More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
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Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
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“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
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Additionally, each book published by IntechOpen contains original content and research findings.
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We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
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Simba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
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IntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
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Since the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\n
Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n
“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\n
Additionally, each book published by IntechOpen contains original content and research findings.
\n\n
We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
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\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"7156",leadTitle:null,fullTitle:"Osteogenesis and Bone Regeneration",title:"Osteogenesis and Bone Regeneration",subtitle:null,reviewType:"peer-reviewed",abstract:"Osteogenesis is a core component of the skeletal system and depends on the well-coordinated proliferation and differentiation of osteogenic cells. Multiple signaling pathways and transcriptional factors tightly regulate the process of osteogenesis. Any abnormities in bone formation could cause severe disorders such as osteogenesis imperfecta and osteoporosis. Bone regeneration, a complex and well-orchestrated physiological process of osteogenesis, remains a medical challenge in the field of orthopedics and maxillofacial surgery. This book provides an overview of the current developments in osteogenesis and bone regeneration, including molecular and cellular mechanisms, physical therapies (low-level laser, distraction osteogenesis), biological therapies (mesenchymal stem cells, stem cell derived exosomes, inflammatory factor, Chinese medicine), as well as tissue engineering approaches promoting bone regeneration by targeting osteogenesis.",isbn:"978-1-78985-768-9",printIsbn:"978-1-78985-767-2",pdfIsbn:"978-1-83962-146-8",doi:"10.5772/intechopen.73955",price:119,priceEur:129,priceUsd:155,slug:"osteogenesis-and-bone-regeneration",numberOfPages:142,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"dbffb762cef8ae7cddbd8a3ebed31d81",bookSignature:"Haisheng Yang",publishedDate:"April 24th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7156.jpg",numberOfDownloads:13289,numberOfWosCitations:6,numberOfCrossrefCitations:13,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:39,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:58,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 14th 2018",dateEndSecondStepPublish:"July 31st 2018",dateEndThirdStepPublish:"September 29th 2018",dateEndFourthStepPublish:"December 18th 2018",dateEndFifthStepPublish:"February 16th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,position:null,outsideEditionCount:null,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Beijing University of Technology",institutionURL:null,country:{name:"China"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1044",title:"Osteoimmunology",slug:"osteoimmunology"}],chapters:[{id:"64747",title:"Bone Development and Growth",doi:"10.5772/intechopen.82452",slug:"bone-development-and-growth",totalDownloads:6210,totalCrossrefCites:10,totalDimensionsCites:23,hasAltmetrics:1,abstract:"The process of bone formation is called osteogenesis or ossification. After progenitor cells form osteoblastic lines, they proceed with three stages of development of cell differentiation, called proliferation, maturation of matrix, and mineralization. Based on its embryological origin, there are two types of ossification, called intramembranous ossification that occurs in mesenchymal cells that differentiate into osteoblast in the ossification center directly without prior cartilage formation and endochondral ossification in which bone tissue mineralization is formed through cartilage formation first. In intramembranous ossification, bone development occurs directly. In this process, mesenchymal cells proliferate into areas that have high vascularization in embryonic connective tissue in the formation of cell condensation or primary ossification centers. This cell will synthesize bone matrix in the periphery and the mesenchymal cells continue to differentiate into osteoblasts. After that, the bone will be reshaped and replaced by mature lamellar bone. Endochondral ossification will form the center of primary ossification, and the cartilage extends by proliferation of chondrocytes and deposition of cartilage matrix. After this formation, chondrocytes in the central region of the cartilage start to proceed with maturation into hypertrophic chondrocytes. After the primary ossification center is formed, the marrow cavity begins to expand toward the epiphysis. Then the subsequent stages of endochondral ossification will take place in several zones of the bone.",signatures:"Rosy Setiawati and Paulus Rahardjo",downloadPdfUrl:"/chapter/pdf-download/64747",previewPdfUrl:"/chapter/pdf-preview/64747",authors:[null],corrections:null},{id:"64162",title:"Wnt Signaling and Genetic Bone Diseases",doi:"10.5772/intechopen.81070",slug:"wnt-signaling-and-genetic-bone-diseases",totalDownloads:879,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The Wnt signal transduction plays a vital role in regulating development throughout the animal kingdom. The Wnt signal transduction is complex, including Wnt ligands, receptors, coreceptors, transducers, transcription factors, antagonists, agonists and their modulators, and target genes. It is classified into β-catenin-dependent canonical and independent non-canonical Wnt (mainly planar cell polarity and Wnt/Ca2+) signaling pathways. Wnt signaling pathway is causative to multiple human diseases. Gene mutations from the components of WNT signaling machinery have been identified to relate with low or high bone mass diseases, such as osteogenesis imperfecta, Robinow syndrome, osteoporosis-pseudoglioma syndrome, and sclerosteosis. In this review, we provide an update of the Wnt signaling pathway and the bone diseases caused by the aberrant components of the pathways.",signatures:"Yanqin Lu and Jinxiang Han",downloadPdfUrl:"/chapter/pdf-download/64162",previewPdfUrl:"/chapter/pdf-preview/64162",authors:[{id:"261467",title:"Dr.",name:"Yanqin",surname:"Lu",slug:"yanqin-lu",fullName:"Yanqin Lu"},{id:"270346",title:"Prof.",name:"Jinxiang",surname:"Han",slug:"jinxiang-han",fullName:"Jinxiang Han"}],corrections:null},{id:"63727",title:"Potential Therapeutic Applications of Exosomes in Bone Regenerative Medicine",doi:"10.5772/intechopen.81069",slug:"potential-therapeutic-applications-of-exosomes-in-bone-regenerative-medicine",totalDownloads:1165,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The ability of bone regeneration is relatively robust, which is crucial for fracture healing, but delayed healing and nonunion are still common problems in clinical practice. Fortunately, exciting results have been achieved for regenerative medicine in recent years, especially in the area of stem cell-based treatment, but all these cell-based approaches face challenging problems, including immune rejection. For this reason, exosomes, stem cell-derived small vesicles of endocytic origin, have attracted the attention of many investigators in the field of bone regeneration. One of the attractive features of exosomes is that they are small and can travel between cells and deliver bioactive products, including miRNA, mRNA, proteins, and various other factors, to promote bone regeneration, with undetectable immune rejection. In this chapter, we intend to briefly update the recent progressions, and discuss the potential challenges in the target areas. Hopefully, our discussion would be helpful not only for the clinicians and the researchers in the specific disciplines but also for the general audiences as well.",signatures:"Jiazhao Yang, Wanbo Zhu, Jinsen Lu, Kai Xie, Shiyuan Fang and Lixin Kan",downloadPdfUrl:"/chapter/pdf-download/63727",previewPdfUrl:"/chapter/pdf-preview/63727",authors:[null],corrections:null},{id:"64527",title:"Role of Inflammatory Factors in Regulation of Osteogenesis in Tissue-Engineered Bone",doi:"10.5772/intechopen.81153",slug:"role-of-inflammatory-factors-in-regulation-of-osteogenesis-in-tissue-engineered-bone",totalDownloads:944,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"It was traditionally considered that the inhibition of inflammatory reaction is necessary for osteogenesis, but the latest issue argued inflammation is unavoidable in the process of bone trauma, and physiological inflammatory reaction is essential to achieve bone formation. Tissue-engineered bone graft is not only associated with osteoblast-related cells; the inflammatory reaction is the initial physiological process, mainly with neutrophil infiltration, which secretes MCP-1, IL-8, and other chemokines and further promotes dendritic cells, lymphocytes, and mononuclear macrophages to move in. The activation pathways of macrophages have a direct effect on the outcome of the inflammatory reaction and the healing, which are divided into the classical approach (M1) and the alternative approach (M2). The M1 pathway secretes IL-1 beta, IL-6, TNF-α, and other pro-inflammatory factors, while the M2 pathway secretes arginase, IL-1Ra, IL-4, and other anti-inflammatory cytokines, also with bone-healing-related growth factors, which promote homing of bone mesenchymal stem cells (bMSCs).",signatures:"Yandong Mu, Lu Yang, Chenglong Li and Wei Qing",downloadPdfUrl:"/chapter/pdf-download/64527",previewPdfUrl:"/chapter/pdf-preview/64527",authors:[null],corrections:null},{id:"64772",title:"Traditional Chinese Medicine Therapy for Targeting Osteoblastogenesis",doi:"10.5772/intechopen.82451",slug:"traditional-chinese-medicine-therapy-for-targeting-osteoblastogenesis",totalDownloads:932,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Osteoblasts are derived from bone marrow mesenchymal stem cell (BMSC) precursors, which differentiate into mature osteoblasts and mediate bone formation. This process is called osteoblastogenesis. A deficiency in osteoblastogenesis of BMSCs can result in bone-related diseases including osteoporosis. Thus, developing drugs for targeting osteoblastogenesis from BMSCs has become one of the therapeutic strategies for osteoporosis. In China, kidney-nourishing Chinese herbal drugs such as ER-Zhi-Wan have been believed to be potential for treating osteoporosis through targeting osteoblast proliferation and differentiation. The key pathways for regulating osteoblastogenesis include canonical and noncanonical Wnt pathway, semaphorin-mediated pathway, and MAPK-mediated BMP2-Smad pathway. Some natural products have been confirmed to regulate more than one pathway and exert multi-target effect through the use of one compound or combined use of more than two compounds, such as wedelolactone and oleonuezhenide. In addition, tissue engineering provides a promising strategy in the field for targeting osteoblastogenesis. New types of biomaterials including hydroxyapatite (HAp) combined with Chinese medicine can exert enhanced effect on osteoblastogenesis and provide new therapy for treating osteoporosis.",signatures:"Yanqiu Liu",downloadPdfUrl:"/chapter/pdf-download/64772",previewPdfUrl:"/chapter/pdf-preview/64772",authors:[null],corrections:null},{id:"64870",title:"Alternative Strategies for Stem Cell Osteogenic Differentiation",doi:"10.5772/intechopen.82333",slug:"alternative-strategies-for-stem-cell-osteogenic-differentiation",totalDownloads:1284,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Discovering strategies that increase the osteogenic differentiation potential of mesenchymal stem cells (MSCs) can lead to new perspectives for bone disease treatments. The possibility to associate the mesenchymal stem cells with scaffolds and to use them in bone regeneration as well as the number of studies to understand the signaling pathway of osteogenesis are increasing. Identifying osteogenic induction factors is extremely important and crucial for the success of bone regeneration. Studies have shown that proteins, such as bone morphogenetic proteins (BMPs), trichostatin A and IGF-1, can be efficiently used for osteogenic regeneration. However, the use of these proteins increases the treatment cost. Fortunately, low-level laser therapy (LLLT) may be a new alternative for adjuvant therapy to treat bone regeneration because it has biostimulatory effects on the conversion of mesenchymal stem cells into osteoblasts and on the induction of ex vivo ossification. The principle of tissue photobiomodulation with LLLT was first described in dermatology for healing wounds; however, other applications have been described, with anti-inflammatory and anti-edema effects and cellular proliferation and differentiation. Following this way, we will discuss some alternative strategies for osteogenic differentiation and suggest that the low-power lasers can be an innovative instrument for cell differentiation.",signatures:"Carla Cristina Gomes Pinheiro and Daniela Franco Bueno",downloadPdfUrl:"/chapter/pdf-download/64870",previewPdfUrl:"/chapter/pdf-preview/64870",authors:[null],corrections:null},{id:"63547",title:"Distraction Osteogenesis in Oral and Craniomaxillofacial Reconstructive Surgery",doi:"10.5772/intechopen.81055",slug:"distraction-osteogenesis-in-oral-and-craniomaxillofacial-reconstructive-surgery",totalDownloads:1875,totalCrossrefCites:2,totalDimensionsCites:8,hasAltmetrics:0,abstract:"Distraction osteogenesis (DO) is a tissue engineering method to regenerate new bone. The application of DO in the field of oral and craniomaxillofacial surgery has provided a promising alternative as it can be integrated with conventional surgical technique for bone lengthening or expansion. This technique has the advantages of providing superior amount of bone lengthening thus eliminating the need of autogenous graft and donor site morbidity, can be applied in young patients and allows simultaneous expansion of the surrounding soft tissues. In this chapter, we provide a comprehensive overview of the background history and development of DO which is based on Ilizarov technique, along with its basic principles, indications, classification of DO devices and protocol in craniomaxillofacial bone lengthening or expansion. Its clinical applications which include alveolar DO, mandible DO, maxilla DO, transport DO and craniofacial DO are clarified. This technique however requires proper understanding of clinical and technical components to avoid potential complications which include relapse, infection, adjacent structure injury, device failure and other complications. The emerging results of research and advances in DO are further elaborated at the end of this chapter.",signatures:"Firdaus Hariri, Siok Yoong Chin, Jonathan Rengarajoo, Qi Chao Foo,\nSiti Nur Nabihah Zainul Abidin and Ahmad Fadhli Ahmad Badruddin",downloadPdfUrl:"/chapter/pdf-download/63547",previewPdfUrl:"/chapter/pdf-preview/63547",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"3516",title:"Topics in Osteoporosis",subtitle:null,isOpenForSubmission:!1,hash:"1f49a9a4e5116c7ddf3398cab80470a4",slug:"topics-in-osteoporosis",bookSignature:"Margarita Valdes Flores",coverURL:"https://cdn.intechopen.com/books/images_new/3516.jpg",editedByType:"Edited by",editors:[{id:"76697",title:"Dr.",name:"Margarita",surname:"Valdés-Flores",slug:"margarita-valdes-flores",fullName:"Margarita Valdés-Flores"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"758",title:"Osteoporosis",subtitle:null,isOpenForSubmission:!1,hash:"b52e42df6cd850721e557bedd3a4a77b",slug:"osteoporosis",bookSignature:"Yannis Dionyssiotis",coverURL:"https://cdn.intechopen.com/books/images_new/758.jpg",editedByType:"Edited by",editors:[{id:"76883",title:"PhD.",name:"Yannis",surname:"Dionyssiotis",slug:"yannis-dionyssiotis",fullName:"Yannis Dionyssiotis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"982",title:"Principles of Osteoarthritis",subtitle:"Its Definition, Character, Derivation and Modality-Related Recognition",isOpenForSubmission:!1,hash:"ede382c82c469265f558306b4fb48137",slug:"principles-of-osteoarthritis-its-definition-character-derivation-and-modality-related-recognition",bookSignature:"Bruce M. 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1. Introduction
Electrophoretic methods compose a family of related techniques that use narrow-bore fused-silica capillaries to perform high efficiency separations of both small and large molecules. These methods are commonly known as capillary electrophoretic methods. Capillary electrophoresis (CE) has, over the years, demonstrated its powerful separation ability in the area of chiral and achiral analysis. This is contributed to the advantages it offers when compared to chromatographic techniques: (1) low consumption of samples and solvents; (2) high separation efficiency and resolution; (3) versatility [1,2].
Two of the most important modes of CE, which will be discussed in this chapter, are capillary zone electrophoresis (CZE) and micellar electrokinetic chromatography (MEKC). CZE is the simplest and the most widely used mode of CE [1]. The separation mechanism of the analytes is based on their difference in charge-to-size ratios and their difference in electrophoretic mobilities, which, in turn, result in different velocities. However, due to the fact that neutral species do not possess an electrophoretic mobility, they cannot be separated by use of this mode.
In order to circumvent this problem, new modes of CE have been suggested as alternatives. MEKC, which combines the best features of both electrophoresis and chromatography, is considered an alternative mode because it can be used for the separation of charged as well as neutral compounds. It involves the introduction of a surfactant at a concentration above the critical micellar concentration (CMC), at which micelles are formed. MEKC was first introduced by Terabe et al. in 1984 [3]. Although it is a form of CE, its separation principle is more similar to HPLC than to CE. In this mode, analytes are separated according to their partitioning between the mobile and stationary phase and, when charged, their electrophoretic mobility. The driving force for the partitioning of analytes is hydrophobicity. In addition, hydrogen bonding, dipole-dipole, and dispersive interactions can contribute to the solute partitioning between the two phases [4-6].
CE was originally considered as a powerful analytical tool for the analysis of biological macromolecules. It has though, over the years, been extensively used for the separation of other compounds, such as chiral drugs, food additives, pesticides, inorganic ions, organic acids, and others. In this chapter, the ability of CE, and particularly CZE and MEKC, to be used for the qualitative and quantitative determination of compounds in pharmaceutical, biological and natural samples is investigated. In each approach, a number of studies are reported and discussed. These studies involve establishment of optimum separation conditions, method validation, optimization of sample-preparation procedure and application for the determination of the analytes under study in real samples. The first part of this chapter involves the determination of polyphenolic compounds using CZE with UV-Vis detector in red and white wines, while the second part involves the determination of pharmaceutical compounds in biological samples, such as blood and urine, using the hyphenated technique CE-MS (mass spectrometry). The third and final part emphasizes the importance of MEKC in chiral analysis since it has been known that usually only one enantiomer is active, while the other may be less active, inactive or has adverse effects.
2. Determination of polyphenolic compounds in natural samples
Polyphenolic compounds exist in a variety of natural products, such as fruits, vegetables, beverages (tea, wine and juices), honey, cacao and herbs. They attract a lot of interest due to their beneficial implication in human health. They have been widely studied due to their antioxidant capacity and their association with several pathological conditions, such as hypertension, cardiovascular disease, dementia, and even cancer [7-9]. Therefore, due to their health significance, numerous analytical methods have, over the last decades, been developed for their separation, identification and quantitation in natural products [10-13].
