Glycated hemoglobin levels in dialysis patients
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{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"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"9864",leadTitle:null,fullTitle:"Hydrology",title:"Hydrology",subtitle:null,reviewType:"peer-reviewed",abstract:"In this book, an attempt is made to highlight the recent advances in Hydrology. The several topics examined in this book form the underpinnings of larger-scale considerations, including but not limited to topics such as large-scale hydrologic processes and the evolving field of Critical Zone Hydrology. Computational modeling, data collection, and visualization are additional subjects, among others, examined in the set of topics presented.",isbn:"978-1-83962-330-1",printIsbn:"978-1-83962-329-5",pdfIsbn:"978-1-83962-331-8",doi:"10.5772/intechopen.87673",price:119,priceEur:129,priceUsd:155,slug:"hydrology",numberOfPages:122,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"02925c63436d12e839008c793a253310",bookSignature:"Theodore V. Hromadka II and Prasada Rao",publishedDate:"February 17th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/9864.jpg",numberOfDownloads:2999,numberOfWosCitations:1,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:8,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:10,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 8th 2020",dateEndSecondStepPublish:"September 11th 2020",dateEndThirdStepPublish:"November 10th 2020",dateEndFourthStepPublish:"January 29th 2021",dateEndFifthStepPublish:"March 30th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"181008",title:"Dr.",name:"Theodore V.",middleName:"V.",surname:"Hromadka II",slug:"theodore-v.-hromadka-ii",fullName:"Theodore V. Hromadka II",profilePictureURL:"https://mts.intechopen.com/storage/users/181008/images/system/181008.jpg",biography:"Hromadka & Associates’ Principal and Founder, Theodore Hromadka II, Ph.D., Ph.D., Ph.D., PH, PE, has extensive scientific, engineering, expert witness, and litigation support experience. His frequently referenced scientific contributions to the hydrologic, earth, and atmospheric sciences have been widely published in peer-reviewed scientific literature, including 30 books and more than 500 scientific papers, book chapters, and government reports. His professional engineering experience includes supervision and development of over 1500 engineering studies. He is currently a faculty member at the United States Military Academy at West Point, New York.",institutionString:"United States Military Academy",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"9",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"United States Military Academy",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"192274",title:"Dr.",name:"Prasada",middleName:null,surname:"Rao",slug:"prasada-rao",fullName:"Prasada Rao",profilePictureURL:"https://mts.intechopen.com/storage/users/192274/images/system/192274.jpg",biography:"Prasada Rao is a Professor in the Civil and Environmental Engineering Department at California State University, Fullerton. His current research areas relate to surface and subsurface flow modeling and computational mathematics. He has worked extensively on developing innovative hydraulic and hydrological modeling solutions to better predict surface flow phenomena along with their impact on groundwater levels. He has also worked on developing parallel hydraulic models for large scale applications. He has taught undergraduate and graduate level courses in hydraulics, hydrology, open channel flow, and hydraulic structures.",institutionString:"California State University, Fullerton",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"California State University, Fullerton",institutionURL:null,country:{name:"United States of America"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"837",title:"Hydrology",slug:"hydrology"}],chapters:[{id:"74255",title:"Hydrometeorology: Review of Past, Present and Future Observation Methods",doi:"10.5772/intechopen.94939",slug:"hydrometeorology-review-of-past-present-and-future-observation-methods",totalDownloads:538,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Hydrometeorology aims at measuring and understanding the physics, chemistry, energy and water fluxes of the atmosphere, and their coupling with the earth surface environmental parameters. Accurate hydrometeorological records and observations with different timelines are crucial to assess climate evolution and weather forecast. Historical records suggest that the first hydrometeorological observations date back to ca 3500 BC. Reviewing these observations in the light of our modern knowledge of the dynamic of atmospheres is critical as it can reduce the ambiguities associated to understanding major fluctuations or evolutions in the earth climate. Today, the ambiguities in hydrometeorological observations have significantly improved due to the advances in monitoring, modeling, and forecasting of processes related to the land-atmosphere coupling and forcing. Numerical models have been developed to forecast hydrometeorological phenomena in short-, medium- and long-term horizons, ranging from hourly to annual timescales. We provide herein a synthetic review of advances in hydrometeorological observations from their infancy to today. In particular, we discuss the role of hydrometeorological records, observations, and modeling in assessing the amplitude and time-scale for climate change and global warming.",signatures:"Mohammad Valipour, Sayed M. Bateni, Nicolas R. Dalezios, Mansour Almazroui, Essam Heggy, Zekai Şen and Andreas N. Angelakis",downloadPdfUrl:"/chapter/pdf-download/74255",previewPdfUrl:"/chapter/pdf-preview/74255",authors:[{id:"337239",title:"Dr.",name:"Sayed",surname:"Bateni",slug:"sayed-bateni",fullName:"Sayed Bateni"},{id:"337240",title:"Dr.",name:"Mohammad",surname:"Valipour",slug:"mohammad-valipour",fullName:"Mohammad Valipour"},{id:"337242",title:"Dr.",name:"Nicolas R.",surname:"Dalezios",slug:"nicolas-r.-dalezios",fullName:"Nicolas R. Dalezios"},{id:"337243",title:"Prof.",name:"Mansour",surname:"Almazroui",slug:"mansour-almazroui",fullName:"Mansour Almazroui"},{id:"337245",title:"Dr.",name:"Essam",surname:"Heggy",slug:"essam-heggy",fullName:"Essam Heggy"},{id:"337246",title:"Prof.",name:"Zekai",surname:"Şen",slug:"zekai-sen",fullName:"Zekai Şen"},{id:"337247",title:"Prof.",name:"Andreas N.",surname:"Angelakis",slug:"andreas-n.-angelakis",fullName:"Andreas N. Angelakis"}],corrections:null},{id:"74366",title:"Perspectives of Hydrologic Modeling in Agricultural Research",doi:"10.5772/intechopen.95179",slug:"perspectives-of-hydrologic-modeling-in-agricultural-research",totalDownloads:294,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"For decades agricultural research was done in the field or laboratories, but with the rise of computer science, hydrologic modeling became another essential tool for environmental impact studies. Many types of models can be used, each with its strengths and weaknesses in terms of accuracy, speed, and amount of input data needed. Models can be used on different scales and simulate very different processes. Based on a literature review, APEX (Agricultural Policy Extender) and SWAT (Soil and Water Assessment Tool) models are the most popular for environmental research in agronomy. An important share of modeling work in agronomic studies is focused on pollution research, mainly nutrient and pesticide leaching and soil erosion processes. Other topics include simulating the effects of irrigation and other agricultural practices and studying the impact of extreme weather events and climate change. When working with model results, it is crucial to be mindful of inevitable uncertainties and consider them during interpretation. Modeling is gaining importance in agronomic research in Slovenia, with many studies done in the recent decade and more underway.",signatures:"Miha Curk and Matjaž Glavan",downloadPdfUrl:"/chapter/pdf-download/74366",previewPdfUrl:"/chapter/pdf-preview/74366",authors:[{id:"82604",title:"Dr.",name:"Matjaž",surname:"Glavan",slug:"matjaz-glavan",fullName:"Matjaž Glavan"},{id:"271728",title:"Ph.D. Student",name:"Miha",surname:"Curk",slug:"miha-curk",fullName:"Miha Curk"}],corrections:null},{id:"73830",title:"Examination of Hydrologic Computer Programs DHM and EDHM",doi:"10.5772/intechopen.94283",slug:"examination-of-hydrologic-computer-programs-dhm-and-edhm",totalDownloads:398,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The Diffusion Hydrodynamic Model or DHM is a coupled one- and two-dimensional (2-D) surface flow model based upon a diffusion formulation of the well-known Navier–Stokes equations, developed by research hydrologists of the USGS (United States Geological Survey) for use in modeling floodplains and dam-break situations. The Fortran 77 source code and various applications were published in 1987 by the USGS as a Technical Report authored by Hromadka and Yen. The DHM program led to the development of several subsequent computational programs such as the FLO-2D computational model and other similar programs. The original DHM program had a limit of applications to problems with no more than 250 nodes and modeling grids. That limitation was recently removed by a program version named EDHM (Extended DHM), which provides for 9999 nodes and grids. However, the computational code is preserved in order that the baseline code algorithmic procedures are untouched. In this paper, the DHM and EDHM are rigorously compared and examined to identify any variations between the two Fortran codes. It is concluded from this investigation that the two sets of algorithm codes are identical, and outcomes from either program are similar for appropriately sized applications.",signatures:"Theodore V. Hromadka II and Prasada Rao",downloadPdfUrl:"/chapter/pdf-download/73830",previewPdfUrl:"/chapter/pdf-preview/73830",authors:[{id:"181008",title:"Dr.",name:"Theodore V.",surname:"Hromadka II",slug:"theodore-v.-hromadka-ii",fullName:"Theodore V. Hromadka II"},{id:"192274",title:"Dr.",name:"Prasada",surname:"Rao",slug:"prasada-rao",fullName:"Prasada Rao"}],corrections:null},{id:"74795",title:"Ecohydrology: An Integrative Sustainability Science",doi:"10.5772/intechopen.94169",slug:"ecohydrology-an-integrative-sustainability-science",totalDownloads:379,totalCrossrefCites:0,totalDimensionsCites:3,hasAltmetrics:1,abstract:"The dynamic of the water cycle in catchments is determined by climate, geology, geomorphology, plant cover ad modified by agriculture, urbanisation, industrial development and hydroengineering infrastructure. Up until the end of the 20th century, water management was dominated by a mechanistic approach, focused on the elimination of threats such as floods and droughts and providing resources for the society with little to no regard for the impact this approach had on the ecosystem. Highlighting of water as a key driver of ecosystem dynamics, and further ecohydrology which highlights water/biota interactions from molecular to catchment scale provide a new perspective, new tools and new systemic solutions for enhancement of catchment sustainability potential WBSRCE (consisting of 5 elements: Water, Biodiversity, Ecosystem Services for Society, Resilience and Culture and Education).",signatures:"Maciej Zalewski",downloadPdfUrl:"/chapter/pdf-download/74795",previewPdfUrl:"/chapter/pdf-preview/74795",authors:[{id:"111006",title:"Prof.",name:"Maciej",surname:"Zalewski",slug:"maciej-zalewski",fullName:"Maciej Zalewski"}],corrections:null},{id:"73550",title:"Interlinking of River: Issues and Challenges",doi:"10.5772/intechopen.93594",slug:"interlinking-of-river-issues-and-challenges",totalDownloads:655,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Climate change events cause erratic spatial and temporal variability in rainfall, temperature, humidity, etc. in long term, and are most severely affecting irrigation, domestic and industrial water supply. At the same time, water availability is also under pressure due to climate change and overexploitation of water resources. In a monsoonal climate that is already erratic and highly seasonal in nature, this increased variability due to climate change will further impact water availability and salt water intrusion. To overcome such problems, one of the most effective ways is interlinking of rivers. It is the interbasin water transfer from the water surplus rivers to water deficit rivers or regions. It will increase water supply, irrigation potential, mitigate floods, and droughts and reduce regional imbalance in the availability of water. Interlinking of rivers will reduce regional imbalances significantly and provide benefits by the way of additional irrigation potential, domestic and industrial water supply, hydropower generation, and transport facilities.",signatures:"Pawan Jeet, Alok Kumar and Prem K. Sundaram",downloadPdfUrl:"/chapter/pdf-download/73550",previewPdfUrl:"/chapter/pdf-preview/73550",authors:[{id:"325776",title:"Dr.",name:"Pawan",surname:"Jeet",slug:"pawan-jeet",fullName:"Pawan Jeet"},{id:"325777",title:"Dr.",name:"Alok",surname:"Kumar",slug:"alok-kumar",fullName:"Alok Kumar"},{id:"325778",title:"Dr.",name:"Prem",surname:"Sundaram",slug:"prem-sundaram",fullName:"Prem Sundaram"}],corrections:null},{id:"73655",title:"Rivers of Lebanon: Significant Water Resources under Threats",doi:"10.5772/intechopen.94152",slug:"rivers-of-lebanon-significant-water-resources-under-threats",totalDownloads:302,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Lebanon is known by tremendous water resources, and this has been often viewed from the considerable number of rivers (i.e. 14 rivers). These rivers are characterized by small catchments and short length. The estimated average annual discharge from these rivers is approximately 2800 million m3. Due to the sloping terrain of Lebanon; however, it was estimated that more than 75% of water from rivers is unexploited it mainly outlets into the sea. The majority of water use from the Lebanese rivers implies domestic, agriculture, as well as some other rivers are used for hydro-power generation where they contribute by about 20% of electricity needed for Lebanon. Lately, and added to water pollution, there is abrupt decline in the discharge from these rivers estimated to more than 60% of their average annual discharge. This unfavorable situation is attributed, in addition to the changing climate, to the anthropogenic interference is the most affecting one and it is represented by over pumping from these rivers and form the recharge zone for groundwater and springs that feed these rivers. This chapter aims at introducing a discussion on the existed challenges on the Lebanese rivers and the proposed and their impact.",signatures:"Amin Shaban",downloadPdfUrl:"/chapter/pdf-download/73655",previewPdfUrl:"/chapter/pdf-preview/73655",authors:[{id:"75122",title:"Prof.",name:"Amin",surname:"Shaban",slug:"amin-shaban",fullName:"Amin Shaban"}],corrections:null},{id:"73259",title:"Statistical Analysis of the Precipitation Isotope Data with Reference to the Indian Subcontinent",doi:"10.5772/intechopen.93831",slug:"statistical-analysis-of-the-precipitation-isotope-data-with-reference-to-the-indian-subcontinent",totalDownloads:434,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The isotopic analysis of precipitation provides useful information on a variety of hydrological and atmospheric processes. The dynamical characteristics of precipitation isotopes have been well investigated, but a systematic study of their statistical behavior seems to be lacking. We have performed the statistical analysis, basically the distribution characteristics of precipitation isotopes vis-a-vis rainfall data for specific regions. The probability distribution functions of precipitation isotopes have been calculated from local to global scales. It has been observed that the isotopic values, in general, followed a pattern that is similar to the normal distribution, though the rainfall distribution patterns are very different. Under certain circumstances, the isotopic distribution patterns closely resemble the normal distribution, implying a well-constrained moisture source contributing to precipitation. The distribution patterns of oxygen and hydrogen isotopes on continental and global scales show similar behavior. It was observed that the distribution patterns of primary isotopic variables (δ18O and δD) are not very sensitive to the outliers. On the contrary, the secondary parameter, d-excess, is very sensitive to outliers, which offers an effective means to quality control of the precipitation isotopic values.",signatures:"Supriyo Chakraborty, Siddharth Birmal, Pramit Kumar Deb Burman, Amey Datye, Fousiya A.A., Aravind G.H., PM. Mohan, Neha Trivedi and Rajendra K. Trivedi",downloadPdfUrl:"/chapter/pdf-download/73259",previewPdfUrl:"/chapter/pdf-preview/73259",authors:[{id:"325291",title:"Dr.",name:"Supriyo",surname:"Chakraborty",slug:"supriyo-chakraborty",fullName:"Supriyo Chakraborty"},{id:"329495",title:"Mr.",name:"Siddharth",surname:"Birmal",slug:"siddharth-birmal",fullName:"Siddharth Birmal"},{id:"329496",title:"Mr.",name:"Pramit",surname:"Deb Burman",slug:"pramit-deb-burman",fullName:"Pramit Deb Burman"},{id:"329497",title:"Mr.",name:"Amey",surname:"Datye",slug:"amey-datye",fullName:"Amey Datye"},{id:"329498",title:"Dr.",name:"Fousiya",surname:"A. A.",slug:"fousiya-a.-a.",fullName:"Fousiya A. A."},{id:"329499",title:"Mr.",name:"Aravind",surname:"G. H.",slug:"aravind-g.-h.",fullName:"Aravind G. H."},{id:"329500",title:"Dr.",name:"Mohan",surname:"P. M.",slug:"mohan-p.-m.",fullName:"Mohan P. M."},{id:"329501",title:"Ms.",name:"Neha",surname:"Trivedi",slug:"neha-trivedi",fullName:"Neha Trivedi"},{id:"329502",title:"Dr.",name:"R. K.",surname:"Trivedi",slug:"r.-k.-trivedi",fullName:"R. K. Trivedi"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6018",title:"Flood Risk Management",subtitle:null,isOpenForSubmission:!1,hash:"e1c40b989aeffdd119ee3876621fa35d",slug:"flood-risk-management",bookSignature:"Theodore Hromadka and Prasada Rao",coverURL:"https://cdn.intechopen.com/books/images_new/6018.jpg",editedByType:"Edited by",editors:[{id:"181008",title:"Dr.",name:"Theodore V.",surname:"Hromadka II",slug:"theodore-v.-hromadka-ii",fullName:"Theodore V. 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The epidemiology of end-stage renal disease (ESRD) varies considerably worldwide. In Thailand, the incidence of ESRD on renal replacement therapy (RRT) increased from 78.9 per million populations in 1999 to 552.8 per million populations in 2009. The yearly incidence of all RRT modalities increased by an average of 34.8% from 2007 to 2009 [1]. According to the estimation by the International Diabetes Foundation, by the year 2025 the frequency of diabetes is expected to increase threefold worldwide [2]. Diabetic nephropathy is the most common cause of ESRD [3], representing 30-47% of the United States and Asian populations undergoing long-term maintenance hemodialysis [4, 5]. Disparities in the incidence of ESRD due to diabetes among ethnic groups have existed for many years, but the magnitude may be increasing.
