarrheal agents. As one of the early mechanisms of damage is production of reactive oxygen species, free radical scavengers such as amifostine can be used for reduction of radiotherapy side effects, but it has a narrow therapeutic time window and potential life-threathening side effects. Several candidate mitigator drugs are under investigation [63].
The immune system has an important role in recognizing and eliminating some tumors. Activation of T cells require a signal between T-cell receptors and the major histocompatibility complex along with a stimulatory checkpoint expressed on T cells called CD-28, and the antigen-presenting cells [64]. Tumors may use immune-checkpoint pathways as a mechanism of immune resistance. Two well-known immune-checkpoint receptors are CTLA-4 (CD152), a negative regulator of T-cell-mediated anti-tumor response, and the programmed cell death protein 1 (PD-1 or CD279), expressed on the surface of activated T cells that interacts with programmed death ligand (PD-L1 and L2), leading to T-cell inactivation [64, 65]. The immune check-point inhibitors (ICI) are monoclonal antibodies that block these pathways, including inhibitors of PD-1, PD-L1, and CTLA-4. Immunomodulating therapy, or immunotherapy act to enhance anti-tumor immune responses by blocking negative regulators of immunity, and has revolutionized cancer therapy by improving survival outcomes and is now the standard treatment of different types of cancer, including several metastatic tumors. Currently approved ICI are the anti-PD-1 pembrolizumab and nivolumab, used for treating melanoma and metastatic non-small-cell lung cancer, the anti-CTLA-4 ipilimumab, a fully humanized monoclonal antibody approved for metastatic melanoma, as well as the anti-PDL-L1 atezolizumab and durvalumab, also for non-small cell lung cancer. Ipilimumab, for instance, competitively binds to CTLA-4, blocking tolerance to self-antigens, without blocking CD28 (a stimulatory checkpoint), increasing T-cell proliferation and activation leading to autoimmune damage to a number of organs, including the entire GI tract. In a similar way, anti-PD1/PDL-1 agents such as nivolumab and pembrolizumab increase T-cell response while reducing self-tolerance, and the result is similar to that seen with ipiliumumab [64, 65, 66, 67]. This kind of damage behaves similarly to that seen on inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis, as well as their clinical presentation, with various degrees of enteral and/or colonic damage ranging from erosions and ulcerations to obstruction, and wall necrosis, and presenting as chronic diarrhea, abdominal pain, GI bleeding and progressive anemia [68]. Histologic findings range from combined acute (e.g., neutrophils) and chronic (i.e., lymphocytes and plasma cells) inflammatory infiltrates, eosinophilia, atrophy, granulomatous reaction, crypt abscesses, and bullous pemphigoid, and in most severe cases an increased apoptotic activity within the crypt epithelium may be seen, affecting small intestine, colon or both [69, 70].Treatment is similar to that given for IBD and may include mesalazine, systemic corticosteroids, and in refractory cases, biologic therapy with infliximab [71, 72].
Another category of oncologic treatment is the called targeted therapy, which acts by identifying and attacking certain types of cancer cells, and by inhibiting oncogenes driving aberrant growth, and may include monoclonal antibodies and small molecule inhibitors. A number of targeted therapies are approved for different types of cancer. Many of them may be associated with different degrees of oral and GI mucositis, particularly cetuximab, erlotinib, gefitinib, lapatinib, sorafenib, and sunitinib, with odds ratio for diarrhea and enteritis ranging from 1.5 to 4.5 [73]. More recently, the HER-2-targeted monoclonal antibody trastuzumab, used for HER-2-overexpressing breast cancer, has been associated with a number of GI manifestations associated to toxicity, including diarrhea, abdominal pain, and ulcerative enterocolitis similar to that seen with ICI. Mechanism underlying GI toxicity remains under investigation, but it seems to be associated with HER-2 receptors in gut epithelial cells [74]. Treatment is empiric, following the same principles as for ICI.
