Rai staging system.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
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\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"7499",leadTitle:null,fullTitle:"Kinetics of Enzymatic Synthesis",title:"Kinetics of Enzymatic Synthesis",subtitle:null,reviewType:"peer-reviewed",abstract:'Kinetics of Enzymatic Synthesis gives insight into different aspects of chemical reactions that are catalyzed by enzymes. This book is divided into two sections: "Enzyme Kinetics" and "Enzymatic Synthesis". The first section consists of two chapters with a halophilic enzyme kinetics and thermodynamic approach towards analyzing the influence of co-solvents on the Michaelis constants of enzyme-catalyzed reactions. The second section consists of three chapters. Production of isoamyl acetate using the enzymatic synthesis method between acetic anhydride and isoamyl alcohol by having enzyme Candida antarctica Lipase B as catalyst in a solvent-free system is discussed in the third chapter. The integrated scheme with the use of the filtrate from the pretreatment of the CS and the growth conditions of Pleurotus cystidiosus is studied in the fourth chapter. The last chapter of this section provides the conditions of the key parameters in microfluidic systems (residence times, flow rates, concentrations) applied for a sequential process from liquid/liquid extraction of LVV-h7.',isbn:"978-1-78985-030-7",printIsbn:"978-1-78985-029-1",pdfIsbn:"978-1-83881-830-2",doi:"10.5772/intechopen.76270",price:119,priceEur:129,priceUsd:155,slug:"kinetics-of-enzymatic-synthesis",numberOfPages:122,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"ec806ce44e877d1bd8d3dcbf1fbc2f3f",bookSignature:"Lakshmanan Rajendran and Carlos Fernandez",publishedDate:"January 30th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7499.jpg",numberOfDownloads:5137,numberOfWosCitations:7,numberOfCrossrefCitations:4,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:7,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:18,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 21st 2018",dateEndSecondStepPublish:"May 8th 2018",dateEndThirdStepPublish:"July 7th 2018",dateEndFourthStepPublish:"September 25th 2018",dateEndFifthStepPublish:"November 24th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"35190",title:"Prof.",name:"Lakshmanan",middleName:null,surname:"Rajendran",slug:"lakshmanan-rajendran",fullName:"Lakshmanan Rajendran",profilePictureURL:"https://mts.intechopen.com/storage/users/35190/images/system/35190.png",biography:"Dr. L. Rajendran is a Professor at the Department of Mathematics, Academy of Maritime Education and Training (Deemed to be University),Chennai , India. He has published 100(National) and 105(International/SCI) publications. He serves as a reviewer in many International Journals. He completed 6 research projects from various funding agencies in India. More than 35 students completed the Ph.D under his guidance.",institutionString:"Academy of Maritime Education and Training",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"207726",title:"Dr.",name:"Carlos",middleName:null,surname:"Fernandez",slug:"carlos-fernandez",fullName:"Carlos Fernandez",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Dr. Carlos Fernandez is a lecturer in analytical chemistry at Robert Gordon University. He has published over 50 peer-reviewed articles. His research interests focus on the use of voltammetric techniques in analytical chemistry as an electrochemical sensor to detect the following analytes: heavy metals for environmental applications, drugs of abuse, amino acids, and pharmaceutical drugs with and without graphene-based compounds. Furthermore, his research emphasizes the utilization of graphene-based compounds and nanocomposites for energy storage devices. He is also interested in the investigation of corrosion processes using electrochemical techniques.",institutionString:"Robert Gordon University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Robert Gordon University",institutionURL:null,country:{name:"United Kingdom"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"50",title:"Enzymology",slug:"biochemistry-genetics-and-molecular-biology-enzymology"}],chapters:[{id:"63618",title:"Kinetics of Halophilic Enzymes",doi:"10.5772/intechopen.81100",slug:"kinetics-of-halophilic-enzymes",totalDownloads:1389,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Hypersaline environments are those with salt concentrations 9–10 times higher (30–35% of NaCl) than sea water (3.5% of NaCl). At high concentrations of soluble salts, cytoplasm—mainly of bacteria and archaea—is exposed to high ionic strength and achieves osmotic equilibrium by maintaining a cytoplasmic salt concentration similar to that of the surrounding media. Halophilic enzymes are extremozymes produced by halophilic microorganisms; they have similar characteristics to regular enzymes but different properties, mainly structural. Among these properties is a high requirement of salt for biological functions. Furthermore, the discovery of enzymes capable of degrading biopolymers offer a new perspective in the treatment of residues from oil deposits, under typically high conditions of salt and temperature, while giving valuable information on heterotrophic processes in saline environments.",signatures:"Luis Alberto Cira-Chávez, Joseph Guevara-Luna, Marisela Yadira\nSoto-Padilla, Brenda Román-Ponce, María Soledad Vásquez-\nMurrieta and María Isabel Estrada-Alvarado",downloadPdfUrl:"/chapter/pdf-download/63618",previewPdfUrl:"/chapter/pdf-preview/63618",authors:[{id:"128805",title:"Dr.",name:"Luis Alberto",surname:"Cira Chávez",slug:"luis-alberto-cira-chavez",fullName:"Luis Alberto Cira Chávez"},{id:"186307",title:"Dr.",name:"María",surname:"Vásquez-Murrieta",slug:"maria-vasquez-murrieta",fullName:"María Vásquez-Murrieta"},{id:"258387",title:"Dr.",name:"Maria Isabel",surname:"Estrada",slug:"maria-isabel-estrada",fullName:"Maria Isabel Estrada"},{id:"270818",title:"MSc.",name:"Joseph",surname:"Guevara Luna",slug:"joseph-guevara-luna",fullName:"Joseph Guevara Luna"},{id:"270819",title:"Dr.",name:"Marisela Yadira",surname:"Soto Padilla",slug:"marisela-yadira-soto-padilla",fullName:"Marisela Yadira Soto Padilla"},{id:"270820",title:"Dr.",name:"Brenda",surname:"Román Ponce",slug:"brenda-roman-ponce",fullName:"Brenda Román Ponce"}],corrections:null},{id:"63433",title:"Thermodynamic Activity-Based Michaelis Constants",doi:"10.5772/intechopen.80235",slug:"thermodynamic-activity-based-michaelis-constants",totalDownloads:988,totalCrossrefCites:2,totalDimensionsCites:5,hasAltmetrics:0,abstract:"The classical approach towards analysing the influence of co-solvents (i.e., cellular molecules that are chemically inert and do not act as reacting agents) on the Michaelis constants of enzyme-catalysed reactions is empirical. More precisely, reaction kinetics is usually mathematically modelled by fitting empirical parameters to experimental concentration vs. time data. In this chapter, a thermodynamic approach is presented that replaces substrate concentrations by thermodynamic activities of the substrates. This approach allows determining activity-based Michaelis constants. The advantage of such activity-based constants \n\n\nK\nM\na\n\n\n over their concentration-based pendants \n\n\nK\nM\nobs\n\n\n is twofold: First, \n\n\nK\nM\na\n\n\n is independent of any co-solvent added (while \n\n\nK\nM\nobs\n\n\n is not) as long as it does not directly interfere with the reaction mechanism (e.g., inhibitor or activator). Second, known \n\n\nK\nM\na\n\n\n values allow predictions of Michalis constants for different enzymes and reactions under co-solvent influence. This is demonstrated for a pseudo-one-substrate peptide hydrolysis reaction as well as for more complex two-substrate alcohol dehydrogenase reactions.",signatures:"Anton Wangler, Mark Jonathan Bunse, Gabriele Sadowski and\nChristoph Held",downloadPdfUrl:"/chapter/pdf-download/63433",previewPdfUrl:"/chapter/pdf-preview/63433",authors:[{id:"251514",title:"Dr.",name:"Christoph",surname:"Held",slug:"christoph-held",fullName:"Christoph Held"},{id:"265768",title:"Prof.",name:"Gabriele",surname:"Sadowski",slug:"gabriele-sadowski",fullName:"Gabriele