In the United States, from 1990 to 1996, the age-adjusted diabetes-related ESRD incidence increased from 299.0 to 343.2 per 100,000 diabetic patients. However, from 1996 to 2006, the age-adjusted diabetes-related ESRD incidence decreased by 3.9% per year from 343.2 to 197.7 per 100,000 diabetic patients [6]. Diabetes-related ESRD incidence in the diabetic population has declined in all age-groups, probably because of a reduction in the prevalence of ESRD risk factors, improved treatment and care, and other factors. An alternative explanation for the decline in diabetes-related ESRD incidence in the diabetic population might be that the patients are not surviving long enough to develop ESRD, which occurs typically between 10 and 15 years after the onset of the disease. Premature mortality among ESRD patients with diabetes as a result of the increasing prevalence of coronary heart disease and stroke by tenfold could reduce the number of people who ultimately develop ESRD [7, 8]. Even though diabetes-related ESRD incidence in the population with diabetes has decreased since 1996, diabetes-related ESRD incidence in the general population and the number of persons initiating treatment for kidney failure each year who have diabetes listed as a primary cause continue to increase [5, 9]. In Europe, data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry shows an 11.9% annual increase in patients with type 2 diabetes entering RRT [10]. The most recent report of the Thailand RRT Registry shows a prevalence of diabetes among patients with ESRD of 47.6% and an incidence of 47.7%. The majority of patients with ESRD secondary to diabetes (51.0%) are treated by hemodialysis, 45.1% by peritoneal dialysis, and 3.9% have functioning renal transplants [1].
Diabetes-related ESRD is a costly and disabling condition with a high mortality rate. These patients are at a higher risk of mortality, mostly from cardiovascular complications, than other patients with diabetes. Apart from cardiac complications, the patients are subject to a wide range of vascular (e.g., peripheral vascular disease, stroke) and infectious complications. Patients with ESRD due to diabetes challenge the nephrologists because they have the greatest number of comorbid conditions, and the greatest dependency during daily activities. The goal of therapy is to improve quality of life, as well as reduce mortality. Attention to several basic principles helps to guide therapy: control of hypertension, control of hyperglycemia, control of lipid abnormalities, treatment of malnutrition, and attention to the effects of erythropoietin. Current cardio- and renoprotective treatment for diabetic nephropathy without ESRD includes optimization of glycemic control. Early intensive glycemic interventions reduce cardiovascular events as well as nephropathy by about half when compared with a conventional glycemic treatment. However, hypoglycemia is common because of impaired renal gluconeogenesis, malnutrition, chronic inflammation, decrease renal insulin clearance and the increased half-life of hypoglycemic agents [11]. Therefore, data are scarce on how diabetes should best be treated in patients in ESRD. In this chapter, we summarize the current evidence for glucose metabolism and glycemic control in diabetic patients on dialysis.
Hyperglycemia is an important factor in the progression of diabetic nephropathy. Early functional changes in diabetic nephropathy include glomerular hyperfiltration, glomerular and tubular epithelial hypertrophy, and the development of microalbuminuria, followed by the development of glomerular basement membrane (GBM) thickening, accumulation of mesangial matrix, and overt proteinuria, eventually leading to glomerulosclerosis and ESRD. Hyperglycemia-induced metabolic and hemodynamic pathways are recognized to be mediators of kidney injury [4].
Glucose transport activity is an important modulator of extracellular matrix formation by mesangial cells. Glucose transporter-1 (GLUT-1) regulates glucose entry into renal cells. Glucose and its metabolites subsequently activate metabolic pathways, and these pathways contribute to mesangial expansion and mesangial cell matrix-production, mesangial cell apoptosis and structural changes [12]. This may result from a similar increase in the mesangial cell glucose concentration, since similar changes in mesangial function can be induced in a normal glucose milieu by over-expression of GLUT1 [13]. Multiple biochemical pathways have been postulated that explain how hyperglycemia causes tissue damage including: non-enzymatic glycosylation that generates advanced glycosylation end products (AGE); activation of protein kinase C (PKC); and acceleration of the polyol pathway. Oxidative stress also seems to be a common theme. These pathways ultimately lead to increased renal albumin permeability and extracellular matrix accumulation, resulting in increasing proteinuria, glomerulosclerosis and ultimately renal fibrosis.
In ESRD, both uremia and dialysis can complicate blood glucose control by affecting the secretion, clearance, and peripheral tissue sensitivity of insulin. The abnormal glucose homeostasis in patients with dialysis is postulated to be multifactorial issues as Figure 1.
Contribution factors for the abnormal glucose metabolism in dialysis patients.
Advanced-stage chronic kidney disease (CKD) or ESRD can show mild fasting hyperglycemia and abnormal glucose tolerance, suggesting that the uremic state alters glucose homeostasis [14]. Insulin resistance is also frequently recognized in uremic patients and is a predictor of cardiovascular mortality in ESRD patients [15]. Impaired insulin sensitivity in the absence of overt diabetes play a central role in the development of atherosclerotic vascular disease [16]. Several clinical studies have noted impaired tissue sensitivity to insulin in diabetic nephropathy [17], and non-diabetic patients exhibit only mild to moderate reductions in renal function [18-20] and in ESRD [21, 22]. However, impaired insulin sensitivity in both dialysis groups after long-term dialysis was still higher than that of the non-dialysis ESRD group while no significant differences were noted between peritoneal dialysis and hemodialysis treatments [23]. The mechanism of increased insulin resistance in patients with kidney disease is not fully understood. Several factors, including uremic toxins, may increase insulin resistance in ESRD, leading to a blunted ability to suppress hepatic gluconeogenesis and regulate peripheral glucose utilization. In addition, in non-diabetic CKD patients, an independent factor for insulin resistance was the amount of total body fat and body mass index [20]. This change occurs in ESRD because of concomitant metabolic acidosis, deficiency of 1,25 dihydroxy-vitamin D, and secondary hyperparathyroidism. In addition, in uremic patients, previous studies have reported that treatment with hemodialysis, active vitamin D, erythropoietin and angiotensin receptor blocker can improve insulin insensitivity [21, 24-26].
Further complicating the effect of dialysis is the glucose load provided by both dialysis modalities. The dextrose concentration in the dialysate can also affect glucose control. In hemodialysis population, dialysates with lower dextrose concentrations are used and may be associated with hypoglycemia. Conversely, dialysates with higher dextrose concentrations are occasionally used in hypoglycemic patients on hemodialysis and low ultrafiltration patients on peritoneal dialysis (PD), but this can lead to hyperglycemia and insulin resistance [27].
Decreasing insulin requirements and frequent hypoglycemia also occur in diabetic patients on dialysis. Renal insulin clearance decreases as glomerular filtration rate decreases to less than 15 to 20 mL/min/1.73 m2 [14]. Hepatic clearance of insulin is also decreased in patients with uremia. In addition, deficient gluconeogenesis along with malnutrition, deficient catecholamine release, and impaired renal insulin degradation and clearance, can contribute to frequent hypoglycemia in patients with CKD [28, 29].
Thus, advanced CKD and ESRD on dialysis exert opposing forces on insulin secretion, action, and metabolism, often creating unpredictable serum glucose values. Some patients who have insulin resistance would need more supplemental insulin. In contrast, the reduced renal gluconeogenesis and insulin clearance seen in ESRD may result in less requirement for insulin treatment. Together, all of these factors contribute to wide fluctuations in plasma glucose levels and increase the risk of both hyperglycemic and hypoglycemic events. Both of these abnormalities are at least partially reversed with the institution of dialysis. As a result, the insulin requirement in any given patient will depend upon the net balance between improving insulin secretion and insulin sensitivity, and restoring normal hepatic insulin metabolism.
Glycemic therapy in patients with diabetes has been shown to improve outcomes, especially microvascular complications in patients without kidney disease [30, 31]. The efficacy of glycemic control depends in part upon the stage at which it is begun and the degree of normalization of glucose metabolism. Glycemic control can partially reverse the glomerular hypertrophy and hyperfiltration that are thought to be important pathogenic pathways for diabetic nephropathy, and decrease the incidence of new-onset microalbuminuria in retrospective [32] and prospective studies of patients with diabetes [31, 33]. Progression of established overt nephropathy can also be stabilized or retarded through strict glycemic control. However, proving the efficacy of this treatment is difficult, and previous studies examining outcomes of glycemic control in dialysis patients gave conflicting results [34]. The benefit of glucose control on progression in patients with CKD who have advanced kidney disease is less well studied.
Interestingly, benefits of glycemic control after pancreas transplantation in patients with type 1 diabetes were observed: mesangial matrix volume, thickening of glomerular and tubular basement membranes, and nodular glomerular lesions were significantly decreased and/or returned to normal compared to the same measurements at zero and ten years [35, 36].
Effects of intensive glycemic control on prevention of macrovascular complications (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease) are less certain, particularly in type 2 diabetes. The 10-year follow-up study of patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated risk reduction for myocardial infarction and death from any cause [37]. More recent studies, including the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), and the Veterans Affairs Diabetes Trial (VA-DT) that targeted even lower hemoglobin A1c (HbA1c) goals (<6–6.5%), failed to show cardiovascular disease risk reduction with more
Several observational studies showed that higher levels of hemoglobin A1c were associated with higher mortality rates in patients with diabetes on long-term dialysis and CKD [41-44]. A previous study demonstrated that a paradoxically lower unadjusted mortality associated with greater hemoglobin A1c levels were found in 23,618 dialysis patients with diabetes. However, after adjusting for markers of malnutrition and inflammation, hemodialysis patients with hemoglobin A1c levels <5% or >7% became associated with greater mortality [45]. The data indicate that competing risk factors related to malnutrition, muscle wasting, and anemia may confound the association between glycemic control and survival in diabetic patients with long-term dialysis. In the study by Williams, hemoglobin A1c levels >11.0% in type 1 diabetes on hemodialysis were required to observe a statistically significant higher mortality risk, but few subjects had hemoglobin A1c levels in this category [46]. In a recent cohort of 54,757 diabetic hemodialysis patients, poor glycemic control (hemoglobin A1c ≥8% or serum glucose ≥200 mg/dL) appears to be associated with high all-cause and cardiovascular death and very low glycemic levels (hemoglobin A1c <7%) are also associated with high mortality risk [47]. In a single interventional study in 83 dialysis patients, patients in the intensive intervention group experienced improved quality of life and a decreased need for amputations and hospitalizations [48]. Larger clinical trials are needed to conclusively prove the concept that better glycemic control is beneficial in patients with advanced CKD. To date, there are no data available from randomized clinical trials targeting different hemoglobin A1c levels and powered for cardiovascular events or mortality in ESRD populations. Careful evaluation of the relationship of hemoglobin A1c with these outcomes in ESRD patients should be a high priority for future research to determine the risks and benefits of different hemoglobin A1c targets.
The Kidney Disease Outcomes Quality Initiative (KDOQI) foundation state that target hemoglobin A1c for people with diabetes should be <7%, irrespective of presence or absence of CKD. This recommendation is in line with diabetes management in the general population [11]. However, very few studies have addressed the benefits and risks of intensive glycemic control in late stages of CKD and ESRD. Recent evidence from randomized studies has highlighted the potential risks of aggressive glycemic control in non-ESRD diabetic populations [38, 39]. Moreover, because many dialysis patients are wasting, malnourished, and non-ambulatory, they may be less able to respond appropriately to hypoglycemia.
The guidelines of the 2012 American Diabetes Association recommend lowering hemoglobin A1c to below or around 7% for many adults, and to implement this soon after the diagnosis of diabetes that is associated with long-term reduction in macrovascular disease [49]. Providers might reasonably suggest more stringent hemoglobin A1c goals (such as <6.5%) for selected individual patients, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Appropriate patients might include those with short duration of diabetes, long life-expectancy, and no significant cardiovascular disease. Less stringent hemoglobin A1c goals (such as <8%) may be appropriate for patients with a history of severe hypoglycemia, limited life- expectancy, advanced microvascular
Glucose homeostasis is altered significantly in patients with uremia. Glycated hemoglobin (expressed as a percentage of total hemoglobin) or hemoglobin A1c measurement is used as an indicator of integrated glucose control. Glycated hemoglobin is formed by the non-enzymatic reaction between glucose and the N-terminal amino group on the beta chain of hemoglobin. The good correlation between hemoglobin A1c and blood glucose in non-CKD type 1 diabetic patients has been documented in the Diabetes Control and Complications Trial (DCCT) [50]. At present, this test is the most accurate method to assess chronic glycemic control based on clinical outcomes associated with certain hemoglobin A1c levels in diabetic patients with normal kidney function [31]. The validity of glycated hemoglobin and hemoglobin A1c has not been rigorously studied in patients with ESRD. These tests may be unreliable in dialysis patients because of assay interference due to the elevated blood urea nitrogen. Glycated hemoglobin tests, such as column- and ion-exchange chromatography and agar gel electrophoresis, are affected by uremia. This is due in part to analytical interference from carbamylated hemoglobin formed in the presence of elevated concentrations of urea, leading to false elevations in the hemoglobin A1c level. Use of agarose affinity chromatography or the thiobarbituric acid method for analyzing hemoglobin A1c can be used reliably in patients with ESRD. Other factors such as shorter life span of red blood cells, iron deficiency anemia, and recent transfusion may also cause underestimation of glucose control in diabetic hemodialysis patients (Table 1). In addition, patients treated with erythropoietin could lead to underestimation of glycemic control by using hemoglobin A1c level, because of the greater proportion of young erythrocytes in the circulation of patients [51]. Therefore, hemoglobin A1c levels tend to underestimate glycemic control in diabetic patients undergoing long-term maintenance hemodialysis [52, 53].
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Carbamylated hemoglobin for charge-dependent chromatography assays | \n\t\t\tErythropoiesis supplement | \n\t\t
Increased glycosylation rate | \n\t\t\tShortened life span of red blood cells | \n\t\t
Uremia | \n\t\t\tBlood transfusions | \n\t\t
Metabolic acidosis | \n\t\t\tHemoglobinopathy | \n\t\t
Glycated hemoglobin levels in dialysis patients
Despite anemia and shortened RBC lifespan in ESRD patients, hemoglobin A1c in the range of 6% to 7% estimates glycemic control similarly to patients without severe renal impairment. Hemoglobin A1c above 7.5% may overestimate hyperglycemia in patients with ESRD [43]. It is important to be aware of the specific assay used and the other factors affecting the accuracy of hemoglobin A1c measurements in ESRD on hemodialysis and peritoneal dialysis.
Another potential method to monitor glycemic control in patients with uremia is glycated albumin. Some studies suggest that glycated albumin more accurately reflects glycemic control in diabetic hemodialysis patients than hemoglobin A1c [54, 55]. However, falsely increased glycated albumin values have been measured in the presence of lipemia, hemolysis, and high bilirubin and uric acid concentrations. In addition, use of glycated albumin is hampered by conditions that alter protein metabolism including ESRD, their lack of availability in routine practice and the lack of established reference levels [56].
Despite the limitations in using hemoglobin A1c in the dialysis population, this test is considered a reasonable measure of chronic glycemic control in this group. Patient self-monitoring of blood glucose is also available for patients to assess the effectiveness of the management plan on glycemic control. It provides real-time assessments of glycemic control and results of self-monitoring of blood glucose can be useful in preventing hypoglycemia and adjusting medications (particularly prandial insulin doses), and physical activity. There are some limitations of this method, because it is subject to errors from poor technique, problems with the meters and strips, and lower sensitivity in measuring low blood glucose levels. However, hemoglobin A1c does not provide a measure of glycemic variability or hypoglycemia. Thus, for patients prone to glycemic variability (especially type 1 patients, or type 2 patients with severe insulin deficiency), glycemic control is best judged by the combination of results of self-monitoring of blood glucose testing and the hemoglobin A1c assay [49]. Hemoglobin A1c may also serve as a check for the accuracy of the patient’s meter and the adequacy of the self-monitoring schedule of blood glucose testing.
Insulin regulates glucose homeostasis at many sites, reducing hepatic glucose output by decreasing gluconeogenesis and glycogenolysis, and increasing the rate of glucose uptake, primarily into muscle and adipose tissue. Insulin affects cells through binding to its receptor on the surface of insulin-responsive cells. The stimulated insulin receptor phosphorylates itself, and several substrates including membranes of the insulin receptor substrate family and initiate downstream signaling events [27].
In healthy non-diabetic people, the pancreatic β-cells secrete half of the daily insulin requirement (approximately 0.5 units/kilogram/day) at a steady basal rate independent of glucose levels and the other half is secreted in response to prandial glucose stimulation [57]. Insulin is secreted into the portal system, it passes through the liver where approximately 75% is metabolized with the remaining 25% metabolized by the kidneys. About 60% of the insulin in the arterial bed is filtered by the glomerulus and 40% is actively secreted into the nephric tubules [58]. Most of the insulin in the tubules is metabolized into amino acids, and only 1% of insulin is secreted intact.
Interestingly, endogenous insulin is substantially degraded by the liver but exogenous insulin is eliminated mainly by the kidney. For diabetic patients receiving exogenous insulin, renal metabolism plays a more significant role since there is no first-pass metabolism in the liver. Insulin is freely filtered at the glomerulus and extensively reabsorbed in the proximal tubule after enzyme degradation into smaller peptides. As renal function starts to decline, insulin clearance does not change appreciably, due to compensatory peritubular insulin uptake [59]. However, once the glomerular filtration rate drops below 20 mL/min, insulin clearance decreases and the half-life of insulin increases, an effect compounded by a decrease in the hepatic metabolism of insulin that occurs in uremia [25]. Glucose and insulin homeostasis are altered in CKD patients even in the early stages of CKD, leading to insulin resistance by various pathways. Studies even in the 1980s showed that, although insulin secretion in CKD is normal, a decreased tissue sensitivity to insulin is responsible for the abnormal glucose uptake [60]. In advanced CKD, particularly in stages 4 and 5, significant metabolic derangements in insulin metabolism occur. Several factors have been implicated in the pathogenesis of insulin resistance including anemia, dyslipidemia, uremia, malnutrition, excess of parathyroid hormone, vitamin D deficiency, metabolic acidosis, and increase in plasma free fatty acids and proinflammatory cytokines. Thus, despite the increase in insulin resistance caused by renal failure, the net effect is a reduced requirement for exogenous insulin in ESRD patients [61]. Despite similar duration of disease and clinical characteristics, patients with type 2 diabetes with ESRD often show marked heterogeneity in terms of insulin requirement and dosages [62]. However, predictors for exogenous insulin requirement in patients with type 2 diabetes undergoing continuous ambulatory peritoneal dialysis (CAPD) have not been defined. Possible factors include β-cell function, endogenous metabolism and elimination of insulin, insulin resistance, body size, carbohydrate intake, and extra glucose absorbed from dialysate fluid [27].
