Features of various viral vectors for gene therapy applications.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"7389",leadTitle:null,fullTitle:"Redefining Standard Model Cosmology",title:"Redefining Standard Model Cosmology",subtitle:null,reviewType:"peer-reviewed",abstract:"The current standard model of cosmology is based primarily on two incompatible theoretical models: (1) the standard model of particle physics, which describes the physics of the very small in terms of quantum mechanics, and (2) the general theory of relativity, which describes the physics of the very large in terms of classical physics. Both these theoretical models are considered to be incomplete in the sense that they do not provide any understanding of several empirical observations, such as the Big Bang, dark matter, dark energy, gravity, and matter-antimatter asymmetry in the universe. The main aim of this book is to discuss these serious problems that threaten to undermine the current standard model of cosmology.",isbn:"978-1-83880-864-8",printIsbn:"978-1-83880-863-1",pdfIsbn:"978-1-83880-865-5",doi:"10.5772/intechopen.75275",price:119,priceEur:129,priceUsd:155,slug:"redefining-standard-model-cosmology",numberOfPages:122,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"25572d83043224835eabdf8632fc64ed",bookSignature:"Brian Albert Robson",publishedDate:"June 12th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7389.jpg",numberOfDownloads:6458,numberOfWosCitations:3,numberOfCrossrefCitations:5,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:7,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:15,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 30th 2018",dateEndSecondStepPublish:"June 20th 2018",dateEndThirdStepPublish:"August 19th 2018",dateEndFourthStepPublish:"November 7th 2018",dateEndFifthStepPublish:"January 6th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"102886",title:"Prof.",name:"Brian Albert",middleName:null,surname:"Robson",slug:"brian-albert-robson",fullName:"Brian Albert Robson",profilePictureURL:"https://mts.intechopen.com/storage/users/102886/images/system/102886.jpeg",biography:"Professor Brian Albert Robson obtained MSc, PhD and DSc degrees in Physics from the University of Melbourne, Australia. He is a Fellow of both the Australian Institute of Physics and the UK Institute of Physics. Currently he is an Honorary Professor in the Research School of Physics, The Australian National University, Canberra. During his academic career, he served for four years as Officer-in-Charge of the Australian National University’s first computer, for nine years as Head of the Department of Theoretical Physics, and for two years as Associate Director of the Research School of Physics and Engineering. Professor Robson has published more than 150 scientific publications mainly in the areas of nuclear physics, particle physics, gravitation and cosmology.",institutionString:"The Australian National University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Australian National University",institutionURL:null,country:{name:"Australia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"633",title:"Physical Cosmology",slug:"cosmology-physical-cosmology"}],chapters:[{id:"66783",title:"Introductory Chapter: Standard Model of Cosmology",doi:"10.5772/intechopen.85605",slug:"introductory-chapter-standard-model-of-cosmology",totalDownloads:1476,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:1,abstract:null,signatures:"Brian Albert Robson",downloadPdfUrl:"/chapter/pdf-download/66783",previewPdfUrl:"/chapter/pdf-preview/66783",authors:[{id:"102886",title:"Prof.",name:"Brian Albert",surname:"Robson",slug:"brian-albert-robson",fullName:"Brian Albert Robson"}],corrections:null},{id:"64538",title:"Tired Light Denies the Big Bang",doi:"10.5772/intechopen.81233",slug:"tired-light-denies-the-big-bang",totalDownloads:1331,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:1,abstract:"More and more problems related to Big Bang have been appeared in recent years. All the problems are due to the Doppler interpretation of redshift. The “tired light” theory, proposed in 1929 by Zwicky and most recently developed by Shao in 2013, gives a new explanation for redshift. The theory has shown that the redshift is induced from the energy loss of photons by the interaction with material particles on their journey through cosmological space. The basic principles related to the energy transfer are mainly the mass-energy equivalence and the Lorentz theory. Problems, such as super velocity, the horizon problem, the cosmological microwave background radiation, and Olbers’ paradox, vanish in the cosmological model of “tired light” theory. The model describes a boundless and timeless Cosmos.",signatures:"Ming-Hui Shao, Na Wang and Zhi-Fu Gao",downloadPdfUrl:"/chapter/pdf-download/64538",previewPdfUrl:"/chapter/pdf-preview/64538",authors:[null],corrections:null},{id:"63285",title:"Model of an Evolving and Dynamic Universe: Creation without a Big Bang",doi:"10.5772/intechopen.80479",slug:"model-of-an-evolving-and-dynamic-universe-creation-without-a-big-bang",totalDownloads:767,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter describes a non-relativistic, dynamic universe that evolves through continuous transformations of energy forms in contradistinction to a devolving Big Bang model. The new cosmology is accurately consistent with Hubble’s galactic redshifts, interpreted as simple Doppler shifts of fleeing galaxies, and as viewed from any arbitrary observer in the universe. It postulates the existence of repulsive electromagnetic (EM) force fields between galaxies, while maintaining the purely gravitational dynamics within each galaxy. Observed cosmic redshifts of galaxies and their apparent velocities and accelerations are matched, if galactic cores are assumed to have an unbalanced electric charge of 3 × 1032 C for an average galaxy with a mass of 4 × 1041 kg. Valid arguments are presented for the probable existence of intergalactic EM fields emanating from Supermassive Black Holes (SMBHs) in galactic cores. Special sections in this chapter are devoted: (a) to suggest plausible sources of new matter creation, (b) to discuss how Quasi-stellar Objects (QSOs or Quasars) can fit into this cosmological model, and (c) to counter critiques of the model.",signatures:"Dietmar E. Rothe",downloadPdfUrl:"/chapter/pdf-download/63285",previewPdfUrl:"/chapter/pdf-preview/63285",authors:[null],corrections:null},{id:"64664",title:"Primordial Magnetic Fields and the CMB",doi:"10.5772/intechopen.81853",slug:"primordial-magnetic-fields-and-the-cmb",totalDownloads:1096,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"The origin of large-scale magnetic fields is one of the most puzzling topics in cosmology and astrophysics. It is assumed that the observed magnetic fields result from the amplification of an initial field produced in the early Universe. If these fields really were present before the recombination era, these could have some effects on big bang nucleosynthesis (BBN) and electroweak baryogenesis process, and it would leave imprints in the temperature and polarization anisotropies of the cosmic microwave background (CMB). In this chapter, we analyze the effects of a background primordial magnetic field (PMF) on the CMB anisotropies and how we can have sight the mechanisms of generation of these fields through these features. We start explaining briefly why primordial magnetic fields are interesting to cosmology, and we discuss some theoretical models that generate primordial magnetic fields. Finally, we will show the statistics used for describing those fields, and by using CLASS and Monte Python codes, we will observe the main features that these fields leave on the CMB anisotropies.",signatures:"Héctor Javier Hortúa and Leonardo Castañeda",downloadPdfUrl:"/chapter/pdf-download/64664",previewPdfUrl:"/chapter/pdf-preview/64664",authors:[null],corrections:null},{id:"64713",title:"Cosmological Solutions to Polynomial Affine Gravity in the Torsion-Free Sector",doi:"10.5772/intechopen.81231",slug:"cosmological-solutions-to-polynomial-affine-gravity-in-the-torsion-free-sector",totalDownloads:951,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"We find possible cosmological models of the polynomial affine gravity described by connections that are either compatible or not with a metric. When possible, we compare them with those of general relativity. We show that the set of cosmological vacuum solutions in general relativity are a subset of the solutions of polynomial affine gravity. In our model, the cosmological constant appears as an integration constant, and, additionally, we show that some forms of matter can be emulated by the affine structure—even in the metric compatible case. In the case of connections not compatible with a metric, we obtain formal families of solutions, which should be constrained by physical arguments. We show that for a certain parametrisation of the connection, the affine Ricci-flat condition yields the cosmological field equations of general relativity coupled with a perfect fluid, pointing towards a geometrical emulation of—what is interpreted in general relativity as—matter effects.",signatures:"Oscar Castillo-Felisola, José Perdiguero and Oscar Orellana",downloadPdfUrl:"/chapter/pdf-download/64713",previewPdfUrl:"/chapter/pdf-preview/64713",authors:[null],corrections:null},{id:"64285",title:"Cosmological Constant and Particle Masses in Conformal Quantum Gravity",doi:"10.5772/intechopen.81875",slug:"cosmological-constant-and-particle-masses-in-conformal-quantum-gravity",totalDownloads:837,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"It has been proposed that the equivalence principle of quantum gravity should be introduced as a fundamental symmetry in quantum gravity to reconcile quantum mechanics and general relativity. Such symmetry extends the equivalence principle of general relativity to the observer frames of reference which are in quantum mechanical motions. That means the quantum state of a particle is relative to the observer frame which can also be itself in a quantum mechanical state. As a consequence, all the physical laws apply not just to the frames of reference in any kind of motion as in the general relativity but also the same in the reference frames in quantum mechanical motions as well. The classical space-time concept therefore requires to be significantly modified. Because of such principle, the quantum gravity should be formulated in the quantum space-time-matter space with local conformal symmetry. In this book chapter, we explore the formulation of the quantum space-time-matter geometry with local conformal symmetry for discussing the relationship between the cosmological constant and quantum gravity as well as the mass spectrum of fundamental particles. The mathematical expressions of the fundamental particle masses and cosmological constant are discussed.",signatures:"Ho-Ming Mok",downloadPdfUrl:"/chapter/pdf-download/64285",previewPdfUrl:"/chapter/pdf-preview/64285",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"3211",title:"Open Questions in Cosmology",subtitle:null,isOpenForSubmission:!1,hash:"6e4e21582afb611a1552d8493d66f82c",slug:"open-questions-in-cosmology",bookSignature:"Gonzalo J. Olmo",coverURL:"https://cdn.intechopen.com/books/images_new/3211.jpg",editedByType:"Edited by",editors:[{id:"61779",title:"Dr.",name:"Gonzalo J.",surname:"Olmo",slug:"gonzalo-j.-olmo",fullName:"Gonzalo J. 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\r\n\tField programmable array (FPGA) is a programmable device that uses prebuilt logic blocks and routing resources to implement the system without adding additional fabrication steps. The reconfigurable system has applications in computational acceleration and prototyping application-specific integrated circuits (ASIC). The final design of ASIC or processor using FPGA will be continue reprogrammed until we have a bug-free design. The demand for FPGA is expected to increase continuously due to increased adoption of FPGA in areas of enterprise businesses as well as ASIC design because they can be dynamically reprogrammed. The optimized FPGAs are more power-efficient than running equivalent workloads on a CPU. The combination of versatility, efficiency, and performance of FPGAs make the design process more data at a lower total cost of ownership (TCO). Seeing the numerous application of FPGAs irrespective of the domain, it is necessary to understand FPGA in-depth in terms of architecture and applications.
",isbn:"978-1-80356-675-7",printIsbn:"978-1-80356-674-0",pdfIsbn:"978-1-80356-676-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"d23889b993e9babdb668001a673adb9a",bookSignature:"Dr. Ajay Kumar Singh",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11946.jpg",keywords:"Field Programmable Array, Architecture, Algorithm, Logic Design, Validation, Logic Simulation, Logic Gate, Challenges in FPGA Design, Power-Efficient, Energy Conversion, Embedded System, Low Power Applications",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 22nd 2022",dateEndSecondStepPublish:"June 1st 2022",dateEndThirdStepPublish:"July 31st 2022",dateEndFourthStepPublish:"October 19th 2022",dateEndFifthStepPublish:"December 18th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Singh's areas of interest are modeling of submicron MOS devices, Low power VLSI circuit design, Nanotechnology, and Renewable energy sources. He has published more than 95 research papers in various International Journals and conferences and reviewed many research papers submitted to various international journals. He has more than 27 years of teaching experience for graduate and undergraduate students. Dr.Singh is a Senior Member of IEEE and Fellow IETE-India.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"192404",title:"Dr.",name:"Ajay",middleName:"Kumar",surname:"Singh",slug:"ajay-singh",fullName:"Ajay Singh",profilePictureURL:"https://mts.intechopen.com/storage/users/192404/images/system/192404.jpg",biography:"Dr Singh is working as Professor in the Electronics and Communication Engineering of NIIT University-Neemarana Rajasthan India. Prior to joining this Unversity, he was Associate Professor in Faculty of Engineering and Technology, Multimedia University-Melaka Malaysia. He has more than 27 years of teaching experience for graduate and undergraduate students. He has successfully supervised 4 PhDs and 7 Master thesis. His areas of interest are modeling of submicron MOS devices, Low power VLSI circuit design, Nanotechnology and Renewable energy sources. He has published more than 95 research papers in various International Journals and conferences and reviewed many research papers submitted to various international journals. He is associated with many research journals in their editorial board. 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Under physiological conditions, β cells synthesize and secrete insulin in response to changes in blood glucose levels. Insulin, in turn, acts on other cells to promote glucose uptake from the blood and thus lower blood glucose levels to normal. Without sufficient numbers of functional β cells, insulin production becomes inadequate and unable to promptly restore normal blood glucose levels. Over time, chronically elevated blood glucose levels, termed hyperglycemia, cause numerous secondary complications, ultimately leading to widespread tissue and organ damage, as well as increased mortality. According to the National Diabetes Statistics Report, 29.1 million people, or 9.3% of the US population, have diabetes [1], with T1DM accounting for roughly 5% of all diagnosed cases in the adult population. The total economic cost of diabetes is estimated to be $245 billion per year, with T1DM costing an estimated $8–14 billion per year. Thus, diabetes poses a significant burden to our society. Unfortunately, no cure exists for T1DM.