Sadowski"},{id:"265769",title:"MSc.",name:"Anton",surname:"Wangler",slug:"anton-wangler",fullName:"Anton Wangler"},{id:"265771",title:"M.Sc.",name:"Mark",surname:"Bunse",slug:"mark-bunse",fullName:"Mark Bunse"}],corrections:null},{id:"64450",title:"Solvent-Free Isoamyl Acetate Production via Enzymatic Esterification",doi:"10.5772/intechopen.81333",slug:"solvent-free-isoamyl-acetate-production-via-enzymatic-esterification",totalDownloads:1011,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Isoamyl acetate is an organic compound which is mainly used as flavor additive in food industries. Traditionally, the food flavor has been produced by extraction from plants, followed by chemical synthesis route which then shifted to biocatalytic route due to consumer’s awareness and inclination toward natural products. This study was carried out to examine the reaction synthesis between acetic anhydride and isoamyl alcohol in the presence of Candida antarctica Lipase-B (CALB) as a catalyst in solvent-free system (SFS). Results show that two reactions took place between acetic anhydride and isoamyl alcohol. The effect of different reaction parameters on the final yield of isoamyl acetate and the optimization of process parameters using a statistical tool were also investigated with response surface methodology (RSM). It was found that the optimum isoamyl acetate yield is at reaction temperature 30°C, acid/alcohol molar ratio 0.10, and enzyme loading 4.14%. The regression coefficient for optimization based on RSM was 0.9961. Errors resulted from model validation is less than 1% and is acceptable for real-life application. RSM model and first principle model were selected to determine the reaction kinetics and yield of reaction for isoamyl acetate. The results showed that RSM model provides a good predication of the esterification system with R2 value of 0.90.",signatures:"Nurhazwani Yusoff Azudin and Syamsul Rizal Abd Shukor",downloadPdfUrl:"/chapter/pdf-download/64450",previewPdfUrl:"/chapter/pdf-preview/64450",authors:[{id:"238365",title:"Associate Prof.",name:"Syamsul Rizal",surname:"Abd Shukor",slug:"syamsul-rizal-abd-shukor",fullName:"Syamsul Rizal Abd Shukor"},{id:"260210",title:"Mrs.",name:"Nurhazwani",surname:"Yusoff Azudin",slug:"nurhazwani-yusoff-azudin",fullName:"Nurhazwani Yusoff Azudin"}],corrections:null},{id:"63010",title:"Obtaining Enzymatic Extract from Pleurotus spp. Associated with an Integrated Process for Conversion of Lignocellulosic Biomass to Bioproducts",doi:"10.5772/intechopen.79848",slug:"obtaining-enzymatic-extract-from-pleurotus-spp-associated-with-an-integrated-process-for-conversion-",totalDownloads:892,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The pretreatment of biomass has been integrated with enzyme production through the recycling of aqueous fractions. A process integrated with Pleurotus cystidiosus was grown, and enzymatic hydrolysis was realized. Samples of every liquid fraction from the fungal growing medium were analyzed to determine the chemical oxygen demand (OCD), glucose (Glu), xylose (Xyl), and total reducing sugars (RS). Separately, to obtain valuable polymers from this integration process, solid hemicellulose and lignin were isolated from the remaining liquid fractions through pH variation. The composition of the samples was determined using scanning electron microscopy (SEM), optical stereoscopic microscopy, and Fourier transform infrared (FTIR) spectroscopy and was compared with commercial homologs. The maximum conversion of cellulose to glucose by the obtained liquid fraction of the fungal medium was 61.3 ± 0.9% of the theoretical conversion yield of the commercial enzyme. Similarly, the conversion of hemicelluloses to xylose was 69.5 ± 1.5%. Finally, in this work, an integrated platform for cellulose, hemicellulose, lignin, enzymatic extract, and sugars production, which also significantly reduces water consumption, was proposed.",signatures:"Alma Hortensia Serafin-Muñoz, Carlos Eduardo Molina-Guerrero,\nBerenice Noriega Luna, Julio César Leal Vaca and Aurelio Alvarez-\nVargas",downloadPdfUrl:"/chapter/pdf-download/63010",previewPdfUrl:"/chapter/pdf-preview/63010",authors:[{id:"246331",title:"Prof.",name:"Carlos Eduardo",surname:"Molina-Guerrero",slug:"carlos-eduardo-molina-guerrero",fullName:"Carlos Eduardo Molina-Guerrero"},{id:"253197",title:"Dr.",name:"Alma Hortensia",surname:"Serafin Muñoz",slug:"alma-hortensia-serafin-munoz",fullName:"Alma Hortensia Serafin Muñoz"},{id:"253200",title:"Dr.",name:"Berenice",surname:"Noriega Luna",slug:"berenice-noriega-luna",fullName:"Berenice Noriega Luna"},{id:"253201",title:"Dr.",name:"Julio Cesar",surname:"Leal Vaca",slug:"julio-cesar-leal-vaca",fullName:"Julio Cesar Leal Vaca"},{id:"261952",title:"MSc.",name:"Aurelio",surname:"Alvarez-Vargas",slug:"aurelio-alvarez-vargas",fullName:"Aurelio Alvarez-Vargas"}],corrections:null},{id:"63025",title:"From a Sequential to a Continuous Approach for LVV-h7 Preparation during Enzymatic Proteolysis in a Microfluidic- Based Extraction Process",doi:"10.5772/intechopen.80228",slug:"from-a-sequential-to-a-continuous-approach-for-lvv-h7-preparation-during-enzymatic-proteolysis-in-a-",totalDownloads:857,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Intensification of process is increasingly interesting in the context of recovery of industrial wastes. Among these compounds, animal blood is underexploited although it is an important source of bioactive peptides. LVV-h7 (LVVYPWTQRF) is one of these bioactive peptides from bovine haemoglobin hydrolysate. Our innovative approach consists of a continuous process involving at microfluidic scale for enzymatic proteolysis of bovine haemoglobin by pepsin, selective extraction of LVV-h7 to an organic solvent during the enzymatic reaction, followed by a second extraction to an aqueous phase for organic solvent recycling. Thus, the obtainment of pure LVV-h7 peptide with an efficient methodology of extraction and solvent recycling was proved.",signatures:"Kalim Belhacene, Ionela Ungureanu, Elena Grosu, Alexandra Blaga,\nPascal Dhulster and Renato Froidevaux",downloadPdfUrl:"/chapter/pdf-download/63025",previewPdfUrl:"/chapter/pdf-preview/63025",authors:[{id:"253535",title:"Prof.",name:"Renato",surname:"Froidevaux",slug:"renato-froidevaux",fullName:"Renato Froidevaux"},{id:"264585",title:"Dr.",name:"Kalim",surname:"Belhacene",slug:"kalim-belhacene",fullName:"Kalim Belhacene"},{id:"264586",title:"Ms.",name:"Ionela",surname:"Ungureanu",slug:"ionela-ungureanu",fullName:"Ionela Ungureanu"},{id:"264587",title:"Ms.",name:"Elena",surname:"Grosu",slug:"elena-grosu",fullName:"Elena Grosu"},{id:"264588",title:"Dr.",name:"Alexandra",surname:"Blaga",slug:"alexandra-blaga",fullName:"Alexandra Blaga"},{id:"264589",title:"Prof.",name:"Pascal",surname:"Dhulster",slug:"pascal-dhulster",fullName:"Pascal Dhulster"},{id:"267268",title:"Dr.",name:"Remi",surname:"Przybylski",slug:"remi-przybylski",fullName:"Remi Przybylski"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"9731",title:"Oxidoreductase",subtitle:null,isOpenForSubmission:!1,hash:"852e6f862c85fc3adecdbaf822e64e6e",slug:"oxidoreductase",bookSignature:"Mahmoud Ahmed Mansour",coverURL:"https://cdn.intechopen.com/books/images_new/9731.jpg",editedByType:"Edited by",editors:[{id:"224662",title:"Prof.",name:"Mahmoud Ahmed",surname:"Mansour",slug:"mahmoud-ahmed-mansour",fullName:"Mahmoud Ahmed Mansour"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10841",title:"Hydrolases",subtitle:null,isOpenForSubmission:!1,hash:"4e868cde273d65a7ff54b1817d640629",slug:"hydrolases",bookSignature:"Sajjad Haider, Adnan Haider and Angel Catalá",coverURL:"https://cdn.intechopen.com/books/images_new/10841.jpg",editedByType:"Edited by",editors:[{id:"110708",title:"Dr.",name:"Sajjad",surname:"Haider",slug:"sajjad-haider",fullName:"Sajjad Haider"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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With an age-adjusted incidence of 4–5 per 100,000 population, chronic lymphocytic leukemia (CLL) is the most common type of leukemia in developed countries. The median age at diagnosis is 72 years, and more men than women (2:1) are affected [1]. CLL is one of the B-cell chronic lymphoproliferative disorders. It is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually monoclonal in origin.