Recent evidence showed that insulin is a anti-inflammatory hormone that suppresses several proinflammatory transcription factors such as nuclear factor κB (NF-κB), early growth response protein 1 and activating protein 1, which all mediate inflammation. An impairment of the action of insulin because of insulin resistance would therefore result in the activation of these proinflammatory transcription factors and in an increase of the expression of the corresponding genes. Derangements in other biologic effects of insulin could be associated with certain pathologic states in CKD such as hypertension and insulin resistance [63, 64].
Previous studies have shown that uremia was associated with an insulin-resistant state, mainly because of decreased insulin-stimulated uptake of glucose by muscle [65]. However, in clinical practice, with progressive renal failure, the insulin requirements of patients with diabetes for glycemic control often tend to decrease [66]. The determinants of insulin requirements in patients with diabetes with ESRD remain uncertain. This can be influenced by factors such as insulin resistance, production and metabolism of endogenous insulin, oral intake, extra carbohydrate absorbed from dialysis solution, and reduction of body weight in uremic patients [27, 67]. Possible factors for this reduction in insulin requirement include reduced renal clearance of both endogenous and exogenous insulin and progressive loss of appetite and body weight in uremic patients. However, several studies have shown similar fasting insulin levels between patients with renal failure and those with normal renal function [27, 68].
In PD patients, the development of insulin resistance after a initial improvement is generally attributed to a high glucose load absorbed from dialysis fluid, contributing to a wide spectrum of metabolic abnormalities including hypertriglyceridemia, poor glycemic control, new-onset diabetes, hypertension and central obesity. An amplifying loop in the process of glucose absorption appears to be a consequence of the modifications in the peritoneum associated with a loss of ultrafiltration capacity [69]. Disturbances of carbohydrate metabolism seem to be even more intense in non-diabetic PD patients than in hemodialysis patients. After PD initiation, a large number of patients developed new-onset hyperglycemia because of their exposure to hypertonic glucose solutions [27, 70, 71]. In fact, glucose absorption through the peritoneum results in significantly higher serum glucose levels than are produced by an equivalent dose of oral dextrose. Wong et al. show considerable variations in the need for insulin treatment and dosages in patients with type 2 diabetes undergoing CAPD despite similar disease duration, dialysis regimens, renal function, and glycemic control [67]. Duration of diabetes, hemoglobin A1c level, and body weight were independent determinants of insulin requirement of patients with type 2 diabetes with ESRD patients undergoing CAPD. Dialysis regimen with estimated amount of glucose absorbed and Kt/V did not predict insulin requirement in these patients. Insulin resistance, insulin requirement, and fasting C-peptide levels, a crude measurement of basal pancreatic β-cell function in patients with diabetes with normal renal function, were not affected by dialysis dosage, reflected by a similar value of Kt/V [67]. Insulin-treated patients had lower C peptide concentrations than non-insulin-treated patients, and insulin dosage required was correlated with duration of diabetes mellitus, implying the significance of β-cell function in determination of insulin requirement in patients with type 2 diabetes with ESRD.
Insulin injection therapy remains the mainstay treatment to achieve good glycemic control in diabetic patients receiving hemodialysis therapy [72]. In hemodialysis patients, the insulin sensitivity normally improves on both an acute and chronic basis [66], mainly by clearing circulating urea, and also insulin clearance. The concentration of glucose and insulin is frequently affected by the dialysis procedure itself. Changes in glucose will vary with the concentration of glucose (dextrose) in the dialysis fluid, to which the patient’s blood is indirectly exposed. Because glucose transfers to the dialysate according to its concentration gradient, dialysate lacking glucose is associated with significant decreases in plasma glucose levels in poorly and well-controlled diabetic patients as well as in some non-diabetic patients, and is no longer used. Plasma insulin levels also are decreased during the hemodialysis treatment, due to clearance by dialysis which varies among membranes and with the fall in glucose. Additional metabolic effects of dialysis include improvement in sensitivity to insulin and decrease in some cases of counter-regulatory hormones (e.g., growth hormone). In poorly controlled patients, hemodialysis-induced clearance of plasma immunoreactive insulin levels may result in hyperglycemia in the post-dialysis period [63].
Various insulin preparations are available in the market. In ESRD patients, insulin doses will need to be reduced, especially after dialysis has been initiated [63]. Sobngwi et al. show that the daily insulin needs on the day after hemodialysis should be decreased approximately 15% compared with the daily insulin needs before hemodialysis, with a significant reduction of basal hourly insulin requirement by 25%, unchanged boluses, and unchanged body weight-indexed total insulin dose in a group of type 2 diabetic patients on maintenance hemodialysis [73]. However, no evidence for the benefit of neutral protamine hagedorn (NPH) insulin or other long-acting insulin in patients with ESRD is available. On the other hand, insulin lispro which has a short onset of action and a short duration of action shows the benefit not only facilitate the correction of hyperglycemia but may also decrease the risk of late hypoglycemic episodes, which is of increased relevance in hemodialysis patients [64] because its pharmacokinetics is less affected in renal failure [74]. Long-acting insulin such as insulin glargine or NPH insulin can be widely used as basal requirements, along with a rapid-acting insulin analogue such as lispro or insulin aspart before meals two or three times daily [57]. When the glomerular filtration rate drops between 10 and 50 mL/min, the total insulin dose should be reduced by 25%. Once the filtration rate is below 10 mL/min, as in ESRD patients, the insulin dose should be decreased by 50% from the previous amount [75].
Unexpected hypoglycemia often occurs in dialysis patients during basal-bolus insulin therapy despite careful adjustment of their insulin dose which may due to 3 main factors: (1) prolongation of the elimination half-life of insulin associated with decreased renal degradation and excretion [68]; (2) impairment of gluconeogenesis by the kidneys and (3) weak gastric peristalsis in diabetic patients on dialysis, with prolongation of stomach food retention, resulting in delays in glucose absorption [76]. It is important to note that the signs and symptoms of hyperglycemia are modified in patients with ESRD [63]. Signs and symptoms of hyperglycemia may involve thirst, fluid overload, and hyperkalemia rather than polyuria. Lacking polyuria, patients experience volume expansion, not contraction; excessive thirst will result in large weight gains, which correlate with poor glycemic control between dialysis treatments. Severe hyperglycemia may result in hyperkalemia and complicate management further. Other findings may be pulmonary edema, hypertension, anorexia, altered mental status, nausea, vomiting, and gastroparesis, although symptoms are frequently nonspecific or lacking.
Therapeutic options for patients with diabetes with CKD and ESRD are limited because a reduced glomerular filtration rate results in the accumulation of certain drugs and/or their metabolism [77]. Most of oral antihyperglycemic drugs include the insulin secretagogues such as sulfonylureas and meglitinides, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors are contraindicated in ESRD patients. However, some agents have been used in patients with CKD and were found to be effective and safe even in those on dialysis. Therefore, some medications may be useful therapeutic options for the management of diabetes in CKD.
As shown in Table 2, insulin secretagogues can be classified as sulfonylureas and meglitinides while alpha-glucosidase inhibitors are modifiers of glucose absorption and thiazolidinediones are insulin sensitizers. Incretin-related therapies include dipeptidylpeptidase-4 (DPP-4) inhibitors and incretin mimetics. DPP-4 inhibitors are oral antidiabetic agents, whereas incretin mimetics are used by subcutaneous injection.
Since many drugs bind to serum protein, primarily albumin and plasma concentration of albumin in patients with renal impairment is commonly decreased, the concentrations of unbound drugs are increased.
Insulin secretagogues increase endogenous insulin levels. These agents work by binding to sulfonylurea receptors or nearby sites, resulting in closure of ATP-sensitive potassium channels of the pancreatic β-cell, depolarization of the cell membranes, calcium influx, and subsequently insulin release [72]. They have a wide volume of distribution and are highly protein-bound. However, only the unbound drug exerts a clinical effect. Because of high protein binding property, dialysis cannot effectively clear elevated levels of sulfonylurea drugs. As these agents increase endogenous insulin levels, they are associated with an increased risk of hypoglycemia. This risk is mitigated when shorter-acting agents are used. Furthermore, many ESRD patients take drugs such as sulfonamides, vitamin K antagonists, beta-blocker, salicylates and fibric acid derivatives which may displace sulfonylureas from albumin, thus increasing the risk of severe hypoglycemia.
Oral anti-diabetic drugs and insulin analogs
* Modify from Masanori Abe, Kazuyoshi Okada and Masayoshi Soma "Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice" Current Drug Metabolsim Volume 12, January 2011, with permission.
The first-generation sulfonylureas-chlorpropamide, acetohexamide, tolbutamide, and tolazamide are almost exclusively excreted by the kidney and are therefore contraindicated in ESRD patients [78]. Second-generation agents include glimepiride and glyburide which are metabolized in the liver. However, their active metabolites are excreted in the urine and so these medications should be avoided in ESRD patients as well [72] but low-dose initiation can be used in patients with CKD [79]. Glipizide and gliclazide are the preferred agents and no dose adjustment has been necessary in a dialysis population [11].
Most sulfonylureas are not suitable for ESRD patients due to the risk of prolonged hypoglycemic; furthermore, metformin is contraindicated [80]. From all medications in this group, the only sulfonylurea recommended in ESRD patients are glipizide and gliclazide which are also metabolized in the liver but has inactive or weakly active metabolites excreted in the urine [57]. Glipizide is eliminated primarily by hepatic biotransformation; < 10% of a dose is excreted as unchanged drug in urine or feces while approximately 90% is excreted as biotransformation products in urine (80%) and feces (10%). The major metabolites of glipizide are products of aromatic hydroxylation that have no hypoglycemic activity. A minor metabolite which accounts for < 2% of a dose, an acetylamino-ethyl benzene derivative, is reported to have 1/10 to 1/3 of the hypoglycemic activity compared to the parent compound. The suggested dose of glipizide is 2.5 to 10 mg/day. In ESRD patients, sustained-release forms should be avoids due to the concerns of hypoglycemia [81].
Repaglinide, nateglinide and mitiglinide are insulin secretagogues that stimulate pancreatic β-cells. They are currently in clinical use because of their rapid onset of action resulting in improvement in hyperglycemia. Like sulfonylureas, nateglinide is hepatically metabolized, with renal excretion of active metabolites. On the other hand, repaglinide is almost completely converted to inactive metabolites in the liver, and less than 10% is excreted by the kidneys [82, 83]. Nateglinide still pose a risk of hypoglycemia especially in ESRD patients. Because of that, this drug is not recommended to use in patients on hemodialysis [82, 83]. However, mitiglinide shows selective action on the ATP-sensitive potassium channel of pancreatic β-cells and the order of affinity is mitiglinide > repaglinide > nateglinide [84]. This result suggests that mitiglinide induces insulin secretion by specifically acting on pancreatic β-cells and has few unwanted effects on the cardiovascular system. Because mitiglinide is rarely accompanied by hypoglycemia, it may be an attractive therapeutic option for patients undergoing dialysis [85]. However, the optimal daily dose of mitiglinide is suggested to be lower in the diabetic hemodialysis patients than that in the diabetic patients with normal kidney function. Mitiglinide has the potential to reduce the number of type 2 diabetics on hemodialysis who ultimately require insulin injection therapy. The daily dose of mitiglinide (23 mg) was adequate, as evidenced by the fact that it was able to induce significant reductions in glycemic parameters such as fasting plasma glucose, hemoglobin A1c, glycated albumin, and homeostasis model assessment for insulin resistance (HOMA-IR) levels [86]. This suggests that appropriate blood glucose levels can be maintained even at a low dose of mitiglinide, not only during the postprandial period but also before meals, due to the prolonged half-life of mitiglinide in patients on dialysis compared with the half-life in those with normal renal function. Abe et al. reported that mitiglinide significantly improved glycemic control, triglyceride levels and interdialytic weight gain even when administered for only a short duration [87]. Thus, mitiglinide not only improved hemoglobin A1c and glycated albumin, the overall index of glycemic control in type 2 diabetes, but also effectively improved fasting plasma glucose in dialysis patients [72, 85].
Metformin, the drug of choice for many patients with type 2 diabetics, is a biguanide that reduces hepatic gluconeogenesis and glucose output. Metformin does not cause increase insulin levels, but rather decreases hepatic glucose output by suppressing fasting gluconeogenesis. It is absorbed via the small intestine and the absolute bioavailability is approximately 50-60%. Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism or biliary excretion [88]. Renal clearance of metformin is approximately 3.5-fold greater than creatinine clearance, which indicates that tubular secretion via human organic cation transporter 2 is the major route of metformin elimination [89]. Single-dose and steady-state pharmacokinetics of metformin were compared between patients with normal renal function (CrCl > 90 mL/min), mild impaired renal function (CrCl 61-90 mL/min) as well as moderate (CrCl 31-60 mL/min) and severe impaired renal function (CrCl 10-30 mL/min). The results show that in patients with moderate to severe impaired renal function, Cmax and AUC are increased 173% and 390%, respectively, compared to the patients with normal renal function [89]. In patients with decreased renal function, based on the measurement of CrCl, the plasma half-life of metformin is prolonged and renal clearance is decreased in proportion to the decrease in CrCl [89]. Therefore, metformin should be avoided in patients with moderate to severe CKD including those on dialysis since the risk of metformin accumulation and lactic acidosis increases in line with the degree of impairment of renal function [90].
Rosiglitazone and pioglitazone are highly potent, selective agonists that work by binding to and activating a nuclear transcription factor, specifically, peroxisome proliferator-activated receptor gamma (PPAR-gamma) which improves insulin resistance in type 2 diabetic patients [91, 92] as well as increase glucose uptake in muscles and adipose tissue, and decrease hepatic glucose production [92, 93]. Both rosiglitazone and pioglitazone have an adequate oral bioavailability and are extensively metabolized by the liver. Rosiglitazone is mainly metabolized by CYP2C8 into inactive metabolites and < 1% of the parent drug appears in the urine in unchanged form [80, 94]. The half-life of rosiglitazone is similar in patients with ESRD and in healthy individuals, and can therefore be administered to ESRD patients without dose adjustment or risk of causing hypoglycemia [95-97]. Pioglitazone is metabolized by CYP3A4 and CYP2C8/9 [98]. Metabolites of pioglitazone are more active than those of rosiglitazone and are excreted predominantly in bile. The pioglitazone metabolites do not accumulate in CKD. The pharmacokinetics profile of pioglitazone was found to be similar in healthy subjects and patients with moderately or severely impaired renal function who did not require dialysis [98]. Moreover, in patients who did require dialysis, pioglitazone was found to have a Tmax of 1.8 h and a half-life of 5.4 h [98]. Therefore, a post-dialysis supplementary dose is not required, and pioglitazone can be administered irrespective of the time of dialysis. Due to the high molecular weight (392 Da), high protein-binding capacity (> 98%) and predominant hepatic metabolism of pioglitazone, its pharmacokinetics is similar in patients with normal renal function and CKD, and in those undergoing dialysis therapy. The main adverse reaction of these agents is edema, especially when they are used in combination with insulin. Because of that, a joint statement of the American Diabetes Association and the American Heart Association recommends avoiding thiazolidinediones in patients in New York Heart Association class III or IV heart failure [99]. Moreover, caution is required in patients in compensated heart failure (New York Heart Association class I or II) or in those at risk of heart failure such as patients with history of myocardial infarction or angina, hypertension, left ventricular hypertrophy, significant aortic or mitral value disease, age greater than 70 years, or diabetes for more than 10 years [99].
Thiazolidinediones have been reported to (1) reduce insulin requirements, (2) ameliorate albuminuria (3) have various roles in lipid metabolism, fibrinolysis, platelet aggregation and coagulation, (4) protect against impairment of endothelial function and (5) have an anti-inflammatory effect [100-103]. When used for the clinical management of type 2 diabetes and ESRD, thiazolidinediones are primarily metabolized in the liver and will not accumulate in patients with CKD. They might also improve uremia-associated insulin resistance and confer benefits at the metabolic, inflammatory, vascular, and hemodynamic levels [100]. The efficacy of this drug in patients with normal renal function is similar to the efficacy in those with mild to moderate renal impairment [104]. Administration of pioglitazone is also associated with mean decreases in triglyceride levels and mean increases in high-density lipoprotein (HDL)-cholesterol without consistent changes in the mean levels of total cholesterol or low-density lipoprotein (LDL)-cholesterol in non-uremic patients [105].
Thiazolidinediones are known to reduce HOMA-IR and levels of high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-alpha (TNF-α), and increase adiponectin levels in patients not undergoing dialysis [72]. In patients undergoing PD, thiazolidinediones have been reported to reduce hs-CRP levels, but levels of interleukin-6 (IL-6) and TNF-α were not reduced [91, 102]. In a short-term study of dialysis patients, thiazolidinediones are reported to reduce the levels of hs-CRP but not adiponectin [106]. It has been reported that pioglitazone treatment reduced the levels of hs-CRP, IL-6 and TNF-α and increased the high-molecular weight adiponectin level even in hemodialysis patients [107]. Moreover, the dosage of erythropoiesis-stimulating agents was significantly reduced during pioglitazone treatment with improvement in insulin resistance and a decrease in the levels of inflammatory cytokines [107].