\nWhile there is currently no cure, several therapies exist to better control blood glucose levels. The most common form of therapy involves use of synthetic insulin, which typically requires multiple insulin injections per day. Unfortunately, this option is cumbersome and unable to restore perfect glucose control. As a result, exogenous insulin therapy delays the onset and reduces the severity of secondary complications but is unable to prevent them [2]. In addition, exogenous insulin therapy can cause hypoglycemia, a potentially life-threatening condition characterized by dangerously low blood glucose levels. The insufficiencies of exogenous insulin therapy arise from the fact that most insulin regimens are unable to mimic normal β cell secretion in response to continually fluctuating blood glucose levels. In an effort to improve upon exogenous insulin therapy and better imitate normal physiology, specialized insulin pumps, dubbed artificial pancreata, have been developed to deliver insulin when needed by continuously monitoring blood glucose levels [3, 4]. Artificial pancreata are able to improve glycemic control, but the implanted glucose sensors inevitably accumulate serum proteins that can compromise the accuracy of glucose measurements and consequently affect the precision of insulin delivered, limiting its long-term effectiveness. Ultimately, exogenous insulin therapies provide a suboptimal therapy for T1DM. Conversely, tighter glucose control can be attained through whole-pancreas transplantation [5], but this therapy is severely hampered by a shortage of donor organs and further complicated by the need for lifelong immunosuppression. Transplantation of pancreatic islets was anticipated to minimize the impact of donor shortage, as islets from one donor could be expanded
Gene therapy-based treatment options have emerged as a promising alternative. Gene therapy refers to any technique aimed at using genes to treat or prevent diseases, whether it be through delivery of a functional gene to replace a defective one or through knockdown of dysfunctional genes using gene silencing technologies. For T1DM, three primary gene therapy approaches have been explored to prevent or treat the disease. First, researchers have attempted to prevent the autoimmune destruction of β cells by modifying the immune system. Second, researchers have attempted to generate surrogate β cells from native non-β cells to replace the function of those cells lost from autoimmune destruction. Third, researchers have taken a more straightforward approach and simply attempted to replace the primary function of β cells—insulin production—to treat T1DM. Not surprisingly, each of these approaches has their own advantages and disadvantages, which we will outline in the following sections.
\nThe most logical therapy for T1DM would be to take preemptive measures and prevent the development of autoimmunity that causes β cell destruction in susceptible individuals. Not surprisingly, many researchers have pursued this strategy as a potential alternative to current treatment options, and to do so, various genetic modifications to both β cells and immune cells have been tested in experimental models of T1DM. First, researchers have sought to induce immune tolerance so that β cell antigens are no longer recognized as foreign. French and colleagues sought to induce immune tolerance by driving intrathymic expression of proinsulin under the control of the major histocompatibility complex (MHC) class II promoter and found that it prevented the onset of T1DM. Similarly, Tian and colleagues transduced autologous bone marrow hematopoietic stem cells of non-obese diabetic (NOD) mice with diabetes-resistant MHC class II I-Aβ chain molecules to examine whether this could prevent the development of diabetes. Indeed, they found that expression of this diabetes-associated allele prevented the development of autoreactive T cells by intrathymic deletion and protected the mice from developing insulitis and diabetes [8]. Second, groups have aimed to modulate the immune system through cytokine-based approaches. For example, gene transfer of transforming growth factor-β and calcitonin gene-related peptide have been shown to prevent the onset of diabetes in NOD mice [9, 10]. Lastly, groups have attempted to modify residual β cells so that they can resist autoimmune destruction, an event that generally occurs through apoptosis. Liu
Although these preventative options have shown promise, they are hampered by several limitations: (1) These strategies rely on the early detection of diabetes. This is difficult because individuals often do not become symptomatic until they have already lost greater than 80% of their β cells. Thus, efforts to protect the remaining β cells would still leave the patient hyperglycemic. (2) T1DM is a multifactorial disease, making it nearly impossible to accurately predict who from the general population will succumb to the disease [12]. Thus, early intervention can be risky and perhaps even accelerate the progression of the disease. (3) The immune system is highly evolved and its complexities are not well understood. Further, innumerable functional redundancies exist that allow the immune system to compensate for the loss of any single factor or pathway. At our current level of understanding, it seems unlikely that selectively targeting a specific component of the immune system could prevent the autoimmune destruction of remaining β cells. As a result, other gene therapy strategies have been explored.
\nThe goal of reprogramming non-β cells into surrogate β cells is to create replacement cells that are as similar to native β cells as possible, including the ability to not only synthesize insulin but also store it within secretory granules and secrete it instantaneously upon elevations in blood glucose levels. The most common way that researchers have done so is by overexpressing β cell-specific transcription factors in non-β cells. Transcription factors are DNA-binding proteins that modulate the rate of transcription of specific genes in a cell type-specific manner. During development, transcription factors play a critical role in executing differentiation programs by driving the expression of cell type-specific genes, and during adulthood, transcription factors are important for maintaining the differentiated status of somatic cells. For β cells, the transcription factors PDX1, NeuroD1, Neurog3, Pax4, Pax6, Nkx6.1, Nkx2.2, and MafA are among the many transcription factors ultimately responsible for directing and/or maintaining the β cell fate.
\nWith the aforementioned knowledge in mind, researchers have attempted to overexpress these transcription factors in a variety of cell types with the hopes of reprogramming them into β cells, including pancreatic exocrine cells [13, 14], keratinocytes [15], hepatic oval stem cells [16], adipose-derived stem cells [17], and hepatocytes. Of these, hepatocytes have been most commonly targeted due to the fact that they are closely related developmentally to β cells and easy to target. PDX1, which regulates early pancreas morphogenesis during development and controls glucose-dependent insulin expression in β cells, has been shown to be indispensable for the conversion of non-β cells into β cells. For example, Ferber
Despite these positive findings, the long-term success of reprogramming strategies will rely on the ability of newly formed β cells to evade preexisting autoimmunity. This is particularly relevant given the abundance and diversity of previously identified autoantigens involved in the autoimmune destruction of native β cells [99]. It is expected that the more similar a surrogate β cell is to a native β cell, the more likely it will be targeted by the host’s immune system and destroyed. For instance, while Ferber
Given the autoimmune nature of T1DM, it may actually be unfavorable to produce surrogate cells that closely resemble native β cells. Since the primary function of β cells is to synthesize and secrete insulin, many groups have taken a humbler approach and simply aimed to restore insulin production in non-β cells, a field known as insulin gene therapy. Although insulin is also an autoantigen known to result in native β cell destruction [28], the theoretical risk of recurring autoimmunity is greatly reduced. Of course, it should be emphasized that β cells are extremely precise in their ability to secrete insulin upon demand, so simply expressing insulin in a non-β cell would likely not be an effective means of treating T1DM. For instance, an individual would not want to be producing high levels of insulin at all times because this would cause hypoglycemic episodes. Thus, to understand whether insulin gene therapy is indeed a viable option to treat T1DM, a clear understanding of the intricacies and aptitude of β cells must first be attained. In the following sections, we will outline what makes a β cell so adept at controlling glycemia and cover what criteria must be met for insulin gene therapy approaches to be successful. We will then present an overview of the field of insulin gene therapy to treat T1DM, with an emphasis on the unique challenges not found in other gene therapy applications. More specifically, we will go into detail about the choice of cell type to target
In order to determine whether insulin gene therapy possesses the necessary elegance to be a viable treatment option, it is important to understand the key features of β cells that make them so adept at controlling glycemia and the minimum requirements that absolutely must be met to replace their function. Native β cells possess several important features that together allow them to precisely control blood glucose levels. Specifically, the β cell has the ability to regulate insulin production at the transcriptional, post-transcriptional, translational, and post-translational levels, as well as the ability to store and secrete insulin in a highly regulated fashion in response to glucose. While no individual feature is sufficient in itself to control glycemia, nor specific to β cells, the combination of features makes it a remarkably competent cell for its task.
\nFirst and most importantly, β cells have the ability to sense and quickly respond to small changes in circulating glucose levels over a broad range of physiological concentrations (2–20 mM) through concentration-dependent entry and metabolism of glucose. They do so through the activity of glucose transporter-2 (GLUT2) and glucokinase. GLUT2 is a transmembrane protein that enables glucose transport across cell membranes, whereas glucokinase is an enzyme that phosphorylates glucose to initiate its intracellular metabolism. GLUT2 and glucokinase have been dubbed the “glucose sensors” of β cells because they enable β cells to sense glucose over a very broad range of concentrations. They are able to do so due to their high Km for glucose (~17 and 8 mM, respectively), which allows their activity to vary substantially based on glucose availability [29].
\nβ cells also have the ability to secrete insulin in a precisely regulated fashion in response to elevations in blood glucose levels. β cells do so through their capacity to (1) synthesize and store large quantities of insulin within secretory vesicles and (2) generate secondary stimulus-secretion coupling signals to activate nearly instantaneous insulin vesicle exocytosis. Remarkably, β cells can secrete substantial quantities of insulin within a minute after exposure to elevated glucose. This is a consequence of their metabolic capabilities; β cells possess a unique combination of metabolic enzymes that ultimately leads to the generation of signals capable of altering insulin secretion in response to glucose metabolism. Namely, β cells, but not other mammalian cell types, have negligible lactate dehydrogenase activity while displaying increased pyruvate carboxylase activity, which directs pyruvate almost entirely toward mitochondria for subsequent metabolism via the tricarboxylic acid cycle and oxidative phosphorylation [30]. In so doing, β cells increase their ratio of ATP/ADP and activate ATP-sensitive K+ channels, a key stimulus leading to insulin vesicle exocytosis.
\nFurthermore, β cells have remarkable control of insulin biosynthesis at the transcriptional, post-transcriptional, translational, and post-translational levels, with each level of control being regulated by glucose availability. At the transcriptional level, increased glucose levels lead to upregulated insulin expression through the enhanced activity of the transcription factors, PDX1 and MafA [31, 32]. At the post-transcriptional and translational levels, β cells have glucose-responsive mechanisms to modulate insulin mRNA stability and the rate of translation, respectively. This glucose-dependent regulation is primarily governed by an RNA-binding protein known as polypyrimidine tract-binding protein (PTB). Association of PTB with a pyrimidine-rich stretch in the 3′ untranslated region (UTR) of the preproinsulin mRNA has been shown to be responsible for glucose-dependent changes in its stability and rate of translation [33, 34]. In fact, the half-life of preproinsulin mRNA has been shown to increase nearly 3-fold as a result of PTB association [35, 36]. At the post-translational level, β cells possess specific enzymes that allow them to process proinsulin—a precursor form—into fully active insulin. Proinsulin conversion involves removal of two basic pairs of amino acids—the C-peptide—and is mediated by the β cell endoproteases, PC1/3 and PC2, and the exopeptidase, carboxypeptidase-H [37, 38]. Altogether, β cells have a variety of glucose-dependent mechanisms to control insulin output.
\nβ cells further refine insulin biosynthesis and secretion in response to other circulating metabolites. First, the gut produces the peptide hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1, which bind specific receptors found predominantly on β cells to bolster insulin production [39]. Second, specific amino acids and free fatty acids can serve as insulin secretagogues. While some amino acids and free fatty acids can actively promote insulin secretion, most of them simply have a role in amplifying the stimulatory effects of glucose [40]. Third, metabolic stress can induce neuronal signals that influence insulin output [41]. Together, these inputs regulate insulin production and secretion from β cells to more precisely maintain glucose levels within a normal range.