\nCLL diagnosis depends on the presentation. For patients presenting with absolute lymphocytosis; CBC, flow cytometry of the peripheral blood, and examination of the peripheral smear are adequate to diagnose CLL [2]. Diagnosis of CLL using these tests requires identification of absolute B lymphocyte count (B-ALC) >5000/micrL sustained for at least 3 months, morphologically mature-appearing small lymphocytes, and flow cytometry showing the typical immunophenotype of CLL cells: extremely low levels of surface membrane immunoglobulin (SmIg) and either Kappa or Lambda (but not both), CD19, CD20, CD23 and CD5 positive cells. Evaluation of the bone marrow is not usually necessary, but is included in the evaluation of patients with unexplained cytopenias. Patients presenting with lymphadenopathy without lymphocytosis will need ideally an excisional lymph node biopsy or alternatively a needle biopsy showing mature lymphocytes with the previously mentioned phenotype to diagnose small lymphocytic lymphoma (SLL) which is considered by WHO the same disease as CLL with different manifestations [3].
\nMonoclonal B cell lymphocytosis is diagnosed when B-ALC is <5000/micrL persistently with no other manifestations of disease activity such as lymphadenopathy, hepatosplenomegaly, disease related cytopenias, or disease related symptoms. Patients with disease related cytopenias are diagnosed with CLL regardless of B-ALC and patients with any of the other manifestations are considered to have SLL [2]. Before 2008, the diagnosis of CLL was based on ALC equal or more than 5000/microL in the setting of appropriate immunophenotype. Patients with an absolute B lymphocyte count (B-ALC) less than 5000/microL and an ALC more than 5000/microL represented an overlap between CLL and monoclonal B cell lymphocytosis. The switch to using B-ALC for the diagnosis of CLL in 2008 eliminated this overlap [4, 5].
\nCLL is commonly thought of as an indolent disease associated with a prolonged clinical course and that patients with CLL will die from unrelated cause rather than the disease itself. It is important to know that this only happens in one third of the patients. More commonly, patients will have two phases of the disease: an initial asymptomatic phase (5–10 years) where the course will be benign, followed by the terminal phase (1–2 years) where performance status will decline due to recurring need for hospitalization. Some patients die quickly within 1–2 years of the diagnosis. Because of this variable natural clinical course of CLL, there have been always efforts to come up with reliable and clinically applicable criteria that would allow recognizing those patients with poor prognosis to start treatment as soon as possible and improve their survival and differentiate them from the other group where the prognosis is good and treatment can be delayed to avoid treatment toxicity [6, 7, 8].
\nRai and Binet staging systems are the most commonly used systems in practice and the international workshop Group on CLL (iwCLL) recommends using an integrated system using both methods [9]. Both systems depend on findings of CBC and physical exam findings only, addition of CT scan of the chest, abdomen, and pelvis is not routinely recommended to stratify patients.
\nRai staging system divides patients into 5 groups (Table 1). It was published initially in 1975, with initial reports showing one quarter of patients fall in stage 0 on presentation, half of patients fall in stages 1 and 2, and a quarter of them fall in stages 3 and 4. Later reports showed that more patients fall in earlier stages because of earlier diagnosis due to the more routine testing being done in recent years including CBC [10]. Median survival decreases from almost 12 years in stage 0 to a year and a half in stages 3 and 4 [11]. In 1980s, this staging system was modified to include three stages based on actuarial survival pattern: Low risk (Rai stage 0), intermediate risk (Rai stages 1 and 2), and high risk (Rai stage 3 and 4). Of note, if complete or partial remission is achieved with successful therapy, and a patient’s stage shifts from a higher risk to a lower risk category, the outlook for survival improves accordingly [12].
\nStage | \nClinical features | \nMedian survival (in years) | \n
---|---|---|
0 (low risk) | \nLymphocytosis only | \n>10 | \n
I and II (intermediate risk) | \nLymphadenopathy (I) and hepatosplenomegaly (II) | \n5–8 | \n
III and IV (high risk) | \nAnemia (III), thrombocytopenia (IV) | \n1.5 | \n
Rai staging system.
Binet staging system takes into consideration five potential sites of involvement: cervical, axillary, and inguinal lymphadenopathy (each area counts as one either unilateral or bilateral), spleen, and liver, in addition to the presence of anemia and/or thrombocytopenia. Based on these factors, Binet staging system divide patients into three groups (Table 2) [13].
\nStage | \nClinical features | \nMedian survival (in years) | \n
---|---|---|
A | \n<3 areas of lymphadenopathy; no anemia or thrombocytopenia | \nComparable to age-matched controls | \n
B | \nThree or more areas of lymphadenopathy; no anemia or thrombocytopenia | \n7 | \n
C | \nHemoglobin <100 g/L or platelets <100 x 109 g/L | \n2 | \n
Binet staging system.
One important practical concept is to reliably differentiate between autoimmune cytopenias and cytopenias related to CLL because patients with autoimmune cytopenias have better outcome than Binet stage C patients although still worse than stage A and they can normalize their counts with treatments directed at the autoimmune cytopenia thus delay CLL treatment [14, 15].
\nBoth systems are not very effective for predicting early disease progression. Although routine imaging is not recommended for staging of patients with CLL, visceral adenopathy may occur in early-stage disease and might predict an early disease progression. It is not known if the presence of visceral adenopathy warrants any specific change in therapy [16].
\nHistorically, the presence of CD38 by flow cytometry appeared to be independently associated with an adverse prognosis as well as Increased levels of ZAP-70 detected by flow cytometry [17]. It is a tyrosine kinase normally expressed by NK and T cells, and required for normal T cell receptor signaling. ZAP-70 is not normally expressed in B lymphocytes, but has been found in a subset of patients with CLL. The clinical significance of CD38 and ZAP-70 have declined overtime with better understanding of CLL cytogenetics.