It can be concluded that even though ESRD and dialysis do not affect the metabolism of thiazolidinediones, the medications in this group are not recommended in ESRD patients due to the associated risk of fluid accumulation and precipitation of heart failure.
Enzyme alpha-glucosidase is located in the gut and hydrolyzed oligosaccharides, trisaccharides and disaccharides into glucose in the brush border of the small intestine. The antihyperglycemic action of alpha-glucosidase inhibitors results from the reversible inhibition of membrane-bound intestinal alpha-glucoside hydrolase enzymes. Alpha-glucosidase inhibitors decrease the rate of breakdown of complex carbohydrates so that less glucose is absorbed and postprandial hyperglycemia is lowered but they do not enhance insulin secretion. The main side effects are gastrointestinal including flatulence and diarrhea.
Acarbose and miglitol slow carbohydrate absorption from the intestine. The levels of these drugs and their active metabolites are higher in patients with renal failure [80], and since data are scarce on the use of these drugs in ESRD, they are contraindicated in ESRD patients [11].
Acarbose is metabolized by intestinal bacteria and digestive enzymes exclusively within the gastrointestinal tract. Within 96 h of ingestion, 51% of an oral dose was excreted in the faces and unabsorbed drug-related radioactivity. Because acarbose acts locally within the gastrointestinal tract, low systemic bioavailability of the parent compound is therapeutically desirable. A fraction of these metabolites (about 34% of the dose) was absorbed and subsequently excreted in urine. The major metabolites have been identified as 4-methylpyrogallol derivatives (such as sulfate, methyl, and glucuronide conjugates). Moreover, one metabolite (formed by cleavage of a glucose molecule from acarbose) also has alpha-glucosidase inhibitory activity. This metabolite, together with the parent compound, recovered from the urine, accounts for < 2% of the total administered dose. Although < 2% of an oral dose of acarbose was absorbed as active drug, patients with severe renal impairment (CrCl < 25 mL/min) attained increases about 5-fold higher for peak plasma concentration of acarbose and 6-fold higher for AUC values than subjects with normal renal function [108]. Because long-term clinical trials in diabetic patients with significant renal dysfunction have not been conducted, treatment of these patients with acarbose is not recommended [108].
Miglitol is not metabolized in humans or other animal species [109]. No metabolites have been detected in plasma, urine, or feces indicating a lack of either systemic or presystemic metabolism. Miglitol is eliminated by renal excretion as unchanged drug [109]. Patients with CrCl < 25 mL/min taking the miglitol 25 mg 3 times daily exhibited a greater than 2-fold increase in miglitol plasma levels when compared to subjects with CrCl > 60 mL/min [109]. Dose adjustment to correct for the increased plasma concentrations is not feasible because miglitol acts locally. However, treatment of patients with CrCl < 25 mL/min with miglitol is not recommended because the safety of miglitol in these patients has not yet been elucidated [109].
The intestinal hormone glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin release from pancreatic β-cells in a glucose-dependent manner and inhibits inappropriate postprandial glucagon release. It also shows gastric emptying and reduces food intake. However, its meal-induced secretion is generally decreased in patients with type 2 diabetes, and this may contribute to the amplification of postprandial hyperglycemia [72]. GLP-1 is rapidly inactivated by the enzyme dipeptidylpeptidase-4 (DPP-4) [110]. Therefore, an effective way to potentiate postprandial GLP-1 response is the use of selective DPP-4 inhibitors [111, 112].
Table 2 shows some of the medications in this group.
Sitagliptin is a highly selective, oral, once-daily administration DPP-4 inhibitor approved for the treatment of patients with type 2 diabetes [113]. DPP-4 inhibitors slow the degradation and the inactivation of the incretins, GLP-1 and glucose-dependent insulinotropic polypeptide [110]. These two incretins regulate glucose homeostasis by stimulating insulin release, while GLP-1 also suppresses glucagon release [72]. Sitagliptin can be used as initial pharmacologic therapy for type 2 diabetes, as a second agent in those who do not respond to a single agent such as a sulfonylurea [114], metformin [115-117], or a thiazolidinedione [118] and as an additional agent when dual therapy with metformin and a sulfonylurea does not provide adequate glycemic control [114]. CYP3A4 is the major CYP isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8. Sitagliptin is primarily renally eliminated with approximately 80% of the oral dose excreted unchanged in the urine [119, 120]. Excretion is thought to be via active secretion and glomerular filtration [119, 121]. Following single oral doses of sitagliptin, plasma level increases with decreasing renal function, as determined by 24 h CrCl. Relative to subjects with normal or mildly impaired renal function, patients with moderate renal insufficiency (CrCl 30-50 mL/min), severe renal insufficiency (CrCl < 30 mL/min, not on dialysis) or ESRD on dialysis have approximately 2.3-fold, 3.8-fold, or 4.5-fold higher plasma sitagliptin exposures, respectively, and the Cmax increased by 1.4-fold to 1.8-fold [122]. Tmax is significantly increased in patients with ESRD, and the terminal half-life increased with decreasing renal function [72]. Compared with values in subjects with normal renal function, the terminal half-life values of sitagliptin in those with mild, moderate, and severe renal impairment, and ESRD were raised to 16.1, 19.1, 22.5 and 28.4 h, respectively, compared to 13.1 h in normal renal function patients [122]. The fraction of dose removed by dialysis was low with 13.5% and 3.5% for dialysis initiated at 4 and 48 h post dose, respectively. Plasma protein binding of 38% was not altered in uremic plasma from patients with renal impairment. Based on these data, in order to achieve plasma sitagliptin concentrations comparable to those in patients with normal renal function, sitagliptin dose adjustments are recommended for patients with type 2 diabetes and moderate to severe renal insufficiency, as well as for those with ESRD requiring dialysis [123]. The usual dose of sitagliptin is 100 mg orally once daily, with reduction to 50 mg for patients with a glomerular filtration rate of 30-50 mL/min, and 25 mg for patients with a glomerular filtration rate less than 30 mL/min [122]. Sitagliptin may be used at does of 25 mg daily in ESRD patients, irrespective of dialysis timing. However, some side effects have been found after administration of sitagliptin such as anaphylaxis, angioedema and Steven-Johnson syndrome. Moreover, the risk of hypoglycemia increases when sitagliptin is used with sulfonylureas.
Vildagliptin is not a CYP enzyme substrate and does not inhibit or induce CYP enzymes, it is unlikely to interact with co-medications that are substrates, inhibitors, or inducers of these enzymes [124, 125]. The efficacy of vildagliptin in humans against the DPP-4 enzyme also shows a low
In patients with mild, moderate and severe renal impairment and ESRD patients on hemodialysis, systemic exposure to vildagliptin was increased (Cmax 8-66%; AUC 32-134%) compared to subjects with normal renal function [72]. However, changes in exposure to vildagliptin did not correlate with the severity of renal function. In contrast, exposure of the main metabolite increased with increasing severity of renal function (AUC 1.6- to 6.7-fold), but this effect has no clinically relevant consequences because the metabolite is pharmacologically inactive. The elimination half-life of vildagliptin is not affected by renal function and it is well-tolerated in this population [127]. According to the label, no dosage adjustment of vildagliptin is required in patients with mild renal impairment. In clinical practice, special precautions are advised for the use of this drug in patients with moderate to severe renal impairment, including those on dialysis [72].
Alogliptin was rapidly absorbed and slowly eliminated primarily via urinary excretion in healthy subjects. In patients with type 2 diabetes, alogliptin is also primarily excreted renally with a renal clearance rate of 165-254 mL/min which is slightly higher than the normal glomerular filtration rate, suggesting the occurrence of some active renal secretion. The results of a single-dose (50 mg) pharmacokinetics study in patients with renal impairment showed an increase in alogliptin exposure compared with healthy volunteers; approximately 1.7-, 2.1-, 3.2- and 3.8-fold increase in patients with mild, moderate, and severe renal impairment, and in patients with ESRD, respectively [127, 128]. According to this data, to achieve plasma alogliptin concentrations comparable to those in patients with normal renal function, alogliptin dose adjustments are recommended for patients with type 2 diabetes and moderate to severe renal insufficiency, including those with ESRD requiring dialysis [72].
Saxagliptin is another DPP-4 inhibitor and its metabolite is pharmacologically active which makes saxagliptin difference from other medications in this group. The metabolism of saxagliptin is primarily mediated by CYP3A4/5 and its major metabolite is also a selective, reversible, competitive DPP-4 inhibitor which is 50% less potent than saxagliptin [129]. Saxagliptin is cleared by both metabolism and renal excretion. However, the degree of renal impairment does not affect the Cmax of saxagliptin or its major metabolite [127]. In subjects with mild renal impairment, AUC from time 0 to infinity (AUC∞) values of saxagliptin and its major metabolite are 1.2- and 1.7-fold higher than mean AUC∞ in controls, respectively, while they are 1.4- and 2.9-fold higher in subjects with moderate renal impairment. Corresponding value are 2.1- and 4.5-fold higher in those with severe impairment [127]. A 4-h dialysis section removes approximately 23% of saxagliptin dose, AUC∞ values for saxagliptin and its major metabolite are correlated with the degree of renal impairment, whereas Cmax values are not well correlated. Renal function should be assessed before initiating saxagliptin therapy and patients with moderate to severe kidney impairment should receive less than 2.5 mg of saxagliptin/day and this drug can still be taken after dialysis in patients with ESRD.
Linagliptin is extensively protein bound (> 80% at the therapeutic dose) which is unlike other DPP-4 inhibitors. Because DPP-4 is expressed in various tissues but soluble DPP-4 is also present in plasma, binding to soluble DPP-4 may influence the pharmacokinetics of linagliptin. High-affinity but readily saturable binding of linagliptin to its target DPP-4 primarily accounted for the concentration-dependent plasma-protein binding at therapeutic plasma concentrations of linagliptin [130]. Fecal elimination is the dominant excretion pathway of linagliptin with 84.7 and 58.2% of the dose whereas renal excretion accounted for 5.4 and 30.8% of the dose administered orally or intravenously, respectively [131]. Renal excretion of unchanged linagliptin is < 1% after administration of 5 mg [132]. As absolute bioavailability is determined to be around 30%, renal excretion is a minor elimination pathway of linagliptin at therapeutic dose levels (compared to other DPP-4 inhibitors) and accordingly, a dose adjustment in patients with renal impairment is not anticipated for linagliptin [72].
GLP-1 belongs to the incretin class of hormones which exert an influence over multiple physiologic functions, including a rapid blood glucose-lowering effect in response to enteral nutrient absorption [72]. Native GLP-1 is rapidly metabolized by DPP-4 which is found in many tissues and cell types, as well as in the circulation [133]. Clearance of native GLP-1 and its metabolites is largely mediated by the kidneys [133]. Incretins, such as GLP-1, enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. Exenatide and liraglutide are GLP-1 receptor agonists that enhance glucose-dependent insulin secretion by pancreatic β-cells, suppress inappropriately elevated glucagon secretion and slow gastric emptying [72].
Exenatide is one of the drugs in this group. The amino acid sequence of exenatide is partially homologous to that of human GLP-1. Exenatide binds and activates the human GLP-1 receptor which leads to an increase in both glucose-dependent synthesis of insulin and secretion of insulin from pancreatic β-cells. Exenatide is a naturally occurring GLP-1 analogue that is resistant to degradation by DPP-4 and has a longer half-life. The kidney provides the primary route for elimination and degradation of exenatide [134]. Given subcutaneously, exenatide undergoes minimal systemic metabolism. In subjects with mild to moderate renal impairment (CrCl 30-80 mL/min), exenatide exposure is similar to that of subjects with normal renal function and no dose adjustment is required. However, in subjects with ESRD receiving dialysis, mean exenatide exposure increased by 3.4-fold compared to that of subjects with normal renal function. Exenatide is contraindicated in patients undergoing hemodialysis, ESRD or in patients who have glomerular filtration rate less than 30 mL/min and it should be used with caution in patients undergone renal transplantation [135]. In patients with ESRD receiving dialysis, single dose of 5 μg exenatide are not well tolerated due to gastrointestinal side effects. Due to the side effects of exenatide such as nausea and vomiting with transient hypovolemia, treatment may worsen renal function. Caution is required when initiating or escalating doses of exenatide from 5 μg to 10 μg in patients with moderate renal impairment (CrCl 30-50 mL/min) [72].
Liraglutide is a once-daily human GLP-1 analog and has a high degree of sequence identity to human GLP-1 [136, 137]. The half-life of liraglutide is approximately 13 h after subcutaneous injection [138] and its metabolism is similar to that of large peptides which is fully degraded in the body [137]. There is no evidence that kidney is a major organ for elimination. Its pharmacokinetics parameters are essentially independent of renal function [139]. Renal dysfunction is not found to increase exposure of liraglutide and patients with type 2 diabetes and renal impairment can be treated with standard regimens of liraglutide [72].
Currently, pramlintide is the only drug in this group which is administered by subcutaneous injection and it is a naturally occurring neuroendocrine hormone co-secreted with insulin by pancreatic β-cells [140]. Amylin regulates gastric emptying [141], suppresses inappropriate postprandial glucagon secretion [142] and reduces food intake [143]. Through the mechanism similar to those of amylin, pramlintide reduces postprandial glucose, improving overall glycemic control [144, 145] and increases satiety resulting in reduced food intake and weight loss [146-148]. The half-life of pramlintide in healthy subjects, which is metabolized primarily by the kidney, is approximately 48 min. Its primary metabolite has a similar half-life and is biologically active. Patients with moderate or severe renal impairment (CrCl > 20 to < 50 mL/min) do not show increased pramlintide exposure or reduced pramlintide clearance when compared with subjects with normal renal function. However, no data is available for dialysis patients and further clinical studies are warranted in this population.
The plasma glucose level below which nearly all filtered glucose is reabsorbed by the kidneys, and above which glucose is excreted in urine, is designated as the renal threshold for glucose (RTG) [149]. In healthy individuals, virtually all filtered glucose is reabsorbed up to a plasma glucose level of approximately 10 mmol/L (180 mg/dL), thus defining RTG [150, 151]. At plasma glucose levels higher than RTG, the renal glucose reabsorptive capacity is saturated and the amount of glucose in urine increases proportionately to plasma glucose concentration [152]. By inhibiting the proximal renal tubule glucose transporter responsible for the majority of glucose reabsorption, sodium glucose co-transporter 2 (SGLT2) inhibitors are predicted to lower RTG, thereby increasing urinary glucose excretion [149]. In patients with diabetes, reduction of RTG is expected to increase urinary glucose excretion and lower plasma glucose concentrations. Unlike other antidiabetic agents which often cause weight gain, the glucose-lowering effect with SGLT2 inhibitors is accompanied by urinary loss of calories, potentially resulting in weight loss. Moreover, SGLT2 inhibitors do not target the major pathophysiological defects in type 2 diabetes mellitus-namely insulin resistance and impaired insulin secretion-they represent a potentially promising new option in the treatment of diabetes [153]. One of the drug in this category is canagliflozin. In preclinical studies, a single oral administration of 3 mg/kg of canagliflozin decreased plasma glucose levels independent of food intake in mice on a high-fat, hyperglycemic diet [153]. In normo-glycemic mice, canagliflozin administration led to a minimal change in plasma glucose levels. Sha et al. show that canagliflozin was well tolerated in healthy men across the range of single does studied up to 800 mg. By inhibiting SGLT2, canagliflozin treatment dose dependently decreased RTG, leading to a dose-dependent increase in urinary glucose excretion [149]. However, no data on its safety and efficacy is available for CKD or dialysis patients and further clinical studies are warranted in this population.
In order to obtain the better control of plasma glucose level and decrease the side effect of some medications in renal patients, combination therapy has been used. Scheen reviewed the use of metformin plus saxagliptin in renal impairment patients [154]. Since saxagliptin’s license was recently extended to include diabetic patients with moderate or severe renal impairment while metformin is still widely prescribed in patients with some degree of renal impairment in real life even though it is contraindicated, the pro and contra of using this combination in type 2 diabetic patients with renal impairment need to be reviewed. Some recent data suggested that both metformin and saxagliptin may be used safely in type 2 diabetic patients with mild-to-moderate renal impairment, provided that dose reduction is made appropriately according to individual CrCl [154]. Because of the absence of pharmacokinetics interactions between the two drugs, this should be also the case with the saxagliptin-metformin combination. In this population, DPP-4 inhibitors offer advantages compared with sulfonylureas, especially because of the absence of hypoglycemia [155, 156]. A retrospective subgroup analysis of data from five randomized, double-blind, placebo-controlled, multicenter, 24-week, Phase III trials showed that saxagliptin 5 mg once-daily monotherapy and as add-on therapy are associated with clinically relevant and significant efficacy for reducing hemoglobin A1c in older patients (≥ 65 years; CrCl: 80±20 mL/min) versus younger patients (< 65 years; CrCl: 119±40 mL/min) [157]. Furthermore, saxagliptin was well-tolerated in older patients with a low incidence of hypoglycemia and no weight gain. Normally, patients with type 2 diabetes and renal impairment are exposed to a higher risk of cardiovascular disease. Therefore, reducing cardiovascular risk in this population should be considered as a main objective and drugs that have proven their efficacy and safety in this regard should be preferred. Treatment with metformin in type 2 diabetic patients is associated with a lower cardiovascular morbidity and mortality, compared with alternative glucose-lowering drugs [158]. It has also been suggested that metformin might exert direct protective effects on the heart [159]. Since both metformin and saxagliptin are excreted via the kidney, dose adjustment is required in case of moderate-to-severe renal impairment (ca. half dose of saxagliptin). Due to major discrepancies exist between guidelines (metformin excluded in case of renal impairment because of the risk of lactic acidosis) and real life, physicians should weigh the benefit/risk ratio carefully before deciding to prescribe or withdraw this combination in renal patients.