According to literature, the simplest CE method, CZE, proved to be the best method for the determination of polyphenolic compounds in wine samples [14-17]. In such studies, and in each case, when the optimum CZE method was applied to different red and white wines, it was established that red wines have higher levels of polyphenolic compounds than white wines and that the polyphenolic composition varies among different wines.
2.1. Method development and validation
In this part of the chapter, a representative study performed recently in Cypriot wines is briefly described [17]. The influence of several experimental parameters is initially illustrated in order to obtain improved selectivity and resolution for the separation of seven flavonoids, which constitute the most important group of polyphenols, and trans-rasveratrol that are usually present in wine. This is accomplished by use of CZE and by examining different sample preparation procedures. Due to the low concentrations of flavonoids in wine and the high complexity of wine matrices, preconcentration methods are required, which can simplify the electropherograms. The optimized CZE and pre-treatment methods proved to be effective in characterizing flavonoids in red and white wine samples.
The effect of column temperature, and concentration and pH of background electrolyte (BGE) were investigated. These parameters, along with the applied voltage, are the most common parameters that are required to be examined in order to optimize a separation in CZE. Figure 1 illustrates the influence of the pH on the resolution and the analysis time. The last two increased with increasing the pH, possibly due to an increase in the negative charge, which resulted in a greater affinity and a higher complexation between borate and phenols. Taking into consideration the migration times, the peak efficiency and the sufficient resolution, the following parameters provided a baseline separation of all polyphenolic compounds: BGE containing 50 mM borate and 10 mM phosphate at pH 9.6 and column temperature of 25 ºC (Figure 1C). The use of alkaline borate-based BGEs, in CZE, resulted in a sufficient separation of polyphenols due to the complex-formation ability of borate. In addition, an increase in the borate concentration from 25 to 50 mM and an increase in the pH value from 9 to 10 resulted in an increase in the migration times of all analytes, while the resolution was significantly improved. At pH 10 though, the analysis time was very long (~ 50 min) and joule heating effects, such as high current generation and peak broadering, were observed. An increase in pH increased the negative charge of the analytes, which, in turn, favored a greater affinity for the buffer and a higher complexation between borate and phenols [18].
Figure 1.
Effect of pH value on the separation of the eight polyphenols. (A) pH 9; (B) pH 9.3; (C) pH 9.6. Conditions: BGE 50 mM borate, 10 mM phosphate and 20 mM SDS; pressure injection, 30 mbar for 3 sec; applied voltage, 25 kV; temperature, 25 ºC; fused-silica capillary, 64 cm (55.5 cm effective length) x 50 μm i.d.; detection, 205 nm. Peak identification: trans-resveratrol (1), epicatechin (2), catechin (3), naringenin (4), kaempferol (5), apigenin (6), myricetin (7), quercetin (8) [17].
The method was then validated by the terms of linearity, precision and LOD. Linearities for the eight analytes were very good, and precision, which was based on the relative standard deviation, was below 1%, indicating an excellent reproducibility. In addition, LODs, which were calculated as three times the standard deviation via the slope of the calibration curve, were between 0.03 and 5.05 μg/mL for all eight polyphenolic compounds.
2.2. Application
The qualitative and quantitative analysis of analytes in real samples is often difficult due to interruptions caused by different interfering substances found in the sample matrix. Therefore, a sample-preparation procedure is a necessary step prior to the electrophoretic analysis, in order to isolate the analytes under study from real samples. Different preconcentration methods have been used over the years, including solid-phase extraction (SPE) with C-18, silica, or other cartridges [14,16,19] and liquid-liquid extraction (LLE) with different organic solvents [10,20,21].
In the study performed in Cypriot wines, the sample preparation procedure was optimized in order to determine the one that was simple, fast and reliable [17]. Therefore, three LLE-procedures (C,D,E), a SPE-procedure (F), a procedure that involve evaporation and reconstitution of wine sample (B) and a direct injection of wine sample after dilution and filtration (A) were compared and the most effective method was applied to Cypriot wines. The electropherograms obtained by use of each sample preparation procedure are illustrated in Figure 2. When no extraction was performed, the electropherograms were complex, while SPE was found to be ineffective for the isolation of polyphenolic compounds from wine samples. LLE with diethyl ether, followed by evaporation of organic layer by nitrogen stream and reconstitution in ethanol proved to be the optimum sample pre-treatment method. When the optimum method was applied to Cypriot wine samples, the quantification of polyphenolic compounds was successfully achieved. It was observed that epicatechin and catechin exist in all wine samples in comparable concentrations, whereas myricetin and quercetin exist only in two of the three wine samples. Polyphenolic composition varies among different wines, because it depends on several factors, such as the type of grapes used, the vivification process used, the type of yeast that participates in the fermentation, weather variations and other biological effects [22].
Figure 2.
Electropherograms of the wine samples obtained using six different sample preparation procedures under optimum conditions. Conditions: BGE 50 mM borate, 10 mM phosphate and 20 mM SDS (pH 9.6); pressure injection, 30 mbar for 3 sec; applied voltage, 25 kV; temperature, 25 ºC; fused-silica capillary, 64 cm (55.5 cm effective length) x 50 μm i.d.; detection, 205 nm. Peak identification: epicatechin (2), catechin (3), myricetin (7), quercetin (8) [17].
Another important observation was that in white wine, the only flavonoid that was detected was catechin at a concentration of 7.3 μg/mL. This was not surprising since the majority of flavonoids in wine come from the extraction derived from grape’s solids. White wine is made by pressing the juice away from the grape’s solids, and then, by allowing it to ferment. So, red wines have higher levels of polyphenolic compounds [23].
3. Determination of pharmaceutical compounds in biological samples
Quantification of drugs in biological fluids, like plasma, has an important role in drug discovery and development. There are two main aspects that are taken into account in order to make the identification of drugs in biological fluids possible. The first aspect is the development of an accurate analytical method, with high sensitivity, capable to identify desirable compounds in concentrations comparable to that in biological fluids. The second one is the exploration of the optimum extraction method that can effectively extract the drug from the biological matrix.
Over the years, CE coupled to electrospray ionization-mass spectrometry (ESI-MS) has been utilized as a bioanalytical tool for the analysis of drug compounds in biological samples [24-29]. Even though the most common detector in CE is the UV detector due to its easy manageability and low cost, it has the drawback of low sensitivity due to the short optical path length. An alternative to this is the use of MS. The coupling of CE with MS is a well-established technique, which combines the high efficiency and resolution that are provided by CE and the detection sensitivity and selectivity and the identification potential that are provided by MS [25,30].
In recent years, a large number of publications have been provided on the general developments and biological applications of CE-ESI-MS [24-29]. Zheng et al. developed a CZE-ESI-MS method for monitoring the antiepileptic drug lamotrigine in human plasma [27]. The optimum conditions were obtained by varying a big number of BGE, sheath liquid and MS spray chamber parameters. In each case, both the CZE separation, as well as the MS detection sensitivity, were evaluated, and the parameter that provided a reasonable compromise between resolution and detection sensitivity was chosen as the optimum. The developed method was then applied to assay blank samples spiked with lamotrigine in order to set up the calibration curve and estimate the limit of detection (LOD). Both linearity of calibration curve and LOD (0.05 μg/mL) were good, and the optimum method was applied to 14 human plasma samples collected from a lamotrigine-treated subject over a period of 96 h after oral administration of 50 mg lamotrigine.
In a 2011 study, Elhamili et al. analyzed the anticancer drug Imatinib by use of CE coupled to ESI time-of-flight MS in human plasma [29]. The CE separation and ESI parameters were initially investigated and optimized in regard to peak efficiency, peak intensity and electrospray stability. The LOD and limit of quantitation (LOQ) were evaluated by injections of standard solutions of the drug compound, and they were determined to 5 and 20 ng/mL, respectively. In addition, the extraction recovery of Imatinib from human plasma using a common liquid-liquid extraction (LLE) method and a new strong cation exchange (SCX) solid-phase extraction (SPE) column was investigated and compared. The highest extraction recoveries were obtained by using the latter method. The SCX-SPE extraction followed by CE-ESI-TOF-MS analysis in patient plasma samples demonstrated good repeatability, linearity and sensitivity for possible therapeutic monitoring of Imatinib level. The authors, in this manuscript, also conclude that this method could be applied for the analysis, quantification, and clinical assessment of other drug compounds and their metabolites.
3.1. Method development
The performance and usefulness of CE-MS is also demonstrated here by providing a more in-depth analysis of a research work that was performed in a blood sample obtained from a patient with Alzheimer´s Disease (AD) [24]. In this study, a CZE-ESI-MS method was developed for the analysis of the acetylcholinesterase inhibitor rivastigmine, using neostigmine bromide as an internal standard, which is highly recommended in order to avoid problems that are related to sample injection [31]. Rivastigmine is a pseudo-irreversible carbamate inhibitor of acetylcholinesterase, and it is clinically used for the symptomatic treatment of mild to moderate AD [32].
In a previous paper, MEKC coupled to a diode-array detector was used for the simultaneous separation of nine acetylcholinesterase inhibitors, including rivastigmine [33]. This method was validated and successfully applied to a real blood sample that was obtained from a patient who was not under any of this medication. The sample was spiked with rivastigmine in order to establish the ability of the method to separate the drug from other components that might exist in the blood sample. In this study, the blood sample was not directly injected into the capillary, because some components that exist in the sample can be absorbed to the capillary wall and deteriorate the performance of the column [34]. The blood sample was therefore diluted ten folds with the BGE [12.5 mM Na2HPO4 / 12.5 mM Na2B4O7 / 20 mM SDS (pH 10)], and it was then spiked with 25 μg/mL of rivastigmine. However, due to the low sensitivity obtained by CE with on-column UV detection, the identification of rivastigmine in biological fluids using CE remained a challenge. In order for the technique to be used for the quantitation of an acetylcholinesterase inhibitor in body fluids, the sensitivity, and consequently the LOD had to be improved. The increased interest in exploring CE-MS and its potential to serve as an alternative method allowed further investigation for the determination of rivastigmine and related drugs in complex biological matrices.
When the CZE-UV method was compared with the CZE-MS, the first demonstrated a shorter analysis time of approximately 2 min due to the shorter effective length, while the S/N for the peak of rivastigmine at the SIM mode was estimated to be eight times bigger than with UV detection. This, in turn, indicated the high specificity and selectivity of the ESI-MS detector [24]. In the CZE-ESI-MS study, several electrophoretic and ESI-MS parameters were also examined, which were classified in three categories: the BGE parameters, such as the concentration, the pH and the use of organic modifier, sheath liquid parameters, such as the composition, the methanol (MeOH) content and the flow rate, and finally some spray chamber parameters, such as the temperature and the flow rate of the drying gas and the nebulizer gas pressure. The effect of each parameter on the S/N, and consequently the LOD, was examined and the optimum one was chosen for further optimization.
In the case of BGE parameters, it was observed that ammonium acetate provided the most reproducible migration times, a concentration of 40 mM ammonium acetate resulted in the highest S/N, while a higher concentration decreased the ratio, probably due to the Joule heating effect that increases the level of noise (Figures 3a & 4a). When the pH was examined, it was concluded that at pH 9, where rivastigmine starts to have a negative charge (pKa=8.6), both the analysis time and resolution increased, and a higher S/N was obtained (Figures 3b & 4b).
Figure 3.
Effect of (a) ionic strength and (b) pH of the BGE on the separation of rivastigmine (2) and I.S (1). Conditions: BGE: ammonium acetate, sheath liquid 1 % acetic acid in water:MeOH (50:50 v/v) at a flow rate of 10 μL/min, analyte and I.S. concentrations 0.3 mg/mL. Drying gas flow rate 6 L/min and temperature 200 ºC, nebulizer gas pressure 20 psi [24].
Figure 4.
Effect of (a) ionic strength of the BGE and (b) pH of the BGE upon S/N ratio. Conditions: BGE: ammonium acetate, sheath liquid 1 % acetic acid in water:MeOH (50:50 v/v) at a flow rate of 10 μL/min, analyte and I.S. concentrations 0.3 mg/mL. Drying gas flow rate 6 L/min and temperature 200 ºC, nebulizer gas pressure 20 psi [24].
As far as the sheath liquid parameters are concerned, it was observed that its composition and its flow rate affected the ESI-MS sensitivity significantly. This was not a surprising observation since the sheath liquid plays an important role in the CE-MS system. The sheath liquid is used as the make-up liquid that can solve the flow-rate incompatibility problems between CE and MS [35]. These problems are encountered because the flow rate through the CE column is very low (nL/min), and it cannot support a stable electrospray, whose flow rate is typically a few μL/min. In addition, the sheath liquid is used for establishing an electrical connection at the cathode end of the CE capillary, and it provides the suitable solvent conditions for the electrospray, which does not depend on the CE BGE [36].
When different sheath liquids were evaluated, the one that was able to support the formation of positively charged ions, and consequently provide the highest S/N, was acetic acid (1%) (Figure 5a). The influence of methanol as an organic modifier in the sheath liquid was also examined, because the use of such solvents allows an easier protonation of the analytes, which results in a higher signal [28]. By varying the percentage of methanol, it was concluded that 50% was the optimum since the noise level was the lowest (Figure 5b). Finally, the flow rate of the sheath liquid was set at 10 μL/min (Figure 5c). Other values were either too low to establish an electric contact that is required to achieve separation, or they affected the spray stability negatively, which, in turn, lead to higher noise levels.
Figure 5.
Effect of (a) sheath liquid composition, (b) sheath liquid organic modifier and (c) sheath liquid flow rate upon S/N ratio. Conditions: BGE: ammonium acetate 40 mM, at pH 9.0; analyte and I.S. concentrations 0.3 mg/mL. Drying gas flow rate 6 L/min and temperature 200 ºC, nebulizer gas pressure 20 psi [24].
The spray chamber parameters, which are the last parameters examined in this study, have an important effect on the response of the MS system. One of these parameters involves the drying gas, which is used for accelerating the buffer desolvation, increasing the MS sensitivity, and eliminating any undesirable ions from entering into the MS system. It was observed that the drying gas flow rate has an effect on the stability of the electrospray, and consequently, the levels of the noise. The flow rate was set at 6 L/min, because at this flow rate an increased number of ions come closer to the liquid-gas interface, and this increases the desolvation velocity [37] (Figure 6a). In addition, other flow rates that were examined in this study either caused an unstable electrospray or lowered the S/N. The drying gas temperature was varied from 150 °C to 350 °C, and the highest S/N was obtained at 200 °C, which was considered as the optimum (Figure 6b). The nebulizer gas pressure was the last parameter examined in this category, and based on the stability of the electrospray and the S/N, 20 psi was selected as the optimum. At 20 psi, the electrospray is more efficient, probably due to an improved ion evaporation process because smaller initial droplets are obtained with higher nebulizer gas pressure (Figure 6c).
Figure 6.
Effect of (a) drying gas flow rate, (b) drying gas temperature and (c) nebulizer gas pressure upon S/N ratio. Conditions: BGE: ammonium acetate 40 mM at pH 9.0, sheath liquid 1 % acetic acid in water:MeOH (50:50 v/v) at a flow rate of 10 μL/min, analyte and I.S. concentrations 0.3 mg/mL [24].
3.2. Method validation
All the parameters mentioned above are the common parameters that need to be examined in a method development process that involves a CE-MS system. These parameters affect the analysis time, resolution, response of the analyte under study, noise level, and sensitivity of the system. All these are important if the developed method is expected to be applied to biological samples for the detection and the quantification of drug and other compounds.
When the optimum conditions for the analysis of rivastigmine were determined, the method was validated in terms of linearity, precision, stability, recovery, LOD and LOQ. Two calibration curves were constructed, in human plasma and in standard solutions, and linearity was good in both cases. The precision, which was evaluated based on migration times and peak areas, was excellent, and particularly in the case where the peak area of the internal standard was also taken into consideration. The LOD and the LOQ were determined based on the standard deviation of the peak area and the slope of the calibration curve. The LOD and the LOQ were calculated as 3 and 10 times the above correlation, respectively. In the plasma sample, the LOD and the LOQ were found to be 2.8 ng/mL and 8.4 ng/mL, respectively, while in standard solutions they were 1.6 ng/mL and 5.0 ng/mL, respectively. These values are considered satisfactory for the accurate and precise quantification of rivastigmine in AD patients treated with the particular drug compound, and this is based on clinical studies that were performed in such patients [38,39].
3.3. Application
Biological matrices are among the most difficult samples to analyze because of the big number of components they contain that they may be adsorbed onto the capillary wall or interfere in the detection and/or separation process. Therefore, before plasma analysis, it is important and necessary to perform a sample preparation procedure. In addition to this, the concentration of most of the analytes in biological samples is low; so, a preconcentration step before the detection and quantitation is required. In many cases, different sample pre-treatment methods are used and compared in order to determine the most effective one, in regard to analyte recovery, difficulty, time and reproducibility. In this study, one LLE and two different SPE procedures were examined. In the case of SPE, two different SPE cartridges were used, a C18 cartridge and an Oasis HLB cartridge. LLE proved to be inefficient for rivastigmine assay, and it was time consuming because the extraction step was followed by additional steps that involved evaporation and reconstitution of the residue in an organic solvent. When the two SPE methods were compared, the C18-SPE cartridge proved to be the optimum, because the S/N was three times higher (S/N=154) than when Oasis HLB cartridge was used (S/N=52), and it provided better recoveries.