\nCurrently, we use cytogenetics, molecular studies, lymphocyte doubling time, and beta-2 microglobulin [18]. Patients with del(13q) have favorable outcome, patients with trisomy 12 have intermediate outcome while patients with del(11q) and del(17p)/P53 have poor outcome. The prognosis of patients with del(11q) has improved with the use of certain treatment regimens (e.g., fludarabine, cyclophosphamide, rituximab) while that of del(17p) or TP53 mutations remains poor despite such treatments. Analysis of CLL8 trial showed worse outcome in patients with SF3B1 and RPS15 gene mutations. Also, patients with complex karyotype and NOTCH1 mutations have more aggressive course.
\nThe lymphocyte doubling time is the number of months it takes the absolute lymphocyte count to double. Doubling time <12 months is associated with a progressive course and a longer doubling time is associated with an indolent course. This factor is somewhat limited in usefulness because it takes time to measure. In patients with early stage disease, the presence of a short doubling time may favor more aggressive therapy. Higher levels of Beta-2 microglobulin (B2M) are associated with poorer outcome. B2M should be interpreted with caution in the context of renal disease, or alternatively GFR-adjusted B2M can be used although lacks validation in prospective studies [19]. Moreover, approximately half of CLL clones will demonstrate unmutated immunoglobulin heavy chain variable regions (IGHV), a finding associated with shorter survival overall and a higher risk of relapse following conventional treatment, including chemoimmunotherapy and hematopoietic cell transplantation [20].
\nAn international group of investigators did a comprehensive analysis [21] to develop a prognostic index for CLL. Using data from 3472 treatment naive patients participating in prospective, randomized clinical trials, five independent prognostic factors were identified: TP53 deletion or mutation, or both, IGHV mutational status, serum B2M concentration, clinical stage, and age. Using weighted grading of the independent factors, a prognostic index was derived that separated patients into four risk groups with significantly different overall survival at 5 years: low (93%), intermediate (79%), high (63%), and very high risk (23%). This chronic lymphocytic leukemia international prognostic index (CLL-IPI) has now been validated by several other groups and is expected to improve patient counseling and the planning of clinical trials. Other risk scores have been proposed, but none of them has been generally accepted. Of note, none of the scores (including the CLL-IPI) affects the decision of when to initiate therapy.
\nIn the 1940’s, steroids were the first systemic therapy for CLL. The risk of infection, other adverse effects from long term steroid use as well as transient nature of responses, steroids do not have a central role in the treatment of CLL. They can be used along with anti-CD 20 Ab to achieve remission in some patients.
\nSteroids were followed by the use of alkylating agent chlorambucil in the treatment of CLL, either in combination or as a single agent. These treatments produced objective response rates but mostly resulted on partial responses [22, 23]. This was followed by a long time period before newer drugs were introduced in the treatment of CLL. Fludarabine has been used in various combinations to improve outcomes in CLL. When compared to CAP (cyclophosphamide, doxorubicin and prednisone), fludarabine showed favorable results [24]. Even when it was compared to chlorambucil, fludarabine induced higher response rates but did not offer any survival advantage at the expense of higher toxicities especially from infection and neutropenia [25]. Cladribine in combination with prednisone achieved response rates similar to fludarabine when compared to chlorambucil but failed to demonstrate any survival benefit [26, 27]. Cyclophosphamide combined with fludarabine in previously untreated patients showed lower prevalence of residual disease and increased progression free survival (PFS) but again no benefit in overall survival (OS) [28]. When rituximab was combined with fludarabine and cyclophosphamide there was an improvement in PFS as well as OS [29]. This was observed across multiple phase 3 randomized trials [30, 31]. Subset analysis of these trials led to the discovery that patients with mutated IGHV status, FCR led to long term remissions [30, 32].
\nIndication for treatment of CLL include severe fatigue, weight loss, night sweats, fever without infection, threatened organ function, progressive lymphadenopathy, anemia or thrombocytopenia that is progressive in nature, autoimmune anemia or thrombocytopenia not responsive to steroids [2]. In addition to these factors, patient age, performance status, presence or absence of del(17p) or TP53 mutation, IGHV mutation status should be assessed prior to initiating treatment in patients with indications to treat. Imaging should be considered as well to evaluate disease burden.
\nThe CLL 8 trial was a pivotal one that established chemoimmunotherapy as the standard of care for patients that can tolerate it. The FCR regimen (fludarabine, cyclophosphamide and rituxan) was compared against FC (fludarabine, cyclophosphamide). Previously untreated CLL patients were randomized to either receive 6 cycles of FCR or FC. The FCR regimen resulted in higher ORR (90% v/s 80%) and CR rates 94% v/s 22%). The median OS was not reached for FCR and was about 86 months for the FC regimen. Subset analysis showed that the maximal benefit was derived by fit patients with CLL, especially those with mutated IGHV [32]. The FCR regimen however has its share of side effects and cannot be given to older patients.
\nThe CCL2M trial looked at the feasibility of Bendamustine-Rituxan (BR) in untreated CLL patients and the results were found to be encouraging [33]. This prompted its comparison to other treatment regimens. The MABLE study looked at BR versus Chlorambucil-Rituxan in patients ineligible to receive fludarabine. Complete response rates were higher in the BR arm (24%) as compared to the chlorambucil-rituxan arm. Overall response rate and overall survival were not different among the two arms. However the PFS (40 months v/s 30 months) and Minimal Residual Disease (MRD) negativity (66% v/s 36%) were higher in the BR arm as compared to the Chlorambucil- rituxan arm [34].
\nCLL10 trial compared BR with FCR. The primary end point was PFS with the objective to assess non inferiority of BR as compared to FCR. The trial confirmed the superiority of FCR therapy (Median PFS 55 vs. 42 months) in fit patients and in patients with IGHV mutated status. However, in patients over 65 years of age the toxicity profile was better with BR.
\nThe CLL11 trial found that chlorambucil-obinutuzumab had better PFS (26.7 months) as compared to rituximab-chlorambucil (16.3 months). The PFS for chlorambucil monotherapy was the shortest (11.1 months). The obinutuzumab-chlorambucil arm also had trend towards OS benefit as compared to the other 2 arms. The study population included CLL patients with comorbidities [35]. Based on these 2 trials both BR and chlorambucil- rituxan or obinutuzumab-chlorambucil are acceptable alternatives in elderly patients or those with comorbidities.
\nOn a similar note, the COMPLEMENT 1 trial showed the combining ofatumumab to chlorambucil in fludarabine ineligible patients showed better PFS (22.4 months) as compared to the monotherapy arm (13.1 months) [36].
\nHowever, with the advent of novel agents the landscape of treatment in CLL has significantly changed. The RESONATE-2 study compared single agent chlorambucil to ibrutinib which is a Bruton’s Tyrosine Kinase inhibitor. The ORR (92% v/s 36%) as well as PFS at 2 years (89% v/s 34%) in favor of ibrutinib (Figure 1). Based on the results of this study ibrutinib was approved for use in the first line setting of CLL. Results from the ECOG ACRIN Cancer research group trial E1912 were recently published. The study compared FCR versus Ibrutinib + Rituxan (IR) in treatment naive patients without deletion 17p. IR was found to be superior to FCR in all subgroups except for the IGHV mutated group. IR group saw significant less neutropenia and infectious complications as well as compared to FCR [38].
\nProgression-free survival of Ibrutinib vs. Chlorambucil [
The alliance intergroup study showed that in older patients above 65, ibrutinib should be the standard of care as PFS was better in the ibrutinib arms then the BR arms [39]. However this study did not suggest a benefit of adding anti-CD 20 MAB therapy to ibrutinib monotherapy. In the older patient group, where chlorambucil is a treatment option, the iLLUMINATE trial showed that ibrutinib plus obinutuzumab combination resulted in better PFS as compared to chlorambucil plus obinutuzumab, albeit with greater serious adverse events [40]. Between the RESONATE-2 study and ECOG ACRIN study, ibrutinib has been established a first line recommendation in both younger as well as older patients with CLL.