\nCombining all the remarkable features of the β cell, the end product is a cell with impressive glucose sensitivity, the ability to control insulin biosynthesis at several levels in a glucose-dependent fashion, and the ability to store, process, and secrete insulin almost instantaneously in response to glucose. The β cell is truly impressive. With this knowledge in mind, it would be easy to argue that insulin gene therapy lacks the sophistication necessary to adequately treat T1DM, especially given its relative simplicity. However, it is important to keep in mind that the most commonly used treatment for T1DM currently involves repeated injections of synthetic insulin. While this treatment option holds very little sophistication or biomimicry, it has still proven effective enough to remain a viable option since it was first employed as a medication in 1922. With that being said, any treatment that could provide better glycemic control while averting the cumbersome nature of synthetic insulin therapy would be a noteworthy improvement. So, beyond the ability to produce insulin alone (a feat that could likely be achieved in any cell type using a strong constitutive promoter), what other features of β cells are absolutely critical for the success of insulin gene therapy applications?
\nGiven that glucose is the primary stimulus leading to the production of insulin and subsequent clearance of itself, the impressive glucose sensitivity conferred by GLUT2 and glucokinase is a necessary feature that must be present in an insulin-producing surrogate β cell. Without these proteins, a surrogate β cell would not be able to precisely sense glucose concentration and control insulin output over a broad range of circulating glucose concentrations. In addition to glucose sensitivity, it is also important that the insulin-producing surrogate cell has the ability to respond to changing blood glucose levels by modulating insulin output. In so doing, insulin output could be adjusted in a physiologically relevant manner to better control glycemia. It is likewise important for an insulin-producing cell to have the ability to process proinsulin into insulin, given that proinsulin has less than 10% of the biological activity of fully processed insulin [42]. Lastly, it would be ideal for an insulin-producing cell to have the ability to package, store, and secrete insulin almost instantaneously in response to elevated blood glucose levels. However, it is debatable whether this last feature is indeed critical to the success of insulin gene therapy. Diabetes is such a devastating disease because of the secondary complications that arise as a consequence of sustained hyperglycemia, not repeated episodes of transient hyperglycemia. Thus, as long as the insulin-producing surrogate cell has the ability to produce sufficient quantities of insulin within a reasonable time frame in a glucose-responsive fashion, the difference between near instantaneous insulin secretion or secretion with a few minutes\' delay may be less critical. The quantity of insulin secreted must simply be large enough to correct hyperglycemia, but not too large as to cause hypoglycemia.
\nThus, a long-lasting treatment for T1DM using insulin gene therapy could be achieved, but several criteria must be considered. First, the appropriate cells must be targeted for insulin production. At a minimum, these cells would need to express the glucose sensors, GLUT2 and glucokinase. Second, insulin transgene expression must be responsive to fluctuating blood glucose levels, being upregulated during hyperglycemia and downregulated during euglycemia. There are a variety of mechanisms available to endow an insulin-producing surrogate β cell with this ability. Third, there must be some mechanism in place for the target cell to process proinsulin into mature insulin. Lastly, an appropriate gene correction tool must be utilized to safely and effectively drive long-term insulin expression.
\nWhile meeting these criteria provides several challenges, treating T1DM through insulin gene therapy presents additional challenges not associated with other gene therapy strategies. First, insulin has a relatively short half-life compared to many other proteins being used for gene therapy applications. For instance, the circulating half-life of coagulation factor IX, which is deficient in hemophilia B patients, is estimated to be around 18–25 hours [43], whereas the circulating half-life of insulin has been estimated to be around 4–6 minutes. To compensate for the short circulating half-life of insulin, it is necessary to produce large amounts of insulin either by developing a highly effective gene expression system or by transducing a larger number of cells than other gene therapy applications. This makes the choice of gene delivery system a critical one, as the delivery vehicle must be produced in great abundance and transduce cells efficiently
At a minimum, the target cells chosen for insulin gene therapy would need to express GLUT2 and glucokinase and have innate mechanisms for glucose-responsiveness, thus giving them the ability to sense and respond to continually fluctuating blood glucose levels. Without them, insulin secretion from surrogate β cells would be far less precise. Besides β cells, the only cells that express both GLUT2 and glucokinase are hepatocytes and cells of the hypothalamus and small intestine. Thus, these cells serve as a nice starting point for targeting of insulin transgene expression. It should be noted, however, that a variety of other cells have been targeted for insulin expression, including skeletal myocytes, fibroblasts, and mesenchymal stem cells. An interesting example is the targeting of skeletal myocytes. Skeletal myocytes do not express GLUT2 or glucokinase. Instead, they express GLUT4 and hexokinase, which each have a higher affinity (i.e. lower Km) for glucose. To endow skeletal myocytes with enhanced glucose sensitivity, Callejas
Intestinal K cells provide a particularly promising cell type for insulin gene therapy applications because they not only express GLUT2 and glucokinase, but they also possess the proinsulin processing enzymes and have the machinery for regulated insulin secretion. Cheung and colleagues exploited these unique advantages to generate insulin-producing surrogate β cells from K cells. To do so, they generated transgenic mice expressing human insulin under control of the GIP promoter, a K cell-specific promoter believed to be regulated by glucose [45]. They found that the GIP promoter was able to target insulin expression to K cells specifically, and the transgenic expression of insulin was effective at promoting normal fasting glucose levels and efficient glucose clearance in response to an oral glucose challenge for up to three months after mice were rendered diabetic with streptozotocin (STZ). However, while their findings hold promise, the translation of this strategy to the clinic will rely on their ability to address the following concerns: (1) The gut is one of the primary hubs for the immune system, and given that insulin itself is an autoantigen responsible for native β cell destruction [46], intestinal K cells may be particularly susceptible to recurring autoimmune attack; long-term protection from autoimmunity must be demonstrated. (2) More importantly, the GIP promoter is not only regulated by glucose intake but also by other sources—most notably fats. Thus, patients receiving this treatment would, at the very least, need to maintain a very strict diet to avoid potentially fatal consequences, like hypoglycemia. Further, another study found that glucose alone does not even regulate insulin secretion when controlled by the GIP promoter [47]. Regulation of the GIP promoter must be more thoroughly examined before moving toward human clinical trials.
\nThe most commonly chosen target cells of insulin gene therapy applications, and the one we have chosen, are hepatocytes. Although hepatocytes do not have the machinery to store insulin within secretory vesicles and secrete it in a regulated fashion, they express GLUT2 and glucokinase and possess a robust capacity to synthesize and secrete proteins constitutively. In addition, hepatocytes are attractive targets for insulin expression because they (1) are closely related to β cells developmentally, (2) play a very important role in glucose homeostasis, and (3) are relatively easy to target. As a result, it has been the most commonly targeted organ for
After choosing an appropriate cell type for insulin production, there are several considerations that must be taken into account when designing the insulin expression cassette. Perhaps the first decision that must be made is which promoter to use to drive insulin expression. One of the most commonly used promoters within the field of gene therapy is the cytomegalovirus (CMV) promoter. The CMV promoter is a mammalian promoter from the human cytomegalovirus that drives strong, constitutive transgene expression. While the CMV promoter has been used quite frequently to drive insulin expression for treatment of T1DM, there is one fundamental reason why these studies could never be translated to the clinic: Insulin expression must be responsive to glucose, being upregulated when blood glucose levels rise and downregulated to low levels during fasting periods. The CMV promoter would drive consistent, high level expression of insulin even during fasting periods, which would ultimately cause blood glucose levels to fall dangerously low. Furthermore, even if regulatory elements were added to the expression cassette to endow glucose-responsiveness to insulin expression, the CMV promoter is so strong that it would override these elements. Thus, a weaker promoter must be used to maintain low levels of insulin production during fasting periods if insulin gene therapy is to be successful in treating T1DM.
\nWeaker tissue-specific promoters have been employed for hepatic insulin gene therapy applications to not only reduce the potential for hypoglycemia but also to improve targeting to the tissue of choice. For instance, several groups have used liver-specific promoters that activate insulin transgene expression in hepatocytes but remain inactive in other cell types. Interestingly, some liver-specific promoters are inherently glucose-responsive, making them a great choice for insulin gene therapy applications. For instance, Chen
To generate a more physiologically mimetic system driving insulin expression, Hsu and coworkers used the rat insulin-1 promoter, creating a system that is activated by both glucose and insulin, similar to native β cells [51]. In so doing, they were successful at driving insulin secretion from Huh7 hepatoma cells
Even if a liver-specific promoter does not possess glucose responsiveness, it can be endowed with sensitivity to glucose through incorporation of GIREs. GIREs are glucose-responsive DNA sequences found in the promoter region of several genes encoding lipogenic enzymes, like L-pyruvate kinase (L-PK), S14, fatty acid synthase, and acetyl-CoA carboxylase [52]. GIREs are composed of two 6-bp motifs known as E boxes, with a consensus sequence of CACGTGnnnnnCACGTG (Figure 1). E boxes are generally recognized by transcription factors harboring basic helix-loop-helix/leucine zipper DNA-binding domains [53]. A specific transcription factor, dubbed carbohydrate response element-binding protein (ChREBP), has been found in great abundance in the liver, as well as the small intestine and adipose tissue, the most active sites of
Glucose-inducible response elements (GIREs) and their transcriptional activators.
Incorporation of GIREs enables glucose-responsive control of gene transcription. GIREs are composed of two 6-bp motifs with a consensus sequence of CACGTG separated by 5 bp. A tetramer of ChREBP-Mlx binds each GIRE to amplify gene transcription in response to elevated glucose levels. GIREs have been identified in liver-specific genes like L-pyruvate kinase (L-PK), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS).
\nThule and colleagues leveraged GIREs to endow glucose-responsiveness to the liver-specific insulin-like growth factor binding protein-1 (IGFBP1) promoter. The IGFBP1 promoter is repressed by insulin, creating a feedback inhibition loop on insulin expression, but it is not inherently influenced by changes in glucose concentrations. To generate glucose-responsive insulin expression, they incorporated GIREs from the L-PK gene directly upstream of the IGFBP1 promoter and found that, depending on the number of GIREs incorporated, a 1.6- to 6.4-fold increase in promoter activity could be produced in response to elevated glucose concentrations in primary hepatocytes
In our lab, we used the liver-specific albumin promoter—which is neither glucose- nor insulin-responsive—and inserted the GIREs from the S14 gene upstream of the albumin promoter to create a system that is unresponsive to insulin but activated by elevated glucose levels (Figure 2) [57]. To test the effect that the S14 GIREs have on glucose-responsive insulin output from the albumin promoter, we first generated insulin expression cassettes containing one to five GIREs. Interestingly, we found that the degree of glucose-induction on insulin output increased as the number of GIREs was increased up to three, after which there was only a marginal enhancement in insulin output. We observed a 9-fold increase in insulin output from primary hepatocytes between low and high glucose conditions when three GIREs were incorporated upstream of the albumin promoter (Figure 3). When we delivered this insulin expression cassette into the livers of STZ-induced diabetic rats through direct injection, we found that fasting blood glucose levels were reduced to normal, blood glucose levels of diabetic rats fed
Elements of the insulin expression cassette—TA1.
TA1 is a 2.1-kb insulin expression cassette containing elements that drive insulin expression in both a liver-specific and glucose-responsive fashion. The albumin promoter is largely responsible for restricting insulin expression to hepatocytes, while the α-fetoprotein transcriptional enhancer, vascular endothelial growth factor (VEGF) translational enhancer, and albumin 3′-UTR also promote liver specificity. Glucose responsiveness is primarily driven by three copies of GIREs, although the albumin 3′-UTR also promotes glucose-responsive insulin biosynthesis.
\nGlucose induction of insulin expression and the effect of hepatocyte-specific enhancer elements on overall insulin output.
The insulin expression cassettes, TA0 and TA1, differ in the presence of α-fetoprotein transcriptional enhancer and the albumin 3′-UTR. Inclusion of these elements greatly increases overall insulin output, while both constructs display similar glucose responsiveness.