The optimum CZE-ESI-MS parameters and the optimum sample preparation procedure were finally applied for the determination of rivastigmine in a plasma sample obtained from an AD patient following rivastigmine patch administration (dose of 9.5 mg/mL rivastigmine/24-h). Figure 7 demonstrates the SIM electropherograms of C18-SPE extract of plasma sample collected 2.0 hours post-application, at m/z 223 and 251, for I.S. and rivastigmine, respectively. The mean (± S.D.) plasma concentration obtained for rivastigmine was 14.6 (± 1.7) ng/mL.
Figure 7.
Electropherograms of C18-SPE extracts of plasma from an AD patient following rivastigmine patch administration in a dose of 9.5 mg/mL / 24-h in the SIM-mode at (a) m/z 223 (I.S.) and (b) m/z 251 (rivastigmine). Conditions: BGE: 40 mM ammonium acetate at pH 9, sheath liquid 1 % acetic acid in water:MeOH (50:50 v/v) at a flow rate of 10 μL/min, analyte and I.S. concentrations 0.3 mg/mL. Drying gas flow rate 6 L/min and temperature 200 ºC, nebulizer gas pressure 20 psi [24].
Based on the studies mentioned above, the CZE-ESI-MS method proved to be a promising technique in drug and pharmaceutical analysis. The development of such a method has several advantages over HPLC-MS and GC-MS. The most important ones are the reduction of the reagents cost, the low injection volume requirements, and the avoidance of disposing large volumes of organic waste. In particular, when the study described here is compared to previous studies, where HPLC-MS and GC-MS were used for the analysis of rivastigmine, the required injection volume of plasma for a single analysis is reduced from microliters [40-43] to nanoliters.
4. Determination of enantiomers in pharmaceutical samples
In the last three decades, there has been a growing interest in the separation, detection and quantification of enantiomers in pharmaceutical, clinical, environmental and food analysis. It has been known that usually only one enantiomer is active while the other may be less active, inactive or has adverse effects. Among the separation techniques, HPLC [44-48] GC [44,45,49] and CE [50-55] are most often applied in chiral analysis. Temperature and derivatization are major problems encountered in GC, and poor separation efficiency is observed in HPLC. CE has proven to be a powerful separation technique in the area of chiral analysis, since it has the major advantage of low consumption of samples and solvents.
The most common modes of chiral CE are electrokinetic chromatography (EKC) in the presence of a chiral selector, MEKC, capillary electrochromatography (CEC), where the chiral selector can be either used as a coating (OT-CEC), a packing (P-CEC) or a monolithic material (M-CEC) in the capillary, and others [55-63]. The prerequisite for separation of enantiomers in CE, as in every chromatographic system, is the formation of either stable diastereoisomers by the use of a chiral derivatization agent or reversible diastereoisomeric complexes with the addition of a chiral substance, (chiral selector). In the first case, the two enantiomers are separated based on their different physicochemical properties, while in the second case, they are separated based on their different mobilities. In general, the “three point rule,” illustrated by Easson and Stedman [64], describes the interactions that are necessary for chiral discrimination. A minimum of three simultaneous interactions have to occur between the chiral selector and one of the enantiomers so that chiral separation is achieved. The other enantiomer, due to spatial restrictions, should have at least two types of interactions, which can be hydrophobic interactions between the hydrophobic core of the polymer and the analyte, electrostatic interactions between the polar head group of the polymer and the analyte, dipole-dipole forces, such as hydrogen bonding between the polar group of the chiral selector and the analyte, and secondary interactions, such as - interactions, ion-dipole bonds, and Van der Waals forces. This difference in the number and type of interactions between the enantiomers and the chiral selector generates a mobility difference between the enantiomer-chiral selector complexes, which is necessary for the achievement of a chiral separation.
A big number of chiral selectors have been widely used, over the years, in CE for improved chiral separations of various classes of analytes. These chiral selectors include cyclodextrins, polymeric surfactants, cyclofructans, macrocyclic antibiotics, crown ethers, and others. Cyclodextrins are molecules with large ring-like structures composed of α-(1,4)-linked D-(+)-glucopyranose units. Native cyclodextrins are cyclic oligosaccharides consisting of six (α-CD), seven (β-CD) and eight (γ-CD) glucopyranose units. The chiral recognition ability of cyclodextrins can be improved by their derivatization with different functional groups, such as methyl-, sulfate-, acetyl- and prolyl-, and with the modification of the hydroxyl groups, which are present on the rim of the CD. The mechanism of enantiomeric discrimination is the inclusion of the hydrophobic group of the analyte into the cavity and interactions of the hydroxyl groups of the C2 and C3 at the upper rim of the CD, such as hydrogen bonds and dipole-dipole interactions.
Navarro et al. [65] developed a CZE method for the analysis of lansoprazole enantiomers in three different pharmaceutical preparations (Davur, Alter and Cinfa). β-CD was used as a chiral selector and sodium sulphite was used as an additive. Recoveries of 91-102% of the label content were obtained, and this demonstrated the potential of the method for the routine quality control of lansoprazole enantiomers in pharmaceutical formulations.
Chai et al. [66] used the chiral selector hydroxypropyl-γ-cyclodextrin in order to separate the antifungal drug iodiconazole and the structurally related triadimenol analogues. This chiral selector provided the best results in regard to resolution due to its large cavity and the hydrogen bonding between the analytes and the cyclodextrin. The mechanism for the chiral discrimination of hydroxypropyl cyclodextrins possibly involves the development of secondary interactions between the chiral analyte and the hydroxypropyl groups on the cyclodextrin rim after the inclusion of the analyte into the cavity. The degree of substitution and the type of the hydroxyalkyl group on the cyclodextrin rim, which influences the depth of the cavity, can therefore change the enantiorecognition ability of the cyclodextrin [67,68].
4.1. Method development and validation
The use of CE, and particularly MEKC, in chiral analysis is demonstrated further here by providing a more in-depth analysis of a research work that was performed in a pharmaceutical formulation that contained one of the enantiomers of Huperzine A [55]. Huperzine A is considered to be a potent, highly specific and reversible inhibitor of acetylcholinesterase with high efficiency and low toxicity. The mechanism of complexation of Huperzine A with acetylcholinesterase is similar to that of other pharmaceutical drugs that are used for the treatment of AD [69]. The (-)-enantiomer of Huperzine A is three times more biologically active than the synthetically racemic mixture, and only this form behaves as a potential acetylcholinesterase inhibitor. Therefore, the development of an analytical method for the enantiomeric separation of the synthetic Huperzine A is of greatest importance.
It is important here to mention that the type of the chiral selector used in this study was the polymeric surfactant. The use of polymeric surfactants in both chiral and achiral CE has attracted considerable attention. In 1994, Wang and Warner [70] were the first to report the use of a polymeric surfactant added to the BGE in MEKC. Polymeric surfactants offer several distinct advantages over conventional micelles [63,71-73]. Firstly, polymerization of the surfactant eliminates the dynamic equilibrium due to the formation of covalent bonds between the surfactant aggregates. This, in turn, enhances stability and improves resolution. Secondly, polymeric surfactants can be used at low concentrations because they do not depend on the CMC. This usually provides higher efficiencies and rapid analysis. They have, over the years, been extensively used in a BGE [74-80], in a polyelectrolyte multilayer coating [63,74,81-83], and in a CE-MS system [84-86].
In this study, the optimal conditions, in regard to resolution, efficiency and analysis time, were initially established by varying different electrophoretic parameters. The BGE type, concentration and pH are usually the first parameters to be examined in a method development procedure. Sodium acetate at acidic and neutral pHs, where the analyte exhibits cationic behavior, was chosen as the optimum. BGEs with basic pHs did not exhibit any enantiomeric discrimination, and the analysis time was very long. The optimum pH was 5.0 because it provided slightly better peak shapes, and the optimum concentration was 50 mM because it provided higher resolution (Figure 8). The very low peak efficiency, which needs to be improved, is clearly illustrated in this figure.
Figure 8.
Effect of BGE concentration on the separation of the enantiomers of Huperzine A: (A) 20 mM, (B) 35 mM and (C) 50 mM. Separation conditions: BGE: sodium acetate (pH 5.0), 0.075% (w/v) poly-LL-SULV; pressure injection, 30 mbar for 3 s; applied voltage, 20 kV; temperature, 25 °C; fused-silica capillary, 64 cm (55.5 cm effective length) x 50 μm i.d.; detection, 230 nm [55].
As far as the chiral selector is concerned, different polymeric surfactants were examined, such as poly(sodium N-undecanoyl-L-leucinate) (poly-L-SUL), poly(sodium N-undecanoyl-LL-leucyl-leucinate) (poly-LL-SULL), poly(sodium N-undecanoyl-LL-leucyl-valinate) (poly-LL-SULV), poly(sodium N-undecanoyl-L-valinate) (poly-L-SUV), poly(sodium N-undecanoyl-L-valyl-glycinate) (poly-L-SUVG), poly(sodium N-undecanoyl-LL-alanyl-valinate) (poly-LL-SUAV), poly(sodium N-undecanoyl-LL-leucyl-alanate) (poly-LL-SULA), and poly(sodium N-undecanoyl-LL-valyl-valinate) (poly-LL-SUVV). The polymeric surfacant poly-LL-SULV, which has shown the best chiral discrimination ability for a number of pharmaceutical compounds [80], was the first to be examined in different concentrations. The concentration of 0.075% w/v was chosen as the optimum, based on analysis time, efficiency and resolution. This concentration though did not provide baseline resolution.
Another parameter examined in order to improve peak efficiency and resolution was the addition of modifiers. None of the organic solvents at different concentrations were able to improve the separation. An alternative to this was the addition of a salt, such as D- and L-alanine tert-butyl ester hydrochloride (D- and L-AlaC4Cl). poly-LL-SULV became insoluble when the salt was added into the BGE. Therefore, the other polymeric surfactants mentioned above were examined at different concentrations. In each case, D- and L-AlaC4Cl were used individually as additives, the electropherograms were obtained, and resolution and efficiency were estimated. Based on this, the combination of poly-LL-SUAV at a concentration of 0.20% (w/v) with L-AlaC4Cl provided the best results.
However, the use of L-AlaC4Cl did not provide satisfactory reproducibility of the migration time and efficiency. This is probably due to the hydrolysis of the salt in an aqueous BGE solution. An alternative involved the use of tert-butanol, one of the hydrolysis products, at different concentrations. Figure 9 clearly demonstrates the improved peak efficiency, in comparison with Figure 8. Each electropherogram was obtained at a different concentration of tert-butanol. A concentration of 10% (v/v) was the optimum, because it provided the highest resolution (1.45) and the highest peak efficiency (Figure 10).
The validation of the method demonstrated good linearities and very low relative standard deviation values, indicating excellent run-to-run and day-to-day reproducibilities. In addition, the LOD and LOQ were determined to be 4.17 μg/mL and 13.92 μg/mL, respectively.
4.2. Application
As previously shown, after method development and validation, the optimum separation conditions are applied to a real sample. In this case, the optimum parameters were applied to a pharmaceutical formulation in order to detect and quantitate the acetylcholinesterase inhibitor (-)-Huperzine A. The extraction procedure followed for extracting Huperzine A from the pharmaceutical formulation proved to be effective because the enantiomer determined in the sample was in a relatively good agreement with the amount that was stated on the bottle. Therefore, the developed MEKC-UV method is able to control the purity of (-)-Huperzine A in pharmaceutical formulations.
Figure 9.
Effect of the concentration of tert-butanol on the separation of the enantiomers of Huperzine A: (A) 5%, (B) 7.5%, (C) 10% and (D) 12% (v/v). Separation conditions: BGE: 50 mM sodium acetate (pH 5.0), 0.2% (w/v) poly-LL-SUAV; pressure injection, 30 mbar for 3 s; applied voltage, 20 kV; temperature, 25 °C; fused-silica capillary, 64 cm (55.5 cm effective length) x 50 μm i.d.; detection, 230 nm [55].
Figure 10.
Effect of the concentration of tert-butanol on the efficiency. Separation conditions: Same as Fig. 4. BGE: 50 mM sodium acetate (pH 5.0), 0.2% (w/v) poly-LL-SUAV; pressure injection, 30 mbar for 3 s; applied voltage, 20 kV; temperature, 25 °C; fused-silica capillary, 64 cm (55.5 cm effective length) x 50 μm i.d.; detection, 230 nm [55].
5. Concluding remarks
Analysis of chiral and achiral analytes in natural, pharmaceutical and biological samples can be extremely difficult. Co-migration may occur, which can cause problems in detection, and the electropherograms obtained can be very complex. In addition, the analytes of interest are usually present in the matrices at very low concentrations. Therefore, all the analytical steps, including method development, detection and sample preparation, which is an essential stage in any analysis process, have to be optimized in order to obtain the desirable sensitivity, resolution, robustness and analysis time.
Among the separation techniques that have so far been used for pharmaceutical, clinical and food analysis, CE has been established as a powerful analytical tool, which has rapidly been developed and matured since its introduction. CE and its related techniques offer a number of advantages, including low consumption of sample and solvents, high separation efficiency, rapid method development, fast migration times, versatility, and simple instrumentation. Another important aspect involves its ability to separate small and large molecules, charged and neutral species, inorganic and organic molecules, synthetic and natural compounds, along with proteins and peptides.
The coupling of CE to MS provides nowadays a promising alternative to UV detection. The combination of high sensitivity, high selectivity, and high specificity provided by MS with high resolution, and high efficiency provided by CE makes it an attractive technique in different fields, such as clinical, forensic, pharmaceutical, and others. However, chiral analysis by use of CE-MS still needs some improvement, in regard to resolution and peak capacity. In addition, contamination of the ionization source induced by the chiral selector added in the BGE is still considered a main problem, even though different procedures have, in recent years, been developed in order to overcome this limitation [87].
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Kapnissi-Christodoulou",authors:[{id:"146302",title:"Dr.",name:"Constantina",middleName:null,surname:"Kapnissi-Christodoulou",fullName:"Constantina Kapnissi-Christodoulou",slug:"constantina-kapnissi-christodoulou",email:"ckapni1@ucy.ac.cy",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Cyprus",institutionURL:null,country:{name:"Cyprus"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Determination of polyphenolic compounds in natural samples",level:"1"},{id:"sec_2_2",title:"2.1. Method development and validation",level:"2"},{id:"sec_3_2",title:"2.2. Application",level:"2"},{id:"sec_5",title:"3. Determination of pharmaceutical compounds in biological samples",level:"1"},{id:"sec_5_2",title:"3.1. Method development",level:"2"},{id:"sec_6_2",title:"3.2. Method validation",level:"2"},{id:"sec_7_2",title:"3.3. Application",level:"2"},{id:"sec_9",title:"4. Determination of enantiomers in pharmaceutical samples",level:"1"},{id:"sec_9_2",title:"4.1. Method development and validation",level:"2"},{id:"sec_10_2",title:"4.2. Application",level:"2"},{id:"sec_12",title:"5. Concluding remarks",level:"1"}],chapterReferences:[{id:"B1",body:'TerabeS.OtsukaK.NishiH.1994Separation of Enantiomers by Capillary Electrophoretic Techniques. J. Chromatogr. A 666295319'},{id:"B2",body:'ChiariM.NesiM.RighettiP. G.1996Capillary Electrophoresis in Analytical Biotechnology. Righetti, PG, Ed.; CRC Press, Inc.: Boca Raton, FL.'},{id:"B3",body:'TerabeS.OtsukaK.IchikawaK.TsuchiyaA.AndoT.1984Electrokinetic Separations with Micellar Solutions and Open-Tubular Capillaries. Anal. Chem. 56111113'},{id:"B4",body:'TerabeS.OtsukaK.AndoT.1985Electrokinetic Chromatography with Micellar Solution and Open-Tubular Capillary. Anal. 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1. Incidence and etiology of plantar fasciitis
About 7% of the population >65 years suffer from a painful heel, even though younger people are often affected, too [1]. The most common cause of this symptom is the so‐called “plantar fasciitis” [2]. This term is widely used, although “plantar fasciopathy” or “plantar fasciosis” would be a better description to point out the degenerative nature of the disease. However, as more than 1100 citations in Pubmed quote “plantar fasciitis” (in comparison with only 50), we will use the traditional term in the following.
Plantar fasciitis has been associated with obesity, with acute or chronic work overload, or with work on hard surfaces [2, 3]. It seems that physiological degeneration of the fascia at the calcaneal insertion exacerbates due to repetitive microtraumas caused by vertical compression [4]. This causes inflammatory tissue reactions. As a result, the fascia is thickened with an associated fluid collection to 4.0 mm and more in ultrasonography [5]. Furthermore, this inflammation may trigger bone formation, the so‐called “plantar heel spur.” This process has been studied intensively by Kumai and Benjamin [6]. They proposed three stages of spur growth: “(a) an initial formation of cartilage cell clusters and fissures at the plantar fascia enthesis; (b) thickening of the subchondral bone plate at the enthesis as small spurs form; and (c) development of vertically oriented trabeculae buttressing the proximal end of larger spurs” [6]. The first description of this spur formation and correlation with the clinical symptoms was carried out by Plettner in 1900 [7]. However, not every heel spur is associated with heel pain, as these spurs are found in 11–16% of the normal asymptomatic population [4]. On the other hand, some patients with painful plantar fasciitis do not have a radiographic confirmation of a spur formation.
A similar mechanism (although caused by longitudinal traction and not by vertical compression) of bone formation has been described at the insertion of the Achilles tendon [8].
According to the American clinical practice guidelines from 2010, diagnosis is established by the typical anamnesis and the characteristic localizations of tenderness. Still, weight‐bearing radiographs are also recommended [9].