Thiazolidinediones are currently considered as the most efficacious class of oral anti-diabetics [160]. However, they carry the burden of weight gain and hemodilution which may lead to cardiovascular complications. It has been considered that the use of a low dose thiazolidinedione in combination with DPP-4 inhibitor may reduce the risk of dose dependent side effects of thiazolidinediones such as weight gain and hemodilution while, simultaneously, this combination may be more effective owing to different mechanisms of action of thiazolidinediones and DPP-4 inhibitors. Roy et al. demonstrated that in aged
The retrospective analysis by Banerji et al. found that the combination of vildagliptin and metformin in type 2 diabetic patients with mild renal impairment is safe and tolerable, similar to that in patients with normal renal function [161]. Furthermore these results were similar to those in patients receiving a combination of thiazolidinedione and metformin. Higher incidence of headache and rash was noted in both vildagliptin groups, whereas those with mild renal impairment receiving thiazolidinedione experienced a higher incidence of peripheral edema.
Unlike typical sulfonylurea agents, mitiglinide, a benzylsuccinic acid derivative, is a rapid- and short-acting insulinotropic sulfonylurea receptor ligand with rapid hypoglycemic action. It alleviates postprandial hyperglycemia and, as a result, improves overall glycemic control [162]. The blood concentration of mitiglinide rapidly increases after oral administration and the drug quickly disappears subsequently; therefore, it is unlikely to exert hypoglycemic effects early in the morning and between meals. Abe et al. demonstrated that add-on therapy of mitiglinide with voglibose may be a therapeutic option for achieving good glycemic control in type 2 diabetic hemodialysis patients with otherwise poor glycemic control [86]. The daily dose of mitiglinide is suggested to be lower in the diabetic hemodialysis patients than that in the diabetic patients with normal kidney function. At low dose (23 mg), mitiglinide was adequate to induce significant reductions in glycemic parameters such as fasting plasma glucose, hemoglobin A1c, glycated albumin levels and HOMA-IR. Mitiglinide also significantly improved glycemic control, triglyceride level and interdialytic weight gain even when it was administered only for a short duration [86].
Nowadays, several types of high-flux dialyzer membranes are on the market. The normally used ones are made from polysulfone, polyethersulfone, cellulose triacetate, polymethylmethacrylate or polyester-polymer alloy. The mechanism of plasma insulin clearance by hemodialysis is mainly by adsorption rather than diffusion or convection since no insulin is not normally detected in either the dialysate or the ultrafiltrate fluid during hemodialysis [163]. Furthermore, the amount of insulin adsorbed differed depending on the dialyzer membrane used. The insulin levels during a dialysis session depend not only on insulin removal by dialysis but also on the secretion of insulin from the pancreatic β-cells; this in turn is determined by the changes in plasma glucose induced by dialysis and the ability of the β-cells to respond to these glucose changes [163]. Therefore, it was suggested that an increase in endogenous insulin secretion may occur in response to hemodialysis treatment, in particular with the polysulfone membrane. On the other hand, plasma glucose levels at the post-dialysis stage were mainly determined by the glucose concentration in the dialysate; this is because the molecular weight of glucose is very small, and glucose rapidly transmigrates across the membrane during hemodialysis treatment. Therefore, plasma glucose levels at the post-dialysis stage should be similar in the case of polysulfone, cellulose triacetate and polyester polymer alloy membranes, regardless of the type of high-flux membrane. However, in the insulin-dependent diabetes mellitus (IDDM) subjects, who lack endogenous insulin secretion, the insulin reduction rate was significantly higher when the polysulfone membrane was used compared with the cellulose triacetate and polyester-polymer alloy membranes. This is because these patients have no residual β-cell function, which is responsible for insulin secretion; therefore, if plasma insulin was removed by hemodialysis, these cells could not have maintained the patients’ insulin levels. Hence, plasma insulin removal is highly significant in the case of diabetic hemodialysis patients with low C-peptide levels, particularly those with type 1 or 2 diabetes with a deteriorated β-cell function [164]. Higher doses of injected insulin or antidiabetic agents might be added in order to achieve good glycemic control in such patients, because the surplus insulin is removed by hemodialysis, particularly when the polysulfone dialyzer is used [163]. Therefore, patient monitoring of blood glucose on the day that hemodialysis is performed could be useful for self-assessment of glycemic state, and if hyperglycemia was recognized, and additional dose of injected insulin after hemodialysis should be considered.
Due to the development in dialyzer technology, it was found that the biocompatible dialyzer membrane used in hemodialysis patients not only causes less hemodialysis-induced inflammation but also achieves better clearance of uremic toxins and medium- to large-sized molecules [165]. Moreover, high-flux dialyzers have been shown to be superior in terms of attenuating hyperlipidemia and alleviating oxidative stress [166, 167]. There is a significant reduction in patients’ plasma insulin at different time point with each type of membranes, because various biological reactions can occur in the course of contact between artificial materials and blood components in the extracorporeal circulation [163]. The clearance of plasma immunoreactive insulin (IRI), a biologically active molecule, is significantly higher in patients used polysulfone membrane than by other membranes such as polyethersulfone, cellulose triacetate, polymethylmethacrylate or polyester-polymer alloy [168]. Moreover, no clinical difference has been found in the reduction rate of IRI between hemodialysis treatments when using either polysulfone, polyethersulfone, cellulose triacetate or polymethylmethacrylate except for polyester-polymer alloy [168]. From these results, it suggests that hemodialysis patients with residual β-cell function, the course of treatment for diabetic control would be unaffected by the differences resulting from the type of membrane used. However, in diabetic hemodialysis patients, particularly in type 1 and type 2 with deteriorated β-cell function, these differences might be very significant. Higher doses of injected insulin might be required to achieve good glycemic control in hyperinsulinemic patients because the surplus insulin is removed by hemodialysis, specifically by polysulfone, polyethersulfone, cellulose triacetate or polymethylmethacrylate, excluding polyester-polymer alloy membrane dialyzer. Polysulfone membrane dialyzer may worsen glycemic control and switching to the polyester-polymer alloy membrane dialyzer which shows a lower IRI clearance rate might improve the glycemic control in hemodialysis patients.
Although diabetes is the most common cause of ESRD and diabetic control is considered as one of the most important factor to prolong patients’ life and improve their quality of life, data are scarce on how diabetes should be best treated in patients with CKD or ESRD. Since the glycemic control and monitoring in CKD and ESRD patients is complex, patient education is also one of the key factors for successful treatment. Moreover, patients with diabetic nephropathy are especially susceptible to hypoglycemia and diabetic drug therapy requires special caution. Adjustment of the type of drugs used or dosage regimen should be individualized based on self-monitored blood glucose patterns.
The correct management of craniofacial differences (CFD’s) -including cleft lip with/without cleft palate (CL ± CP)- is still a challenge for clinicians treating such conditions, due to its treatment length and the different aspects that have to be holistically addressed in accordance with overall and craniofacial growth and development, speech and hearing, facial esthetics, and psychological self-perception of patients with such characteristics.
Although a universal treatment protocol has not been agreed among craniofacial teams worldwide [1], several parameters of evaluation and treatment have been set and reviewed periodically, following the recommended practices for the care of patients with craniofacial differences made by the ACPA (American Cleft-Palate Craniofacial Association) [2] (revised in 2018), based on the call of the Surgeon General of the United States on the needs for children with special health care [3]. A summary of such parameters appears below:
(a) The interdisciplinary team management of patients with craniofacial differences is essential; (b) Clinical expertise in diagnosis and treatment and optimal care for these patients is provided by teams with enough exposure to these patients each year; (c) The first evaluation is within the first few days or weeks of life (ideal), but referral for team evaluation and management is appropriate at any age; (d) Since the beginning, the family of a child with a craniofacial difference must be assisted in adjusting to the birth and consequent demands and stress of having a child with CFD; (e) Responsible adults must receive information about treatment procedures, options, risk factors, benefits, and costs to take informed decisions on the child’s behalf, and to prepare the whole family for all recommended procedures. The family (and patient, when is mature enough) participation and collaboration in treatment planning should be actively asked; (f) Team recommendations are basic to develop and implement treatment plans; (g) Complex diagnostic and surgical procedures should be restricted to centers with experienced health professionals; (h) Each team must be sensitive to linguistic, cultural, ethnic, psychosocial, economic, and physical factors affecting the relationships among the team, the patient and family; (i) Longitudinal follow-up of patients, including appropriate documentation and record-keeping is essential to monitor both short-term and long-term outcomes and falls under the responsibility of each team; (j) The effects on growth, function, appearance satisfaction and psychosocial well-being of the patient should be considered when performing evaluation of treatment outcomes.
Following these parameters, this chapter explain in detail our craniofacial orthodontics treatment algorithms for the patient with unilateral cleft lip and palate (UCLP) from mixed dentition onwards, which addressed all topics related with diagnosis and treatment planning for adolescents and young adults affected with this craniofacial difference.
Mars et al. in 1987 introduced the GOSLON yardstick [4], which has become the standard diagnostic tool for patients with UCLP worldwide. Ozawa et al. in 2011 expanded the same classification for bilateral clefts [5]. This classification, based on dental casts, has proven to be a good and simple option to grade the malocclusion present and to give some hints on the level of difficulty in its correction. Other broader approaches -such as the original Huddart-Bodenham classification (used in deciduous dentition only) [6], or its modification used in both deciduous and permanent dentitions (proposed by Mossey et al. [7])-, are also other interesting approaches to classify all dental components present in UCLP and BCLP malocclusions. However, those indexes missed a common aspect that cannot be forgotten in a craniofacial orthodontic evaluation: the facial pattern in three dimensions that could worsen (or improve) the existing CL ± CP condition. The GOSLON does not consider frontal and lateral facial photographs or cephalometric radiographs, which are regular diagnostic records in orthodontics (taken digitally for these patients in the XXI century). These records are important to detect left-to-right bone vertical discrepancies that could make some UCLP cases more difficult to correct properly than previously thought. This is the reason why the orthodontic diagnosis (and its indicated treatment) cannot be established solely from study dental models. The GOSLON yardstick can be used as a classification system, but not as a determiner of treatment complexity without considering the 3D facial aspects of a complex malocclusion.
Having as a start point the GOSLON yardstick, our unit has developed a modified GOSLON yardstick (named GOSLON+), based not only on dental casts but also on frontal and facial digital photographs and radiographs. These records can be used to accurately determine the involvement of craniofacial orthodontics and craniofacial surgery in the resolution of unilateral (and bilateral) cases, depending on the degree of asymmetry associated with the cleft, following all aspects involved in a complete orthodontic diagnosis. The following diagram and the accompanying patients’ photographs (with full records) demonstrate our current diagnosis categories and changes in the treatment of patients with UCLP (modified from the original GOSLON) (Table 1, Figure 1), [4] Our modified classification considers the influence of facial and occlusal 3D aspects in the craniofacial overall diagnosis and the need for additional treatment created by the existing frontal asymmetry.
Group | Characteristics | Treatment | Prognosis |
---|---|---|---|
1± |
| Surgical orthodontics and surgical treatment for class II malocclusion. | Good/Fair (Depending of Degree of Facial Asymmetry [+]) |
2± |
| Surgical orthodontics and surgical treatment for moderate or complex class I malocclusion. | Excellent (None [−] to some Degree of Facial Asymmetry [+]) |
3± |
| Surgical orthodontics and surgical treatment for mild class III malocclusion. | Good/Fair (Depending of Degree of Facial Asymmetry [+]) |
4± |
| Surgical orthodontics and surgical treatment for severe class III malocclusion. | Fair (Depending of Degree of Facial Asymmetry [+]) |
5± |
| Surgical orthodontics and step-wise surgical treatment for extreme class III malocclusion. (Maxillary Osteogenic Distraction and Orthognathic Surgery). | Fair (Depending of Degree of Facial Asymmetry [+]) |
Modified GOSLON yardstick (GOSLON+) for patients with UCLP. A similar table apply to patients with BCLP.
Facial and intraoral characteristics of patients presenting the five different degrees of GOSLON+ yardstick. Observe that treatment prognosis further decreases when frontal and lateral facial photographs are included in the treatment algorithm to manage successfully the existing alveolar clefts.
It is well known that not all clefts are similar [6, 8, 9, 10, 11]. Moreover, patients affected by UCLP have some degree of facial asymmetry that affects the prognosis (Figure 1). This fact must be considered within the orthodontic-surgical diagnosis. Accordingly, their ortho-surgical treatment plan should not be the same either, due to the type and extension of cleft, the timing for the initiation of those treatments, and the individual needs for surgical treatment influencing the selection of surgical techniques. In addition to these factors that have a negative influence on facial growth, the expertise of the ortho-surgical team and the interdisciplinary management given to the patient is the last -but not the least- item to be considered for obtaining a satisfactory treatment outcome [12].
Based on this improved GOSLON classification, a description of the surgical orthodontic management for average and wide clefts will be addressed. After that, two different surgical orthodontics algorithms will be presented, with clinical cases to summarize the decision-making process applied in the surgical orthodontic care of patients with UCLP with different degrees of sagittal and transversal maxillary-mandibular involvement in the Clínica Noel Foundation at Medellin, Colombia, S.A.
The alveolar cleft -the space between the maxillary segments anterior to the incisor foramen- represents a lack of continuity of both maxillary dental arch and basal bone. Spatially, it can be represented as a pyramid placed on its side, with its base towards the labial side and its apex located in a posterior and superior position inside the cleft maxilla [13]. This gap should be ideally filled by a cancellous bone graft to restore its basal and alveolar normal architecture. This defect gives origin to a particular kind of critical-size segmental defect that creates a significant challenge for craniofacial surgeons, maxillofacial surgeons and craniofacial orthodontists [14].
From all the alternatives to fill completely the maxillary cleft, the secondary (intermediate or late) alveolar bone grafting (SABG) is still the gold standard treatment to restore the alveolar anatomy, either in mixed dentition or early permanent dentition [15]. The objectives of SABG include (1) to restore and stabilize the normal architecture of the maxilla; (2) to allow eruption of permanent lateral incisor and canine; (3) to provide support and elevation of the affected wing base; (4) to close present oronasal fistulas and (5) to provide “adequate” bone support to be restored later with prostodontics with/without dental implants, in case that a closure of the gap with dental eruption cannot be achieved [16, 17]. It has been our approach to limit its objectives to the first three in mixed dentition patients, due to the uncertain nature in time of this type of autografts and the impediment for free dental movement created by cortical grafts at early ages. However, two controversies proposed by Vig still remained valid today: which is the best bone graft type and the best donor site for harvesting? and what is the best timing for maxillary (dento-alveolar) expansion in patients requiring SABG [17]? A third controversy refers to whether the alveolar cleft can be repaired by a combination of bio-engineering alternatives currently available nowadays. Our treatment rationale tries to solve the first two questions as follows:
Several aspects have to be considered for obtaining a successful bone graft in such patients:
During mixed dentition stage, orthodontic treatment can be used previous to surgical treatment to increase maxillary dental arch width and length using the Quad-Helix [18, 19, 20, 21] (Figure 2). This appliance -developed by Ricketts while he was part of the Cleft Palate Clinic at UIC (currently the UIC Craniofacial Center) [22] and improved by Wilson and Wilson in the 80’s [20] and others- is currently applied to correct the collapse of the lateral maxillary segment behind the protruding premaxillary process [23]. In patients with UCLP, the bony palate anatomy presents a primary unilateral deficiency worsen by contraction of scar tissue, as a result of the neonatal surgical palatal closure [19, 23]. In addition to the dento-alveolar effect obtained in patients without clefts, the main bony effect of the Quad-Helix in UCLP cases is the expansion of the lateral maxillary shelves when the de-rotation of the maxillary molars is achieved [19, 23]. In such cases, dento-alveolar expansion before surgery results in similar treatment outcomes than in patients with maxillary expansion [24], with the benefit of working with minimum risk of creating secondary maxillary fistulas. Dento-alveolar expansion could also be obtained by other orthodontic appliances such as the reverse Quad-Helix (with poor correction of the molar rotation) [25], conventional or modified jointed fan (or butterfly) expander [26, 27, 28], NiTi palatal expander [29], or self-ligation appliances [30].
Recovery of normal transversal maxillary width with correct maxillary alignment after the use of Quad-Helix. a. Before Quad-Helix, b. At removal time. Notice the change in the cleft architecture and the creation of alveolar spacing for the alignment of the right maxillary canine.
Dento-alveolar maxillary expansion is usually followed by maxillary dentition segmental leveling and alignment (using an anterior [3*2] utility arch) [21, 31, 32, 33, 34]. In order to obtain similar results than those achieved using an inverse treatment protocol (alveolar grafting followed by orthodontics with maxillary expansion) [24], an orthodontic approximation of maxillary segments using a sectional arch approach -after obtaining proper maxillary width but before surgery- should be considered. In older patients, a mini-screws based molar distalization plus orthodontic dental retraction -by controlling the mesial inclination of the canine for greater bone approximation- is often required to create an alveolar defect with parallel walls to minimize the alveolar gap size when a segmental surgery is planned (Figure 3) [35, 36].
Modified First-Phase Orthodontic Strategies. In addition to the a. maxillary utility arch, two other strategies have been useful in the correct alignment of the maxilla prior to surgery: b. sectional approximation of maxillary segments; and c. mini-screw based distalization.