\nTo improve our insulin expression cassette, we investigated whether inclusion of various liver-specific enhancer elements could further enhance insulin production. Specifically, we incorporated a transcriptional enhancer from the human α-fetoprotein gene, an intron from the human growth hormone gene previously shown to improve mRNA processing efficiency, a translational enhancer from the vascular endothelial growth factor (VEGF) gene that functions as an internal ribosomal entry site, and the 3′-UTR from the human albumin gene that also contains an intron to improve mRNA processing (Figure 3). The ability of each element to enhance glucose-inducible insulin expression was first examined by transducing primary rat hepatocytes
We confirmed the utility of this improved insulin construct
Another novel feature of our insulin expression cassette is the presence of the albumin 3′-UTR. As mentioned previously, the albumin 3′-UTR contains an intron that improves mRNA processing. However, in addition to that, it also contains two pyrimidine-rich stretches known to bind PTB [58]. PTB is a ubiquitously expressed mRNA binding protein that serves as a common mediator of mRNA stability. As mentioned previously, PTB binding sequences are also found in the 3′-UTR of the preproinsulin gene. This is a particularly important feature for hepatic insulin gene therapy applications, as the half-life of preproinsulin mRNA has been reported to be less than 6 hours in hepatocytes. That is much less than the 29–77 hours found in β cells. Perhaps even more importantly, the presence of PTB binding sites would also confer glucose-responsive control of preproinsulin mRNA translation in hepatocytes [34]. Thus, the presence of the albumin 3′-UTR endows hepatocyte-derived surrogate β cells with improved mRNA processing and stability, as well as glucose-responsive control of translation.
\nOne final consideration when designing an expression cassette for insulin gene therapy is the preproinsulin sequence used. A mature insulin molecule is composed of two polypeptide chains—the A and B chains—linked together by two disulfide bonds. However, the insulin gene produces a single preproinsulin polypeptide that contains two basic pairs of amino acids separating the A and B chains, known as the C-peptide, as well as a 24-residue signal peptide. The signal peptide is removed as preproinsulin is translocated into the rough endoplasmic reticulum, forming proinsulin. Proinsulin undergoes further maturation within secretory granules through the action of prohormone convertases PC1/3 and PC2, as well as carboxypeptidase-H. These enzymes are co-packaged with proinsulin in secretory granules and together act to remove C-peptide and produce mature insulin. However, prohormone convertases PC1/3 and PC2 are only found in β cells and other cells with the regulated secretory pathway, like pituitary cells and intestinal K cells. Thus, for insulin gene therapy applications to be successful, it is important to maintain proinsulin processing, even if researchers choose to target cell types that do not have the regulated secretory pathway, like hepatocytes. In these instances, modifications can be made to the preproinsulin sequence to bypass the necessity of PC1/3 and PC2. The most commonly used modification is incorporation of furin cleavage sites [59, 60]. Furin is a ubiquitously expressed endoprotease that can efficiently cleave proteins at paired basic amino acid sites. Through incorporation of furin cleavage sites, any cell of the body can produce fully functional insulin.
\nFurther modifications can be made to the preproinsulin sequence to enhance bioactivity or production for insulin gene therapy applications. First, the preproinsulin sequence can be mutated to alter the stability of the resulting insulin molecules. The most prevalently used mutation is the B10 mutation—a naturally occurring mutation where the histidine residue at position 10 on the B chain is replaced by aspartic acid [59, 61]. This mutation results in enhanced stability and the accumulation of 10- to 100-fold more mature insulin than wild-type insulin. Other mutations have been found to result in highly potent insulin analogues, including HisA8, ArgA8, and GluB10 [61].
\nAnother way the preproinsulin sequence can be modified is through codon optimization. A codon is a series of three nucleotides that encode a specific amino acid. There are 64 different codons but only 20 different amino acids, which means that many amino acids are encoded by multiple codons. It is generally acknowledged that different organisms have codon preferences as a result of the composition of their respective tRNA pool. In other words, specific codons are preferred by specific organisms because they have that specific tRNA in greater abundance. It is thought that cDNA sequences with optimized codons will achieve faster rates of translation and accuracy, thus improving translational efficiency and production of the transgene product. For gene therapy applications, this has been shown to improve the potency of treatment. For instance, Cantore
In summary, there is some flexibility in the design of the expression cassette for insulin gene therapy applications; the relatively small size of the preproinsulin gene is advantageous for the design of an expression cassette and its subsequent delivery to target cells. Regulatory elements capable of improving cell type specificity, overall insulin output, and glucose responsiveness can be employed to yield insulin expression with greater precision. In addition, the preproinsulin sequence itself can be modified to improve production and functionality. Once a sufficient level of control has been attained over insulin expression, it then becomes a matter of delivering the expression cassette to target cells in a safe and efficient manner.
\nWhen choosing a delivery vehicle for insulin gene therapy applications, two important considerations must be taken into account. First, the delivery vehicle must be able to promote long-term insulin expression. This is important because an antibody response from the initial treatment will reduce the efficacy of subsequent treatments. Thus, repeated administration of most delivery vehicles is largely ineffective, especially if it occurs more than two weeks after the initial treatment. Second, it must be possible to affordably and reliably produce the gene delivery vehicle in the large quantities needed for gene therapy. This is particularly important in the field of insulin gene therapy because the insulin molecule has a relatively short circulating half-life, estimated at around 4–6 minutes [63]. As a result, a greater number of cells must be targeted for insulin expression than other gene therapy applications.
\nMany gene delivery vehicles exist and can be broadly grouped into two categories: viral and non-viral. Non-viral methods have the advantages of being safer and inducing less of an immune response. However, non-viral methods typically only drive transgene expression transiently, as most are incapable of supporting chromosomal integration. In addition, they tend to deliver genes inefficiently
Dose-dependent effect of insulin minicircle DNA treatment on hyperglycemia in rats.
STZ-induced diabetic rats were intravenously injected with the indicated dose of TA1m minicircle DNA and measured for both fasting (A) and
Effect of repeated administration of insulin minicircle DNA on fasting hyperglycemia in diabetic rats.
STZ-induced diabetic rats were intravenously injected with 0.8 μg/gm body weight of TA1m via tail vein, and blood glucose measurements were made after a 4-hour fast. TA1m was able to correct diabetic hyperglycemia for nearly a month before the effects began to diminish. A second TA1m injection (0.8 μg/gm body weight) was made on the 26th day and was able to re-correct fasting blood glucose levels, thus demonstrating that a substantial humoral response had not been mounted against the minicircle DNA.
\nWe have also explored the use of viral delivery vehicles, as viruses are highly evolved and proficient at delivering genetic information into target cells. Of course, viral vectors will inevitably elicit an immune response, with some viruses invoking a greater immune response than others. Several viral vectors have been used for insulin gene therapy, with each possessing their own unique features. Refer to Table 1 for an overview of the features inherent to various viral vectors.
\nViral vector | \nPackaging capacity | \nLength of expression | \nRelative viral titer | \nTransduction efficiency | \nInfect both dividing and non-dividing cells | \nImmunogenicity | \n
---|---|---|---|---|---|---|
Adenovirus | \n7.5 kb | \nTransient | \n+++ | \n+++ | \nYes | \nHigh | \n
Adeno-associated virus | \n4.5 kb | \nTransient and Stable | \n++ | \n++ | \nYes | \nLow | \n
Oncoretrovirus | \n8 kb | \nStable | \n+ | \n+ | \nNo | \nModerate | \n
Lentivirus | \n8 kb | \nStable | \n+ | \n++ | \nYes | \nLow | \n
Features of various viral vectors for gene therapy applications.
Adenovirus, adeno-associated virus, oncoretrovirus, and lentivirus are the most commonly used delivery vehicles for gene therapy applications. Each viral vector possesses their own unique features that affects their suitably for insulin gene therapy applications.
\nAdenoviruses were among the first viral vectors used in the field of insulin gene therapy due to their ability to be produced in very high titers and transduce non-dividing cells with high efficiency. These features allow researchers to transduce a large number of cells
Effect of TA1 on hyperglycemia in diabetic rats when delivered via adenovirus.
STZ-induced diabetic rats were injected with 2 × 1010 adenoviral pfu/rat, and both fasting (A) and
More recently, researchers have generated a newer version of “gutted” adenoviral vector that has been stripped of all viral coding sequences, greatly reducing their immunogenicity [68, 69]. This is an important advancement in the field of gene therapy because adenoviral vectors have proven so immunogenic in past human clinical trials that their administration led to the death of a patient in 1999, temporarily halting progress in the field of gene therapy [70, 71]. Immunogenicity is undoubtedly a very large concern with adenoviral vectors, so any improvement is useful. However, it seems unlikely that immunogenicity will ever be completely eliminated from adenoviral vectors, or any viral vector for that matter. Further advancements have now made it possible to improve upon the innate capabilities of adenoviral vectors by adding the potential to integrate their genetic cargo into a host\'s genome and drive long-term transgene expression. The advancement was a result of the merging of two technologies, where chromosomal integration is mediated by the Sleeping Beauty (SB) transposon system and efficient gene delivery accomplished by the gutted adenoviral vectors. DNA transposons translocate from one DNA site to another through a simple cutting-and-pasting process, enabling the integration of defined DNA sequences into mammalian genomes [72]. To achieve stable transgene expression using this system, two separate adenoviral vectors must be administered and co-transduce a single cell. The first vector represents the transposon donor vector, which contains a transposon encoding the transgene of interest. The second vector encodes the SB transposase, which mediates relocation. This system has been used successfully to enable persistent phenotypic correction of hemophilia B in dogs [72] and holds great potential for the treatment of other diseases that require persistent gene expression.
\nTo combat issues related to immunogenicity and short-term expression, other groups have employed adeno-associated virus (AAVs). AAVs are able to transduce both dividing and non-dividing cells. In dividing cells, AAVs are able to integrate transgenes into the host\'s genome at a specific site on chromosome 19 [73]. Within non-dividing cells, the AAV genetic cargo remains largely episomal, as the chromatin is less accessible. AAVs are less immunogenic than adenoviral vectors and are reported to cause relatively long-term transgene expression in non-dividing cells. The primary disadvantage of using AAVs is that their packaging capacity is less than 5 kb, limiting the use of larger expression cassettes with greater complexity for regulated expression. However, the preproinsulin gene is quite small, so even when the gene is accompanied with multiple regulatory elements in a complex expression cassette, the maximum size limitation is unlikely to become an issue for insulin gene therapy applications. Indeed, AAVs have been used to successfully drive insulin expression within non-β cells. Park
Retroviral vectors are another widely used gene delivery vehicle, owing to their ability to integrate their genetic cargo into a host\'s genome and attain sustained gene expression. However, retroviral vectors are greatly limited by their inability to integrate their cargo into the chromosomes of non-dividing cells, a problem that severely hinders their utility in insulin gene therapy applications. In cases where retroviral vectors have been used to deliver insulin, hepatocyte proliferation must first be stimulated [75]. This, of course, greatly limits the translation of retroviral vectors for treatment of T1DM. Retroviral vectors have also been shown to have a preference to integrate their genetic cargo in close proximity to the transcriptional regulatory sequences of proto-oncogenes, as observed in 1999 following the treatment of nine severe-combined immunodeficiency patients [76]. Insertional mutagenesis led to the development of leukemia in four of the nine patients, ultimately halting the field of clinical gene therapy temporarily. All in all, retroviral vectors do not possess favorable features for insulin gene therapy applications.
\nLentiviral vectors are a type of retrovirus that provide two key advantages over other retroviruses: (1) they are able to integrate their genetic cargo into the genome of both dividing and non-dividing cells and (2) have less preference to integrate near regulatory sequences of proto-oncogenes, reducing the risk of insertional mutagenesis [77, 78]. Their ability to transduce non-dividing cells is critical for gene therapy strategies, as most cells of the body are either non-dividing or slowly dividing. An additional advantage of lentiviral vectors is that they do not elicit a strong immune response. Unfortunately, lentiviral vectors possess two major pitfalls limiting their widespread translation to human clinical trials: (1) Lentiviral vectors are difficult to produce in high titer [79] and (2) the efficiency of lentiviral transduction
To combat issues related to lentivirus infectivity, researchers have modified lentiviral vectors to improve their
Overall, insulin gene therapy provides a promising alternative to current treatments for T1DM. Although this treatment option will inevitably lack the full sophistication of native β cells, it would certainly improve upon current treatment options. Insulin gene therapy opens the possibility of having a one-time treatment option that can provide long-term correction of diabetic hyperglycemia through physiologically relevant mechanisms, like glucose-dependent alterations in insulin transcription and translation. Further, the simplicity of the treatment should yield reproducible results with excellent success rates and additionally help newly-formed insulin-producing surrogate β cells evade recurring autoimmunity. However, several hurdles must still be overcome.
\nIn order for the treatment to be a viable option, long-term insulin expression must be driven to avoid repeated injection. However, the viral vectors currently used to drive long-term transgene expression, like lentivirus, are generally difficult to produce in high titer and limited by their transduction efficiency. As a result, most successful long-term efforts in the field have employed the CMV promoter, which can only drive strong constitutive expression of insulin. In order to take those research efforts to the next level, weaker tissue-specific promoters must be used that drive low basal levels of insulin expression during fasting periods and substantially upregulated insulin expression upon increases in glucose availability. To date, this has yet to be achieved. We are currently exploring several viral vectors for their capacity to deliver our insulin expression cassette—which has elements to drive liver-specific, glucose-responsive insulin expression —at a therapeutic level. In so doing, we hope to produce an affordable, long-term treatment option for patients with T1DM.