\nRecently, CLL14 trial studied the combination of fixed-duration venetoclax and obinutuzumab versus obinutuzumab and chlorambucil in 432 treatment-naïve patients with CLL and coexisting medical conditions. Patients were evenly randomized to receive 12 months of venetoclax alongside 6 months of obinutuzumab or 6 months of obinutuzumab followed by 6 months of chlorambucil. Results from the trial showed the venetoclax combination reduced the risk of disease progression or death by 67% versus obinutuzumab plus chlorambucil in patients with treatment-naïve CLL and co-existing medical conditions (HR, 0.33; 95% CI, 0.22-0.51; P < .0001). The overall response rate (ORR) was 85% with venetoclax/obinutuzumab versus 71% in the control arm (P = .0007). The complete response (CR) or CR with incomplete hematologic recovery (CRi) rates were 50% versus 23%, respectively. The rate of minimal residual disease (MRD)-negativity in the bone marrow was 57% in the venetoclax arm compared with 17% in the obinutuzumab/chlorambucil arm. The MRD-negativity rates in the peripheral blood were 76% versus 35%, respectively. Venetoclax and obinutuzumab combination is the only chemotherapy-free option with fixed duration that proven to provide such a durable response.
\nIbrutinib provides durable responses and is well tolerated in patients with del(17p). Historically this group of patients generally have poorer outcomes as compared to patients with CLL but without del(17p) [41]. Other treatments in the front-line setting are listed in NCCN for these patients however none of them are very effective. The CAPTIVATE trial is currently on going looking at venetoclax along with ibrutinib in the upfront setting.
\nIs summary, as far as front line therapy is concerned, for fit patients with IGVH mutated status it is reasonable to use chemo-immunotherapy such as FCR or BR. All other patients including young or older patients with high risk disease such as those with unmutated IGHD, 17p del or p53 mutation or 11q deletion it’s recommended to treat with a novel agent such as ibrutinib as there has been accumulating evidence of better efficacy when compared to chemoimmunotherapy alone.
\nThe International Workshop on CLL (iwCLL) defines relapsed disease when it occurs in patients who have previously achieved either a complete or partial remission but then develop progressive disease after a period of 6 months or more. Patients who fail to achieve either a partial or complete remission with therapy or those who develop disease progression within 6 months of last therapy are defined to have refractory disease. This distinction is principally made because many patients with progressive disease occurring later after the discontinuation of treatment can be successfully retreated using the same medication, or by switching to other available treatments. In contrast, patients who have refractory disease are unlikely to respond to a trial of the previously used therapy and have a much poorer prognosis [2]. Of note, The iwCLL response criteria were originally developed using data from patients treated with single agents (i.e., fludarabine, chlorambucil). As first-line therapy has evolved, the overall response rate and median progression-free survival have increased. The definitions of relapsed and refractory disease will likely change as therapy improves especially that we depend on expected progression free survival (PFS) in practice more than the 6 months rule to choose the next regimen as illustrated below.
\nThe choice of treatment at relapse should consider how soon the relapse happens after initial treatment. If it happens sooner than the expected median PFS for the specific regimen is considered “Early relapse”, while it is considered “Late relapse” when it happens after the expected median PFS [42]. Prospective trials have reported median PFS for different regimens, as a rule of thumb, progression within 2–3 years of initial treatment with fludarabine, cyclophosphamide, and rituximab (FCR) or within 1 year of other chemoimmunotherapy regimens may be considered to have early relapse.
\nFor early relapsing CLL, it’s recommended to start a targeted therapy with either ibrutinib, idelalisib plus rituximab, or venetoclax with or without rituximab rather than retreatment with the prior therapy or a trial of another chemoimmunotherapy regimen. One series reported the median survival of 42 patients unresponsive to fludarabine as 48 weeks and only 11% responded to other chemoimmunotherapies [43]. The optimal length of treatment has not been defined but common practice to continue until disease progression or unacceptable toxicity.
\nIbrutinib: it is a common treatment of choice for patients with refractory or early relapsing disease. Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor [44]. The RESONATE trial which is a multicenter open label phase III trial showed better overall response rate (ORR), PFS, and overall survival (OS) compared to ofatumumab (an anti-CD20 monoclonal antibody) in patients with refractory/relapsed CLL, these benefits were found across all subgroups of patients, including those with high-risk features such as del(17p). This late observation was confirmed in the RENONATE-17 trial in 2016 where ORR was 83% at a median follow up of 28 months in 144 patients with relapsed/refractory CLL/SLL with del(17p) [45, 46]. Expected side effects from ibrutinib include diarrhea, fever, and nausea. Higher rates of atrial fibrillation (6–16%) and pneumonitis were noted in the clinical trials [47], atrial fibrillation is usually manageable without discontinuation of the drug. Another important side effect is increased risk of bleeding, ibrutinib should be used with caution if patient is on one anti-platelet medicine and should be avoided if on two anti-platelets or anticoagulants as fatal cases of bleeding happened in those scenarios. Also, Ibrutinib should be discontinued 3–7 days before and after surgery to decrease risk of perioperative bleeding. Patients should be also reminded to avoid NSAIDs [48]. Ibrutinib is associated with a usually “transient” lymphocytosis that peaks after approximately 4–8 weeks and resolves in the majority despite continued drug exposure with a median duration of 14 weeks. The starting dose of ibrutinib is 420 mg orally once daily, except for patients with mild liver impairment (child-pugh class A), the starting dose is reduced to 140 mg daily since it’s metabolized in the liver and is contraindicated in moderate to severe liver impairment.
\nIdelalisib: It is an oral inhibitor of phosphoinositide 3′-kinase (PI3K) delta. It is given in combination with Rituximab. A phase 3 multicenter trial compared Idelalisib and rituximab vs. placebo and rituximab in 220 patients with relapsed CLL showed superior ORR, PFS, and OS (81%, 93%, and 92%, respectively), these benefits were seen in all prespecified subgroups, including those with 17p deletion, TP53 mutation, and IGHV mutations [49]. Possible side effects include: pneumonia and febrile neutropenia most commonly, but also fatigue, nausea, and diarrhea have been reported. Idelalisib can cause severe elevations in AST and ALT, it is reversible on holding the drug and never led to permanent discontinuation in clinical trials. The starting dose is 150 mg twice daily. Other possible combinations are Idelalisib plus Bendamustine plus Rituxan or idelalisib plus ofatumumab, those combinations led to more grade 3 toxicities and treatment related deaths, respectively, so extreme caution should be paid while choosing patients for these combinations [50, 51]. As with ibrutinib, idelalisib can cause transient lymphocytosis that peaks in the second week of treatment and resolves spontaneously by week 12, adding Rituximab decrease its severity and shortens its duration. CMV monitoring and prophylaxis against Pneumocystis pneumonia (PCP) are important with idelalisib use. It carries a boxed warning regarding hepatotoxicity, colitis, and pneumonitis.
\nDuvelisib: it is an oral inhibitor of PI3K delta and gamma isoforms. The phase 3 DUO trial was the largest trial to study the efficacy of duvelisib, it included 319 patients assigned to duvelisib vs. ofatumumab. Duvelisib had higher ORR and median PFS (74% and 13.3 months, respectively) [52]. Duvelisib is usually reserved for patients with multiply relapsed disease, usually after treatment with ibrutinib and venetoclax, with or without prior chemoimmunotherapy. The starting dose is 25 mg administered orally twice a day over a 28-day treatment cycle. Toxicities include opportunistic infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Hepatic function and blood counts must be monitored for hepatotoxicity and neutropenia. Like idelalisib, it is recommended to use PCP and CMV prophylaxis.