The suggested order of orthopedic-orthodontic procedures would be as follows: 1. Dento-alveolar maxillary expansion; 2. Maxillary segmental dental leveling and alignment; 3. Mini-screw based molar distalization (if needed in patients that have passed the appropriate timing for grafting) and 4. Orthodontic approximation of maxillary segments.
At the time of bone grafting, many craniofacial centers around the world use SABG during mixed dentition (5 to 12 years of age) before or during permanent canine eruption, taking advantage of the growth potential of the maxilla at this stage [37]. In our center, we use Intermediate or late SABG during mixed or early permanent dentition for GOSLON1–3 patients only. We usually perform such procedure in agreement with dental age characteristics of teeth around the cleft (permanent canine and lateral incisor when present). The ideal age range for surgical procedure should be when the canine on the cleft side is from less than 5 mm of its eruption place to a partially erupted canine (1/3 to ½ of crown visible). Late SABG cases with narrow alveolar clefts at the right age allows to work with bone graft stimulation (either with compression osteogenesis or RPE) to obtain excellent results in both cases (Figure 4) [24, 37]. Using SABG as an alveolar bone matrix, we achieve high degree of success in correcting the canine eruption and migration pathway [38]. The bone graft would give temporary bone support for the eruption of lateral incisor and/or canine without affecting the growth of the midface, with good outcomes similar to other centers in the world when compared with gingivoperiosteoplasty [21, 39]. Ideally, a complete closure of the space with no need for lateral incisor prosthesis is achieved when the migration of the canine occurs.
Intraoral Results of Iliac Crest Late Secondary Alveolar Bone performed at the Correct Time. a. Despite the fact that all teeth around the cleft were erupted at the initial evaluation, the patient still had intermediate mixed dentition and remaining eruption potential in the lateral incisor adjacent to the alveolar cleft; b. After late SABG and finishing restorative dentistry procedures. Note the closure of the alveolar cleft and the normal gingival architecture obtained by the application of orthodontic compression osteogenesis after cancellous iliac bone grafting.
In chosen candidates, cancellous iliac crest bone from the inner anterior portion of the crest is usually required to close mild-to-moderate type of fistulas (patients with UCLP GOSLON1 to 3 at the appropriate age) (Figure 4). This approach is used to restore momentarily alveolar bone continuity needed for dental movement [40, 41]. Figure 4 shows a case with such approach, with an excellent outcome. However, other harvesting sites such as tibia, mandibular symphysis or retromolar area can be successfully used for this purpose [23, 42, 43].
Of all types of bone graft (cortical, cancellous, or mixed), the fresh autogenous cancellous bone is the “ideal” source for reconstruction of bone integrity, due to the fact that it provides living bone cells and is immune-compatible enough to allow osteogenesis and full integration with the maxilla [40]. Autografts have as its main characteristic osteoproduction [44] -bone growth obtained from combined properties of osteoinduction (recruitment, proliferation, and transformation of osteoprogenitor MSC’s into osteoblasts) [45], osteopromotion (process of secondary support of bone healing and tissue regeneration, without capability of initiate bone formation) [46], osteoconduction (process of osseous and vascular cell ingrowth inside the 3D matrix scaffolding) [47], and “relative” osteogenesis (process of deposition of newly formed bone by osteoblasts at the fracture site)- that enhance osteoprogenitor MSC’s response according with autologous graft type. Allografts also share other advantages such as biocompatibility, and mechanical resistance vs. orthodontic remodeling depending on the graft source [48]. Iliac crest site morbidity, accessibility, and availability of areas of graft harvesting of other donor places create a supposedly difficulty that could be overcome with sufficient surgeon’s exposure to this approach [49] in a capabilities-based curriculum [50]. When a successful incorporation (or modeling) of a graft is achieved, the term osseointegration can be used under this definition (Figure 4) [51]. An optional surgical procedure for treating wide alveolar clefts will be described later.
At the Pre-surgical Planning Time of Post-Surgical Procedures. In cases where lateral incisor in the cleft area is partially missing, split in two by the cleft (creating two “real” supernumerary teeth), or absent, all options involved in the dental restoration of the patient must be considered:
When the lateral (and central incisor or canine, depending on the location of the cleft) present a missing portion, a composite restoration could be required either during or once the orthodontic treatment is finished to improve esthetic appearance (Figure 4).
Lateral incisor supernumeraries present additional difficulties to be addressed: their crowns usually are of decreased size, and the roots are short and with many irregularities and dehiscenses along the root length. Performing restorative procedures, such as extensive composite restauration on the wider tooth, are in order if the chosen supernumerary has its root firmly embedded in bone and the final orthodontic placement of the tooth leaves the root with enough alveolar bone on both sides.
If the lateral incisor is missing, an option would be to take advantage of performing an intermediate SABG followed by the mesial eruption of the canine. Later on, restorative procedures in conjunction with orthodontics will convert the canine anatomy in lateral anatomy, although some differences between normal and converted teeth remain regarding color and crown emergent profile from gingiva (Figure 5).
Intraoral Results of Guided Migration of Permanent Canine through SABG performed at the Correct Time. After successful SABG, the left maxillary canine was directed to erupt in a mesial position from its initial site. Note the hypertrophic gingiva surrounding the teeth on the repaired cleft site. The patient will require cosmetic dentistry procedures in addition to the correct bucco-lingual root torques delivered by the use of lower first bicuspid brackets on the maxillary canine (to act as lateral incisor) and first bicuspid (to act as canine). Protraction of the upper first molar to obtain a well-established class II relationship is under way.
Orthodontic procedures (regarding bracket type and bracket positioning -proper height and buccal-lingual crown inclination of canine and first bicuspid on the cleft side), periodontal procedures (to maintain or recover -partial or totally- the periodontal anatomy affected by decreased gingival thickness as a consequence of mesenchymal deficiency in patients GOSLON3+, 4, 4+, 5 and 5+) (Figure 6) and/or additional cosmetic dentistry/prosthodontic procedures (to transform with such strategies the maxillary canine in lateral incisor and the maxillary bicuspid in canine, and perform additional restorative work if needed) are necessary after SABG surgical procedure for an adequate dental characterization with good-to-fair periodontal condition (Figures 7 and 8). Optional plastic surgery procedures could be needed as well.
Periodontal Results of Connective Tissue Graft and Enamel Matrix Protein Application after Ortho-Surgical Procedures. This experimental procedure in cleft patients allow the clinicians working in poor anatomic conditions -due to the negative influence of a mesenchymal deficiency- to partially recover gingival architecture at the short-term follow-up. Long-term follow-up will give us answers regarding the success of the obtained periodontal stabilization. a. Initial intraoral left close-up photo. The patient has a wide left alveolar cleft with dental inclination of left permanent central incisor (moderate), and left permanent canine (severe); b. Intermediate intraoral left close-up photo. After a segmental maxillary advancement, moderate loss of periodontal attachment and apical migration of gingival margins was observed; c. After connective tissue graft plus enamel matrix protein infiltration. Notice the gain on gingival margins and periodontal thickness as a result of this approach; Surgical sequence: d. Harvesting of palatal connective tissue graft; e. graft waiting to be inserted below gingiva; f. Graft placement under keratinized gingiva; g. Emdogain® syringe used in this case.
Patient with UCLP GOSLON2 treated at Mixed Dentition stage. Initial records: a. Frontal facial photograph; b. Periapical radiograph of the alveolar cleft; c. Intraoral frontal view; Final records: d. Frontal facial photograph; e. Periapical radiograph of the alveolar cleft; f. Intraoral frontal view. The application of the compression osteogenesis strategy was fundamental to obtain normal periodontal architecture in the grafted area of the alveolar cleft.
Patient with UCLP GOSLON2 treated at Permanent Dentition stage. Initial records: a. Frontal facial photograph; b. Intraoral frontal view; Final records: c. Frontal facial photograph; d. Intraoral frontal view. A relatively normal dental and gingival architecture was obtained after the surgical management of a Two-piece LeFort I.
Our retention protocol for patients with normal skeletal relationships (GOSLON2 and 2+) or with mild skeletal discrepancies (GOSLON1, 1+ and 3) use Essix-type retainers. As our treatment approach is directed to obtain a maxillary arch without dental spaces if possible, we seldom use wrap-around maxillary retainers with dental temporary replacements. Our countdown-to-retention includes periodontal evaluation and treatment in patients with GOSLON3+ and more, to address the thin and receding gingiva in cleft-adjacent teeth, associated with genetically-driven periodontal ligament loss described previously (Figure 6). In those cases (which have received correction of existing moderate to severe skeletal discrepancies previously), a periodontal connective tissue graft plus dentin matrix protein injections to increase gingival volume and tissue support, and a dual retention strategy with an additional bonded lingual retainer in the maxillary anterior teeth is used.
Young patients affected by UCLP who have severe restriction of maxillary growth and wide oronasal fistulas (GOSLON4, 4+, 5 and 5+), or adult patients with UCLP in all categories of the GOSLON+ yardstick, have been historically (and unsuccessfully) treated using alveolar bone grafting (secondary or tertiary). In addition, inadequate closure of primary incisions, post-operative wound dehiscence and infections could potentially make bone grafting healing worse [35]. Mars et al. recognized that unilateral alveolar bone grafting success was limited to young patients with “average” maxillary growth (patients GOSLON1, 1+, 2, 2+, and 3) and normal gingival thickness compared with an age-matched normal population [4]. What was the problem? They found out that with increased limitation in maxillary craniofacial growth in patients with UCLP, there was an important compromise in making the maxillary segments meet closely to complete a successful bone graft and a greater difficulty to obtain a fair maxillary dentition by subsequent orthodontic treatment [4].
In order to obtain a surgically-created one-piece maxilla [52], craniofacial centers worldwide use strategies based on segmental maxillary advancements (described by Schuchardt [53]). This surgical technique and its modifications were currently used to manage the surgical closure of open bite [54, 55], transverse maxillary deficiency [55, 56, 57], or excess [55, 58]. The last two findings are common in patients with UCLP. After proper soft tissue management of severe and longstanding oronasal fistulas [12], this approach favors the 3D maxillary architecture prior to secondary orthognathic surgery, reduces prosthodontic needs and creates a more cost-effective alternative than using either conventional LeFort I advancement plus extensive prosthodontic replacement or interdental osteogenic distraction [58].
A combination of surgical fistula closure followed by a combination of Le Fort I advancements in two segments [59] plus immediate or delayed alveolar bone graft, depending on the need and extension of additional distraction osteogenesis/orthognathic surgery has been used regularly at the Clínica Noel Foundation since 2015, modified from Stal et al. [12] (Figure 9). This maxillary procedure could be performed alone or in combination with BSSO during the same surgical procedure. This modified approach produce good bone blood flow [60], and stability [61], with fair gingival architecture due to pre-existing periodontal conditions that can be worsened in some cases by local tension on the flaps during gingival closure [59] (Figure 5). Good-to-fair results regarding non-tension flap closure, bone-to-bone contact, and secondary bone healing have been obtained, depending on the degree of cleft maxillary hypoplasia present. For these patients, these successive surgical steps (oronasal fistula treatment followed by segmental maxillary approximation) could be realized previous or simultaneously to the placement of a narrow tertiary alveolar bone grafting and the realization of additional surgical mandibular procedures during orthognathic surgery.
Application of Segmental Maxillary Advancement to reduce the Alveolar Cleft prior to Final Bone Grafting. Pre-surgical records. a. Close-up of alveolar cleft, b. Occlusal view, c. Periapical radiograph, d. CT close-up occlusal view: 10 mm gap between internal radicular surfaces, e. CT occlusal maxillary view; Post-surgical records. f. Close-up of alveolar cleft, g. Occlusal view, h. Periapical radiograph, i. CT close-up occlusal view: 5 mm gap between internal radicular surfaces, j. CT occlusal maxillary view. The left segmental advancement reduced in half the distance to be covered by a tertiary bone grafting and increased the chances of closure success.
Distraction osteogenesis is a treatment technique that deals with the genesis and growth of new bone in a specific body area, through the application of gradual tensile stress [62, 63, 64, 65, 66]. Distraction Osteogenesis can be applied to the surgical correction of hypoplasias of the craniofacial skeleton to replace extensive bone and soft tissue deficiencies without requiring the use of bone grafts [67]. This technique additionally provides the benefit of expanding the overlying soft tissues, which are frequently deficient in these patients.
After the introduction of gradual elastic maxillary distraction to advance a segmental Le Fort I osteotomy (an incipient form of Distraction Osteogenesis -DO) by Wassmund [68], maxillary DO using facemask and elastic traction was successfully reintroduced by Molina and coworkers 60 years later [69], after several animal studies corroborated its feasibility [70, 71]. After the arrival of the Rigid External Distraction (RED) technique for its use for upper and mid-face hypoplasia in 1997 [72], Polley and Figueroa applied their maxillary DO technique in cleft patients [73, 74] and Figueroa and co-workers reported their immediate and long results in this population [75, 76]. In patients with either UCLP or BCLP that present severe maxillary hypoplasia (GOSLON 5 and 5+), worsened by previous pharyngeal repairs that apply additional tension to an already deficient cleft maxillary development, this alternative surgical technique allows the progressive forward displacement of the maxillary complex, while exerts moderate but increasing tension in the pharyngeal musculature that favors their rearrangement in the final maxillary position [73, 74, 75, 76].
Patients prior to the surgical procedure received preferably a customized rigid labial-palatal arch with external vertical hooks adapted partially from a face-bow, or with detachable external hooks located distal to the lateral incisors (Figure 10). These orthodontic options facilitate further distraction modifications and appliance removal in dental settings. After this, the patient was submitted to a high LeFort I osteotomy (in segments according to cleft type), avoiding tooth germs and external halo frame positioning. After 5–7 days latency period, active distraction is performed at 1 mm/day at 0.5 mm each 12 hours, until an additional 20% of the planned DO is achieved. Orthodontic follow-up is highly recommended to control the amount of distraction remaining, to change the direction of distraction when needed, and to give additional instructions to the patient and relatives on how to adjust the distraction if any AP and transverse maxilla-mandible asymmetry is developing. The average amount of maxillary RED distraction in such cases was 9.6 mm [76]. A consolidation period of 3+ months with the distractor in place must be observed to allow maxillary bone to mature from the initially delayed woven bone and guaranteed the obtained results.
Intraoral Tooth-Supported Devices for RED system. a. Customized rigid labial-palatal arch with external vertical hooks adapted partially from a face-bow, b. Customized rigid labial-palatal with detachable external hooks located distal to the lateral incisors.
Despite the appearance of other maxillary DO external and internal devices, the RED system allows the application of important pulling forces to advance the receding maxillary complex without risking external frame integrity, permits to correct direction of distraction due to their flexibility in distractors’ positioning on vertical and horizontals bars [77], and manage a wider range of maxillary distraction than internal DO devices. A maxillary cleft case treated with this approach appears below (Figure 11).
Patient with Maxillary Cleft undergoing Maxillary RED. a. Before maxillary DO; b. During Distraction Osteogenesis; c. After DO. Notice the improvement on maxillary projection at the infraorbital level.
Adult patients affected by CL ± CP require reduced treatment times while obtaining optimal craniofacial results. After obtaining a one-piece maxilla (Except in patients GOSLON2, some GOSLON2+, and GOSLON3 that finished ortho-surgical treatment at the end of SABG) and at the end of maxillary DO in patients GOSLON5 and 5+, the Craniofacial Ortho-Surgical team has to properly plan and execute orthognathic surgery that address three-dimensionally all problems related with the surgical correction of an asymmetric patient. Could a combination of treatments according to the state of the art be used to reduce treatment times in an interdisciplinary scheme? There are several contemporary alternatives from the orthodontic-surgical treatment stand point that can be used in this scenario: First, the re-appearance of self-ligating systems (with passive -regular [e.g. Damon™ System, Ormco Corp., Orange, CA] or CAD-CAM individualized brackets [e.g. Insignia™ System, Ormco Corp., Orange, CA]-, or interactive brackets [e.g. CCO™ System, Dentsply Sirona Orthodontics, York, PA]), and second, the spreading use of Surgical Treatment Acceleration (Surgery-First and Surgery-Early surgical approaches).
Both alternatives are not new. Passive Self-Ligation is an old therapeutic alternative available for clinical use in the 70’s [78] and 80’s [79]. The concept was commercially reintroduced in the late 90’s by the Ormco™ Task Force, to give origin to the Damon™ System [80, 81]. One of its objectives is supposedly to reduce clinical activity time and treatment time -reduction in wire changes and face-to-face clinical activity-, and increase clinical efficiency by simplifying orthodontic mechanics and materials. The passive effect of friction reduction by bracket design is especially noticed during tooth leveling and alignment in severe dental crowding, dentoalveolar expansion, and in less extent during major tooth movements [80, 81]. The second objective is to take advantage of the active use of orthodontic archwires with variable activation temperature. This is the most important change from early self-ligating appliances. Buehler and coworkers were the first to explain the physical properties of the Variable Transformation Temperature concept [82], while Tien and collaborators in 1982 described its application in orthodontics [83]. Later, Burstone and others published on the alloy characteristics and clinical behavior in depth [84, 85, 86, 87]. Thermo-activated wires allow clinicians (1) to use a differential alloy sequence, that permit early cross-sectional form changes and wire gauge increments to fill entirely the bracket’s slot at early treatment stages with early effect of torque, and (2) to take advantage of wider archforms than in current straight-wire systems. This characteristic is potentiated with self-ligation to produce a “free” vestibular tooth movement by using wider arch shapes on unconventional alloys in a shorter period of time [88, 89, 90]. Total appointment time and treatment length could be shorter due to the fulfillment of both objectives in most cases. However, no differences in the positions of incisors and the transverse dimension changes of the maxillary arch were found when self-ligated appliances and conventional-ligated appliances plus Quad-Helix were compared [91]. There is insufficient evidence to justify or contraindicate its use in surgical orthodontics in patients with CL ± CP [30].