\nA medical telemonitoring system is one of the telecommunication techniques that access delivery to healthcare services and one of the main applications for Medical Information Communication Technology (MICT). Recently, Information and Communication Technology (ICT) for medical and healthcare application has drawn substantial attention, which plays an important role to support dependable and effective medical technologies to solve significant problems in any society. The WBAN technology has proved out newly in the latest standardization as IEEE 802.15.6 [1]. WBAN standard aims to provide an international standard for short range, low power, and extremely reliable wireless communication within the surrounding area of the human body, supporting an enormous range of data rates from 75.9 Kbps narrow band (NB) up to 15.6 Mbps ultra-wide band (UWB) for various sets of applications [2]. WBAN technology is growing as a key technology for MICT to transfigure the future of healthcare; therefore, WBANs have been attracting a great treaty of attentions from researchers both in academia and industry in the last few years [3]. A QoS is a major concern for WBAN medical application. Therefore, the researcher concerning QoS issues in WBANs should handle all of that very seriously in an effective way [4]. The cellular standards have been adopted by the European Union (EU) as a mandatory standard for member states and are spreading throughout much of the world. The cellular standards have been developed by considering enhancement in all aspects such as transmission speed, transmission way, data rate, error correction capabilities, channel capacity and QoS as general. UMTS is the main standard of the third generation (3G) with Wide Code Division Multiply Access (WCDMA) air interface, and LTE is the main standard of the fourth generation (4G). The bandwidth of a WCDMA is 5 MHz, and it is enough to provide data rates of 144 and 384 Kbps and even 2 Mbps in good conditions. On the other hand, LTE provides UL peak rates of 75 Mb/s, and QoS facilities permitting a transfer latency of less than 5 ms in the radio access network and supports accessible carrier bandwidth from 1.4 to 20 MHz. UMTS and LTE are used to cover both Frequency Division Duplex (FDD) and Time Division Duplex (TDD) operations and integrate a wide variety of wireless multimedia services with high data transmission rates, capable of providing much more than basic voice calls [5, 6, 7].
\nThe way to connect WBAN technology network with other networks such as cellular networks UMTS and LTE is a key point for this chapter to serve the WBAN medical data transmission through the readily existing cellular networks. Therefore, the concept is to use the error controlling coding and decoding based on the concatenated channel codes with the cellular readily existing codes to design the “Medical Network Channel (MNC)” system. Reliable transmission of medical data is critical and essential since it is related to diagnosis and treatments of human body diseases. In ICT field, the reliable transmission procedures must guarantee detection and correction of erroneous transmissions. However, the transmission channel is often subject to various disturbances and interferences from the external environment conditions (noise).
\nThe chapter focuses on the dependability of medical telemonitoring system from WBANs through UMTS and LTE via “Medical Network Channel (MNC)” system. Dependability of medical data transmission via MNC is defined as the probability of the “Medical Network Channel (MNC)” system to operate successfully, which means transmitted medical data reach their destination completely uncorrupted and guarantee minimum performances with lower error rate as much as possible under different environmental conditions. There are different methods that can be employed to overcome the channel impairments, such as increasing transmission power or the use of error control coding schemes in information theory field. A high level of reliability can be obtained by introducing redundancy bits in the signal transmission (encoding).
\nMedical Network Channel (MNC) system has been introduced to solve the reliability issues for medical data transmission when considering different QoS levels. The WBAN medical data are sensitive and any type of noise can corrupt them during transmission. Although the cellular standards include significant amounts of error detection and correction techniques, which are designed for daily life conversation mainly, some errors may still be present in the received data, and these transmission errors are not serious for the daily communication, but when considered for medical uses, they can have fatal outcomes. For that reason, the UMTS and LTE codes are designed for certain levels of channel condition, and if the error becomes more than the estimated condition, then the error becomes more serious and the cellular network standards perform worse using the preexisting error detection and correction capability. The Medical QoS levels have different reliability required based on the BER for different medical data and other constraints [8].
\nThe error control coding plays an important role in modifying the reliability issues. The concatenated codes are one of the error control coding techniques that have been widely adopted due to their simplicity and effectiveness [10]. Therefore, the chapter proposes a novel way of conducting error control encoding and decoding with QoS constraints by using the concatenated code techniques to build the MNC system. Consequently, the MNC intends to add extra channel code in order to combine the WBANs and the cellular networks and optimize the technical parameters for this extra channel depending on the reliability required for the medical data QoS levels and channel conditions as well. Therefore, the adaptive external channel code choice has six pairs of encoding and decoding, three for QoS levels (high, medium, and low) and then two for the channel condition (normal and worse). The restriction of UMTS or LTE channel codes is a standard, which is fixed by the European Telecommunication Standard Institute (ETSI) [5, 6, 7]. The technical parameters cannot be changed in order to provide good system performance. The only way is to design and optimize good adaptive extra outer channel codes with strong decoding capabilities resulting in better performance for MNC to transmit the WBAN medical data robustly.
\nThe objective of the chapter is to design a reliable and dependable MNC system through the cellular networks to provide reliable transmission for all QoS medical data coming from WBANs. The structural design of MNC is based on channel coding of those using concatenated channel code techniques in the serial manner which adds extra channel codes to the cellular UMTS or LTE codes. The inner channel codes in MNC are cellular network standard UMTS or LTE error correction codes that cannot be changed in order to enhance the error performances, with regard to the international standards. On the other hand, the extra outer channel code in MNC is a changeable parameter for achieving different QoS constraints of medical data, which used the convolution code as the main error correction technique. Then, it will add end-to-end connection of WBANs to this MNC system using WBAN standard error correction techniques itself. According to QoS of WBANs O/P, MNC can be with or without extra code.
\nThis chapter reflects about categorizing the eighth level QoS of WBANs to three different QoS (lower, medium, and higher) set levels. To achieve the chosen QoS, there is a need for adaptive external code with limited or strong error correcting capability with high, medium, or low coding rate and redundancy. Through those techniques, the MNC system is adaptive to varying propagation conditions and also adaptive to various QoS constraints. Therefore, the work here focuses to overcome different PHY errors that may occur during the transmission in an unpredictable way, making the channel situation time-to-time change, such as Gaussian noise AWGN, Rayleigh fading, or burst noise.
\nThe “Medical Network Channel (MNC)” system is a new system adopted in this chapter, which works to serve transmission of medical data robustly from WBANs through the cellular standard networks. It is mainly based on the error control coding techniques to ensure the dependability required for such medical data. The idea of the concatenated codes was used for connecting the WBANs with the cellular networks. The purpose is to have reliable and dependable medical data transmissions through the readily existing cellular network.
\n\n\nFigure 1\n shows the whole “Medical Network Channel (MNC)” system that is the core base of this chapter. The different medical data QoS levels from the WBANs have been considered in designing the phase as well as the different assumed channel conditions. The structural design of the proposal is described in \nFigure 2\n by using the concatenated code techniques for different QoS of WBANs. The inner code for the MNC structure is introduced in \nTable 1\n. The UMTS and LTE provide both error detection and error correction as channel coding scheme. Here, it is assumed that the inner channel of the “Medical Network Channel (MNC)” system uses uplink UMTS channel as Common Packet Channel (CPCH) working by the convolution code rate 1/2. Similarly, the downlink UMTS channel was assumed using Forward Access Channel (FACH) working by the convolution code rate 1/3. Furthermore, LTE was assumed using Broadcast Channel (BCH) working by the convolution code rate 1/3.
\nMedical network channel codes via cellular networks.
The medical network channel system for QoS of WBAN medical data.
\n | TRCH type | \nCoding type | \nCoding rate R and constraint length K | \nNumber of encoded bits | \n
---|---|---|---|---|
\n | \nCPCH | \nConvolution | \nR = 1/2 & K = 9 | \nDi = 2*Ki + 16 | \n
\n | \nFACH | \nConvolution | \nR = 1/3 & K = 9 | \nDi = 3*Ki + 24 | \n
\n | \nBCH | \nConvolution | \nR = 1/3 & K = 7 | \nDi = 3*Ki + 18 | \n
The inner cellular network code techniques.
The technical parameters for the extra channel detailed here by using extra outer encoder as convolution encoder are concatenated to the inner cellular standard channel codes. Among all the FEC codes, the convolution codes have great advantages using continuous data streams and can manage the performance with only two parameters: the code rate R and the constraint length K. Also, convolution codes have high error correction in comparison to block codes and less complexity in comparison to turbo codes. The soft decoding algorithm and the hard decoding algorithm, can make easily changes in the performances. Since the extra channel is a key point to have high performance for “Medical Network Channel (MNC)”-proposed system, the choice here of the extra code is driven by convolution codes. The outer channel is the existing WBAN channel that uses BCH code as a main code to correct the error. The system “Medical Network Channel (MNC)” has been considering the performance with and without end-to-end connection of the WBAN codes. The assumption is that the medical data coming from the WBANs with transmission rate 75.9Kb/s are entering the extra outer channel that will be the only optimized channel in “Medical Network Channel (MNC)” system, and then are entering the inner cellular channels within data rate less than the channel capacities.
\nThe “Medical Network Channel (MNC)”-proposed system is dependable, which ensures to give the different QoS level of medical data transmission within acceptable performance capability such as 10−3,10−5 and 10−7 BER for low, medium, and high QoS levels within higher required bit energy to interference (Eb/No) values as possible under different assumed noise conditions. The WBAN has eight QoS levels. The QoS levels for the medical data have divided to three parts as lower priority QoS level, medium priority QoS level, and higher priority QoS level. Depending on these priority levels, the proposed system MNC has been designed as shown in \nFigure 2\n.
\n\n\nTable 2\n shows all the error-correcting capabilities related to the UL and DL inner channels’ technical capabilities for the UMTS and LTE with regard to the international standards of error correction code.
\n\n | Data rate | \nR | \nK | \nG | \nDfree\n | \nError (t) | \nGuard space (g) | \nTrellis paths (E) | \nSum Wd\n | \n
---|---|---|---|---|---|---|---|---|---|
\n | \n144Kb/s | \n1/2 | \n9 | \n[561 753] | \n12 | \n6 | \n\n\n | \n256*L | \n122,694 | \n
\n | \n144Kb/s | \n1/3 | \n9 | \n[557 663 711] | \n18 | \n9 | \n\n\n | \n256*L | \n2275 | \n
\n | \n75 Mb/s | \n1/3 | \n7 | \n[133 171 165] | \n15 | \n7 | \n\n\n | \n64*L | \n416 | \n
The inner cellular network code capabilities.
The criteria of the extra code selections in “Medical Network Channel (MNC)” system have two main parts in the structure: the fixed parts, which are related to the cellular standard networks or WBAN technology, and the changeable parts, which are external that are added to receive the medical data only.
\nThe assumption in this chapter is a WBAN chip installed in the mobile device to carry-on the medical data via the cellular systems through the “Medical Network Channel (MNC)” system to ensure the reliability required for the different sets of medical data. The extra code is adaptive by carrying parameters that are selectable with regard to the two main requirements: first, with regard to various kinds of the QoS of medical data entering the extra code from the WBAN code and second, with regard to the kind of the channel conditions that affected the transmission in PHY channels.
\nThe goal of “Medical Network Channel (MNC)” is figured out by designing the extra code with regard to the QoS by analyzing the WBAN medical data QoS needed. \nTable 3\n categorizes the QoS of the WBAN medical data into three sets, with regard to the priority level, in order to design the MNC system. The first set is the highest priority level such as a biological signal (ECG, EMG, and EEG), the second set is a medium priority level such as medical data (temperature, blood pressure, and blood sugar), and the third set is the lowest priority level such as data management, audio, and video.
\nQoS data sets | \nCode | \nR & K | \nG | \ndfree\n | \nt | \nSum Wd\n | \nII Size | \n
---|---|---|---|---|---|---|---|
\n | \n\n | \n1/2 & 8 | \n[247 371] | \n10 | \n5 | \n10,970 | \n126 bits/block | \n
\n | \nOuter | \n1/3 & 8 | \n[225 331 367] | \n16 | \n8 | \n425 | \n189 bits/block | \n
\n | \n\n | \n1/4 & 8 | \n[235 275 313 357] | \n22 | \n11 | \n169 | \n252 bits/block | \n
Designing parameters of MNC adaptive codes related to QoS priority levels.