6.2 Drugs associated with diarrhea due to microscopic enteral mucosal damage
A number of drugs are associated with an increased risk of microscopic enteritis and/or colitis, in some cases eosinophilic enteritis, or even may resemble microscopic enteral damage of other diseases, such as celiac disease. Microscopic enteritis encompasses a group of disorders characterized by microscopic mucosal and/or mucosal inflammatory infiltrates by a number of different inflammatory cells, including lymphocytes (i.e., lymphocytic enteritis/colitis), eosinophils (e.g., eosinophilic enteritis/colitis), and lymphocytes along with collagen deposits (i.e., collagenous sprue/collagenous colitis), in absence of significant macroscopic mucosal damage, leading to watery diarrhea [50, 75, 76, 77]. In the small bowel, microscopic enteritis may also be associated with mucosal atrophy in some cases, and the clinical picture may be that of malabsorptive diarrhea, with foul-smelling feces, steatorrhea, and anemia [76]. In most cases an autoimmune predisposition has been proposed, but when disease develops during or shortly after a specific drug use, causality for drug-induced disease can be proposed according to a World Health Organization system based on temporal sequence, prior information of the drug, dose–response relationship, exclusion of other etiologies, and re-challenge [78]. Pathophysiology mechanisms are not clear, and may involve activation of the immune system in response to exposure to luminal antigenic factors, including drug-itself, metabolites, bile-acids, or may be associated with changes in microbiota linked to long-term drug use, such as in PPI.
A number of drugs have been linked to microscopic colitis, including aspirin, NSAID, PPI, SSRI, particularly sertraline, clozapine, ticlopidine, flavonoids and acarbose [51]. A recent case–control study found a significant increased risk for microscopic colitis with current use of NSAID, PPI, and SSRI with adjusted odd ratios of 1.86, 3.37 and 2.03 respectively. Current PPI use was associated also with increased risk of both lymphocytic (OR 2.06) and collagenous colitis (OR 5.3), whereas current NSAID use was associated with increased risk of collagenous colitis (OR 2.32), and current SSRI use increased risk of lymphocytic colitis (OR 2.28). Long-term PPI and/or NSAID use had the highest odds ratio (4.6 and 4.8 respectively) for developing microscopic colitis [79]. As previously mentioned, NSAID may affect any part of the GI tract, by a number of different pathophysiologic mechanisms. In the small intestine NSAID-associated damage ranges from microscopic enteritis to severe mucosal affection with erosions and/or ulcers. Histologic manifestations of NSAID may resemble those of celiac disease, with villous blunting and intraepithelial lymphocytosis, and can be found in any part of the small intestine [80].
Eosinophilic enteritis and colitis are included in the group of eosinophilic gastrointestinal disorders, and are characterized by a high eosinophilic infiltrate in the gut wall, without evidence of other causes. Pathophysiology involves a combination of genetic predisposition, dysbiosis, and a triggering factor, usually an allergen, that may include drugs, followed by recruitment and activation of eosinophils to sites of inflammation regulated by pro-inflammatory cytokines [81]. Drugs such as clozapine, naproxen, carbamazepine, and rifampicin have been associated with increased eosinophilic infiltrate in the distal ileum and colon [77]. More recently the anti-CTLA-4 check-point inhibitor ipilimumab and the anti-PD1 nivolumab have been link to eosinophilic enteritis [70]. Other immunosuppressant drugs such as mycophenolate mofetil, a drug used to prevent acute allograft rejection may affect both small bowel and colon, causing an eosinophilic-associated damage, with features similar to those of acute graft-versus-host disease [82].
Angiotensin II receptor inhibitors (AT-II RI) are one of the most common drugs for treating high blood pressure, with a generally safe side-effect profile. In 2012 a case series of 22 patients developing chronic diarrhea and weight loss while taking olmesartan was published. None had positive celiac serology, and a combination of villous atrophy and variable degrees of inflammation including collagen deposits was observed in small intestine biopsies, with clinical and histologic recovery after discontinuation of the drug [83]. More recently, other AT-II RI have been also associated with different degrees of enteropathy. A systematic review included 248 cases, most of which were associated with olmesartan (94%), however telmisartan, irbesartan, valsartan, losartan and eprosartan also were reported to be associated with various degrees of enteropathy. Interestingly, despite negative serology in most cases, 71% had a positive HLA-DQ2 or DQ-8, haplotypes associated with celiac disease [84].