2. Treatment with LD‐EBRT
2.1. Biological effects of LD‐EBRT on lymphocytes and inflammatory processes
Single doses of external beam radiotherapy (EBRT) in the range of 0.3–1 Gy are called “low dose EBRT” (LD‐EBRT). These single fractions are applied two or three times a week until a total dose of about 3–6 Gy is reached. Such radiotherapeutic concepts are used for diverse nonmalignant conditions, e.g., osteoarthrosis, tendinopathy, epicondylitis, or bursitis. A comprehensive review of the historical developments in LD‐EBRT for benign diseases is given by Trott [10].
In contrast, EBRT in oncology is characterized by much higher single and total doses. “Normofractionation” describes single doses of 1.8–2 Gy, applied about five times a week. To treat breast cancer, the total doses of about 62 Gy are necessary, in prostate cancer even more than 72 Gy. From a radiobiological point of view, these high cumulative doses are used to induce DNA double strand breaks. Due to errors in a repair mechanism (nonhomologous end joining), dicentric chromosomes can occur. These can result in unfinished mitoses, the so‐called “mitotic catastrophe,” the main mechanism to reduce clonogenic survival in tumor cells [11]. High doses of EBRT induce local inflammation and tissue reactions.
The much lower doses of LD‐EBRT act via different mechanisms. In the last two decades, several anti‐inflammatory effects have been discovered, contrary to the effects of the above‐mentioned high EBRT doses.
In vitro LD‐EBRT has been shown to induce apoptosis in peripheral blood mononuclear cells (PBMC) [12]. Interestingly, there was not a linear correlation between dose and the amount of apoptotic cells. Instead, the maximal induction of apoptosis was observed after a single dose between 0.3 and 0.7 Gy, higher doses (up to 3 Gy) not being more effective [12].
Furthermore, doses between 0.1 and 0.5 Gy reduced the adhesion of PBMC significantly to endothelial cells (ECs) in vitro, probably by suppressing the expression of L‐selectin on the surface of PBMC [13]. This is a very important finding, as the adhesion of leukocytes to the cells of the vessel wall is the first event of tissue invasion in inflammatory processes [13]. An-other reason for the reduced adhesion between PBMC and EC was identified by Rödel et al. [14]: In irradiated EC mRNA expression and protein secretion of transforming growth factor β1 (TGF‐β1) were highest after 0.5 Gy, higher doses resulted in a decline to basal levels [14]. Neutralization TGF‐β1 with specific antibodies restored the adhesion between PBMC and EC. These in vitro results were confirmed in vivo in a mouse model for 0.3 Gy [15]. TGF‐β expression is dependent on activation of the nuclear factor‐kappa B (NF‐κB) [16]. Also, NF‐kB DNA‐binding activity showed a biphasic response to LD‐EBRT with a first maximum at 0.5 Gy, a relative minimum between 0.6 and 0.8 Gy, and a second increase at 1 and 3 Gy [16]. The above‐mentioned findings show a biphasic time course with reduced adhesion of PBMC 4 and 24 h after LD‐EBRT, with a relative maximum of adhesion after 12h [17].
A third mechanism was the suppression of nitric oxide (NO) production in activated macrophages by LD‐EBRT between 0.3 and 1.25 Gy [18]. As the expression of inducible nitric oxide synthases (iNOS) proteins was not altered, the LD‐EBRT seemed to act at the translational or posttranslational level. Furthermore, a dose of 0.5 Gy significantly reduced oxidative burst and superoxide production of stimulated macrophages [19]. A diminished release of reactive oxygen species (ROS) can also contribute to the anti‐inflammatory effects of LD‐EBRT.
Taken together, all of these pathways and mechanisms showed a similar dose dependence with a maximum effect between 0.3 and 0.7 Gy regarding a discontinuous dose‐effect relation [20].
There are several in vivo studies in different animal models about the effects of LD‐EBRT, especially on osteoarthritis. A comprehensive overview is given in Ref. [20], however, as they are not directly related to calcaneodynia, we will not further comment on them.
2.2. Results of randomized trials on radiotherapy for painful heel spur
Since 1937 [21] for decades, large retrospective studies on the efficacy of LD‐EBRT in calcaneodynia have been published (overview in 22). In 1970, one negative randomized trial was reported and heavily criticized but had not been repeated [23]. Starting in the 1980s, patients were systematically clinically examined and interrogated in a structured manner to try to control for diverse risk factors and to compare the efficacy of different fractionation schemes and total doses [24].
It took until the past decade to perform and report prospectively randomized trials to proof the efficacy of LD‐EBRT and to identify the optimal dose fractionation schedule. In the following, we report the design and the results of these trials. Table 1 gives a short overview of the studied dose concepts and the results. Due to methodological reasons, we will describe the studies not following their publications dates, but according to a systematic order.
2.2.1. Clinical proof of the efficacy of LD-EBRT
Since the publication of the first randomized trial on LD-EBRT in 1970, the efficacy of LD‐EBRT was questioned [23]. Goldie et al. randomized 399 patients, however, only nine patients suffered from calcaneodynia. This is why these results cannot be extrapolated to LD‐EBRT of a painful heel spur. Furthermore, endpoints were not clearly defined, and therapy was started in an acute stage of the disease [25].
The landmark study to prove the efficacy of LD‐EBRT was performed by the German cooperative group on the radiotherapy for benign diseases (GCGBD) under the responsibility of Niewald et al. [26]. A very low dose EBRT (6 × 0.1 Gy applied twice a week up to a total dose of 0.6 Gy) was randomized to a standard dose LD‐EBRT (6 × 1 Gy twice a week up to a total dose of 6 Gy). In the case of an unfavorable response after 3 months, the patient was offered a second treatment series (“reirradiation”) applying a standard dose. The dosage of the experimental arm was chosen to examine if very low doses are effective at all. Second, it acted as a placebo irradiation, as a sham irradiation was regarded unethical. LD‐EBRT was applied using a linear accelerator (4‐ to 6‐MV photons) using lateral parallel opposing fields.
Inclusion criteria were tenderness of the calcaneus with a limitation of the painless walking distance and duration of the symptoms for more than 6 months. Furthermore, a radiological proof of a heel spur was required, and the patients had to be least 40 years of age. Patients with previous traumata to the foot, rheumatic or vascular diseases, lymphatic edema, pregnancy, or breastfeeding were excluded. Concomitant therapy with oral analgesics was not limited. However, local injections with steroids during the study period were not permitted.
Initially, 200 patients were planned [27] to detect a difference of 10% in the quality of life (QOL) sum score (SF‐12) [28] and calcaneodynia sum score (CS) [29] (Table 2) with a power of 80% and an error probability of 5%. Furthermore, the visual analogue scale (VAS) to evaluate pain intensity was used. However, after randomization of 66 patients and interim analysis of 62 patients (4 had to be excluded due to a withdrawal of informed consent or violation of the inclusion criteria), the differences in efficacy between the two treatment arms were so pronounced, that the trial was closed early.
Author
Year
N
Standard arm
Experimental arm
Results
Conclusions
Niewald et al. [26]
2012
66
6 × 1 Gy twice a week
6 × 0.1 Gy
3 months: VAS/CS/SF12 sig. better with standard
1. Dose‐response relationship
1 year: less second treatment series with standard
2. Proof of therapeutic effect of LD‐EBRT
Heyd et al. [30]
2007
130
6 × 1 Gy twice a week
6 × 0.5 Gy
6 months: CS no sig. differences
6 × 0.5 Gy as standard fractionation
Ott et al. [32]
2014
457
6 × 1 Gy twice a week
6 × 0.5 Gy
6 weeks, 2.5 years: VAS/CS no sig. differences
6 × 0.5 Gy as standard confirmed
Niewald et al. [25]
2015
127
6 × 1 Gy twice a week
12 × 0.5 Gy thrice a week
3 months: VAS/CS/SF12 no sig. differences
Efficacy not increased with 12 × 0.5 Gy standard still 6 × 0.5 Gy
Table 1.
Summary of contemporary randomized trials on LD‐EBRT of painful heel spurs: tested schedules, results, and conclusions.
Criteria
Extent of symptoms/alteration
Points
1. Pain symptoms
S = Pain at strain
6 / 4 / 2 / 0
(total: 30%)
N = Pain during night time D = Pain during day time (continuously) R = Pain at rest (following any kind of strain) I = Pain at initiation of movement/morning stiffness none = 6 ; slight = 4 ; moderate = 2 ; severe = 0 points ⇨
None Orthopedic shoe, insoles, heel cushion One cane or crutch Two canes or crutches ⇨
15 10 5 0
3. Professional activities (total: 20%)
No limitation, maximum professional strain possible Slight limitation, normal professional work possible Moderate limitation, reduced professional activity Severe limitation, daily professional work impossible ⇨
20 10 5 0
4. Daily/leisure activities (total: 15%)
No limitation of daily and leisure activities and sports Slightly limitation/reduced leisure activities and sports Moderate limitation/no leisure activities and sports Complete limitation of any daily and leisure activities ⇨
15 10 5 0
5. Gait/limp (total: 20%)
No limp, normal walking is possible without a limitation Slightly altered, limp after walking > 1 km (2 blocks) Moderately altered, limp after walking < 1 km (2 blocks) Severely altered, normal walking is impossible ⇨
20 10 5 0
Total score
Sum of the single scores 1 + 2 + 3 + 4 + 5 ⇨
Table 2.
Calcaneodynia score of the GCG‐BD [29], based on [31].
The mean age of patients was 54 years in the standard dose group and 58 years in the 6 × 0.1 Gy group. Sixty‐one patients had a plantar, one patient a dorsal heel spur. In mean, patients in the standard dose group suffered for 15.3 months before the start of LD‐EBRT, in the 6 × 0.1 Gy group for 18.8 months. Twenty‐one patients had symptoms on both sides. In 28 patients the pain irradiated into the calf, only in 18 patients it was localized to the sole of the foot. Two patients had received surgery for LD‐EBRT.
Three months after therapy VAS values, CS‐ and QOL‐scores were significantly better after the standard dose in comparison with the very low dose treatment arm. The higher pain relief resulted in a better QOL. Twelve months after therapy about 64% of the patients after 6 × 0.1 Gy had to receive a second treatment series due to insufficient treatment results, in comparison with only 17% of the patients in the standard dose treatment group. As the second series was applied with a standard dose (6 × 1 Gy), patients in the 6 × 0.1 Gy group who were reirradiated showed equally favorable results compared with those in the standard‐dose group who did not receive a second course [26]. This is why the second treatment series in this clinical setting acted as a “salvage therapy.” Another interesting finding was that patients with a good response already at 3 months remained stable or even improved at 12 months. Furthermore, this underlines the long‐lasting efficacy of LD‐EBRT.
Acute side effects or long‐term toxicity did not occur.
In conclusion, this randomized trial established a dose‐response‐relationship of the analgesic effect of LD‐EBRT, thus providing a clinical and methodological proof of the efficacy of 6 × 1 Gy LD‐EBRT on the clinical course of painful heel spurs. The early termination of the study was justified due the interim analysis showing significant differences in the clinical outcome between both treatment arms. Still, the trial was not blinded, so both the patients and the staff were aware of the received dose. With modern linear accelerators, a complete blinding of the staff is nearly impossible. The only option would be a shame irradiation with closed collimator jaws, reducing the dose to the unavoidable “leakage” radiation. A much easier and straight forward way was used in the above‐mentioned study by application of a minimal physical dose with 0.1 Gy. Another critical point might be that only half of the patients were examined 12 months after therapy (n = 36). This reduces the reliability of the study results at this time point. However, this does not affect the results concerning treatment efficacy 3 months after LD‐EBRT.
Another potential confounder not only in this study but also in all other published prospective and retrospective case series might be that a lot of the patients had received diverse and other conservative therapies before being referred to LD‐EBRT. An interaction between one of these other treatments and LD‐EBRT cannot be ruled out due to methodological reasons. This reflects clinical reality. Still, an interaction between one of these therapies and LD‐EBRT is rather unlikely and counter‐intuitive, as patients were referred to LD‐EBRT after the clinical failure of all the other conservative treatments.
2.2.2. Looking for the minimum effective dose: optimization of fractionation and total dose of LD-EBRT
2.2.2.1. Single dose 0.5 vs. 1 Gy
Two randomized studies investigated the efficacy of 0.5 Gy single dose in comparison to 1 Gy.
The first trial was conducted by Heyd et al. [30]. They randomized 130 patients between 6 × 0.5 Gy twice weekly (low dose) and 6 × 1 Gy (standard dose). A linear accelerator was used, applying a single field technique.
Inclusion criteria were clinical signs of a painful heel spur, radiological evidence of spur formation, patient age ≥30 years and a relapse after previous conservative treatments, in patients >45 years LD‐EBRT could be used as the primary treatment. Endpoints of the study were changes in the “original” calcaneodynia score [31], that was documented before LD‐EBRT, at the end of the course, and 6 weeks and 6 months afterward.
One hundred and thirty patients were randomized. Mean age was 58.4 years. A 102 patients suffered from a plantar, one patient from a dorsal, and 27 patients from combined spurs. In mean, patients had been suffering from symptoms for 9.8 months. The symptoms had been present in 58 patients for less than 6 months, in 72 patients for a longer time. In 7 heels LD‐EBRT was the first therapeutic approach.
At the end of LD‐EBRT, 66% in the low dose group vs. 59% in the standard dose experienced an improvement in symptoms, 6 weeks later 80 vs. 85%. At this time point, 1.5% in each group reported an increase in symptoms, 19 vs. 14% no change. No statistically significant differences were noted. In case of insufficient treatment results patients were offered a second EBRT series. Thus 26 vs. 37% were treated a second time. Six weeks after that, 71 vs. 79% of these patients reported a further improvement. Six months after LD‐EBRT 88% of the patients in both groups had an amelioration of their symptoms, the remaining patients reported no change. During the EBRT series a slight increase in pain was reported by 26 vs. 29% of the patients. No other acute or late toxicity occurred.
In conclusion, 6 × 0.5 Gy twice weekly was as effective as 6 × 1 Gy.
These results were confirmed by a second randomized trial [32, 33]. Ott et al. randomized 457 patients between 6 × 0.5 Gy (low dose) and 6 × 1 Gy (standard dose). In contrast to the above‐cited “Heyd‐study” [30] an X‐ray unit (orthovoltage) and not linear accelerators was used. Patients received a single field (6 × 8 cm on the plantar calcaneus) with 150 kV, 15 mA, 1 mm Cu‐filter, with source‐to‐skin distance (SSD) of 40 cm. Six weeks after the LD‐EBRT a second series was offered to patients with an insufficient response. The endpoint was pain reduction. CS score and VAS values were measured before and at the end of LD‐EBRT (early response), 6 weeks (delayed), and 2.5 years (long‐term) afterward.
With a median follow‐up of 32 months the mean VAS values before treatment, for early, delayed, and long‐term response for the 0.5 and 1.0 Gy groups were 65.5 ± 22.1 and 64.0 ± 20.5 (p = 0.19), 34.8 ± 24.7 and 39.0 ± 26.3 (p =0.12), 25.1 ± 26.8 and 28.9 ± 26.8 (p =0.16), and 16.3 ± 24.3 and 14.1 ± 19.7 ( p =0.68) [31]. Similar results were obtained for the CS score without any significant differences between both dose groups.
Taken together, the above‐mentioned studies proofed an equivalent clinical efficacy of 6 × 0.5 Gy in comparison to 6 × 1 Gy, thus defining a new clinical treatment standard with six times 0.5 Gy twice weekly as the minimum effective dose.
Before proofing 0.5 Gy as the new standard single dose, another randomized study tried to increase efficacy in reaching the “old” cumulative dose of 6 Gy with a single dose of 0.5 Gy. Niewald et al. randomized between 6 × 1 Gy twice a week (old “standard dose”) and 12 × 0.5 Gy three times a week (“experimental dose”) [25]. The aim was not just to get comparable results, but to further improve the analgesic effects. Linear accelerators (6 MV photons) applying a lateral opposing field technique were used.
Inclusion and exclusion criteria were quite similar to the ones used in the landmark study [26]: Clinical evidence of a painful heel spur, and duration of the symptoms for more than 6 months; radiological proof of a spur formation; age at least 40 years; Karnofsky‐Index at least 70%. Patients with previous radiotherapy or previous trauma to the foot, rheumatic or vascular diseases, lymphatic edema, pregnancy, breastfeeding, or severe psychiatric disorders were excluded. Concomitant therapy with analgesics was allowed. However, patients receiving surgery or shock wave therapy after randomization were excluded.
Endpoints were the SF‐12 sum score, the CS sum score (Table 2), and VAS. Follow‐up was scheduled every 6 weeks for 1 year.
Two‐hundred and forty patients were calculated to detect a difference of 15% in the VAS and CS score, with a power of 80%, and an error probability of 5%. After randomization of 127 patients and an interim analysis of 107 patients, the study was closed early, as the intended increase in analgesic efficacy by the experimental treatment was very unlikely to be achieved.
The mean age of the patients in the standard group was 56.1 Gy in comparison with 58.1 Gy in the experimental group. The mean duration of symptoms before initiation of LD‐EBRT was 17 vs. 16 months. In 98% of the standard group and 93% of the experimental group a plantar spur was treated, in 2 and 7% a combined (plantar and dorsal) spur.
Results after 3 months have been issued so far [25], longer follow‐up has yet to be published. After 3 months, there were no significant differences neither in the VAS (standard 42.3 vs. experimental 44.4) nor the CS sum score (28 vs. 28.4) nor in the QOL (SF‐12) scores. Although longer follow‐up has to be awaited, a further increase in the analgesic effect by applying 12 × 0.5 Gy three times a week is unlikely. This is why this fractionation schedule is currently not recommended, as it does not follow the “as low as reasonable achievable” principle of radiation protection.