\nVenetoclax: it is an oral inhibitor of BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of CLL cells. Initial phase 2 trials showed ORR more than 65% for venetoclax [53, 54]. The MURANO trial, an international phase 3 trial, compared Venetoclax plus rituximab vs. bendamustine plus rituximab in 389 patients with relapsed/refractory CLL showed higher PFS of 85% and OS of 92% at 2 years for the venetoclax arm, this effect was maintained in high risk patients and older adults. Patients assigned to venetoclax arm were also more likely to achieve undetectable minimal residual disease (uMRD) which is a status predictive of superior PFS [55]. The most common toxicities are pancytopenia, diarrhea, and upper respiratory tract infection. Because venetoclax increases risk of TLS, high risk patients (i.e. any lymph node >10 cm or lymph node >5 cm and ALC >25 x 109/L) should receive the first few doses in the inpatient setting with IV hydration, use of allopurinol or rasburicase, and frequent monitoring of TLS labs. Venetoclax is started at 20 mg daily and increased gradually over 5 weeks to a final daily dose of 400 mg. Rituximab is started after the patient has completed the escalation schedule and received the 400 mg dose for 7 days. It is common practice to use venetoclax after ibrutinib failure.
\nAlthough both options are valid in late relapsed CLL patients, each option has its advantages and disadvantages. Targeted therapy is generally the preferred option because they have better PFS and may improve OS, the best example on that is the MURANO trial mentioned above, patients who relapsed after 24 months of initial treatment with bendamustine and rituximab were included in the study, and still they had better PFS and OS [55]. Targeted therapy also offers the convenience of an oral regimen. On the other hand, retreatment with initial chemoimmunotherapy regimen may be considered for patients who experienced minimal toxicity with the initial treatment, targeted therapy is associated with unique toxicities and is often administered without breaks until the time of progression. In a phase 2 study, patients who were initially treated with FCR and relapsed after 3 years showed median survival of 5 years and estimated five-year survival rate of 70% when they were retreated with FCR, although the toxicities, especially myelosuppression, were more frequent [56].
\nPatients with CLL experience serial relapses and many will be treated with each of these agents at some point during their disease course. A preferred order for their use has not been established. A choice is primarily made based on the patient’s prior treatment and the regimens’ expected toxicities.
\nIn the setting of approval of novel agents in the treatment of CLL the number of transplants that are being performed in Europe and the United States are decreasing. In the chemoimmunotherapy era, patients with TP53 deletion/mutation, fludarabine refractoriness, early relapse (<24 months) after FCR treatment were in the highest risk group. Allogeneic Stem Cell Transplant (SCT) would be considered in these patients as the only viable treatment option. Today however, these patients have ibrutinib, idelalisib and venetoclax and various combination of novel agents with immunotherapy as possible treatment options. There are no randomized clinical trials that compare the outcomes of allogeneic SCT with conventional chemotherapy, chemoimmunotherapy or novel therapy regimens. Most transplants offered for CLL use reduced intensity conditioning (RIC), however no trials have been conducted to compare it to myeloablative conditioning. RIC resulted in reduced toxicity without compromising engraftment and anti-tumor activity [60]. Follow up results for studies with RIC indicate that about 40% of patients achieve long term disease control and RIC also overcomes the negative prognostic effect of TP53, fludarabine refractoriness as well as that of SF3B1 and NOTCH gene mutations [61, 62, 63]. Generally, allogeneic transplants are no longer offered to patients with del(17p) in first remission. In the relapsed setting the role of SCT must be weighed against the comorbidities, prior therapies, and duration of response to prior therapies as well as current mutation status including TP53, NOTCH1 and SF3B1. Patient must be informed about the side effect profile and non-relapse mortality associated with allogeneic transplant compared to the toxicity and side effect profile of novel agents. (Figure 2).
\nHematopoietic SCT for CLL by year [
MRD in CLL is assessed most commonly using multiparametric flow cytometry with a sensitivity to detect <1 CLL cell in 10,000 leukocytes. MRD – undetectable (MRD-U) has been defined detection of <1 CLL cell per 10,000 leukocytes [2]. MRD-U in the blood or bone marrow strongly correlates with longer PFS in the patients treated with chemoimmunotherapy has been noted in numerous studies [30, 57, 64]. However, MRD- U is rarely achieved in patients who are on ibrutinib, a drug that offers significant clinical benefit in PFS and survival in CLL patients [66]. So, there is consensus that while MRD- U is generally a favorable outcome for patients but its exact use case scenario in clinical practice is yet to be determined. As of now the potential use of MRD status in CLL patients is in the context of clinical trials, as a surrogate for PFS depending on the type of treatment used and possibly as a replacement for clinical and radiographic response assessments in the future.
\nMaurice Richter initially described the transformation of CLL into an more aggressive form of lymphoma and since then this has been recognized as Richter’s Transformation (RT) [67]. In most cases RT consists of transformation of CLL into Diffuse Large B Cell Lymphoma (DLBCL), however other aggressive lymphomas have been reported. As of now the reported incidence of RT in the era of novel agents is not very different from the incidence of RT in the chemoimmunotherapy era [68, 69] with incidence rates varying from 3–20% among various studies. RT is suspected when there is rapid clinical deterioration, worsening discordant lymphadenopathy to new onset cytopenia. However, its presentation can be varied. When RT is suspected a comprehensive evaluation with a PET/CT, image guided biopsy as well as a bone marrow biopsy is required. SUV of greater than 10 can distinguish RT form CLL with high sensitivity (91%) and specificity (95%) [70]. However, this has been disputed in the setting of novel agents and thus a concern for RT necessitates a biopsy of the index lesion preferably. RT primarily arises in the background of TP53 disruption and complex karyotype. MYC activation and CDKN2A/B likely play an important role in RT. Clonally related RT patients (>80% of RT DLBCL) respond very poorly to traditional chemotherapy for DLBCL, whereas clonally unrelated DLBCL RT patients respond to traditional chemotherapy just as de novo DLBCL. Thus, determination of clonal evolution is important but difficult to determine [71].Trials performed prior to the use of novel agents used R-CHOP or similar regimens as the standard therapy to treat RT. Fit patients who achieve a complete response or good partial response achieve benefit from a post induction strategy involving stem cell transplant [72]. Novel combinations, PDL-1 blockade and CAR-T or bispecific antibodies are being currently investigated as potential treatment options [72]. Figure 3 below shows a suggested treatment approach algorithm for suspected patients with RT.