7. Conclusion
Drugs are a common cause of chronic diarrhea and enteropathy by a number of mechanisms including intrinsic mode of action, malabsorption, dysbiosis, increased GI motility, alterations in water and electrolyte absorption and secretion mechanisms, autoimmune macroscopic or microscopic damage, and cytotoxic effect. Site of damage may include either part of the small intestine, colon, or both, and can be manifested by malabsorptive, inflammatory or watery diarrhea. In most cases diarrhea subsides after drug withdrawal, but in some cases a number of inflammatory conditions requiring other forms of therapy may be needed.
\n',keywords:"drugs, medications, chronic diarrhea, enteropathy, malabsorption, side-effect, bowel inflammation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80978.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80978.xml",downloadPdfUrl:"/chapter/pdf-download/80978",previewPdfUrl:"/chapter/pdf-preview/80978",totalDownloads:284,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 3rd 2022",dateReviewed:"February 15th 2022",datePrePublished:"March 25th 2022",datePublished:null,dateFinished:"March 25th 2022",readingETA:"0",abstract:"Over 700 drugs have been implicated as cause of chronic diarrhea and potential enteral damage. Pathophysiologic mechanisms include intrinsic malabsorption as their main mode of action (i.e., acarbose or orlistat), increased risk of microscopic colitis/enteritis (proton-pump inhibitors (PPI), non-steroidal anti-inflammatory drugs (NSAID), selective serotonin reuptake inhibitors (SSRI)), dysbiosis (antibiotics, metformin, PPI), and microscopic or overt enteropathy (angiotensin inhibitors, antineoplastic agents, targeted therapy and check-point inhibitors). According to type, diarrhea can be malabsorptive, inflammatory or mixed, and may affect different portions of small intestine, colon, or both. Drug-induced enteropathy ranges from asymptomatic histological changes to macroscopic damage similar to that seen in inflammatory bowel disease. Treatment may include discontinuation of drug, correction of dysbiosis, and in severe cases, directed therapy towards intestinal wall inflammatory states, in similar mode as in other inflammatory bowel diseases.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80978",risUrl:"/chapter/ris/80978",signatures:"Octavio Gómez-Escudero",book:{id:"11272",type:"book",title:"Benign Anorectal Disorders - An Update",subtitle:null,fullTitle:"Benign Anorectal Disorders - An Update",slug:null,publishedDate:null,bookSignature:"Dr. Alberto Vannelli and Dr. Daniela Cornelia Lazar",coverURL:"https://cdn.intechopen.com/books/images_new/11272.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-706-9",printIsbn:"978-1-80355-705-2",pdfIsbn:"978-1-80355-707-6",isAvailableForWebshopOrdering:!0,editors:[{id:"34524",title:"Dr.",name:"Alberto",middleName:null,surname:"Vannelli",slug:"alberto-vannelli",fullName:"Alberto Vannelli"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Mechanisms of enteral damage",level:"1"},{id:"sec_3",title:"3. Maldigestion and malabsorption",level:"1"},{id:"sec_3_2",title:"3.1 Drugs associated with interference in digestion and/or malabsorption processes",level:"2"},{id:"sec_5",title:"4. Alterations in motility and water absorption/secretion",level:"1"},{id:"sec_5_2",title:"4.1 Drugs associated with diarrhea due to dysmotility and/or alterations in water absorption and/or secretion",level:"2"},{id:"sec_7",title:"5. Dysbiosis",level:"1"},{id:"sec_7_2",title:"5.1 Drugs associated with diarrhea due to dysbiosis",level:"2"},{id:"sec_9",title:"6. Mucosal damage",level:"1"},{id:"sec_9_2",title:"6.1 Drugs associated with diarrhea due to macroscopic enteral mucosal damage",level:"2"},{id:"sec_10_2",title:"6.2 Drugs associated with diarrhea due to microscopic enteral mucosal damage",level:"2"},{id:"sec_12",title:"7. 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\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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from Tehran University of Medical Sciences, Iran. He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. 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