2.2.2.2. Single dose 0.3 vs. 1 Gy
Further reduced single doses in LD‐EBRT (with the exception of 0.1 Gy [26]) have never been tested in a prospectively randomized clinical trial. In radiotherapy of degenerative joint disorders, single doses of about 0.3–0.4 Gy were established by von Pannewitz in the late 1920s and published in 1933 and 1970 [34, 35]. However, two studies on calcaneodynia have raised serious concerns on single doses as low as 0.3 Gy.
Seegenschmiedt et al. analyzed treatment efficacy in 141 patients (170 irradiated heels), who were treated from 1984–1994 with X‐ray units (250 kV/200 kV, 20 mA, 40 cm SSD), applying a single field of 6 × 8 cm [24]. Seventy‐two heels received 12 Gy with 6 × 1 Gy (three times a week) –6 weeks break – 6 × 1 Gy (group A), 50 heels were treated with 10 × 0.3 Gy every day (group B1), and 38 heels 10 × 0.5 Gy every day (group B2). The endpoint was the value of a semiquantitative pain score 3 months and in mean 4 years after LD‐EBRT.
The median age of patients was 55 years in group A and 59 years in group B1/B2. The mean duration of symptoms before LD‐EBRT was 8 months, in one‐third, the symptoms persisted for more than 6 months.
Complete pain remission was achieved in 68–71% of the patients without significant differences between the treatment groups. However, there were differences in the clinical course of patients with partial remission of the symptoms: The best results in these patients were achieved during longer follow‐up in group B1 (10 × 0.5 Gy), followed by group A (6 × 1–6 × 1 Gy), followed by group B2 (10 × 0.3 Gy). The latter group showed a significantly worse amelioration of symptoms than the other groups.
A reduced efficacy was also reported in another retrospective case series, comprising 673 heels treated with a single dose of 0.3 Gy three times weekly up to 1.5 Gy (X‐ray) [36]. In case of insufficient treatment results the patients were offered a second course. After the first treatment, only 13% reported CR, nearly all patients had undergone a second LD‐EBRT.
Taken together, to the best of our current knowledge a single dose of 0.5 Gy is standard of care and should only be modified in controlled clinical trials.
2.3. Risk factors potentially associated with treatment failure
In Table 3 selected contemporary randomized trials and patient series are shown broken down into several factors that might be correlated with treatment efficacy. For a better overview, we did not differentiate between univariate and multivariate analyses. We did not try to collect all ever published data.
2.3.1. History of symptoms
Duration of symptoms before start of LD‐EBRT has been shown to be correlated with treatment efficacy in numerous studies.
Muecke et al. analyzed in a retrospective multicenter study 502 patients [22]. Duration of symptoms ≤6 months was associated with 76% treatment success vs. 44% after a history >6 months. Also Seegenschmiedt et al. found in their large collectives a correlation between the duration of heel pain and treatment outcome [24]. A significant influence of duration of symptoms before LD‐EBRT was also reported in 73 heels by Schneider et al. [37]. With a history of 3–6 months, the VAS value was reduced by 85%, 28 months after LD‐EBRT in comparison with a reduction of 58% with a history > 6 months. Similar results were obtained by Hermann et al. in 285 heels comparing <12 month history of pain vs. >12 months [38].
In contrary, another study could not confirm these results [30].
2.3.2. Gender
To the best of our knowledge, in no study, an influence of gender on treatment outcome has been confirmed [22, 24, 30, 38, 39]. In contrast to radiotherapy for oncological indications with high doses, efficacy and tolerability of LD‐EBRT seems to be the same concerning gender.
2.3.3. Patients’ age
Several studies described a correlation between older age and better treatment results, at least 6 weeks after LD‐EBRT [37]. Age somewhat over 50 years seems to be important: >50 years [40], > 53 [38], or > 58 [22]. For a possible explanation see Section 2.3.7.
However, other studies found no influence of this patient characteristic on treatment outcome [24, 30, 39].
2.3.4. Initial increase in pain during LD-EBRT
A very precise registration of changes in pain intensity (VAS) was done by Schneider at al. [37]. Sixty‐two patients (73 treated heels) were prospectively scored every week during LD‐EBRT, at the end of therapy, 6 weeks, 28 months, and 40 months later. Additionally, subjective mechanical heel stress during LD‐EBRT was estimated. A linear accelerator (10 MV) was used, applying one single field with a size of 12 × 17 cm. Patients were treated twice a week to a total dose of 5 Gy, with increasing single fraction doses (0.25 – 0.25 – 0.5 – 1 – 1 – 1 – 1 Gy). Mean patient age was 54 years, and all had a radiologically proven plantar spurn, mean symptom duration before LD‐EBRT was 6.5 months. Nearly all patients had received other conservative therapies before LD‐EBRT with insufficient results.
Interestingly, VAS scores decreased continuously during LD‐EBRT: before treatment the mean value was 6.3 ± 1.5, after the first week of LD‐EBRT 6.2 ± 1.8, after the second week 5.5 ± 2 (p < 0.05), after the third 4.7 ± 2.4, and 3.8 ± 2.1 at the end of therapy (p < 0.001). Six weeks later the value further decreased to 3 ± 2.5 (p < 0.004), 28 months after LD‐EBRT to 1.6 ± 2.2 (p < 0.01). One year later no further decrease was noticed (1.8 ± 2.3). Only two patients reported intensification of pain during the LD‐EBRT series. However, these data are not to be extrapolated, as increasing single doses (see above) were used to avoid this phenomenon.
In standard schedules with fixed single doses a slight increase in pain during the treatment series was reported by 26% (during 6 × 0.5 Gy) vs. 29% (6 × 1 Gy) of the patients [30]. Unfortunately, a possible correlation of this phenomenon with definite treatment results was not investigated.
Without further quantification, another study (6 × 1 vs. 6 × 0.1 Gy) stated, that this initial increase in symptoms “had no influence on the final pain relief 3 and 12 months after treatment” [26]. Older studies postulated a temporary reduction of the pH value in the irradiated tissues at the beginning of the treatment series, without consequences for the long‐term efficacy of LD‐EBRT [41].
This is contrasted by observations of LD‐EBRT in peritendinitis humeroscapularis [42]. In 73 patients (86 shoulders) initial increase of pain during the treatment course was significantly associated with a good response.
2.3.5. Use of megavoltage techniques/linear accelerators
Muecke et al. analyzed in a retrospective multicenter study the influence of different treatment techniques in 502 patients [22]. Treatment failure was defined as pain persistence after LD‐EBRT and recurrence of pain during follow‐up. Treatment with MV (6–10 MV) was a significant prognostic factor for pain relief in multivariate analysis, as MV was associated with an eight‐year event‐free probability of 68 vs. 61% after X‐ray beams (175 kV). There are two possible explanations for this finding: besides the possibility of a random result, the authors postulate a more homogenous dose distribution with MV treatment in comparison with KV [22].
2.3.6. Number of therapy courses required
Schneider et al. reported an efficacy of just one‐third after a second LD‐EBRT course (so‐called “re‐irradiation”) in comparison with the effects of the first course [37]. Out of 73 heels treated with 5 Gy LD‐EBRT 18 heels received reirradiation due to insufficient treatment response. However, pain reduction measured by means of changes in VAS shortly after the second course and during long‐term follow‐up was significantly diminished in comparison with the efficacy of the first course (about 30% reduction in pain at the last evaluation vs. 86%).
Similar results were obtained in the large retrospective series (502 patients) by Muecke et al. [22]. Treatment failure was significantly associated with the number of treatment series: eight‐year event‐free probability was about 70% after the first course in comparison with just about 30% after reirradiation.
A systematic study on the efficacy of a reirradiation has been published by Hautmann et al. [43]. Eighty‐three patients (101 heels) with insufficient response to the first course or recurrent pain afterward due to plantar fasciitis (83 heels), or achillodynia (28 heels) received a second LD‐EBRT course in median 10 weeks (range 4 weeks to 63 months) after the first LD‐EBRT. About 75% of the patients were treated with 6 × 1 Gy, the others 6 × 0.5 Gy. The pain was assessed using the numeric rating scale (NRS) before and at the end of LD‐EBRT, 6, and 12 weeks, and 6, 12, and 24 months thereafter.
Before reirradiation NRS values were 6 (interquartile range 5–8), at the end of LD‐EBRT 5 (2–6), 6 weeks later 2 (1–4), at 12 weeks 1 (0–3), at 6 months 0 (0–2), at 12 and 24 months 0 (0–1). Interestingly, not only the patients with recurrent pain after the first course but also patients with insufficient responses to the first course experienced a profound and long‐lasting amelioration of their symptoms after the second course.
This is why a second treatment course should be recommended in case of insufficient efficacy of the first course.
2.3.7. Heel stress during LD-EBRT
A significant correlation between avoidance of heel stress during LD‐EBRT and efficacy of LD‐EBRT 6 weeks after therapy was reported by Schneider et al. in 73 heels [37]. With a Pearson\'s correlation coefficient of -0.467 (p < 0.01) there was an impressing influence of this variable on pain reduction measured by VAS values. However, this correlation was not seen 28 and 40 months after LD‐EBRT.
An intuitive explanation is given by the authors [37]: As patient age was associated with positive treatment results, too, they proposed that older patients are often retired, thus being able to take more care of their heels.
2.3.8. Spur size
Interestingly, all randomized trials required the radiological proof of a heel spur before including patients into the studies. Furthermore, most of the prospective and retrospective series warranted such an objective sign. However, as a substantial part of the patients suffers from plantar heel pain without having developed a heel spur, LD‐EBRT should be effective in these patients, too.
Hermann et al. analyzed treatment efficacy in 250 patients (285 heels), who received LD‐EBRT predominantly with 6 × 1 Gy [38]. In this series, 33% of the treated heels were without radiological evidence of a spur. In 185 patients a spur was confirmed with a mean length of 6.5 mm (range 0.6–25 mm). Patients without evidence of a plantar heel spur had a significantly higher chance of CR after LD‐EBRT (43 vs. 35%). Furthermore, the length of the spurs correlated directly with treatment outcome. Spurs >6.5 mm had just a 30% chance of experiencing CR in comparison with shorter ones. No statistical differences were found between treatment results of heels without spurs and those with spurs ≤6.5 mm.
Miszczyk et al. reported on 327 patients (623 LD‐EBRT series) mostly treated with X‐ray (180 kV, usually 1mm Cu filters) with single doses of 1.5 Gy (range 1–3 Gy) up to a total dose between 9 and 12 Gy (range 1–45 Gy) [39]. Mean spur size was 9 mm (range 1–30 mm). With a mean follow‐up of 74 months, no correlation between spur size and duration of pain relief was found. Analysis concerning spur length and treatment outcome in itself were unfortunately not reported.
2.3.9. The combination of different factors
Multivariate logistic regression enables the identification of factors independently predicting treatment outcome. By combining these factors, models can be calculated, that predict treatment outcome with a high probability. An example from the study of Hermann et al. is given in Table 4: in 285 heels treated with 6 × 1 Gy/6 × 0.5 Gy the influences of the patient characteristics age, spur length, and duration of symptoms before LD-EBRT alone and in combination were calculated [38]. The best results were obtained for patients > 53 years, spur length <6 mm, and a duration of symptoms <12 months with a probability for CR of 55% (CI 36–73%) and PR of 38% (CI 22–58%). Without these characteristics, the chance for CR was just 18% (CI 9–33%), for PR 31% (17–48%).
entire dorsal foot vs. calcaneus vs. insertion of plantar fascia
Dose
6 × 1 vs. 6 × 0.5 Gy
6 × 1 Gy vs. 6 × 0.1 Gy
12, 3, 5 Gy
5 Gy (increasing single dose)
1.5 (1–3) up to 9–12 Gy (1–45)
5–10 × 0.5–1 Gy
6 × 1 Gy6 × 0.5 Gy
6 × 1 Gy
0.3–1.5 Gy; 2–3x weekly 2.5–18.76 Gy
Potential factors
History of symptoms
0
n.i.
+
+
0
+
+
+
+
Gender
0
n.i.
0
n.i.
0
0
0
n.i.
n.i.
Patient\'s age
0
n.i.
0
+
0
+
+
+
n.i.
Initial worsening of pain during LD‐EBRT
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
MV vs. KV
n.i.
n.i.
n.i.
n.i.
n.i.
+
n.i.
n.i.
0
Number of therapy series
n.i.
n.i.
n.i.
+
n.i.
+
n.i.
n.i.
+
Heel stress during LD‐EBRT
n.i.
0
n.i.
+
n.i.
n.i.
n.i.
n.i.
n.i.
Table 3.
Factors associated with treatment efficacy in contemporary studies.
Note: 0: no correlation with treatment outcome; +: correlation with treatment outcome; n.i.: not investigated; prospect: prospective case series; rand: randomized clinical trial; retrospect: retrospective case series; KV: kilovoltage; MV: megavoltage.
Patient\'s age >53
No spur or spur ≤6.5 mm
Duration of symptoms <12 months
Probability of
No change
Partial remission
Complete remission
1
1
1
0.07 (0.03–0.14)
0.38 (0.22–0.58)
0.55 (0.36–0.73)
1
1
0
0.13 (0.07–0.28)
0.37 (0.21–0.57)
0.50 (0.30–0.70)
1
0
1
0.15 (0.06–0.24)
0.53 (0.33–0.72)
0.32 (0.17–0.53)
1
0
0
0.25 (0.13–0.45)
0.48 (0.27–0.69)
0.27 (0.13–0.48)
0
1
1
0.17 (0.10–0.31)
0.33 (0.19–0.50)
0.50 (0.33–0.66)
0
1
0
0.34 (0.20–0.53)
0.40 (0.24–0.59)
0.26 (0.13–0.45)
0
0
1
0.30 (0.20–0.46)
0.29 (0.18–0.43)
0.41 (0.27–0.56)
0
0
0
0.51 (0.35–0.69)
0.31 (0.17–0.48)
0.18 (0.09–0.33)
Table 4.
Probabilities (95%‐CI) for NC, PR and CR calculated by polytomous logistic regression in dependence of the risk factors age, spur length, and duration of symptoms before LD‐EBRT according to Hermann et al. in a collective of 285 heels treated with 6 × 1/6 × 0.5 Gy (taken from [38]).
2.4. Technique
In modern radiotherapeutic departments, X‐ray sources are less and less available. This is why nowadays most patients are treated with linear accelerators, which were initially developed for the treatment of oncological diseases. However, these machines can be used in the treatment of benign diseases without any modifications or problems. Due to the high efforts in physical, technical, and organizational quality assurances for the operation of an accelerator or an X-ray source, the concentration on accelerators and their use for all indications is recommended.
For irradiation of the heel, the patient has to be placed on the treatment couch with the feet toward the gantry of the accelerator (so‐called “feet first”). Two different patient positions are widely used. He can be placed in supine position, with the irradiated leg is stretched out, while the other leg is angled. Another option is to place the patient in a lateral decubitus position on the side of the involved heel. Again, the symptomatic leg is stretched, while the contralateral leg is bent, with a cushion placed beneath the knee. Using X‐rays, the ipsilateral knee is bent by 90% and the foot is positioned on the treatment table. One anterior‐posterior (AP) beam is usually applied in this technique.
For the treatment itself, there are also two different options. Irradiation may be given as a single stationary field (SSD 100cm by convention). Alternatively, parallel opposing fields from 0° and 180° gantry position (in decubitus position) or lateral opposing fields (90° and 270° in supine position) are also applicable but take a little bit longer in daily clinical practice. The hypothetical advantage of using two opposing fields is a uniform dose distribution in the entire beam path in the calcaneus (Figure 1). However, there has never been a clinical proof, whether this theoretical assumption translates into any clinical advantage for the patient. When applying opposing fields, the dose is specified according to the ICRU 50 report, normally in the center of the calcaneus.
Figure 1.
Dose distribution of two different treatment techniques generated in a treatment planning system (XIO®). In A and B just one single 6 MV photon field (8 × 8 cm) is applied, while C and D shows the dose distribution with two opposing fields from 0 and 180°. In the upper row, the so‐called “beams eye views” are given, while in the lower row the respective dose distributions on an axial CT scan directly at the calcaneal insertion are shown. Note the more uniform dose distribution with opposing fields. The 95% isodose is given as a green line (2.85 Gy). This dose encompasses larger parts of the calcaneal bone in D (opposing fields) than in B (single field). More information is given in Section 2.4.
A third option is the so‐called “plantar field” with the patient lying in prone position. A single field is positioned directly over the plantar insertion/calcaneus, potentially with rotations of the patient table and the gantry to compensate for inclinations of the patients surface in the irradiated field. However, this technique is regarded problematic when using linear accelerators due to the dose build‐up effect in the critical tissue depth. This problem is illustrated in Figure 2: photons with 6 MV reach just the half of the prescribed dose at the skin level, 100% is reached at 1.5 cm tissue depth. This would result in an insufficient dose in the critical structures (plantar fascia and heel spur). To overcome this problem, a silicone flap of about 1 cm diameter must be positioned on the skin before radiation.
Figure 2.
Depth curves of different megavoltage energies. Blue 6 MV photons, red 15 MV photons. At the surface of the body/skin (depth 0 mm), only half (or even less with 15 MV) of the prescribed dose is applied. By physical interactions between photons and the tissue/water, there is a steep increase in dose. A 100% is reached at 1.5 cm depth with 6 MV and at about 3 cm depth with 15 MV. KV‐radiation reaches the maximum dose directly under the surface/skin (not shown). More information is given in Section 2.4.