“Medical Network Channel (MNC)” used the three sets later to design and optimize the MNC system depending on that. The first set highest priority level will carry on through strong design MNC achieving 10−7 BER, then the second set medium priority design system achieves 10−5 BER, and then the third set lowest priority design system achieves 10−3 BER within higher Eb/No as possible.
\nIn the “Medical Network Channel (MNC)” super PHY channel, the remaining error from the inner cellular decoder optimized the technical parameters of the extra outer code as shown in \nTable 3\n.
\nThe system design that is detailed above has been adjusted for the different QoS levels of medical data. The technical parameters of the extra channel codes have been fixed for the “Medical Network Channel (MNC).” The capabilities have been determined for the AWGN channel and for the Rayleigh fading with a parameter distribution function equal to 0.55. However, for seeking the reality, these channel conditions may be good or worse than those determined. \nTable 4\n details all the “Medical Network Channel (MNC)” adaptive design parameters with regard to the capability of correcting the channel errors.
\nI/P | \n100 Kb/s [51 bits/s length] | \n||
---|---|---|---|
\n | \n\n | \n||
\n | \n\n | \n\n | \n\n | \n
\n | \n(2,1,8) Dfree 10 T = 5 I/P 63b/s O/P 126 b/s | \n(3,1,8) Dfree 16 T = 8 I/P 63b/s O/P 189 b/s | \n(4,1,8) Dfree 22 T = 11 I/P 63b/s O/P 252 b/s | \n
\n | \n(2,1,9) Dfree 12 T = 6 I/P 126 b/s O/P 252 b/s | \n(2,1,9) Dfree 12 T = 6 I/P 189 b/s O/P 378 b/s | \n(2,1,9) Dfree 12 T = 6 I/P 252 b/s O/P 504 b/s | \n
\n | \n(3,1,9) Dfree 18 T = 9 I/P 126 b/s O/P 378 b/s | \n(3,1,9) Dfree 18 T = 9 I/P 189 b/s O/P 567 b/s | \n(3,1,9) Dfree 18 T = 9 I/P 252 b/s O/P 756 b/s | \n
\n | \n(3,1,7) Dfree 15 T = 7 I/P 126 b/s O/P 378 b/s | \n(3,1,7) Dfree 15 T = 7 I/P 189 b/s O/P 567 b/s | \n(3,1,7) Dfree 15 T = 7 I/P 252 b/s O/P 756 b/s | \n
All error-correcting capabilities for MNC-proposed system codes.
The error-bound probabilities are calculated depending on the inner, outer, and extra outer decoders separately. Continuously, the code performance is analyzed in terms of decoded BER. BER is normally calculated as a function of Eb/No. Here Eb represents the average energy transmitted per information bit and No represents the single-sided power spectral density of the assumed AWGN channel.
\nThe performance bounds theoretically are driven under AWGN with and without adding WBANs end to end to “Medical Network Channel (MNC)”-proposed system. Then, the performance bounds theoretically are driven under Rayleigh fading channel without adding WBANs end to end; this step is only to demonstrate the feasibility of the “Medical Network Channel (MNC)” system and to find out the numbers of errors in the output of inner cellular decoders and to test the optimized extra channel code theoretically in “Medical Network Channel (MNC)” for different QoS medical data levels under AWGN and Rayleigh fading channels.
\n\n\nTable 5\n explains all the technical parameters used in the theoretical evaluations. The theoretical bound follows number of steps to calculate the error probabilities for the adaptive “Medical Network Channel (MNC)” concatenated channel codes: the first step in the O/P of the inner cellular decoders, then second in the O/P of the extra channels decoders (the three sets for different QoS levels), and at last, in the O/P of the WBAN outer decoders. These numerical evaluations have been done in the two assumed inner cellular channel codes: UMTS and LTE.
\nQoS data | \nCode | \nR & K | \nG | \ndf\n | \n\n\n | \nSum of Wd\n | \n
---|---|---|---|---|---|---|
\n | \n\n | \n1/3&7 | \n[133 171 165] | \n15 | \n29!/15! × 14! 77558760 | \nWd = ∑[7 8 22 44 22 94 219] = 416 | \n
\n | \nInner | \n1/2&9 | \n[561 753] | \n12 | \n23!/12! × 11! 1352078 | \nWd = ∑ [33 281 2179 15035 105166] = 122694 | \n
\n | \n\n | \n1/3&9 | \n[557 663 711] | \n18 | \n35!/18! × 17! 4.5376e+009 | \nWd = ∑[11 32 195 564 1473] = 2275 | \n
\n | \n\n | \n1/2&8 | \n[247 371] | \n10 | \n19!/10! × 9! 92378 | \nWd = ∑[2 22 60 148 340 1008 2642 6748] = 10970 | \n
\n | \nOuter | \n1/3&8 | \n[225 331 367] | \n16 | \n32!/16! × 15! 300540195 | \nWd = ∑[1 24 113 287] = 425 | \n
\n | \n\n | \n1/4&8 | \n[235 275 313 357] | \n22 | \n43!/22! × 21! 1.0520e+012 | \nWd = ∑[2 10 108 10 11 54 64] = 169 | \n
Error correcting code capabilities for MNC system.
The theoretical calculations for the error bound of the “Medical Network Channel (MNC)”-proposed system via AWGN could be done as many steps in the decoding side as in (Eq. (1)–(11)). The inner and extra channel used convolutional decoder that works using Viterbi algorithm and the outer WBAN channel used the block code decoder. First of all, the UMTS inner decoder calculates the first inner probability bit errors
where
where
Generally speaking, the data stream coming from the cellular inner codes feed to the extra outer codes. The code performance of the extra outer code is a function of the cellular inner code. Second, the extra outer decoder calculates the second outer probability bit errors
The outer code performances of the MNC system can be calculated by Eq. (6) for lower, medium, and higher QoS classes of medical data depending on the parameters applied to the extra channel. The last step is introduced by calculating the final outer code performance of the system. The WBAN decoder (63, 51, 2) calculates the last probability bit error
By using Eq. (9) as a function of Eq. (6) to calculate the final bound, we can have Eq. (10).
\nThen, by applying Eq. (10) in Eq. (7), we will have the final MNC system by adding WBAN code end to end for all QoS assumed and via AWGN channel in Eq. (11).
\nThe theoretical calculations for the error bound of the MNC system via Rayleigh fading channel could be done by the same steps of calculating it via AWGN channel without end-to-end connection of the WBANs. For this part, the
where \n
where
Generally speaking, the data stream coming from the cellular inner code feeds the extra channel code. The code performance of the extra outer code is a function of the inner cellular code. Second, the outer decoder calculates the second outer probability bit errors
Then, the extra outer code performances of super PHY channel MNC system under Rayleigh fading can be calculated by Eq. (19).
\nThe theoretical performances have been calculated for the MNC system with different QoS levels by using the cellular standards as an inner code via AWGN and Rayleigh fading noisy channels.
\nThe first case is via WBANs. In this case, where the inner codes work as a UMTS channel, there are two kinds of codes, when using the cellular parameters in \nTable 2\n. One is the error probability as in Eq. (20) for UL and other is the error probability as in Eq. (21) for DL.
\nIn the second step in the O/P of the extra channel code, there are three targeting QoS levels. Therefore, the probability of the error can be calculated from Eq. (5) as in Eq. (22)–Eq. (24) for the different code sets.
\nFrom here, the error probability for the “Medical Network Channel (MNC)”-proposed system without end-to-end connection of WBANs can be calculated from Eq. (6) as six levels of error probability as in Eq. (25).
\nThe final steps here can be done when the WBANs are connected end to end through the system. Therefore, using Eq. (25) in Eq. (11), we can have the final error probability of the system.
\nThe second case is via WBANs. In this case where the inner codes work as an LTE channel, when using the LTE cellular parameters in \nTable 2\n, we will have the probability of errors as in Eq. (27).
\nIn the second step in the O/P of the extra channel code, there are three targeting QoS levels. Therefore, the probability of the error can be calculated from Eq. (5) as in Eq. (22)–(24) for the different code sets. From here, the error probability for the MNC system without end-to-end connection of WBANs through the LTE can be calculated from Eq. (6) as six levels of error probability as in Eq. (28).
\nThe final step here can be done when the WBANs are connected end to end through the proposed system. Therefore, using Eq. (28) in Eq. (11), we can have the final error probability of the “Medical Network Channel (MNC)” system.
\nThe third case is via Rayleigh fading. In this case where the inner codes work as a UMTS channel, there are two kinds of codes: UL and DL. By using the cellular parameters, we will have the probability of errors as in Eq. (30) in the case of UL and Eq. (31) in the case of DL.
\nIn the second step in the O/P of the extra channel code, there are three targeting QoS levels. Therefore, the probability of the error can be calculated from Eq. (18) as in Eq. (32)–(34).
\nFrom here, the error probability for the “Medical Network Channel (MNC)”-proposed system without end-to-end connection of WBANs could be calculated from Eq. (19) as three levels of error probability as in Eq. (35).
\nThe fourth case is via Rayleigh fading. In the case where the inner codes work as an LTE channel, when using the cellular parameters in Eq. (17), we will have the probability of errors as Eq. (36).
\nThen, from here, the error probability for the “Medical Network Channel (MNC)” system without end-to-end connection of WBANs can be calculated from Eq. (19) as three levels of error probability as in Eq. (37).
\nFinally, \nTable 6\n shows the numerical evaluation of the “Medical Network Channel (MNC)” system with different categories, with the inner channel as UMTS UL, DL, and LTE as well. Regarding to the figures results, \nFigure 3\n shows the theoretical performance when the channel is affected by AWGN for MNC via UMTS networks. \nFigure 4\n shows the theoretical performance when the channel is affected by Rayleigh fading for MNC via UMTS networks. \nFigure 5\n shows the theoretical performance when the channel is affected by AWGN for MNC via LTE networks. Finally, \nFigure 6\n shows the theoretical performance when the channel is affected by Rayleigh fading for MNC via LTE networks.
\nThe results via AWGN | \n||||||
---|---|---|---|---|---|---|
Eb/No\n | \n0 dB | \n1 dB | \n2 dB | \n3 dB | \n4 dB | \n5 dB | \n
WBANs | \n0.1763 | \n0.1379 | \n0.0933 | \n0.0515 | \n0.0215 | \n0.0062 | \n
LTE | \n0.3256 | \n0.0807 | \n0.0143 | \n0.0017 | \n0.0001 | \n0.0000 | \n
Low-QoS | \n2.7957 | \n0.1717 | \n0.0054 | \n0.0001 | \n0.0000 | \n0.0000 | \n
Medium-QoS | \n0.0755 | \n0.0042 | \n0.0001 | \n0.0000 | \n0.0000 | \n0.0000 | \n
High-QoS | \n0.0251 | \n0.0014 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n
Low-QoS-WBANs | \n1.0000 | \n0.0506 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n
Medium-QoS-WBANs | \n0.0127 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n
High-QoS-WBANs | \n0.5854 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n
\n | \n||||||
Eb/No\n | \n0 dB | \n1 dB | \n2 dB | \n3 dB | \n4 dB | \n5 dB | \n
UMTS-UL | \n4.9532 | \n0.0001 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n
Low-QoS | \n1.9352 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n
Medium-QoS | \n9.0438 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n
High-QoS | \n4.5376 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n0.0000 | \n
Theoretical error bit performances for MNC system.
All priority results via UMTS under AWGN theoretically.
All priority results via UMTS under Rayleigh fading theoretically.
All priority results via LTE under AWGN theoretically.
All priority results via LTE under Rayleigh fading theoretically.
The main purpose of “Medical Network Channel (MNC)” systems is to have a reliable medical network channel via the cellular infrastructure networks by end-to-end WBAN connection. Therefore, the stanchions establishment of “Medical Network Channel (MNC)” with error controlling coding and decoding through existing infrastructure networks such as UMTS and LTE is introduced in this chapter with an end-to-end connection of WBANs and without the connection of WBANs considering the medical data coming from different sources. The understanding of the eight levels of the QoS medical data has been done well; however, the optimizations here have been classified into three classes (lower, medium, and higher) for all medical QoS data. Therefore, the MNC system is a novel way considering the dependability issues by this way for the first time with regard to the QoS constraint for the different medical applications of WBANs. Although the adaptive extra outer code for “Medical Network Channel (MNC)” is based on the convolution code, the choice of the technical parameters is different from one to another depending on the QoS targeted and on the capability of cellular standard itself, which is a remaining error in the O/P of the inner cellular code.