Surgical Treatment Acceleration is not a new technique either. During the 1960–1970’s, the early orthognathic surgery approaches were performed without orthodontist intervention (Surgery first -independent-), and subsequent orthodontic treatment was poorly encouraged by maxillofacial surgeons afterwards [92, 93, 94]. Several problems, including the lack of interrelation of orthodontic and surgical treatments, and difficulties for space generation needed for correct orthodontic decompensation, aroused from these early attempts. After the realization that occlusal relationships were a key component of orthognathic surgery results, the orthodontist gained a role in both craniofacial and maxillofacial teams with the objective to eliminate dental compensations before surgery and facilitate posterior orthodontic treatment [95]. The basic sequence of procedures is still applied today. However, creating a maxilla-mandibular decompensation, alignment, and correct maxilla-mandibular anterior and transversal relationships is a long process, even today. A different approach was proposed by Epker and Fish in [96]. They affirmed that it was best to perform surgical procedures as soon as possible to obtain immediate post-surgical benefits for orthodontic treatment (accelerated orthodontic movement after surgery following surgical correction), surgical improvement (early recovery of facial and dental function), and functional aspects (improvements on speech and deglution). Sugawara and Tohoku University/University of Connecticut group in 2009 proposed their Surgery First Approach (SFA) -also called Surgery-First/Early Orthognathic Approach (SFEA) [97]- combined with Skeletal Anchorage System (SAS) for the treatment of a skeletal Class III patient, obtaining excellent results based on the premises mentioned previously [98]. In 2019, the same group published its extensive follow-up on Temporo-Mandibular Symptoms and Function in Class III malocclusion using SFEA compared with Orthodontics-First Approach (OFA) patients, without significant differences between groups [99]. CES University, in conjunction with the mentioned consortium [100], and with the Universidad del Valle [101] have applied SFEA schemes in Latin-American patients. SFEA rely on performing orthognathic surgery at the beginning of treatment with minimal preoperative orthodontics [102]. This treatment protocol allows the reduction in time of pre-surgical treatment (obtaining one-year reduction in average), with the patient’s benefit of an early improvement in facial esthetics. It can be applied not only in patients with UCLP and Class III malocclusion (GOSLON3+ onwards), but also in patients with UCLP and Class II malocclusion (GOSLON 1 and 1+), with or without skeletal vertical discrepancies.
Chang Gung Memorial Hospital group general guidelines for such approach states the following advantages of the procedure as follows [103, 104]: (1) Shorter pre-surgical orthodontic treatment time; (2) Reduction in the difficulty of post-surgical treatment through Regional Acceleratory Phenomena (RAP) [104]; (3) Possibility of planning and computer-guided execution (CAD-CAM); (4) Same effect on ATM as with traditional scheme, in addition to the surgical and functional advantages already mentioned. The post-operative rapid (accelerated) orthodontic tooth movement after SFEA in both dental arches is significant and is due to the increase in odontoclasts activity and dentoalveolar metabolic changes [105]. However, some disadvantages of SFEA include: (1) The need of careful orthodontic-surgical planning; (2) The preparation of the orthodontic-surgical team; (3) The appearance of possible post-surgical orthodontic problems; (4) A poor post-operative stability [97], in opposition to favorable long-term stability reported previously [96].
Mahmood and coworkers suggested that implementing a modified Surgery-Early protocol to speed-up final orthodontic-surgical treatment for CL ± CP patients would be useful [102]. However, Seo and coworkers found smaller incisor overjet, maxillary intercanine and intermolar ratios, and ratio of intercanine and intermolar distance in a group of surgical patients with UCLP and Class III malocclusion prepared to be treated with SFEA, than in a non-cleft group with a dentofacial deformity. The same group had also smaller anterior teeth contact number and larger incisor overjet than patients with UCLP and Class III malocclusion treated with a conventional protocol [106]. These difficulties have to be weighed when planning surgical procedures under this approach.
As a summary of the SFEA application, this modified version of the steps for performing orthognathic surgery under this approach are [103]: (1) Short period (≤6 months) of AP and vertical maxilla-mandibular decompensating orthodontics before the operation; (2) Reduction of possible dental collisions and minimal decompensation of mandibular teeth, through segmental maxillary surgery planning, surgically assisted rapid palatal expansion, or post-operative orthodontic tooth movement; (3) First / Early Modified Surgery 3D Model; (4) First/Early surgery based on specific therapeutic planning. Total treatment time is shortened in around 1 year, depending of the complexity of the remaining orthodontic treatment [103]. Treatment results of a patient with UCLP GOSLON4+ are shown in Figure 12.
Patient with UCLP undergoing maxillo-mandibular asymmetry correction through Surgery-First/Early Approach and Passive Self-ligation. a. and b. Before treatment; c. and d. Previous to Surgery-Early Approach. Noticed the dental changes obtained in the maxillary dentition by the use of passive self-ligation appliances; e. and f. After Surgery-Early Approach; d. After the end of treatment. Treatment time before treatment-surgery: 6 months, 25 days; Total Treatment time: 20 months, 25 days.
The anterior information can be summarized to perform apparently different treatment choices in a rational order that will allow clinicians to identify the increasing difficulty of surgical orthodontic approaches used in the resolution of alveolar cleft with or without distraction osteogenesis and final orthognathic surgery (Figures 13 and 14).
Mixed dentition treatment algorithm for patients with UCLP. The final prognosis and outcome using this approach depends on severity of the cleft, the degree of mandibular deviation, and the surgical ability of the craniofacial team to obtain the desired goals.
Alternative treatment algorithm for adult patients with UCLP. A more expedite protocol following the same parameters (severity of the cleft, degree of mandibular deviation, and surgical ability of the craniofacial team) is performed in all patients with UCLP who have non-repaired clefts and require a definitive solution to their craniofacial difference.
Orthodontic treatment for patients with unilateral cleft lip and palate varies in the level of difficulty due to the increased involvement of orthodontic and surgical procedures involved, the correct timing of applying the complete treatment strategy, and the need of additional procedures to treat several dental anomalies present in teeth adjacent to the cleft, such as dental form and size anomalies, localized enamel hypoplasia, abnormal teeth number, and dental formation disturbances.
Our modified GOSLON+ yardstick allow us to categorize patients with UCLP in several discrete groups according to maxillary growth. Our treatment algorithms allow us to deliver appropriate treatment of the adolescent and young adult patients requiring effective orthodontic intervention for all surgical needs in our patient-based hospital settings in Colombia.
To CES University, who allowed me to experience all procedures described in this chapter.
To Universidad de Antioquia for their support.
To Clínica Noel Foundation to allow me access to all records used in this chapter.
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Satué, A. Hernández and A. Muñoz",authors:[{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo"}]},{id:"55356",doi:"10.5772/intechopen.68617",title:"Neutrophils in Rheumatoid Arthritis: A Target for Discovering New Therapies Based on Natural Products",slug:"neutrophils-in-rheumatoid-arthritis-a-target-for-discovering-new-therapies-based-on-natural-products",totalDownloads:2057,totalCrossrefCites:9,totalDimensionsCites:12,abstract:"Rheumatoid arthritis (RA) is a systemic autoimmune disorder with an important inflammatory component in joints. Neutrophils are the most abundant leukocytes in inflamed joints, and play an essential role in the initiation and progression of RA. Neutrophil effector mechanisms include the release of proinflammatory cytokines, reactive oxygen and nitrogen species (ROS and RNS), and granules containing degradative enzymes, which can cause further damage to the tissue and amplify the neutrophil response. Therefore, the modulation of neutrophil migration and functions is a potential target for pharmacological intervention in arthritis. The pharmacologic treatment options for RA are diverse. The current treatments are mostly symptomatic and have side effects, high costs, and an increased risk of malignancies. Because of these limitations, there is a growing interest in the use of natural products as therapies or adjunct therapies. Herbal products have attracted considerable interest over the past decade because of their multiple beneficial effects such as their antioxidant, anti-inflammatory, antiproliferative, and immunomodulatory properties. This chapter focuses on the role of neutrophils in the pathogenesis of arthritis and the action of substances from natural products as putative antirheumatic therapies.",book:{id:"5834",slug:"role-of-neutrophils-in-disease-pathogenesis",title:"Role of Neutrophils in Disease Pathogenesis",fullTitle:"Role of Neutrophils in Disease Pathogenesis"},signatures:"Elaine Cruz Rosas, Luana Barbosa Correa and Maria das Graças\nHenriques",authors:[{id:"64332",title:"Dr.",name:"Maria Das Graças",middleName:null,surname:"Henriques",slug:"maria-das-gracas-henriques",fullName:"Maria Das Graças Henriques"},{id:"197932",title:"Dr.",name:"Elaine",middleName:"Cruz",surname:"Rosas",slug:"elaine-rosas",fullName:"Elaine Rosas"},{id:"199677",title:"MSc.",name:"Luana",middleName:null,surname:"Correa",slug:"luana-correa",fullName:"Luana Correa"}]},{id:"46041",doi:"10.5772/57335",title:"An Insight into the Abnormal Fibrin Clots — Its Pathophysiological Roles",slug:"an-insight-into-the-abnormal-fibrin-clots-its-pathophysiological-roles",totalDownloads:3892,totalCrossrefCites:4,totalDimensionsCites:11,abstract:null,book:{id:"3836",slug:"fibrinolysis-and-thrombolysis",title:"Fibrinolysis and Thrombolysis",fullTitle:"Fibrinolysis and Thrombolysis"},signatures:"Payel Bhattacharjee and Debasish Bhattacharyya",authors:[{id:"88185",title:"Prof.",name:"Debasish",middleName:null,surname:"Bhattacharyya",slug:"debasish-bhattacharyya",fullName:"Debasish Bhattacharyya"},{id:"170045",title:"Ms.",name:"Payel",middleName:null,surname:"Bhattacharjee",slug:"payel-bhattacharjee",fullName:"Payel Bhattacharjee"}]},{id:"39110",doi:"10.5772/48250",title:"Laboratory Reference Intervals in Africa",slug:"laboratory-reference-intervals-in-africa",totalDownloads:4489,totalCrossrefCites:0,totalDimensionsCites:10,abstract:null,book:{id:"2607",slug:"blood-cell-an-overview-of-studies-in-hematology",title:"Blood Cell",fullTitle:"Blood Cell - An Overview of Studies in Hematology"},signatures:"Clement E. Zeh, Collins O. Odhiambo and Lisa A. Mills",authors:[{id:"141066",title:"Dr",name:"Clement",middleName:null,surname:"Zeh",slug:"clement-zeh",fullName:"Clement Zeh"}]}],mostDownloadedChaptersLast30Days:[{id:"66797",title:"Blood Transfusion Reactions",slug:"blood-transfusion-reactions",totalDownloads:2617,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Blood transfusion reaction/adverse transfusion reactions could be fatal/severe or mild, immediate or delayed, immunological or nonimmunological, and infectious or noninfectious, and attention is paid particularly to the incidence, possible causes and pathophysiology, clinical features, and management of each type with the aim of improving awareness and raising consciousness towards improving blood safety and judicious use of blood so as to forestall these blood transfusion reactions as much as possible. This chapter serves as a synopsis to adverse blood reactions, which are very common but apparently more often under-recognized and/or under-reported particularly in developing countries. This should sharpen the consciousness of all health practitioners involved in blood transfusion services towards taking measures at preventing transfusion reactions right from donor selection up to the infusion of blood into the recipients.",book:{id:"6905",slug:"blood-groups",title:"Blood Groups",fullTitle:"Blood Groups"},signatures:"John Ayodele Olaniyi",authors:[{id:"202764",title:"Dr.",name:"John",middleName:null,surname:"Olaniyi",slug:"john-olaniyi",fullName:"John Olaniyi"}]},{id:"49387",title:"Thalassemia — From Genotype to Phenotype",slug:"thalassemia-from-genotype-to-phenotype",totalDownloads:4877,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Thalassemia encompasses serious diseases with complex pathophysiology that is difficult to explain since it is considered a group of defects with similar clinical effects, still not a single disorder.",book:{id:"4729",slug:"inherited-hemoglobin-disorders",title:"Inherited Hemoglobin Disorders",fullTitle:"Inherited Hemoglobin Disorders"},signatures:"Ghada Y. El-Kamah and Khalda S. Amr",authors:[{id:"58735",title:"Prof.",name:"Ghada",middleName:null,surname:"El-Kamah",slug:"ghada-el-kamah",fullName:"Ghada El-Kamah"},{id:"176872",title:"Prof.",name:"Khalda",middleName:null,surname:"Amr",slug:"khalda-amr",fullName:"Khalda Amr"}]},{id:"51831",title:"Disorders Mimicking Myelodysplastic Syndrome and Difficulties in its Diagnosis",slug:"disorders-mimicking-myelodysplastic-syndrome-and-difficulties-in-its-diagnosis",totalDownloads:4511,totalCrossrefCites:1,totalDimensionsCites:6,abstract:"Myelodysplastic morphology of blood cells can be encountered not only in myelodysplastic syndrome (MDS) but also in nonclonal disorders like viral, bacterial, parasitic infections, juvenile rheumatoid arthritis, polyarteritis nodosa, immune thrombocytopenic purpura (ITP), iron deficiency anemia, megaloblastic anemia, dysgranulopoietic neutropenia, congenital neutropenia, cases with microdeletion 22q11.2, malignant lymphoma, after administration of granulocyte colony stimulating factor, chemotherapy, steroids, smoking, alcohol, posttransplantation, copper deficiency also, together with or without cytopenia. Absence of cytogenetic abnormality in 50–70% of cases with MDS, some overlapping morphological and/or pathophysiological features make it challenging to differentiate between MDS and other diseases/disorders like aplastic anemia, refractory ITP, copper deficiency. Transient genetic abnormalities including monosomy 7 in megaloblastic anemia; increased immature myeloid cells in bone marrow of cases with copper, vitamin B12, or folic acid deficiency in the setting of cytopenia and dysmorphism may also lead to the misdiagnosis of MDS. On the other hand, there are also cases of transient MDS. In this chapter, a literature is be presented to draw attention of the readers on the disorders that mimic MDS. Additionally, our personal experiences are also be shared. Awareness of disorders mimicking MDS may prevent over- or underdiagnosis of MDS.",book:{id:"5276",slug:"myelodysplastic-syndromes",title:"Myelodysplastic Syndromes",fullTitle:"Myelodysplastic Syndromes"},signatures:"Lale Olcay and Sevgi Yetgin",authors:[{id:"184156",title:"Prof.",name:"Lale",middleName:null,surname:"Olcay",slug:"lale-olcay",fullName:"Lale Olcay"}]},{id:"64871",title:"Diagnosis and Classification of Myelodysplastic Syndrome",slug:"diagnosis-and-classification-of-myelodysplastic-syndrome",totalDownloads:3212,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by morphological dysplastic changes in one or more of the major hematopoietic cell lines. MDS can present with varying degrees of single or multiple cytopenias including neutropenia, anemia and thrombocytopenia. Presentation of MDS can range from asymptomatic to life threatening. MDS diagnosis and classification present important challenges, particularly in the distinction from benign conditions. French-American-British (FAB) classification proposed a classification based on easily obtainable laboratory information and was recommended in early and as modified by guidelines of new classification of World Health Organization (WHO). The strategy of diagnostic laboratory in MDS depends on morphological changes and is based on existence of dysplastic changes in the peripheral blood and bone marrow including peripheral blood smear, bone marrow aspirate smear and bone marrow trephine biopsy. The correct morphological interpretation and the use of cytogenetics, immunophenotyping, immunohistochemistry and molecular analysis will give valuable information on diagnosis and prognosis.",book:{id:"7138",slug:"recent-developments-in-myelodysplastic-syndromes",title:"Recent Developments in Myelodysplastic Syndromes",fullTitle:"Recent Developments in Myelodysplastic Syndromes"},signatures:"Gamal Abdul Hamid, Abdul Wahab Al-Nehmi and Safa Shukry",authors:[{id:"36487",title:"Prof.",name:"Gamal",middleName:null,surname:"Abdul Hamid",slug:"gamal-abdul-hamid",fullName:"Gamal Abdul Hamid"},{id:"273724",title:"Dr.",name:"Safa",middleName:null,surname:"Shukry",slug:"safa-shukry",fullName:"Safa Shukry"},{id:"277511",title:"Dr.",name:"Abdulwahab",middleName:null,surname:"Al-Nehmi",slug:"abdulwahab-al-nehmi",fullName:"Abdulwahab Al-Nehmi"}]},{id:"70780",title:"Laboratory Diagnosis of β-Thalassemia and HbE",slug:"laboratory-diagnosis-of-thalassemia-and-hbe",totalDownloads:1400,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"β-Thalassemia and HbE, each, is a syndrome resulted from quantitative and qualitative defects of β-globin chain, respectively. In addition to history retrieve and physical examination, diagnosis of these disorders requires laboratory information. Laboratory tests that are conventionally performed to diagnose the β-thalassemia and HbE are classified into two groups, based on the purposes, including the screening tests and confirmatory tests. The screening tests are aimed to screen for carriers of the β-thalassemia and HbE, while confirmatory tests are the tests performed to definitely diagnose these disorders. This chapter will explain all of these tests, the information of which will be useful for those who are working and interested in the β-thalassemia and HbE.",book:{id:"8450",slug:"beta-thalassemia",title:"Beta Thalassemia",fullTitle:"Beta Thalassemia"},signatures:"Thanusak Tatu",authors:null}],onlineFirstChaptersFilter:{topicId:"183",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82161",title:"Blood Groups More than Inheritance of Antigenic Substances: Susceptibility to Some Diseases",slug:"blood-groups-more-than-inheritance-of-antigenic-substances-susceptibility-to-some-diseases",totalDownloads:7,totalDimensionsCites:0,doi:"10.5772/intechopen.104593",abstract:"Blood group antigens represent polymorphic traits inherited among individuals and populations. The objective of this chapter is to review articles that have reported; the association between blood group antigens and susceptibility to some diseases. Findings showed that O blood group had a greater frequency of severe infections such as E coli, cholera and blood group A was associated with incidence