3. Toxicity and potential risks of LD‐EBRT
Patients are often sent to the radiotherapist after a long unsuccessful history of diverse conservative treatments. The reason for this is a widespread fear among general practitioners that LD‐EBRT might be associated with severe side effects and risks. These fears are not substantiated, as reactions of the nerves or vessels require much higher doses than used for LD‐EBRT. For example, a dose of 45 Gy in normofractionated oncological therapy is considered to be safe for the spinal cord and therefore daily clinical practice [44]. Peripheral nerves are even more radioresistant. Acute or chronic side‐effects have never been reported in all contemporary studies on LD‐EBRT.
3.1. Acute reactions of the skin
Acute side effects are negligible, as very low doses of ionizing radiation (in comparison with oncological treatments) are applied to a distal extremity. The total dose of LD‐EBRT with 3 or 6 Gy is far too low to cause any acute or late reactions on the skin overlaying the calcaneus. During normofractionated EBRT (single doses of 1.8–2 Gy, treatment on 5 days a week) erythema and mild edema develop at about 30 Gy [45]. Hyperpigmentation occurs at about 45 Gy, moist epitheliolyses at about 50 Gy. A 50–60 Gy might cause telangiectasias years after the therapy. This is why there is no report on acute treatment side effects in LD‐EBRT until now to the best of our knowledge.
3.2. Initial increase in pain during LD‐EBRT
About one‐third of the patients might experience a slight increase in pain during LD‐EBRT. In the randomized trial by Heydt et al. this phenomenon was seen in 26% (during 6 × 0.5 Gy) vs. 29% (6 × 1 Gy) [30]. It does not seem to be correlated with treatment outcome; further detailed information is given in Section 2.3.4.
3.3. Impairment of gonad function
The dose scattered to the male gonads is somewhat higher than to the ovaries. Jansen et al. calculated for 6 × 0.5 Gy about 1.5 mSv received by the testes and 0.75 mSv to the ovaries [46]. Comparable results have repeatedly been measured in the past [47, 48].
Taken together, the dose received by the gonads is insignificant. As the distal extremity is irradiated, scattered dose to the gonads is comparable to normal diagnostic radiological imaging [49]. The hereditary effects of these doses are very small and very likely negligible [46].
Although spermatogonial cells are very radiosensitive, a single dose of at least 100 mSv is needed to induce a temporary failure of spermatogenesis [50]. A single dose of 1000 mSv (equivalent to 1 Gy photon irradiation) results in an azoospermia for 9–18 months [51]. Interestingly, fractionated doses harm these cells even more. A temporary oligospermia is reported after receiving several fractions up to a cumulative dose of 160 mSv [52]. An azoospermia lasting for 14–22 months has been reported for fractionated doses of 620–860 mSv [53]. The actually during LD‐EBRT received testicular dose is about 100 times smaller than the lowest dose causing temporary changes in testicular tissues.
The dose to the testicles can be further reduced by utilizing a special testicular shielding. However, clinically meaningful dose reductions have been only measured in MV treatment of subdiaphragmatic/pelvine lymphatic regions or tumors [54, 55].
The mean lethal dose for human oocytes has been estimated at 2 Gy (2000 mSv) [56]. Permanent ovarian failure after radiotherapy is age dependent: in perimenopausal women, a dose of 6 Gy is sufficient [57], while in younger women up to 20 Gy are tolerated. The dose scattered to the ovaries during LD‐EBRT for calcaneodynia cannot cause such sequelae (0.75 mSv).
Naturally, pregnancy has to be excluded in all premenopausal women before beginning with LD‐EBRT, to avoid any risk to the fetus.
3.4. Induction of malignancies
So far, no studies with long‐term observation periods have been published, describing a case of malignancy induced by LD‐EBRT for calcaneodynia. However, induction of malignancies is a stochastic effect of ionizing radiation. This means that there is no threshold dose—in contrast for example to the above‐mentioned reactions of the skin. A photon can accidentally trigger a mutation, which in turn leads to tumor formation many years later. The higher the radiation dose, the higher the probability of such an event occurring.
The best available data on tumor induction of full dose EBRT in oncology has been collected in patients treated with breast cancer. Almost 11,000 patients have been followed for over 20 years. The risk of a radiation‐induced tumor was approx. 1% per decade after radiotherapy [58].
To estimate the risk associated with much lower doses of LD‐EBRT, mathematical models on the basis of epidemiological long‐term observations of atomic bomb victims have been developed by the ICRP [59].
Jansen et al. applied the ICRP model on LD‐EBRT of a painful heel spur [46]. Assumed was a single field entering at the foot sole with a size of 8 × 10 cm, 200 kV photons, SSD 40 cm. For an LD‐EBRT series with 6 × 1 Gy the average attributable lifetime risk for induction of a fatal tumor was calculated to be about 0.5 in a thousand patients. An important risk factor for radiogenic‐induced cancer is the patient\'s age by the time the radiation exposure occurs. The risk is already reduced in the 3rd decade of the patient\'s life, it starts to decrease steadily from the age of 40 [60]. Applying these calculations, the estimated lifetime risk per one thousand patients for a fatal tumor accounts for the age of 25 0.6 (male)/0.8 (female), for the age of 50 0.2/0.3, for the age of 75 0.07/0.1 [46].
However, it must be critically noted that this mathematical model was developed for radiation protection and relates to the exposure of complete organ systems with approx. 1 Gy. Therefore, other groups argue that a significantly lower risk of radiogenic cancer induction— approx. ten times less—should be adopted [49, 61]. Furthermore, taken the new standard scheme with 6 × 0.5 Gy into account, these risks are additionally halved.
This risk (max. 1/1000, very likely much lower) must be seen in relation to the tumor risk of the not additionally radiotherapeutical‐treated population. In 2008, the lifetime risk of a man in Germany to suffer from cancer was 50.7% (25.9% to die from malignancy), in women 42.8% and 20.2% respectively [62].
By limiting the application of LD‐EBRT treatment to patients > 30 years of age, an exposure of the juvenile “relatively higher risk” patient population is avoided.
4. Future perspectives: Definition of questions in further randomized trials and future research
4.1. Target volume definition in LD‐EBRT
Traditionally target volume definition has been quite large. Field sizes of 12 × 17cm were treated, including the entire dorsal and middle foot, and not just the calcaneus [37, 82] (Figure 3A).
Figure 3.
Field definitions in LD‐EBRT of a painful plantar heel spur/fasciitis. (A) traditional field definition including the entire dorsal and middle foot. (B) In randomized trials and large prospective series commonly used field definition encompassing the entire calcaneus, including insertion of the plantar fascia and the Achilles tendon. (C) Proposed small field definition for localized painful plantar fasciitis/plantar spur, encompassing only the painful area with 2 cm margins extending into the neighboring areas (calcaneus, fascia, fat pad).
In the recent randomized trials and prospective observational studies target volume definition was more restricted and confined to the calcaneus (Figure 3B). “The target volume consisted of the calcaneus and the region of the plantar aponeurosis” [26]. “The ventral margin is corresponding to the ventral surface of the calcaneus, the plantar and dorsal margins are surrounding the soft‐tissue border, and the cranial margin is below the ankle” [30]. “Target volume is the calcaneus, normally with a field size of 6 cm × 8 cm” [32]. “The calcaneus and the plantar aponeurosis were included in the target volume” [25].
In a German national survey 2001 on LD‐EBRT of painful heel spurs the target volume definition “large” (dorsal and middle foot) vs. “small” (entire calcaneus) was not correlated with treatment outcome [83]. Consequently, very large field definitions should be regarded as obsolete.
However, as the pathophysiological cause of calcaneodynia is thought to be a localized inflammatory process (see Section 1), it is questionable, whether the entire calcaneus has to be irradiated (as long as there are not a plantar as well as a painful dorsal spurs). There are some clinical data that support a further restriction of target volume definition.
Field sizes have been given in the study by Miszczyk et al. on 327 patients treated with X‐ray beams [39]. Target volume was “… the insertion of the plantar fascia with a calcaneal spur and a reasonable margin. The field size varied from 27 to 150 cm2 (mean 47 cm2).” However, although not explicitly stated, no correlation was found between field size and duration of pain relief after LD‐EBRT. Treatment efficacy in itself was apparently not investigated.
In the above‐mentioned series of 285 heels Hermann et al. analyzed treatment efficacy in dependence of field sizes, too [38]. The mean field size was 74 cm2. No correlation between field size (smaller vs. larger than 74 cm2) with treatment efficacy was found. Further analyses of small fields (< 6 × 6 cm), medium‐sized fields (36–64 cm2) and larger fields revealed no significant differences.
This is why it seems to suffice to encompass the painful region with 2 cm margins extending into the neighboring areas (calcaneus, fascia, fat pad; Figure 3C). However, this recommendation is deducted from pathophysiological considerations and the above‐mentioned case series. A randomized trial is necessary to proof clinical equivalence of a field definition “entire calcaneus” (Figure 3B) vs. “insertion of the plantar fascia” (Figure 3C).
4.2. Fractionation of LD‐EBRT
The optimal fractionation schedule has not been elucidated yet. All randomized trial used twice weekly treatments. Only one experimental arm was scheduled three times a week [25]. In a National Survey in Germany with 146 answering institutions, about 45% applied two fractions and 37.5% three fractions weekly [83].
Interestingly, in the landmark study by von Pannewitz a fractionation schedule of only once per week was established [34]. Until now, there is no proof of a higher efficacy applying LD‐EBRT twice or three times per week.
In radiotherapy of another benign disease (endocrine orbitopathy) a 1 Gy per week over 20 weeks schedule was more effective than the standard schedules (10 × 2 Gy or 10 × 1 Gy every working day) [84]. Although other immunological mechanisms cause endocrine orbitopathy in comparison with plantar fasciitis, there is sufficient clinical evidence to test in a randomized trial different fractionation schedules (twice a week vs. once a week, possibly thrice a week).
4.3. Comparison of LD‐EBRT with other therapies
Other therapies than LD‐EBRT have been applied in painful heel spur. In the following, just a rough overview can be given.
Different kinds of insoles and foot orthoses have been developed. The goal was to reduce plantar contact pressure and to distribute the pressure uniformly over the whole rearfoot [63]. Magnetic insoles do not seem to provide additional benefit [64]. As a short‐term treatment, low‐Dye taping techniques are often used. However, in a randomized trial only a modest improvement in ‘first‐step’ pain was seen in comparison with sham‐intervention [65].
Manual stretching is often recommended. A systematic review of six studies found only statistically significant differences in comparison with the control in one study combining calf muscle and plantar fascia stretches [66].
Several trials have investigated acupuncture. A systematic review from 2010 showed (limited) evidence for the effectiveness [67]. A randomized trial published in 2014 recruited 84 patients [68]. The authors concluded, that “dry needling provided statistically significant reductions in plantar heel pain, but the magnitude of this effect should be considered against the frequency of minor transitory adverse events.”
Ultrasound therapy has led to questionable results [69], but a randomized trial on cryo‐ultrasound with about 100 patients published in 2014 showed good effectiveness [70].
Low‐level laser light (635 nm), given twice a week for a total of six applications, reduced in a randomized trial VAS scores significantly after 8 weeks in comparison with placebo [71]. However, the study comprised of just 69 patients; other similar studies have not been reported so far.
Extracorporeal shock waves are widely applied. Three metaanalyses comprising at least five randomized trials found significant short‐term pain relief and improved functional outcomes for this therapeutic option [72–74]. Another study compared the analgesic efficacy of ultrasound and shock wave therapy in 47 patients [75]. The results suggested that the shock wave therapy had greater analgesic efficacy.
Another basic approach is the oral administration of nonsteroidal anti‐inflammatory drugs (NSAID) to achieve a symptomatic relief. Injections into the painful area are also recommended. A recent review summarized ten randomized trials on corticosteroid injections into the plantar fascia [76]. A significant effect of the steroids on the pain has been shown. However, it was usually short‐term, lasting 4–12 weeks in duration. No advantage of ultrasound‐guided injection techniques in comparison with palpation guidance was found, and no superiority of one type of corticosteroid over another was seen. A longer lasting pain relief has been suggested by a small randomized trial of botulinum toxin injections [77]. Another option is the injection of autologous platelet‐rich plasma. A recent review identified three randomized trials, all showing promising results [78]. However, a very small trial challenged this method of plasma preparation, as the same clinical effectivity was observed after the injection of whole blood [79].
Different surgical approaches have been developed. Releases of the plantar fascia are done, in some studies combined with a spur resection [80]. Due to a probably faster recovery after surgery with comparable functional results endoscopic procedures are recommended nowadays [81]. Surgery is usually indicated after failure of conservative therapies as the ultimate “salvage‐therapy.”
There is only a limited amount of studies randomizing patients between LD‐EBRT and the above‐mentioned alternative therapies.
Canyilmaz et al. randomized 123 patients between LD‐EBRT (6 × 1 Gy, three times a week) and 1 ml injection of 40 mg methylprednisolone and 0.5 ml 60 mg 1% lidocaine under the guidance of palpation [85]. After 3 and 6 months, VAS values and CS‐scores were compared between both groups. After 3 months, the results in the radiotherapy arm were significantly superior compared with those after injections.
To corroborate these findings, similar studies should be conducted. Furthermore, more studies randomizing LD‐EBRT against other therapies (e.g. extracorporeal shock waves) are needed. A minimum size of 50 patients per treatment arm should be assured to gain more statistically relevant results. Recruiting patients without prior excessive other therapies for these studies would be optimal.
The goal must be an evidence‐based algorithm defining the therapeutic sequence of the different conservative treatment modalities for plantar fasciitis.
5. Conclusions
LD‐EBRT for painful plantar fasciitis/heel spur is an effective and safe treatment option for patients over 30 years of age and after exclusion of pregnancy. A fractionation of 6 × 0.5 Gy twice weekly up to a total dose of 3 Gy is currently recommended. In the case of an insufficient response a second course can be offered to the patient.
Randomized trials on target volume definition and further optimization of LD‐EBRT fractionation are currently in the process of planning. Further trials to compare the different conservative therapies for plantar fasciitis with each other are necessary to allow the development of an evidence‐based treatment algorithm.
Acknowledgments
This chapter is dedicated to Professor Gisela Hermann‐Brennecke on the occasion of her 70th birthday.