\nAlthough the current cellular standard has strong error detection and correction capability, it is designed well for the daily life communication without considering medical data transmission, and in some hard noisy channel situations that exceed the design capabilities, the cellular network cannot perform well. Therefore, the Medical Networks channel MNC system has been introduced new novel approach to connect WBANs end-to-end via the cellular networks by providing very large BER for the different assumed QoS levels of medical data to be transmit robustly and achieving the enhancement Eb/No gap under all the environments condition that assumed in compare to conventional cellular system alone. Then the adaptive “Medical Network Channel (MNC)” system overcomes the weakness of cellular networks with regard to the dependability issues and provides even better performance than the cellular network for the purpose of medical data transmission. These performances allow MNC equivalence for transmitting medical data by the highest possible level of the dependability required. In regard to achieving different QoS of WBAN requirements, the results in \nTable 6\n and BER \nFigures 3\n–\n6\n cleared all the study cases carefully for adaptive “Medical Network Channel (MNC)” system. Generally, the adaptive medical network channel introduced in this chapter is through the cellular networks. However, all communication network standards can be applied using error correcting techniques to be adaptive for medical data transmission.
\nThe first author would like to express thanks to the academic supervisor Prof. Ryuji Kohno for his help and guidance and to all Kohno-Lab members in Yokohama National University. Correspondingly, the first author would like to express thanks to the dean and engineering members in Sudan International University.
\nThere is no conflict of interest for this work from anyone.
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In 2010, he received a Ph.D. in Egyptology from the University of Basel, Switzerland.\nFrom 2012 to 2017, Dr. Pereira was a post-doctoral fellow at CHAM/FCSH – Universidade Nova de Lisboa.\nIn 2018, he became an Onassis Fellow, hosted by the Department of Mediterranean Studies, University of the Aegean, Greece. \nIn 2019, he became an auxiliary researcher at CHAM/FCSH – Universidade Nova de Lisboa. He teaches Middle Egyptian grammar, Hieratic, and disciplines regarding Egyptology, and the history of Phoenician and Greek expansion in the Mediterranean basin. \nIn 2021, he was awarded a CAARI Scholar in Residence Fellowship.",institutionString:"Universidade NOVA de Lisboa",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Universidade Nova de Lisboa",institutionURL:null,country:{name:"Portugal"}}},equalEditorTwo:null,equalEditorThree:null,productType:{id:"4",chapterContentType:"chapter",authoredCaption:"Authored by"}},{type:"book",id:"10342",title:"Ovarian Cancer",subtitle:"Updates in Tumour Biology and Therapeutics",isOpenForSubmission:!1,hash:"25a0adac7f6afa7bcd0b6daa3ef6b538",slug:"ovarian-cancer-updates-in-tumour-biology-and-therapeutics",bookSignature:"Gwo-Yaw Ho and Kate Webber",coverURL:"https://cdn.intechopen.com/books/images_new/10342.jpg",editedByType:"Edited by",editors:[{id:"297757",title:null,name:"Gwo-Yaw",middleName:null,surname:"Ho",slug:"gwo-yaw-ho",fullName:"Gwo-Yaw Ho"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10485",title:"Fibroids",subtitle:null,isOpenForSubmission:!1,hash:"64ad14b1aba83e47fb100fa63e21533e",slug:"fibroids",bookSignature:"Hassan Abduljabbar",coverURL:"https://cdn.intechopen.com/books/images_new/10485.jpg",editedByType:"Edited by",editors:[{id:"68175",title:"Prof.",name:"Hassan",middleName:"S",surname:"Abduljabbar",slug:"hassan-abduljabbar",fullName:"Hassan Abduljabbar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:67,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"30747",doi:"10.5772/27200",title:"Cervical Cancer in Sub Sahara Africa",slug:"cervical-cancer-in-sub-sahara-africa",totalDownloads:8076,totalCrossrefCites:24,totalDimensionsCites:36,abstract:null,book:{id:"951",slug:"topics-on-cervical-cancer-with-an-advocacy-for-prevention",title:"Topics on Cervical Cancer With an Advocacy for Prevention",fullTitle:"Topics on Cervical Cancer With an Advocacy for Prevention"},signatures:"Atara Ntekim",authors:[{id:"69178",title:"Dr.",name:"Atara",middleName:"I",surname:"Ntekim",slug:"atara-ntekim",fullName:"Atara Ntekim"}]},{id:"43348",doi:"10.5772/55562",title:"Molecular Mechanisms of Platinum Resistance in Ovarian Cancer",slug:"molecular-mechanisms-of-platinum-resistance-in-ovarian-cancer",totalDownloads:4257,totalCrossrefCites:20,totalDimensionsCites:30,abstract:null,book:{id:"3449",slug:"ovarian-cancer-a-clinical-and-translational-update",title:"Ovarian Cancer",fullTitle:"Ovarian Cancer - A Clinical and Translational Update"},signatures:"Gonzalo Tapia and Ivan Diaz-Padilla",authors:[{id:"157073",title:"Dr.",name:"Ivan",middleName:null,surname:"Diaz-Padilla",slug:"ivan-diaz-padilla",fullName:"Ivan Diaz-Padilla"},{id:"166871",title:"Dr.",name:"Gonzalo",middleName:null,surname:"Tapia Rico",slug:"gonzalo-tapia-rico",fullName:"Gonzalo Tapia Rico"}]},{id:"37219",doi:"10.5772/47914",title:"Determining Factors of Cesarean Delivery Trends in Developing Countries: Lessons from Point G National Hospital (Bamako - Mali)",slug:"determining-factors-of-cesarean-delivery-trends-in-developing-countries-lessons-from-point-g-nat",totalDownloads:3047,totalCrossrefCites:7,totalDimensionsCites:21,abstract:null,book:{id:"952",slug:"cesarean-delivery",title:"Cesarean Delivery",fullTitle:"Cesarean Delivery"},signatures:"I. Teguete, Y. Traore, A. Sissoko, M. Y. Djire, A. Thera, T. Dolo, N. Mounkoro, M. Traore and A. Dolo",authors:[{id:"87496",title:"Dr.",name:"Ibrahima",middleName:null,surname:"Teguete",slug:"ibrahima-teguete",fullName:"Ibrahima Teguete"}]},{id:"31273",doi:"10.5772/31669",title:"Aqueous Extract of Human Placenta",slug:"aqueous-extract-of-human-placenta-as-a-therapeutic-agent",totalDownloads:5593,totalCrossrefCites:5,totalDimensionsCites:20,abstract:null,book:{id:"702",slug:"recent-advances-in-research-on-the-human-placenta",title:"Recent Advances in Research on the Human Placenta",fullTitle:"Recent Advances in Research on the Human Placenta"},signatures:"Piyali Datta Chakraborty and Debasish Bhattacharyya",authors:[{id:"88185",title:"Prof.",name:"Debasish",middleName:null,surname:"Bhattacharyya",slug:"debasish-bhattacharyya",fullName:"Debasish Bhattacharyya"},{id:"127848",title:"Dr.",name:"Piyali Datta",middleName:null,surname:"Chakraborty",slug:"piyali-datta-chakraborty",fullName:"Piyali Datta Chakraborty"}]},{id:"27121",doi:"10.5772/27439",title:"Clinical Risk Factors for Preterm Birth",slug:"clinical-risk-factors-for-preterm-birth",totalDownloads:8765,totalCrossrefCites:9,totalDimensionsCites:19,abstract:null,book:{id:"776",slug:"preterm-birth-mother-and-child",title:"Preterm Birth",fullTitle:"Preterm Birth - Mother and Child"},signatures:"Ifeoma Offiah, Keelin O’Donoghue and Louise Kenny",authors:[{id:"68552",title:"Dr.",name:"Ifeoma",middleName:null,surname:"Offiah",slug:"ifeoma-offiah",fullName:"Ifeoma Offiah"},{id:"70166",title:"Prof.",name:"Louise",middleName:null,surname:"Kenny",slug:"louise-kenny",fullName:"Louise Kenny"},{id:"74717",title:"Dr.",name:"Keelin",middleName:null,surname:"O'Donoghue",slug:"keelin-o'donoghue",fullName:"Keelin O'Donoghue"}]}],mostDownloadedChaptersLast30Days:[{id:"58219",title:"Congenital Abdominal Anomalies",slug:"congenital-abdominal-anomalies",totalDownloads:1420,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Introduction: Abdominal anomalies that appear during intrauterine life are complex due to many organs that are affected. In cases, the ultrasound appearance is a cystic image with different content and the differential diagnosis is often difficult. Body—research methods: the organs affected by abdominal congenital anomalies involve the gastrointestinal tract (stomach, duodenum, small bowel or colon, and gall bladder), the kidney and urinary tract, the peritoneal cavity (ascites), suprarenal glands, and tumors of the reproductive system (especially the ovaries). In order to identify the affected structures, it is mandatory to know the normal aspect of the abdominal content at different gestational ages. The diagnosis may be very difficult, but its accuracy is important, considering the need of further counseling the couple. In minor conditions, without chromosomal anomalies or associations, the outcome is usually good, and there are even possibilities of in utero treatment. In severe conditions, with poor outcome, the couple can choose to terminate the pregnancy, after counseling is provided. Conclusion: abdominal congenital anomalies are common findings in ultrasound screenings for anomalies in all the trimesters of pregnancy and their recognition is important for subsequent management.",book:{id:"6307",slug:"congenital-anomalies-from-the-embryo-to-the-neonate",title:"Congenital Anomalies",fullTitle:"Congenital Anomalies - From the Embryo to the Neonate"},signatures:"Ples Liana and Anca Lesnic",authors:[{id:"212333",title:"Associate Prof.",name:"Liana",middleName:null,surname:"Ples",slug:"liana-ples",fullName:"Liana Ples"}]},{id:"64417",title:"Introductory Chapter: A Comprehensive Approach to the Process of Breastfeeding",slug:"introductory-chapter-a-comprehensive-approach-to-the-process-of-breastfeeding",totalDownloads:1306,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"6191",slug:"selected-topics-in-breastfeeding",title:"Selected Topics in Breastfeeding",fullTitle:"Selected Topics in Breastfeeding"},signatures:"René Mauricio Barría P",authors:[{id:"88861",title:"Dr.",name:"R. 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The objective of this chapter is therefore to systematically search the literature and analyse the available evidence including preoperative workup, prophylactic antibiotics, skin disinfection, preoperative bladder catheterization as well as details of the individual steps of the actual operation itself such as skin incision types, preparation of soft tissue and womb, removal of the placenta, cervical dilatation and stitching of the womb, peritoneum, rectus muscle, fascia, subcutaneous fat, and skin. We systematically searched for meta-analysis, systematic reviews, and big studies and evaluated the evidence for each individual step.",book:{id:"6707",slug:"caesarean-section",title:"Caesarean Section",fullTitle:"Caesarean Section"},signatures:"Jan-Simon Lanowski and Constantin S. von Kaisenberg",authors:[{id:"100660",title:"Prof.",name:"Constantin",middleName:"Sylvius",surname:"Von Kaisenberg",slug:"constantin-von-kaisenberg",fullName:"Constantin Von Kaisenberg"},{id:"240353",title:"Dr.",name:"Jan-Simon",middleName:null,surname:"Lanowski",slug:"jan-simon-lanowski",fullName:"Jan-Simon Lanowski"}]},{id:"18348",title:"Anaesthetic Considerations during Laparoscopic Surgery",slug:"anaesthetic-considerations-during-laparoscopic-surgery",totalDownloads:28978,totalCrossrefCites:1,totalDimensionsCites:5,abstract:null,book:{id:"916",slug:"advanced-gynecologic-endoscopy",title:"Advanced Gynecologic Endoscopy",fullTitle:"Advanced Gynecologic Endoscopy"},signatures:"Maria F. Martín-Cancho, Diego Celdrán, Juan R. Lima, Maria S. Carrasco-Jimenez, Francisco M. Sánchez-Margallo and Jesús Usón-Gargallo",authors:[{id:"14715",title:"Prof.",name:"Francisco M.",middleName:null,surname:"Sánchez-Margallo",slug:"francisco-m.-sanchez-margallo",fullName:"Francisco M. Sánchez-Margallo"},{id:"29449",title:"Dr.",name:"Maria Fernanda",middleName:null,surname:"Martín-Cancho",slug:"maria-fernanda-martin-cancho",fullName:"Maria Fernanda Martín-Cancho"},{id:"39772",title:"Dr.",name:"Juan R.",middleName:null,surname:"Lima",slug:"juan-r.-lima",fullName:"Juan R. 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Dymond",authors:[{id:"155683",title:"Dr.",name:"Murray R.",middleName:null,surname:"Bakst",slug:"murray-r.