\nRichter transformation. Adapted by ASH education handbook [
Hypogammaglobulinemia is the most predominant inherent immune defect in CLL patients, with subtypes IgG3 and IgG4 particularly affected. Hypogammaglobulinemia becomes more pronounced with longer disease duration and advanced-stage disease. There is generally no reversal in this defect, even with response to therapy. However, in one report, ibrutinib therapy resulted in partial reconstitution of humoral immunity, with an increase in IgA levels [73]. The most common site of infection in CLL patients is the respiratory tract, which may be related to serum IgA and IgG4 deficiencies and possibly to mucosal immune defects. The majority of patients with CLL will develop hypogammaglobulinemia at some point in the course of their disease. The use of prophylactic intravenous immunoglobulin (IVIG) to restore IgG levels is controversial. For most patients with CLL, prophylactic IVIG is
CLL is frequently associated with autoimmune phenomena, the most common being autoimmune hemolytic anemia (AIHA) [75]. Up to 33% of CLL cases have a positive direct antiglobulin test (DAT) during the course of disease, but overt AIHA occurs much less frequently. In a report of 1203 patients with CLL consecutive cases reported from a single institution, 52 (4.3%) cases of AIHA were observed, 19 at the time of diagnosis [76]. The prevalence of AIHA in patients with CLL have been reported in the range of 4–10%. It increases with disease stage. The autoantibodies that cause AIHA can be produced by nonmalignant B cells or, less commonly, by the malignant CLL clone itself [77, 78]. In practice, AIHA may occur in patients with no other requirement for treatment, or in patients in whom chemotherapy treatment is imminent or already started. Factors associated with an increased risk of development of AIHA at diagnosis included a high white blood count, older age, and male sex. AIHA alone was not itself associated with poor prognosis. The diagnosis of AIHA is usually based on the presence of an isolated fall in hemoglobin associated with a positive DAT, increased reticulocytes, and serum bilirubin. There have been no controlled trials of treatment for AIHA in CLL and the treatment approach is based on personal and institutional experience. In general, AIHA is responsive to CLL treatment, but if there is no indication to treat CLL, AIHA should be treated as a separate entity with steroids and other immune suppressants, the details of which is beyond the scope of this chapter. There has been controversy whether some chemotherapy agents, particularly purine analogs, induce or worsen AIHA. In a trial comparing outcomes of treatments using chlorambucil, fludarabine, or fludarabine in combination with cyclophosphamide, a positive DAT was found in 14%, and AIHA occurred in 10% of patients [75]. AIHA occurred more often in patients treated with chlorambucil than fludarabine, and occurred least frequently in patients receiving the combination of fludarabine and cyclophosphamide. For patients requiring therapy, a positive DAT test had poor prognostic significance, even in the absence of AIHA. The results suggest that the most successful treatment of AIHA in patients requiring chemotherapy treatment is the treatment associated with the best response rate.
\nIn summary, there has been a significant change in how we manage patients in CLL over the last 5 years. We have shifted away from chemoimmunotherapy towards novel agents such as BTK, PIK3, and BCL-2 inhibitors, which are not only more efficacious but are also safer and better tolerated. New prognostic models are being developed, and it appears that MRD directed therapy will become the norm in the future. Many clinical trials are looking at various combinations of novel therapies, with a defined period of treatment based on MRD analysis, to enable patients to have a period of treatment-free remission instead of continuous therapy.
\nOptimization algorithms are systems that determine an optimal set of parameters that minimize or maximize a cost, or objective, function subject to constraints. Optimization applications are common in engineering and other scientific and mathematical fields. For a typical engineering optimization application, a cost, or objective, function mathematically describes a metric of the error between a desired performance and actual performance over a constrained solution space. For such applications, optimization algorithms would determine an optimal set of parameters that minimize the cost function subject to physical constraints, such as the optimal parameters result in a stable system. As computing power has increased, many multi-modal optimization problems have been solved using heuristic evolutionary optimization algorithms. An evolutionary algorithm is an optimization search algorithm that is loosely based on the principles of evolution and natural genetics and uses operators such as reproduction, selection, recombination and mutation [1]. Popular evolutionary algorithms include genetic algorithms [2], differential evolution [3], particle swarm optimization [4], simulated annealing [5] and colony optimization [6, 7]. Although no algorithm can solve all types of optimization problems [8, 9], genetic algorithms and differential evolution algorithms have become popular in engineering optimization applications because these method are simple, effective and flexible.
Because no algorithm can solve all types of optimization problems [8, 9], hybrid algorithms that combine the elements of an evolutionary algorithm with one or more evolutionary algorithms or search algorithms have been developed and have been shown to be effective search algorithms [10]. Because genetic algorithms and differential evolution algorithms have become popular in engineering optimization applications, this chapter presents a hybrid genetic, differential evolution algorithm. The algorithm uses an elitist, ranking, random selection method. Elitist selection methods assure the survival of the fittest individual, which is the candidate solution with the best optimization criterion cost, during the selection process. The fittest individual is also assured selection in all recombination and mutation operations. Except for the fittest individual which is guaranteed selection, the candidate solutions that survive the selection process are randomly selected for a differential evolution operator to improve convergence, a differential evolution mutation operator to improve diversity and a recombination operator that improves both convergence and diversity. The selection probabilities for the mutation and recombination operators are dynamic and change each generation, or algorithm iteration, to maintain a constant population size. After generating new candidate solutions using these operators, the new candidate solutions are added to the set of candidate solutions that survived the selection process. Except for the fittest individual (which is guaranteed selection), candidate solutions are randomly selected for Taguchi crossover [11] which is an effective recombination operator that creates near optimal new candidate solutions from two or more parent candidate solutions. Section 2 of this chapter describes the basic elements of genetic and differential evolution algorithms. Section 3 describes this chapter’s algorithm in detail. In Section 4, this algorithm is applied to 13 commonly used global numerical optimization test functions, including a spherical, three hyper-ellipsoid, the sum of different powers, Rastrigin’s, Schwefel’s, Griewank’s, Rosenbrock’s valley, Styblinski-Tang, Ackley’s Path, Price-Rosenbrock, and Eggholder’s functions.
Genetic algorithms and differential evolution algorithms are evolutionary algorithms that typically define objective functions so that the set of parameters being optimized are represented in a vector [3]. Parameter constraints are implemented by restricting the available solution spaces for each parameter in the vector. The basic design strategy for such genetic and differential evolution algorithms is to determine evolutionary operators that balance the algorithm’s ability to both effectively search the solution space and converge to an optimal solution.
Genetic algorithms and differential evolution algorithms typically begin by randomly selecting
Initialize population {
Select
Generate new candidate solutions using a mutation operator
Generate new candidate solutions using a recombination operator
Add the new
where
Genetic operators such as recombination and mutation generate a combination of new candidate solutions that can be either similar or diverse from the candidate solutions in the mating pool. Controlling the ratio of the diversity and similarity of new candidate solutions added to a population each generation is a fundamental design parameter of any search algorithm [14]. Creating diversity, or exploration, is the process of generating candidate solutions that lie in previously unevaluated regions of the search space. Creating similarity, or exploitation, on the other hand, is the process of generating candidate solutions within a neighborhood of previously visited points so as to converge to an optimal point in the neighborhood. Exploration and exploitation are typically conflicting processes of a search algorithm because a lack of diversity can result in a population converging to a local minima or maxima and a lack of similarity can impede convergence. Therefore, every search algorithm needs to design an effective ratio of exploration and exploitation of a search space. In general, an optimal ratio of diversity and similarity is not only dependent on the search algorithm but also the cost, or objective, function. For example, determining the optimal solution of a unimodal objective function typically requires less exploration than determining an optimal solution of a multi-modal objective function that typically requires more exploration. Also, different generations, or iterations, of a search algorithm typically have a different optimal ratios of exploration and exploitation. For example, a search algorithm’s early generations require more exploration than exploitation until the neighborhood of the optimal solution is found. After the neighborhood of the optimal solution is found, a search algorithm’s generations require more exploitation and less exploration. Therefore, the goal of any search algorithm is to design a ratio of adding diverse new candidate solutions and similar new candidate solutions to each generation so that the algorithm can effectively determine optimal solutions for different types of objective functions.
Genetic algorithms and differential evolution algorithms typically use three operators, selection, mutation and recombination, for controlling the ratio of adding diverse and similar new candidate solutions to their populations. Selection operators control the ratio of exploration and exploitation by varying the selection process. A selection operator that is designed to select the most fit candidate solutions, the candidate solutions with the best costs when evaluated with respect to the optimization criterion, biases the selection process away from exploration and towards exploitation. A selection operator that is designed to select the least fit candidate solutions biases the selection process away from exploitation and towards exploration.