Abbreviations
AP
anterior‐posterior
CI
confidence interval
CR
complete remission
CS
Calcaneodynia score
Cu
chemical element symbol for copper
EC
endothelial cells
GCG‐BD
German Cooperative Group on Radiotherapy for Benign Diseases
Gy
Gray
ICRP
International Commission on Radiological Protection
IL
interleukin
iNOS
inducible nitric oxide synthases
KV
kilovoltage
LD‐EBRT
low dose external beam radiotherapy
mA
milliampere
mRNA
messenger ribonuclein acid
mSv
milliSievert
MV
megavoltage
NC
no change
NF‐κB
nuclear factor kappa B
NO
nitric oxide
NSAID
non‐steroidal anti‐inflammatory drug
PBMC
peripheral blood mononuclear cells
PR
partial remission
QOL
quality of life
ROS
reactive oxygen species
SSD
skin‐to‐source distance
TGF‐β1
transforming growth factor β1
VAS
visual analogue scale
\n',keywords:"low dose radiotherapy, heel spur, plantar fasciitis, reizbestrahlung, target volume definition",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/53798.pdf",chapterXML:"https://mts.intechopen.com/source/xml/53798.xml",downloadPdfUrl:"/chapter/pdf-download/53798",previewPdfUrl:"/chapter/pdf-preview/53798",totalDownloads:2597,totalViews:768,totalCrossrefCites:0,dateSubmitted:"June 1st 2016",dateReviewed:"November 24th 2016",datePrePublished:null,datePublished:"May 17th 2017",dateFinished:"January 8th 2017",readingETA:"0",abstract:"Degenerative changes in the plantar fascia may cause the so‐called “painful heel” with typical projections of tenderness. This condition is often associated with a plantar heel spur. Radiotherapy with low doses (LD‐EBRT) has been well known for its anti‐inflammatory potential. In the recent years, several microbiological mechanisms were elucidated to explain immunomodulation by LD‐EBRT. Furthermore, a randomized study proved the clinical efficacy of this therapy in plantar fasciitis. Two other trials defined a fractionation schedule of 6 × 0.5 Gy twice weekly as the new standard therapy. Taken together, LD‐EBRT is an effective and safe therapeutic option for patients over 30 years of age and after exclusion of pregnancy. In case of an insufficient response, a second course can be offered to the patient. There are still open questions concerning target volume definition and fractionation of LD‐EBRT. Furthermore, studies randomizing LD‐EBRT with other conservative therapeutic approaches are missing.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/53798",risUrl:"/chapter/ris/53798",signatures:"Robert Michael Hermann, Frank Bruns and Mirko Nitsche",book:{id:"5611",type:"book",title:"Radiotherapy",subtitle:null,fullTitle:"Radiotherapy",slug:"radiotherapy",publishedDate:"May 17th 2017",bookSignature:"Cem Onal",coverURL:"https://cdn.intechopen.com/books/images_new/5611.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-953-51-3150-2",printIsbn:"978-953-51-3149-6",pdfIsbn:"978-953-51-4833-3",isAvailableForWebshopOrdering:!0,editors:[{id:"43940",title:"Dr.",name:"Cem",middleName:null,surname:"Onal",slug:"cem-onal",fullName:"Cem Onal"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"192941",title:"Prof.",name:"Robert",middleName:"Michael",surname:"Hermann",fullName:"Robert Hermann",slug:"robert-hermann",email:"hermann@strahlentherapie-westerstede.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Hannover Medical School",institutionURL:null,country:{name:"Germany"}}},{id:"194730",title:"Dr.",name:"Mirko",middleName:null,surname:"Nitsche",fullName:"Mirko Nitsche",slug:"mirko-nitsche",email:"Nitsche@strahlentherapie-bremen.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"194927",title:"Dr.",name:"Frank",middleName:null,surname:"Bruns",fullName:"Frank Bruns",slug:"frank-bruns",email:"bruns.frank@mh-hannover.de",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Incidence and etiology of plantar fasciitis",level:"1"},{id:"sec_2",title:"2. Treatment with LD‐EBRT",level:"1"},{id:"sec_2_2",title:"2.1. Biological effects of LD‐EBRT on lymphocytes and inflammatory processes",level:"2"},{id:"sec_3_2",title:"2.2. Results of randomized trials on radiotherapy for painful heel spur",level:"2"},{id:"sec_3_3",title:"Table 1.",level:"3"},{id:"sec_4_3",title:"2.2.2. Looking for the minimum effective dose: optimization of fractionation and total dose of LD-EBRT",level:"3"},{id:"sec_4_4",title:"2.2.2.1. Single dose 0.5 vs. 1 Gy",level:"4"},{id:"sec_5_4",title:"2.2.2.2. Single dose 0.3 vs. 1 Gy",level:"4"},{id:"sec_8_2",title:"2.3. Risk factors potentially associated with treatment failure",level:"2"},{id:"sec_8_3",title:"2.3.1. History of symptoms",level:"3"},{id:"sec_9_3",title:"2.3.2. Gender",level:"3"},{id:"sec_10_3",title:"2.3.3. Patients’ age",level:"3"},{id:"sec_11_3",title:"2.3.4. Initial increase in pain during LD-EBRT",level:"3"},{id:"sec_12_3",title:"2.3.5. Use of megavoltage techniques/linear accelerators",level:"3"},{id:"sec_13_3",title:"2.3.6. Number of therapy courses required",level:"3"},{id:"sec_14_3",title:"2.3.7. Heel stress during LD-EBRT",level:"3"},{id:"sec_15_3",title:"2.3.8. Spur size",level:"3"},{id:"sec_16_3",title:"Table 3.",level:"3"},{id:"sec_18_2",title:"2.4. Technique",level:"2"},{id:"sec_20",title:"3. Toxicity and potential risks of LD‐EBRT",level:"1"},{id:"sec_20_2",title:"3.1. Acute reactions of the skin",level:"2"},{id:"sec_21_2",title:"3.2. Initial increase in pain during LD‐EBRT",level:"2"},{id:"sec_22_2",title:"3.3. Impairment of gonad function",level:"2"},{id:"sec_23_2",title:"3.4. Induction of malignancies",level:"2"},{id:"sec_25",title:"4. Future perspectives: Definition of questions in further randomized trials and future research",level:"1"},{id:"sec_25_2",title:"4.1. Target volume definition in LD‐EBRT",level:"2"},{id:"sec_26_2",title:"4.2. Fractionation of LD‐EBRT",level:"2"},{id:"sec_27_2",title:"4.3. Comparison of LD‐EBRT with other therapies",level:"2"},{id:"sec_29",title:"5. Conclusions",level:"1"},{id:"sec_30",title:"Acknowledgments",level:"1"},{id:"sec_32",title:"Abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'Yi TI, Lee GE, Seo IS, Huh WS, Yoon TH, Kim BR. Clinical characteristics of the causes of plantar heel pain. Ann Rehabil Med. 2011;35:507–513. DOI: 10.5535/arm.2011.35.4.507'},{id:"B2",body:'Irving DB, Cook JL, Young MA, Menz HB. Obesity and pronated foot type may increase the risk of chronic plantar heel pain: a matched case‐control study. BMC Musculoskelet Disord. 2007;8:41. DOI: 10.1186/1471‐2474‐8‐41'},{id:"B3",body:'Sahin N, Oztürk A, Atıcı T. Foot mobility and plantar fascia elasticity in patients with plantar fasciitis. Acta Orthop Traumatol Turc. 2010;44:385–91. 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Low‐Level laser therapy at 635 nm for treatment of chronic plantar fasciitis: a placebo‐controlled, randomized study. J Foot Ankle Surg. 2015;54:768–72. DOI: 10.1053/j.jfas.2014.12.014'},{id:"B72",body:'Yin MC, Ye J, Yao M, Cui XJ, Xia Y, Shen QX, Tong ZY, Wu XQ, Ma JM, Mo W. Is extracorporeal shock wave therapy clinical efficacy for relief of chronic, recalcitrant plantar fasciitis? A systematic review and meta‐analysis of randomized placebo or active‐treatment controlled trials. Arch Phys Med Rehabil. 2014;95:1585–1593. DOI: 10.1016/j.apmr.2014.01.033'},{id:"B73",body:'Aqil A, Siddiqui MR, Solan M, Redfern DJ, Gulati V, Cobb JP. Extracorporeal shock wave therapy is effective in treating chronic plantar fasciitis: a meta‐analysis of RCTs. Clin Orthop Relat Res. 2013;471:3645–3652. DOI: 10.1007/s11999‐013‐3132‐2'},{id:"B74",body:'Zhiyun L, Tao J, Zengwu S. Meta‐analysis of high‐energy extracorporeal shock wave therapy in recalcitrant plantar fasciitis. Swiss Med Wkly. 2013;143:w13825. DOI: 10.4414/smw.2013.13825'},{id:"B75",body:'Krukowska J, Wrona J, Sienkiewicz M, Czernicki J. A comparative analysis of analgesic efficacy of ultrasound and shock wave therapy in the treatment of patients with inflammation of the attachment of the plantar fascia in the course of calcaneal spurs. Arch Orthop Trauma Surg. 2016. [Epub ahead of print] DOI: 10.1007/s00402‐016‐2503‐z'},{id:"B76",body:'Ang TW. The effectiveness of corticosteroid injection in the treatment of plantar fasciitis. Singapore Med J. 2015;56:423–432. DOI: 10.11622/smedj.2015118'},{id:"B77",body:'Díaz‐Llopis IV, Gómez‐Gallego D, Mondéjar‐Gómez FJ, López‐García A, Climent‐Barberá JM, Rodríguez‐Ruiz CM. Botulinum toxin type A in chronic plantar fasciitis: clinical effects one year after injection. Clin Rehabil. 2013;27:681–685. DOI: 10.1177/0269215512469217'},{id:"B78",body:'Franceschi F, Papalia R, Franceschetti E, Paciotti M, Maffulli N, Denaro V. Platelet‐rich plasma injections for chronic plantar fasciopathy: a systematic review. Br Med Bull. 2014;112:83–95. DOI: 10.1093/bmb/ldu025'},{id:"B79",body:'Vahdatpour B, Kianimehr L, Ahrar MH. Autologous platelet‐rich plasma compared with whole blood for the treatment of chronic plantar fasciitis; a comparative clinical trial. Adv Biomed Res. 2016;5:84. DOI: 10.4103/2277‐9175.182215'},{id:"B80",body:'Tomczak RL, Haverstock BD. A retrospective comparison of endoscopic plantar fasciotomy to open plantar fasciotomy with heel spur resection for chronic plantar fasciitis/heel spur syndrome. J Foot Ankle Surg. 1995;34:305–311. DOI: 10.1016/S1067‐2516(09)80065‐3'},{id:"B81",body:'Chou AC, Ng SY, Koo KO. Endoscopic plantar fasciotomy improves early postoperative results: a retrospective comparison of outcomes after endoscopic versus open plantar fasciotomy. J Foot Ankle Surg. 2016;55:9–15. DOI: 10.1053/j.jfas.2015.02.005'},{id:"B82",body:'Mantell BS. Radiotherapy for painful heel syndrome. Br Med J. 1978;2:90–91. PMID: 667574'},{id:"B83",body:'Micke O, Seegenschmiedt MH. Radiotherapy in painful heel spurs (plantar fasciitis): results of a national patterns of care study. Int J Radiat Oncol Biol Phys 2004;58:828–843. DOI: 10.1016/S0360‐3016(03)01620‐1'},{id:"B84",body:'Kahaly GJ, Rösler HP, Pitz S, Hommel G. Low‐ versus high‐dose radiotherapy for Graves’ ophthalmopathy: a randomized, single blind trial. J Clin Endocrinol Metab. 2000;85:102–108. DOI: 10.1210/jcem.85.1.6257'},{id:"B85",body:'Canyilmaz E, Canyilmaz F, Aynaci O, Colak F, Serdar L, Uslu GH, Aynaci O, Yoney A. Prospective randomized comparison of the effectiveness of radiation therapy and local steroid injection for the treatment of plantar fasciitis. Int J Radiat Oncol Biol Phys. 2015;92:659–666. DOI: 10.1016/j.ijrobp.2015.02.009'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Robert Michael Hermann",address:"hermann@strahlentherapie-westerstede.com",affiliation:'
Center for Radiotherapy and Radiooncology, Bremen and Westerstede, Westerstede, Germany
Department of Radiotherapy and Special Oncology, Hannover Medical School, Hannover, Germany
Center for Radiotherapy and Radiooncology, Bremen and Westerstede, Westerstede, Germany
Department of Radiotherapy, Karl‐Lennert Cancer Center, University of Schleswig‐Holstein, Kiel, Germany
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This problematic is particularly relevant with medical imaging data, where linear techniques are frequently unsuitable for capturing variations in anatomical structures. In many cases, there is enough structure in the data (CT, MRI, ultrasound) so a lower dimensional object can describe the degrees of freedom, such as in a manifold structure. Still, complex, multivariate distributions tend to demonstrate highly variable structural topologies that are impossible to capture with a single manifold learning algorithm. This chapter will present recent techniques developed in manifold theory for medical imaging analysis, to allow for statistical organ shape modeling, image segmentation and registration from the concept of navigation of manifolds, classification, as well as disease prediction models based on discriminant manifolds. We will present the theoretical basis of these works, with illustrative results on their applications from various organs and pathologies, including neurodegenerative diseases and spinal deformities.",book:{id:"7342",slug:"manifolds-ii-theory-and-applications",title:"Manifolds II",fullTitle:"Manifolds II - Theory and Applications"},signatures:"Samuel Kadoury",authors:null},{id:"62804",doi:"10.5772/intechopen.79383",title:"Recent Advances of Manifold Regularization",slug:"recent-advances-of-manifold-regularization",totalDownloads:1100,totalCrossrefCites:0,totalDimensionsCites:3,abstract:"Semi-supervised learning (SSL) that can make use of a small number of labeled data with a large number of unlabeled data to produce significant improvement in learning performance has been received considerable attention. Manifold regularization is one of the most popular works that exploits the geometry of the probability distribution that generates the data and incorporates them as regularization terms. There are many representative works of manifold regularization including Laplacian regularization (LapR), Hessian regularization (HesR) and p-Laplacian regularization (pLapR). Based on the manifold regularization framework, many extensions and applications have been reported. In the chapter, we review the LapR and HesR, and we introduce an approximation algorithm of graph p-Laplacian. 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Based on the assumption that informative and discriminative representation of the data lies on a low-dimensional smooth manifold which implicitly embedded in the original high-dimensional space, manifold learning aims to learn the low-dimensional representation following some geometrical protocols, such as preserving piecewise local structure of the original data. Manifold learning also plays an important role in the applications of computer vision, i.e., face image analysis. According to the observations that many face-related research is benefitted by the head pose estimation, and the continuous variation of head pose can be modelled and interpreted as a low-dimensional smooth manifold, we will focus on the head pose estimation via manifold learning in this chapter. Generally, head pose is hard to directly explore from the high-dimensional space interpreted as face images, which is, however, can be efficiently represented in low-dimensional manifold. 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Important theorems pertaining to isometric surfaces are stated and a theorem due to Bonnet is obtained. A transformation for the connection forms is developed. It is proved that the angle of deformation must be harmonic, and that the differentials of many of the important variables generate a closed differential ideal. This implies that a coordinate system exists in which many of the variables satisfy particular ordinary differential equations, and these results can be used to characterize Bonnet surfaces.",book:{id:"5488",slug:"manifolds-current-research-areas",title:"Manifolds",fullTitle:"Manifolds - Current Research Areas"},signatures:"Paul Bracken",authors:[{id:"92883",title:"Prof.",name:"Paul",middleName:null,surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}]},{id:"53552",doi:"10.5772/65948",title:"Sub-Manifolds of a Riemannian Manifold",slug:"sub-manifolds-of-a-riemannian-manifold",totalDownloads:1754,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"In this chapter, we introduce the theory of sub-manifolds of a Riemannian manifold. The fundamental notations are given. The theory of sub-manifolds of an almost Riemannian product manifold is one of the most interesting topics in differential geometry. According to the behaviour of the tangent bundle of a sub-manifold, with respect to the action of almost Riemannian product structure of the ambient manifolds, we have three typical classes of sub-manifolds such as invariant sub-manifolds, anti-invariant sub-manifolds and semi-invariant sub-manifolds. In addition, slant, semi-slant and pseudo-slant sub-manifolds are introduced by many geometers.",book:{id:"5488",slug:"manifolds-current-research-areas",title:"Manifolds",fullTitle:"Manifolds - Current Research Areas"},signatures:"Mehmet Atçeken, Ümit Yıldırım and Süleyman Dirik",authors:[{id:"191326",title:"Prof.",name:"Mehmet",middleName:null,surname:"Atceken",slug:"mehmet-atceken",fullName:"Mehmet Atceken"},{id:"196148",title:"Dr.",name:"Umit",middleName:null,surname:"Yildirim",slug:"umit-yildirim",fullName:"Umit Yildirim"}]}],mostDownloadedChaptersLast30Days:[{id:"73123",title:"Some Applications of Clifford Algebra in Geometry",slug:"some-applications-of-clifford-algebra-in-geometry",totalDownloads:831,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In this chapter, we provide some enlightening examples of the application of Clifford algebra in geometry, which show the concise representation, simple calculation, and profound insight of this algebra. The definition of Clifford algebra implies geometric concepts such as vector, length, angle, area, and volume and unifies the calculus of scalar, spinor, vector, and tensor, so that it is able to naturally describe all variables and calculus in geometry and physics. Clifford algebra unifies and generalizes real number, complex, quaternion, and vector algebra and converts complicated relations and operations into intuitive matrix algebra independent of coordinate systems. By localizing the basis or frame of space-time and introducing differential and connection operators, Clifford algebra also contains Riemann geometry. Clifford algebra provides a unified, standard, elegant, and open language and tools for numerous complicated mathematical and physical theories. Clifford algebra calculus is an arithmetic-like operation that can be well understood by everyone. This feature is very useful for teaching purposes, and popularizing Clifford algebra in high schools and universities will greatly improve the efficiency of students to learn fundamental knowledge of mathematics and physics. So, Clifford algebra can be expected to complete a new big synthesis of scientific knowledge.",book:{id:"8760",slug:"structure-topology-and-symplectic-geometry",title:"Structure Topology and Symplectic Geometry",fullTitle:"Structure Topology and Symplectic Geometry"},signatures:"Ying-Qiu Gu",authors:[{id:"314607",title:"Dr.",name:"Ying-Qiu",middleName:null,surname:"Gu",slug:"ying-qiu-gu",fullName:"Ying-Qiu Gu"}]},{id:"52596",title:"Symplectic Manifolds: Gromov-Witten Invariants on Symplectic and Almost Contact Metric Manifolds",slug:"symplectic-manifolds-gromov-witten-invariants-on-symplectic-and-almost-contact-metric-manifolds",totalDownloads:1525,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In this chapter, we introduce Gromov-Witten invariant, quantum cohomology, Gromov-Witten potential, and Floer cohomology on symplectic manifolds, and in connection with these, we describe Gromov-Witten type invariant, quantum type cohomology, Gromov-Witten type potential and Floer type cohomology on almost contact metric manifolds. 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Manifold regularization is one of the most popular works that exploits the geometry of the probability distribution that generates the data and incorporates them as regularization terms. There are many representative works of manifold regularization including Laplacian regularization (LapR), Hessian regularization (HesR) and p-Laplacian regularization (pLapR). Based on the manifold regularization framework, many extensions and applications have been reported. In the chapter, we review the LapR and HesR, and we introduce an approximation algorithm of graph p-Laplacian. We study several extensions of this framework for pairwise constraint, p-Laplacian learning, hypergraph learning, etc.",book:{id:"7342",slug:"manifolds-ii-theory-and-applications",title:"Manifolds II",fullTitle:"Manifolds II - Theory and Applications"},signatures:"Xueqi Ma and Weifeng Liu",authors:null},{id:"79892",title:"βI-Compactness, βI*-Hyperconnectedness and βI-Separatedness in Ideal Topological Spaces",slug:"-em-em-sub-em-i-em-sub-compactness-em-em-sub-em-i-em-sub-hyperconnectedness-and-em-em-sub-em-i-em-su",totalDownloads:77,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Let XτI be an ideal topological space. A subset A of X is said to be β-open if A⊆clintclA, and it is said to be βI-open if there is a set O∈τ with the property 1 O−A∈I and 2 A−clintclO∈I. The set A is called βI-compact if every cover of A by βI-open sets has a finite sub-cover. The set A is said to be cβI-compact, if every cover Oλ:λ∈Λ of A by β-open sets, Λ has a finite subset Λ0 such that A−∪Oλ:λ∈Λ0∈I. The set A is said to be countably βI-compact if every countable cover of A by βI-open sets has a finite sub-cover. An ideal topological space XτI is said to be βI∗-hyperconnected if X−cl∗A∈I for every non-empty βI-open subset A of X. Two subsets A and B of X is said to be βI-separated if clβIA∩B=∅=A∩clβB. Moreover, A is called a βI-connected set if it can’t be written as a union of two βI-separated subsets. An ideal topological space XτI is called βI-connected space if X is βI-connected. In this article, we give some important properties of βI-open sets, βI-compact spaces, cβI-compact spaces, βI∗-hyperconnected spaces, and βI-connected spaces.",book:{id:"10677",slug:"advanced-topics-of-topology",title:"Advanced Topics of Topology",fullTitle:"Advanced Topics of Topology"},signatures:"Glaisa T. Catalan, Michael P. Baldado Jr and Roberto N. Padua",authors:[{id:"425714",title:"Prof.",name:"Michael",middleName:null,surname:"Baldado",slug:"michael-baldado",fullName:"Michael Baldado"},{id:"438024",title:"Dr.",name:"Glaisa",middleName:"Tinguha",surname:"Catalan",slug:"glaisa-catalan",fullName:"Glaisa Catalan"},{id:"486473",title:"Dr.",name:"Roberto N.",middleName:null,surname:"Padua",slug:"roberto-n.