-bakst",fullName:"Murray R. Bakst"},{id:"167852",title:"Dr.",name:"Jessica",middleName:null,surname:"Dymond",slug:"jessica-dymond",fullName:"Jessica Dymond"}]}],onlineFirstChaptersFilter:{topicId:"189",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"80860",title:"From Open to Minimally Invasive: The Sacrocolpopexy",slug:"from-open-to-minimally-invasive-the-sacrocolpopexy",totalDownloads:52,totalDimensionsCites:0,doi:"10.5772/intechopen.101308",abstract:"With an increased demand for pelvic organ prolapse surgeries as the population ages, mesh-related osteomyelitis will become more prevalent. This case series enriches the paucity of data on management options for delayed osteomyelitis related to pelvic organ prolapse mesh. A literature review revealed no case reports of delayed onset osteomyelitis presenting up to a decade after colpopexy mesh placement. We present three cases of delayed osteomyelitis, their presentation, diagnosis and management at a tertiary academic referral center. Patients presented between 1 and 10 years after mesh colpopexy. Three different mesh materials were utilized during the initial procedures: Restorelle Y, Gynamesh and Gore-Tex mesh. The first case demonstrates failed expectant management with eventual surgical intervention on a medically compromised patient. The two subsequent cases describe elective complete mesh resection after several prior failed mesh revision attempts. This short case series and literature review illustrates that mesh-related osteomyelitis after a remote sacrocolpopexy carries significant morbidity. Mesh removal by means of minimally invasive surgery in the hands of an experienced surgical team utilizing DaVinci Robotic System is a good option and may lead to best patient outcomes.",book:{id:"11040",title:"Hysterectomy - Past, Present and Future",coverURL:"https://cdn.intechopen.com/books/images_new/11040.jpg"},signatures:"Adriana Fulginiti, Frank Borao, Martin Michalewski and Robert A. Graebe"},{id:"80782",title:"Cases of Postpartum Hemorrhage and Hysterectomy in Thailand’s Northern and Northeastern Provincial Hospitals",slug:"cases-of-postpartum-hemorrhage-and-hysterectomy-in-thailand-s-northern-and-northeastern-provincial-h",totalDownloads:49,totalDimensionsCites:0,doi:"10.5772/intechopen.102948",abstract:"PPH is a major cause of maternal death. Hysterectomy is safe to treat uncontrollable PPH. However, it may not be the best option for women who want to have children. The risk score tool to detect PPH earlier is needed in low-resource cities such as Chiang Rai and Sakon Nakhon province. This study aims to perform a risk score tool to prevent PPH in the northern and northeastern hospitals in Thailand; using mixed methods, identify risk factors for PPH from 20 articles globally and in Thailand using Med Calc, and develop the tool for prediction of PPH; and tool testing and a one-year follow-up on PPH-related hysterectomy cases. Results showed that this risk score tool can detect PPH earlier, reducing the number of PPH and hysterectomy cases. This risk score tool needs to be implemented in the same situations as hospitals to save pregnant women’s lives.",book:{id:"11040",title:"Hysterectomy - Past, Present and Future",coverURL:"https://cdn.intechopen.com/books/images_new/11040.jpg"},signatures:"Thawalsak Ratanasiri, Natakorn I. 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This chapter touches briefly on the history of this procedure, its present aspects and general advice for these women who may need a hysterectomy, and finally the direction of new developments about it.",book:{id:"11040",title:"Hysterectomy - Past, Present and Future",coverURL:"https://cdn.intechopen.com/books/images_new/11040.jpg"},signatures:"Zouhair Odeh Amarin"},{id:"80589",title:"Perspective Chapter: Total Vaginal Hysterectomy for Unprolapsed Uterus",slug:"perspective-chapter-total-vaginal-hysterectomy-for-unprolapsed-uterus",totalDownloads:74,totalDimensionsCites:0,doi:"10.5772/intechopen.101383",abstract:"Vaginal hysterectomy was the first method to extract the uterus. Vaginal hysterectomy goes back a long way into the history of medicine. Although the first hysterectomy was carried out by Themison of Athens in the year 20 B.C., the idea of extracting the uterus through the vagina was first mentioned in 120 B.C. by Soranus of Ephesos, a distinguished obstetrician. The first elective vaginal hysterectomy was performed by J. Conrad Langenbeck in 1813. The patient was a 50-year-old multipara, who suffered from chronic pelvic pain attributed to a prolapsed uterus with a hard, bleeding tumor. The operation was carried out in challenging conditions, without anesthesia, proper instruments, or surgical assistants. Until the early 1950s, vaginal hysterectomy was the method of choice for removing the uterus. With the widespread introduction of general anesthesia and antibiotic therapy, the site of vaginal hysterectomy was taken over by abdominal hysterectomy. With the introduction of minimally invasive surgery in gynecology, vaginal hysterectomy has regained its place. Harry Reich performed the first total laparoscopic hysterectomy in 1989, being one of the most renowned vaginal surgeons, and he still claims at the beginning of the 21st century that … when the first choice of approach for hysterectomy is possible, is the vaginal route. This chapter presents the relevant anatomy from the point of view of the vaginal surgeon and the standard technique used by the author in over 5,000 vaginal hysterectomies. All intraoperative drawings and photographs are original.",book:{id:"11040",title:"Hysterectomy - Past, Present and Future",coverURL:"https://cdn.intechopen.com/books/images_new/11040.jpg"},signatures:"Petre Bratila"},{id:"80400",title:"Laparoscopic Hysterectomy in Morbidly Obese Patients",slug:"laparoscopic-hysterectomy-in-morbidly-obese-patients",totalDownloads:43,totalDimensionsCites:0,doi:"10.5772/intechopen.101307",abstract:"The following chapter will focus on laparoscopic hysterectomy in morbidly obese patients. The discussion reviews the physiological changes associated with morbid obesity and the potential implications on pneumoperitoneum during laparoscopic surgery. Important considerations such as perioperative care and operating room setup are discussed. Additionally, obtaining abdominal access, reviewing the surgical approach, and post-operative considerations are all highlighted within this chapter.",book:{id:"11040",title:"Hysterectomy - Past, Present and Future",coverURL:"https://cdn.intechopen.com/books/images_new/11040.jpg"},signatures:"Merima Ruhotina, Annemieke Wilcox, Shabnam Kashani and Masoud Azodi"},{id:"80238",title:"Surgical Site Infection after Hysterectomy",slug:"surgical-site-infection-after-hysterectomy",totalDownloads:117,totalDimensionsCites:0,doi:"10.5772/intechopen.101492",abstract:"Surgical site infections (SSIs) are associated with increased morbidity, mortality, and healthcare costs. SSIs are defined as an infection that occurs after surgery in the part of the body where the surgery took place. Approximately 1–4% of hysterectomies are complicated by SSIs, with higher rates reported for abdominal hysterectomy. Over the past decade, there has been an increasing number of minimally invasive hysterectomies, in conjunction with a decrease in abdominal hysterectomies. The reasons behind this trend are multifactorial but are mainly rooted in the well-documented advantages of minimally invasive surgery. Multiple studies have demonstrated a marked decrease in morbidity and mortality with minimally invasive surgeries. Specifically, evidence supports lower rates of SSIs after laparoscopic hysterectomy when compared to abdominal hysterectomy. In fact, the American College of Obstetricians and Gynecologist recommends minimally invasive approaches to hysterectomy whenever feasible. This chapter will review the current literature on surgical site infection (SSI) after hysterectomy for benign indications.",book:{id:"11040",title:"Hysterectomy - Past, Present and Future",coverURL:"https://cdn.intechopen.com/books/images_new/11040.jpg"},signatures:"Catherine W. Chan and Michael L. 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Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"August 12th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. 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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},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",editor:{id:"205604",title:"Dr.",name:"Tomas",middleName:null,surname:"Jarzembowski",slug:"tomas-jarzembowski",fullName:"Tomas Jarzembowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKriQAG/Profile_Picture_2022-06-16T11:01:31.jpg",biography:"Tomasz Jarzembowski was born in 1968 in Gdansk, Poland. He obtained his Ph.D. degree in 2000 from the Medical University of Gdańsk (UG). After specialization in clinical microbiology in 2003, he started studying biofilm formation and antibiotic resistance at the single-cell level. In 2015, he obtained his D.Sc. degree. His later study in cooperation with experts in nephrology and immunology resulted in the designation of the new diagnostic method of UTI, patented in 2017. He is currently working at the Department of Microbiology, Medical University of Gdańsk (GUMed), Poland. Since many years, he is a member of steering committee of Gdańsk branch of Polish Society of Microbiologists, a member of ESCMID. He is also a reviewer and a member of editorial boards of a number of international journals.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorTwo:{id:"484980",title:"Dr.",name:"Katarzyna",middleName:null,surname:"Garbacz",slug:"katarzyna-garbacz",fullName:"Katarzyna Garbacz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003St8TAQAZ/Profile_Picture_2022-07-07T09:45:16.jpg",biography:"Katarzyna Maria Garbacz, MD, is an Associate Professor at the Medical University of Gdańsk, Poland and she is head of the Department of Oral Microbiology of the Medical University of Gdańsk. She has published more than 50 scientific publications in peer-reviewed journals. She has been a project leader funded by the National Science Centre of Poland. Prof. Garbacz is a microbiologist working on applied and fundamental questions in microbial epidemiology and pathogenesis. Her research interest is in antibiotic resistance, host-pathogen interaction, and therapeutics development for staphylococcal pathogens, mainly Staphylococcus aureus, which causes hospital-acquired infections. Currently, her research is mostly focused on the study of oral pathogens, particularly Staphylococcus spp.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorThree:null,editorialBoard:[{id:"190041",title:"Dr.",name:"Jose",middleName:null,surname:"Gutierrez Fernandez",slug:"jose-gutierrez-fernandez",fullName:"Jose Gutierrez Fernandez",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"University of Granada",institutionURL:null,country:{name:"Spain"}}},{id:"156556",title:"Prof.",name:"Maria Teresa",middleName:null,surname:"Mascellino",slug:"maria-teresa-mascellino",fullName:"Maria Teresa Mascellino",profilePictureURL:"https://mts.intechopen.com/storage/users/156556/images/system/156556.jpg",institutionString:"Sapienza University",institution:{name:"Sapienza University of Rome",institutionURL:null,country:{name:"Italy"}}},{id:"164933",title:"Prof.",name:"Mónica Alexandra",middleName:null,surname:"Sousa Oleastro",slug:"monica-alexandra-sousa-oleastro",fullName:"Mónica Alexandra Sousa Oleastro",profilePictureURL:"https://mts.intechopen.com/storage/users/164933/images/system/164933.jpeg",institutionString:"National Institute of Health Dr Ricardo Jorge",institution:{name:"National Institute of Health Dr. Ricardo Jorge",institutionURL:null,country:{name:"Portugal"}}}]},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. 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He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. 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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. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"117248",title:"Dr.",name:"Andrew",middleName:null,surname:"Macnab",slug:"andrew-macnab",fullName:"Andrew Macnab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"322007",title:"Dr.",name:"Maria Elizbeth",middleName:null,surname:"Alvarez-Sánchez",slug:"maria-elizbeth-alvarez-sanchez",fullName:"Maria Elizbeth Alvarez-Sánchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",country:{name:"Mexico"}}},{id:"337443",title:"Dr.",name:"Juan",middleName:null,surname:"A. Gonzalez-Sanchez",slug:"juan-a.-gonzalez-sanchez",fullName:"Juan A. Gonzalez-Sanchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico System",country:{name:"United States of America"}}},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}}]}},subseries:{item:{id:"10",type:"subseries",title:"Animal Physiology",keywords:"Physiology, Comparative, Evolution, Biomolecules, Organ, Homeostasis, Anatomy, Pathology, Medical, Cell Division, Cell Signaling, Cell Growth, Cell Metabolism, Endocrine, Neuroscience, Cardiovascular, Development, Aging, Development",scope:"Physiology, the scientific study of functions and mechanisms of living systems, is an essential area of research in its own right, but also in relation to medicine and health sciences. The scope of this topic will range from molecular, biochemical, cellular, and physiological processes in all animal species. Work pertaining to the whole organism, organ systems, individual organs and tissues, cells, and biomolecules will be included. Medical, animal, cell, and comparative physiology and allied fields such as anatomy, histology, and pathology with physiology links will be covered in this topic. 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\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
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",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",keywords:"Human Activity, Pollutants, Reduced Risks, Population Growth, Waste Disposal, Remediation, Clean Environment"},{id:"41",title:"Water Science",scope:"