of smallpox and some bacterial infections. These are principally based on presence or absence of “H-like” and “A and B-like” antigens markers. Antigens A, B and H are connected to N-glycans of vWF and reduces the half-life of the protein (10 hours) for group O while non-O groups, 25 hours. The loss of A, B, and H antigens as malignancy progresses was linked to potential metastasis. Similarly, some tumors have A or A-like antigens this explains the propensity of group A to develop tumors. Blood type incompatibility between mother and foetus sensitizes the mother to develop alloantibodies that could potentially cause death of the foetus in utero, a condition known hydrops. Reviewed articles have reported close link between blood group antigens and susceptibility diseases. More studies are required to rationalize the mechanism associated to this.",book:{id:"10728",title:"Blood Groups - More Than Inheritance of Antigenic Substances",coverURL:"https://cdn.intechopen.com/books/images_new/10728.jpg"},signatures:"Williams Bitty Azachi and Kuschak Mathias Dakop"},{id:"80344",title:"RH Groups",slug:"rh-groups",totalDownloads:25,totalDimensionsCites:0,doi:"10.5772/intechopen.102421",abstract:"In 1939, a mother gave birth to a stillborn baby and underwent blood transfusion with ABO-matched blood from her husband. This resulted in a hemolytic transfusion reaction (HTR). Levine and Stetson postulated that a novel antigen was present in the baby and father, which was absent in the mother. Therefore, the mother’s immune system recognized this antigen and produced antibodies against it. This condition has been known as the hemolytic disease of the newborn for a long period of time. Since the antenatal management of the fetus has been developed, the term has been modified to hemolytic disease of the fetus and newborn (HDFN). This case led to the discovery of the antibody against the first antigen of the RH blood group system, the D antigen. To date, 56 antigens have been recognized within the RH blood group system. The five main antigens are D, C, c, E, and e. As observed in the above-mentioned case, the antibodies against these antigens are implicated in HTR and HDFN.",book:{id:"10728",title:"Blood Groups - More Than Inheritance of Antigenic Substances",coverURL:"https://cdn.intechopen.com/books/images_new/10728.jpg"},signatures:"Amr J. Halawani"},{id:"80254",title:"Neutrophil-Specific Antigens: Immunobiology, Genetics and Roles in Clinical Disorders",slug:"neutrophil-specific-antigens-immunobiology-genetics-and-roles-in-clinical-disorders",totalDownloads:34,totalDimensionsCites:0,doi:"10.5772/intechopen.102431",abstract:"Neutrophils are the most abundant nucleated cells in blood circulation and play important roles in the innate and adaptive immune responses. Neutrophil-specific antigens, only expressed on neutrophils, are glycoproteins originally identified in studies on neonatal neutropenia due to fetal-maternal incompatibility and autoimmune neutropenia of infancy. The most investigated neutrophil–specific antigens are the NA and NB antigens that their incompatibilities also cause transfusion-induced febrile reactions and acute lung injury, a potentially fatal reaction, and in bone marrow transplantation, causing graft rejection. NA antigens are members of the immunoglobulin superfamily and are low-affinity Fc-receptors FcγRIIIb (CD16b). Fc receptors connect the F(ab), the antigen-binding fragment of the antibody molecules, to neutrophils and lead them to recognize and phagocytize the targeted antigens. The NB (CD177) antigen belongs to the urokinase-type Plasminogen Activator Receptor Superfamily (uPAR, CD59, Ly6), but its specific functions have not been fully determined. It is known, however, that NB antigen binds proteinase-3 (PR3 to the neutrophil membrane), a serine protease. In clinical studies, it was also demonstrated that NB expression is highly elevated in Polycythemia Vera and is unexpectedly expressed in some cancer tissues. Neutrophil-specific antigens are examples of antigens that have important biological and clinical activities beyond antigenicity.",book:{id:"10728",title:"Blood Groups - More Than Inheritance of Antigenic Substances",coverURL:"https://cdn.intechopen.com/books/images_new/10728.jpg"},signatures:"Parviz Lalezari and Behnaz Bayat"},{id:"80716",title:"The ABO Blood Group System and Plasmodium falciparum (Pf ) Infection in Three Ethnic Groups Living in the Stable and Seasonal Malaria Transmission Areas of Burkina Faso (BF)",slug:"the-abo-blood-group-system-and-plasmodium-falciparum-pf-infection-in-three-ethnic-groups-living-in-t",totalDownloads:92,totalDimensionsCites:0,doi:"10.5772/intechopen.102475",abstract:"Genetic factors, including red blood cell polymorphisms, influence the severity of disease due to infection with Plasmodium falciparum (Pf). Studies show that these genetic factors associated with malaria susceptibility or resistance vary geographically, ethnically, and racially. We performed cross-sectional surveys in population living in rural villages from three ethnic groups. The blood group (BG) was determined genetically using two polymorphisms (rs8176719 and rs8176746). Out of 548 participants, 29.7% were Mossi, 38.2% were Fulani, and 32.1% were Rimaibe. The distribution of BG was, respectively, A: 25.5%, B: 26.6%, AB: 7.3%, and O: 40.5%. BG O was not only the common blood type overall, but was higher in Fulani (52.6%) than others. Fulani was associated with a reduced risk of infection and lower parasite densities than sympatric populations. The subjects with non-O blood were less susceptible to malaria infection. An association between ethnicity and malaria infection during the high transmission season as well as an association between the non-O blood group and malaria infections according to ethnicity was found. This was also true when ethnic groups were considered separately. Our results have demonstrated that the Fulani are not only less susceptible to Pf malaria infection, but when infected have lower parasite densities. Individuals with non-O blood are at lower risk of infection.",book:{id:"10728",title:"Blood Groups - More Than Inheritance of Antigenic Substances",coverURL:"https://cdn.intechopen.com/books/images_new/10728.jpg"},signatures:"Edith Christiane Bougouma, Alphonse Ouedraogo and Sodiomon Bienvenu Sirima"},{id:"80474",title:"ABO Blood Group and Thromboembolic Diseases",slug:"abo-blood-group-and-thromboembolic-diseases",totalDownloads:40,totalDimensionsCites:0,doi:"10.5772/intechopen.102757",abstract:"Thromboembolic diseases are usually inherited in the family. The tendency to repeat in an individual is a phenomenon that allows it to be studied. The inheritance and recurrence of thromboembolic diseases, of course, have individual risk factors for this occurrence. In the past, the ABO blood group was only needed for transfusion and organ transplant therapy. Over time, scientists think that blood type is a risk factor for certain diseases, including thromboembolism. Many studies divide between type O and non-O blood groups, both of which are distinguished by the presence of antigens on the cell surface and antibodies in the plasma of individuals. Type O does not have A, B antigens but has antibodies against A, B antigens, and vice versa for the non-O type. Many studies have shown that the non-O blood group has a risk factor for thromboembolic diseases, commonly due to higher levels of von Willebrand factor (VWF) and factor VIII (FVIII). These thromboembolic events can occur in arteries or venous. Thromboembolic manifestations are often associated with cardiovascular diseases for arterial thrombosis; and deep vein thrombosis (DVT) and pulmonary embolism (PE) for venous thromboembolism (VTE).",book:{id:"10728",title:"Blood Groups - More Than Inheritance of Antigenic Substances",coverURL:"https://cdn.intechopen.com/books/images_new/10728.jpg"},signatures:"Yetti Hernaningsih"},{id:"78997",title:"ABO Blood Groups and Risk of Glioma",slug:"abo-blood-groups-and-risk-of-glioma",totalDownloads:59,totalDimensionsCites:0,doi:"10.5772/intechopen.100566",abstract:"Gliomas are one of the most common primary brain tumors and the etiology of gliomas remains unknown in most cases. The aim of this case–control study was to investigate possible association between incidence in relation to glioma and certain blood groups. This study included 100 histopathologically verified cases of glioma and 200 age and sex-matched controls without malignant diseases that were admitted to the same hospital. The results revealed that the patients with group AB were at 3.5-fold increased risk of developing glioma compared to the patients with other ABO blood groups. In this particular study, there was more male patients with glioma with the blood group AB. However, mechanisms that explain the relationship between the blood groups ABO and a cancer risk are unclear. Several hypotheses have been proposed, including the one with a modulatory role of blood group ABO antigens. In addition, the blood group ABO system regulates the level of circulating proinflammatory and adhesion molecules which play a significant role in the tumorigenesis process. Additionally, the recent discovery that includes the von Willebrand factor (vWF) as an important modulator of angiogenesis and apoptosis provides one plausible explanation as regards the role of the blood group ABO in the tumorigenesis process. To our knowledge, this is the first study that examined the relationship of blood group in patients diagnosed with glioma among the Serbian population. Moreover, for the first time our study results suggested that blood group AB increased the risk of glioma. The results of this study suggested that the blood group AB could be one of hereditary factors which had an influence on the occurrence of glioma. The further research is needed on a larger sample, to confirm these findings and the possible mechanisms by which the ABO system contributes to the pathology of glioma.",book:{id:"10728",title:"Blood Groups - More Than Inheritance of Antigenic Substances",coverURL:"https://cdn.intechopen.com/books/images_new/10728.jpg"},signatures:"Ana Azanjac Arsic"}],onlineFirstChaptersTotal:7},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517",scope:"Paralleling similar advances in the medical field, astounding advances occurred in Veterinary Medicine and Science in recent decades. These advances have helped foster better support for animal health, more humane animal production, and a better understanding of the physiology of endangered species to improve the assisted reproductive technologies or the pathogenesis of certain diseases, where animals can be used as models for human diseases (like cancer, degenerative diseases or fertility), and even as a guarantee of public health. Bridging Human, Animal, and Environmental health, the holistic and integrative “One Health” concept intimately associates the developments within those fields, projecting its advancements into practice. This book series aims to tackle various animal-related medicine and sciences fields, providing thematic volumes consisting of high-quality significant research directed to researchers and postgraduates. It aims to give us a glimpse into the new accomplishments in the Veterinary Medicine and Science field. By addressing hot topics in veterinary sciences, we aim to gather authoritative texts within each issue of this series, providing in-depth overviews and analysis for graduates, academics, and practitioners and foreseeing a deeper understanding of the subject. Forthcoming texts, written and edited by experienced researchers from both industry and academia, will also discuss scientific challenges faced today in Veterinary Medicine and Science. In brief, we hope that books in this series will provide accessible references for those interested or working in this field and encourage learning in a range of different topics.",coverUrl:"https://cdn.intechopen.com/series/covers/13.jpg",latestPublicationDate:"June 17th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"19",title:"Animal Science",coverUrl:"https://cdn.intechopen.com/series_topics/covers/19.jpg",isOpenForSubmission:!0,editor:{id:"259298",title:"Dr.",name:"Edward",middleName:null,surname:"Narayan",slug:"edward-narayan",fullName:"Edward Narayan",profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",biography:"Dr. Edward Narayan graduated with Ph.D. degree in Biology from the University of the South Pacific and pioneered non-invasive reproductive and stress endocrinology tools for amphibians - the novel development and validation of non-invasive enzyme immunoassays for the evaluation of reproductive hormonal cycle and stress hormone responses to environmental stressors. \nDr. Narayan leads the Stress Lab (Comparative Physiology and Endocrinology) at the University of Queensland. A dynamic career research platform which is based on the thematic areas of comparative vertebrate physiology, stress endocrinology, reproductive endocrinology, animal health and welfare, and conservation biology. \nEdward has supervised 40 research students and published over 60 peer reviewed research.",institutionString:null,institution:{name:"University of Queensland",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null},{id:"20",title:"Animal Nutrition",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",isOpenForSubmission:!0,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. He teaches various degree courses in zootechnics, sheep production, and agricultural sciences and natural resources.\n\nDr. Ronquillo’s research focuses on the evaluation of sustainable animal diets (StAnD), using native resources of the region, decreasing carbon footprint, and applying meta-analysis and mathematical models for a better understanding of animal production.",institutionString:null,institution:{name:"Universidad Autónoma del Estado de México",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null},{id:"28",title:"Animal Reproductive Biology and Technology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/28.jpg",isOpenForSubmission:!0,editor:{id:"177225",title:"Prof.",name:"Rosa Maria Lino Neto",middleName:null,surname:"Pereira",slug:"rosa-maria-lino-neto-pereira",fullName:"Rosa Maria Lino Neto Pereira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9wkQAC/Profile_Picture_1624519982291",biography:"Rosa Maria Lino Neto Pereira (DVM, MsC, PhD and) is currently a researcher at the Genetic Resources and Biotechnology Unit of the National Institute of Agrarian and Veterinarian Research (INIAV, Portugal). She is the head of the Reproduction and Embryology Laboratories and was lecturer of Reproduction and Reproductive Biotechnologies at Veterinary Medicine Faculty. She has over 25 years of experience working in reproductive biology and biotechnology areas with a special emphasis on embryo and gamete cryopreservation, for research and animal genetic resources conservation, leading research projects with several peer-reviewed papers. Rosa Pereira is member of the ERFP-FAO Ex situ Working Group and of the Management Commission of the Portuguese Animal Germplasm Bank.",institutionString:"The National Institute for Agricultural and Veterinary Research. Portugal",institution:null},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:13,paginationItems:[{id:"82285",title:"Parvovirus Vectors: The Future of Gene Therapy",doi:"10.5772/intechopen.105085",signatures:"Megha Gupta",slug:"parvovirus-vectors-the-future-of-gene-therapy",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg",subseries:{id:"19",title:"Animal Science"}}},{id:"81793",title:"Canine parvovirus-2: An Emerging Threat to Young Pets",doi:"10.5772/intechopen.104846",signatures:"Mithilesh Singh, Rajendran Manikandan, Ujjwal Kumar De, Vishal Chander, Babul Rudra Paul, Saravanan Ramakrishnan and Darshini Maramreddy",slug:"canine-parvovirus-2-an-emerging-threat-to-young-pets",totalDownloads:15,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg",subseries:{id:"19",title:"Animal Science"}}},{id:"81271",title:"The Diversity of Parvovirus Telomeres",doi:"10.5772/intechopen.102684",signatures:"Marianne Laugel, Emilie Lecomte, Eduard Ayuso, Oumeya Adjali, Mathieu Mével and Magalie Penaud-Budloo",slug:"the-diversity-of-parvovirus-telomeres",totalDownloads:38,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg",subseries:{id:"19",title:"Animal Science"}}},{id:"79209",title:"Virtual Physiology: A Tool for the 21st Century",doi:"10.5772/intechopen.99671",signatures:"Carmen Nóbrega, Maria Aires Pereira, Catarina Coelho, Isabel Brás, Ana Cristina Mega, Carla Santos, Fernando Esteves, Rita Cruz, Ana I. Faustino-Rocha, Paula A. Oliveira, João Mesquita and Helena Vala",slug:"virtual-physiology-a-tool-for-the-21st-century",totalDownloads:151,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Veterinary Anatomy and Physiology",coverURL:"https://cdn.intechopen.com/books/images_new/10665.jpg",subseries:{id:"19",title:"Animal Science"}}}]},overviewPagePublishedBooks:{paginationCount:11,paginationItems:[{type:"book",id:"7233",title:"New Insights into Theriogenology",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7233.jpg",slug:"new-insights-into-theriogenology",publishedDate:"December 5th 2018",editedByType:"Edited by",bookSignature:"Rita Payan-Carreira",hash:"74f4147e3fb214dd050e5edd3aaf53bc",volumeInSeries:1,fullTitle:"New Insights into Theriogenology",editors:[{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. 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His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334239",title:"Prof.",name:"Leung",middleName:null,surname:"Wai Keung",slug:"leung-wai-keung",fullName:"Leung Wai Keung",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Hong Kong",country:{name:"China"}}}]}},subseries:{item:{id:"25",type:"subseries",title:"Evolutionary Computation",keywords:"Genetic Algorithms, Genetic Programming, Evolutionary Programming, Evolution Strategies, Hybrid Algorithms, Bioinspired Metaheuristics, Ant Colony Optimization, Evolutionary Learning, Hyperparameter Optimization",scope:"Evolutionary computing is a paradigm that has grown dramatically in recent years. This group of bio-inspired metaheuristics solves multiple optimization problems by applying the metaphor of natural selection. It so far has solved problems such as resource allocation, routing, schedule planning, and engineering design. Moreover, in the field of machine learning, evolutionary computation has carved out a significant niche both in the generation of learning models and in the automatic design and optimization of hyperparameters in deep learning models. This collection aims to include quality volumes on various topics related to evolutionary algorithms and, alternatively, other metaheuristics of interest inspired by nature. For example, some of the issues of interest could be the following: Advances in evolutionary computation (Genetic algorithms, Genetic programming, Bio-inspired metaheuristics, Hybrid metaheuristics, Parallel ECs); Applications of evolutionary algorithms (Machine learning and Data Mining with EAs, Search-Based Software Engineering, Scheduling, and Planning Applications, Smart Transport Applications, Applications to Games, Image Analysis, Signal Processing and Pattern Recognition, Applications to Sustainability).",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11421,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"111683",title:"Prof.",name:"Elmer P.",middleName:"P.",surname:"Dadios",slug:"elmer-p.-dadios",fullName:"Elmer P. 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