-padua",fullName:"Roberto N. Padua"}]},{id:"53552",title:"Sub-Manifolds of a Riemannian Manifold",slug:"sub-manifolds-of-a-riemannian-manifold",totalDownloads:1754,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"In this chapter, we introduce the theory of sub-manifolds of a Riemannian manifold. The fundamental notations are given. The theory of sub-manifolds of an almost Riemannian product manifold is one of the most interesting topics in differential geometry. According to the behaviour of the tangent bundle of a sub-manifold, with respect to the action of almost Riemannian product structure of the ambient manifolds, we have three typical classes of sub-manifolds such as invariant sub-manifolds, anti-invariant sub-manifolds and semi-invariant sub-manifolds. In addition, slant, semi-slant and pseudo-slant sub-manifolds are introduced by many geometers.",book:{id:"5488",slug:"manifolds-current-research-areas",title:"Manifolds",fullTitle:"Manifolds - Current Research Areas"},signatures:"Mehmet Atçeken, Ümit Yıldırım and Süleyman Dirik",authors:[{id:"191326",title:"Prof.",name:"Mehmet",middleName:null,surname:"Atceken",slug:"mehmet-atceken",fullName:"Mehmet Atceken"},{id:"196148",title:"Dr.",name:"Umit",middleName:null,surname:"Yildirim",slug:"umit-yildirim",fullName:"Umit Yildirim"}]}],onlineFirstChaptersFilter:{topicId:"165",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:333,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:11,numberOfPublishedChapters:144,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:124,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:113,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:23,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:12,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{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"}}}},{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"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"August 16th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. 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He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",isOpenForSubmission:!0,editor:{id:"205604",title:"Dr.",name:"Tomas",middleName:null,surname:"Jarzembowski",slug:"tomas-jarzembowski",fullName:"Tomas Jarzembowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKriQAG/Profile_Picture_2022-06-16T11:01:31.jpg",biography:"Tomasz Jarzembowski was born in 1968 in Gdansk, Poland. He obtained his Ph.D. degree in 2000 from the Medical University of Gdańsk (UG). After specialization in clinical microbiology in 2003, he started studying biofilm formation and antibiotic resistance at the single-cell level. In 2015, he obtained his D.Sc. degree. His later study in cooperation with experts in nephrology and immunology resulted in the designation of the new diagnostic method of UTI, patented in 2017. He is currently working at the Department of Microbiology, Medical University of Gdańsk (GUMed), Poland. Since many years, he is a member of steering committee of Gdańsk branch of Polish Society of Microbiologists, a member of ESCMID. He is also a reviewer and a member of editorial boards of a number of international journals.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorTwo:{id:"484980",title:"Dr.",name:"Katarzyna",middleName:null,surname:"Garbacz",slug:"katarzyna-garbacz",fullName:"Katarzyna Garbacz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003St8TAQAZ/Profile_Picture_2022-07-07T09:45:16.jpg",biography:"Katarzyna Maria Garbacz, MD, is an Associate Professor at the Medical University of Gdańsk, Poland and she is head of the Department of Oral Microbiology of the Medical University of Gdańsk. She has published more than 50 scientific publications in peer-reviewed journals. She has been a project leader funded by the National Science Centre of Poland. Prof. Garbacz is a microbiologist working on applied and fundamental questions in microbial epidemiology and pathogenesis. Her research interest is in antibiotic resistance, host-pathogen interaction, and therapeutics development for staphylococcal pathogens, mainly Staphylococcus aureus, which causes hospital-acquired infections. Currently, her research is mostly focused on the study of oral pathogens, particularly Staphylococcus spp.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",isOpenForSubmission:!0,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:21,paginationItems:[{id:"83000",title:"Purine and Pyrimidine Pathways as Antimalarial Targets",doi:"10.5772/intechopen.106468",signatures:"Yacoba V.T. Minnow and Vern L. 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Saxena",hash:"105e347b2d5dbbe6b593aceffa051efa",volumeInSeries:1,fullTitle:"Influenza - Therapeutics and Challenges",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}]},{type:"book",id:"7064",title:"Current Perspectives in Human Papillomavirus",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7064.jpg",slug:"current-perspectives-in-human-papillomavirus",publishedDate:"May 2nd 2019",editedByType:"Edited by",bookSignature:"Shailendra K. Saxena",hash:"d92a4085627bab25ddc7942fbf44cf05",volumeInSeries:2,fullTitle:"Current Perspectives in Human Papillomavirus",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}]},{type:"book",id:"7123",title:"Current Topics in Neglected Tropical Diseases",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7123.jpg",slug:"current-topics-in-neglected-tropical-diseases",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Alfonso J. Rodriguez-Morales",hash:"61c627da05b2ace83056d11357bdf361",volumeInSeries:3,fullTitle:"Current Topics in Neglected Tropical Diseases",editors:[{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null}]},{type:"book",id:"7839",title:"Malaria",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7839.jpg",slug:"malaria",publishedDate:"December 11th 2019",editedByType:"Edited by",bookSignature:"Fyson H. Kasenga",hash:"91cde4582ead884cb0f355a19b67cd56",volumeInSeries:4,fullTitle:"Malaria",editors:[{id:"86725",title:"Dr.",name:"Fyson",middleName:"Hanania",surname:"Kasenga",slug:"fyson-kasenga",fullName:"Fyson Kasenga",profilePictureURL:"https://mts.intechopen.com/storage/users/86725/images/system/86725.jpg",biography:"Dr. Kasenga is a graduate of Tumaini University, Kilimanjaro Christian Medical College, Moshi, Tanzania and Umeå University, Sweden. He obtained a Master’s degree in Public Health and PhD in Public Health and Epidemiology. He has a background in Clinical Medicine and has taken courses at higher diploma levels in public health from University of Transkei, Republic of South Africa, and African Medical and Research Foundation (AMREF) in Nairobi, Kenya. Dr. Kasenga worked in different places in and outside Malawi, and has held various positions, such as Licensed Medical Officer, HIV/AIDS Programme Officer, HIV/AIDS resource person in the International Department of Diakonhjemet College, Oslo, Norway. He also managed an Integrated HIV/AIDS Prevention programme for over 5 years. He is currently working as a Director for the Health Ministries Department of Malawi Union of the Seventh Day Adventist Church. Dr. Kasenga has published over 5 articles on HIV/AIDS issues focusing on Prevention of Mother to Child Transmission of HIV (PMTCT), including a book chapter on HIV testing counseling (currently in press). 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He was elected a Yangtze River Scholars Distinguished Professor in 2013, a member of the International Statistical Institute (ISI) in 2016, a member of the board of the International Chinese Statistical Association (ICSA) in 2018, and a fellow of the Institute of Mathematical Statistics (IMS) in 2021. He received the ICSA Outstanding Service Award in 2018 and the National Science Foundation for Distinguished Young Scholars of China in 2012. He serves as a member of the editorial board of Statistics and Its Interface and Journal of Systems Science and Complexity. He is also a field editor for Communications in Mathematics and Statistics. His research interests include biostatistics, empirical likelihood, missing data analysis, variable selection, high-dimensional data analysis, Bayesian statistics, and data science. He has published more than 190 research papers and authored five books.",institutionString:"Yunnan University",institution:{name:"Yunnan University",country:{name:"China"}}},{id:"1177",title:"Prof.",name:"António",middleName:"J. R.",surname:"José Ribeiro Neves",slug:"antonio-jose-ribeiro-neves",fullName:"António José Ribeiro Neves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1177/images/system/1177.jpg",biography:"Prof. António J. R. Neves received a Ph.D. in Electrical Engineering from the University of Aveiro, Portugal, in 2007. Since 2002, he has been a researcher at the Institute of Electronics and Informatics Engineering of Aveiro. Since 2007, he has been an assistant professor in the Department of Electronics, Telecommunications, and Informatics, University of Aveiro. He is the director of the undergraduate course on Electrical and Computers Engineering and the vice-director of the master’s degree in Electronics and Telecommunications Engineering. He is an IEEE Senior Member and a member of several other research organizations worldwide. His main research interests are computer vision, intelligent systems, robotics, and image and video processing. He has participated in or coordinated several research projects and received more than thirty-five awards. He has 161 publications to his credit, including books, book chapters, journal articles, and conference papers. He has vast experience as a reviewer of several journals and conferences. As a professor, Dr. Neves has supervised several Ph.D. and master’s students and was involved in more than twenty-five different courses.",institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"11317",title:"Dr.",name:"Francisco",middleName:null,surname:"Javier Gallegos-Funes",slug:"francisco-javier-gallegos-funes",fullName:"Francisco Javier Gallegos-Funes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/11317/images/system/11317.png",biography:"Francisco J. Gallegos-Funes received his Ph.D. in Communications and Electronics from the Instituto Politécnico Nacional de México (National Polytechnic Institute of Mexico) in 2003. He is currently an associate professor in the Escuela Superior de Ingeniería Mecánica y Eléctrica (Mechanical and Electrical Engineering Higher School) at the same institute. His areas of scientific interest are signal and image processing, filtering, steganography, segmentation, pattern recognition, biomedical signal processing, sensors, and real-time applications.",institutionString:"Instituto Politécnico Nacional",institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"428449",title:"Dr.",name:"Ronaldo",middleName:null,surname:"Ferreira",slug:"ronaldo-ferreira",fullName:"Ronaldo Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428449/images/21449_n.png",biography:null,institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"165328",title:"Dr.",name:"Vahid",middleName:null,surname:"Asadpour",slug:"vahid-asadpour",fullName:"Vahid Asadpour",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/165328/images/system/165328.jpg",biography:"Vahid Asadpour, MS, Ph.D., is currently with the Department of Research and Evaluation, Kaiser Permanente Southern California. He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:null,institution:null},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"417317",title:"Mrs.",name:"Chiedza",middleName:null,surname:"Elvina Mashiri",slug:"chiedza-elvina-mashiri",fullName:"Chiedza Elvina Mashiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"352140",title:"Dr.",name:"Edina",middleName:null,surname:"Chandiwana",slug:"edina-chandiwana",fullName:"Edina Chandiwana",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"342259",title:"B.Sc.",name:"Leonard",middleName:null,surname:"Mushunje",slug:"leonard-mushunje",fullName:"Leonard Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"347042",title:"Mr.",name:"Maxwell",middleName:null,surname:"Mashasha",slug:"maxwell-mashasha",fullName:"Maxwell Mashasha",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"2941",title:"Dr.",name:"Alberto J.",middleName:"Jorge",surname:"Rosales-Silva",slug:"alberto-j.-rosales-silva",fullName:"Alberto J. Rosales-Silva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"437913",title:"Dr.",name:"Guillermo",middleName:null,surname:"Urriolagoitia-Sosa",slug:"guillermo-urriolagoitia-sosa",fullName:"Guillermo Urriolagoitia-Sosa",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"435126",title:"Prof.",name:"Joaquim",middleName:null,surname:"José de Castro Ferreira",slug:"joaquim-jose-de-castro-ferreira",fullName:"Joaquim José de Castro Ferreira",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"437899",title:"MSc.",name:"Miguel Angel",middleName:null,surname:"Ángel Castillo-Martínez",slug:"miguel-angel-angel-castillo-martinez",fullName:"Miguel Angel Ángel Castillo-Martínez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"289955",title:"Dr.",name:"Raja",middleName:null,surname:"Kishor Duggirala",slug:"raja-kishor-duggirala",fullName:"Raja Kishor Duggirala",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jawaharlal Nehru Technological University, Hyderabad",country:{name:"India"}}}]}},subseries:{item:{id:"93",type:"subseries",title:"Inclusivity and Social Equity",keywords:"Social Contract, SDG, Human Rights, Inclusiveness, Equity, Democracy, Personal Learning, Collaboration, Glocalization",scope:"
\r\n\tThis topic is dedicated to the efforts and promotion of UNESCO SDG4, the UNESCO initiative on the future of education, and the need for a new social contract for education. It aims to disseminate knowledge on policies, strategies, methods, and technologies that increase the resilience and sustainability of the development of the future of education and the new social contract for education. It will also consider the global challenges such as globalization, demographic change, digital transformation, climate change, environment and the social pillars of sustainable development.
\r\n
\r\n\tResponses to the pandemic and the widespread discontent that preceded it must be based on a new social contract and a New Global Deal for education that ensures equal opportunities for all and respects all people’s rights and freedoms (UNESCO; 2021). Such a new social contract, as proposed by UNESCO, must be based on the general principles underlying human rights - inclusion and equality, cooperation and solidarity, and collective responsibility and interconnectedness - and be guided by the following fundamental principle: Ensure that everyone has access to quality education throughout their lives.
\r\n
\r\n\tWe face the dual challenge of delivering on the unfulfilled promise of ensuring the right to quality education for every child, youth, and adult, as well as fully realizing the transformative potential of education as a pathway to a more sustainable collective future. To achieve this, we need a new social contract for education that eliminates inequities while transforming the future. This new social contract must be based on human rights and the principles of non-discrimination, social justice, respect for life, human dignity, and cultural diversity. It must include an ethic of care, reciprocity and solidarity. The new social contract builds on inclusiveness, equity, lifelong learning, SDG, collaboration and personal learning in a global context for democracy.
\r\n
\r\n\tAt an international level, the adoption of the Open Educational Resources recommendation and the Open Science recommendation represents an important step towards building more open and inclusive knowledge societies as well as the achievement of the UN 2030 Agenda. Indeed, implementing the recommendations will help to achieve at least five more Sustainable Development Goals (SDGs) that are intertwined with the topic of this book series, namely SDG 5 (Gender equality), SDG 9 (Industry, innovation and infrastructure), SDG 10 (Reduced inequalities within and across countries), SDG 16 (Peace, justice and strong institutions) and SDG 17 (Partnerships for the goals).
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/93.jpg",hasOnlineFirst:!1,hasPublishedBooks:!1,annualVolume:11977,editor:{id:"210060",title:"Prof. Dr.",name:"Ebba",middleName:null,surname:"Ossiannilsson",slug:"ebba-ossiannilsson",fullName:"Ebba Ossiannilsson",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6LkBQAU/Profile_Picture_2022-02-28T13:31:48.png",biography:"Professor Dr. Ebba Ossiannilsson is an independent researcher, expert, consultant, quality auditor and influencer in the fields of open, flexible online and distance learning (OFDL) and the 'new normal'. Her focus is on quality, innovation, leadership, and personalised learning. She works primarily at the strategic and policy levels, both nationally and internationally, and with key international organisations. She is committed to promoting and improving OFDL in the context of SDG4 and the future of education. Ossiannilsson has more than 20 years of experience in her current field, but more than 40 years in the education sector. She works as a reviewer and expert for the European Commission and collaborates with the Joint Research Centre for Quality in Open Education. Ossiannilsson also collaborates with ITCILO and ICoBC (International Council on Badges and Credentials). She is a member of the ICDE Board of Directors and has previously served on the boards of EDEN and EUCEN. Ossiannilsson is a quality expert and reviewer for ICDE, EDEN and the EADTU. She chairs the ICDE OER Advocacy Committee and is a member of the ICDE Quality Network. She is regularly invited as a keynote speaker at conferences. She is a guest editor for several special issues and a member of the editorial board of several scientific journals. She has published more than 200 articles and is currently working on book projects in the field of OFDL. Ossiannilsson is a visiting professor at several international universities and was recently appointed Professor and Research Fellow at Victoria University of Wellington, NZ. Ossiannilsson has been awarded the following fellowships: EDEN Fellows, EDEN Council of Fellows, and Open Education Europe. She is a ICDE OER Ambassador, Open Education Europe Ambassador, GIZ Ambassador for Quality in Digital Learning, and part of the Globe-Community of Digital Learning and Champion of SPARC Europe. On a national level, she is a quality developer at the Swedish Institute for Standards (SIS) and for ISO. She is a member of the Digital Skills and Jobs Coalition Sweden and Vice President of the Swedish Association for Distance Education. She is currently working on a government initiative on quality in distance education at the National Council for Higher Education. 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\r\n
\r\n\tThis topic will focus on the current challenges and advantages in the diagnosis and treatment of bacterial infections. We will discuss the host-microbiota relationship, the treatment of chronic infections due to biofilm formation, and the development of new diagnostic tools to rapidly distinguish between colonization and probable infection.
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