Mutation operators for a typical genetic algorithm or differential evolution algorithm randomly modify individuals from the mating pool to increase the diversity of a population. As a result, a typical mutation operator increases the exploration of unevaluated regions of the search space. However, some mutation operators only slightly alter individuals from the mating pool. In such cases, these types of mutation operators can be classified as an exploitation operator because most of the mutated individual is preserved and the mutated individual still remains in the neighborhood of the parent candidate solution. A recombination operator for a typical genetic algorithm or differential evolution algorithm combines two or more parent individuals, or candidate solutions, from the mating pool to generate a new and possibly more fit candidate solution. As a result, a typical recombination operator generates new candidate solutions within a neighborhood of the parent candidate solutions. From this perspective, a recombination operator increases exploitation and improves the convergence of the algorithm. However, when recombination uses a mutated candidate solution, recombination can create a new candidate solution in a previously unevaluated region of the search space. In such cases, recombination operators can improve exploration of the search space. In most cases, mutation operators improve a population’s diversity and recombination operators improve an algorithm’s convergence rate; however, in practice, the combination of selection, mutation and recombination determines the ratio of exploration and exploitation in both genetic algorithms and differential evolution algorithms.
This hybrid genetic, differential evolution algorithm determines a best solution with respect to an optimization criterion that has a solution space which is the subset of an
Initialize population {
Ranking and stochastic selection {
Differential evolution operator to improve convergence
Differential evolution mutation operator to improve diversity
Recombination operator to improve convergence and diversity
Ensure new solutions are in the solution space
Taguchi crossover {
where
To generate the initial population of
where
This selection of initial candidate solutions can be adapted for other types of
where
If appropriate, these initial candidate solutions could be converted to rectangular coordinates using
This algorithm uses an elitist, linear ranking, random selection method. Because the selection operator is elitist, the fittest individual, or the candidate solution vector with the best optimization criterion cost, is guaranteed to survive the selection process. Elitist selection algorithms can increase an algorithm’s exploitation and therefore increase the algorithm’s ability to converge, especially when steady-state misadjustment is significant [15]. Linear ranking selection methods evaluate each candidate solution by the cost function and rank the candidate solutions according to their costs [16, 17]. Starting with the candidate solution with the best cost, each candidate solution is assigned a selection probability in linearly decreasing increments so that all candidate solutions have a nonzero probability of selection. This method of selection allows diverse candidate solutions that might contain useful vector elements but have a poor cost to survive the selection process. This can improve an algorithm’s exploration and prevent the algorithm from converging in a local minima or maxima.
The selection operator is the first operation performed for each generation, or iteration of the algorithm. At the start of the algorithm’s
where
Because this algorithm uses an elitist selection method, the best candidate solution is assured survival during the selection process which implies that
Substituting Eq. (6) into Eq. (5), and the resulting equation into Eq. (7),
Solving Eq. (8), an elitist selection method requires that
where
The set of surviving candidate solutions are referred to as the mating pool. After this selection method, the mating pool’s mean size is
where
which is the expected number of candidate solutions that survive this elitist linear ranking selection process during the
Differential evolution algorithms generate new candidate solutions by adding a weighted difference between two randomly selected candidate solutions to a third randomly selected candidate solution. For this algorithm, the differential evolution operator to improve convergence generates a new candidate solution,
where
Because this algorithm is an elitist algorithm, the best candidate solution,
A plot showing an example of the differential evolution operator that improves convergence for a two dimensional cost function,
On average, this operator creates
new candidate solutions.
Because differential evolution algorithms generate new candidate solutions by adding a weighted difference between two randomly selected candidate solutions to a third randomly selected candidate solution, the differential evolution operator creates new candidate solution vectors that contain elements that are different from the candidate solutions that formed the new solution vector. As a result, the differential evolution operator is often referred to as a mutation operator whether the operator creates similarity or diversity. In this chapter, the differential evolution operator that increases diversity is referred to as the differential evolution mutation operator.
For this algorithm, the differential evolution mutation operator generates a new candidate solution,
where
Because this algorithm is an elitist algorithm, the best candidate solution,
The mean number of mutant solutions created by this process is
Taguchi crossover can greatly increase convergence rates [11, 18]. As a result, when the differential evolution operators discussed earlier are combined with Taguchi crossover, this algorithm can converge too quickly. To prevent this algorithm from converging too quickly into a local minima or maxima, a recombination operator that creates a pair of new candidates is added to this algorithm. To improve convergence, this recombination operator generates a new candidate solution,
To improve diversity, this recombination operator generates the another candidate solution by circularly shifting the elements of the newly formed candidate solution,
Because this algorithm is an elitist algorithm, the best candidate solution,
new candidate solutions.
A candidate solution is considered infeasible if it does not lie within the solution space. If a new candidate solution is infeasible, that solution is made feasible by one of two methods. If a convergence operator, such as the differential evolution for convergence or the recombination operator for convergence, creates an infeasible candidate solution, the infeasible solution vector is moved to the nearest edge of the solution space by changing the vector’s elements that lie outside solution space to the nearest edge of the solution space. This method attempts to generate feasible solutions within the neighborhood of the original infeasible solution so that the intent of the convergence operator that created the infeasible solution is maintained.
If a diversity operator, such as the differential evolution mutation for diversity operator or the recombination operator for diversity, creates an infeasible solution, the infeasible solution vector is moved into the solution space by performing a spatially circular shift of the infeasible solution vector’s elements. For example, if an infeasible solution,
where
where
A crossover operator is a recombination operator that combines the elements from two or more parent candidate solutions to generate a new offspring candidate solution. Taguchi crossover generates new candidate solutions by intelligently selecting elements from the two or more parent solutions vectors [11]. Taguchi crossover is a simple design of experiments method that creates a near optimal candidate solution from the parent candidate solutions. Consequently, Taguchi crossover can greatly increase an algorithm’s rate of convergence [11, 18].
Before selecting candidate solutions for Taguchi crossover, all new candidate solutions created by the other operators are added to the mating pool. The mean number of candidate solutions in the mating pool at this stage can be obtained by summing Eq. (14), Eq. (15) and Eq. (18) which implies that the mean number of candidate solutions in the mating pool at this stage is
where
Because this is an elitist algorithm, the best candidate solution is always selected for Taguchi crossover. The other candidate solutions from the mating pool are selected randomly for Taguchi crossover with a probability of
On average, the Taguchi crossover operator creates
new candidate solutions.
Because the selection operator, the differential evolution operators, the recombination operators and Taguchi crossover operator generate a random number of new candidate solutions, the population size and mating pool size vary each generation, or iteration of the algorithm. After the Taguchi crossover operator, the average number,
To maintain the population’s size,
Substituting Eq. (23) into Eq. (24) and solving for
where
To evaluate this algorithm’s ability to solve optimization problems, the algorithm was applied to 13 commonly used global numerical optimization test functions. Table 1 lists these 13 cost functions,
Function | Solution space |
---|---|
Optimization test functions and their solution spaces.
A plot of the two dimensional Schwefel’s function.
A plot of the two dimensional Eggholder’s function.
For all functions and dimensions, the initial population,
Cost Fn | Mean Iter St Dev Iter | Mean St Dev Evals | Mean Iter St Dev Iter | Mean St Dev Evals. | |||||
---|---|---|---|---|---|---|---|---|---|
43 | 30 | 3950 | 4250 | 130 | 105 | 58,000 | 90,300 | ||
22 | 17 | 2000 | 2400 | 4 | 3 | 2600 | 4200 | ||
45 | 31 | 4150 | 4300 | 137 | 110 | 61,000 | 94,400 | ||
22 | 17 | 2050 | 2400 | 4 | 3 | 2500 | 4300 | ||
44 | 39 | 4000 | 5450 | 1170 | 975 | ||||
15 | 20 | 1350 | 2800 | 1540 | 1650 | ||||
68 | 71 | 6200 | 9950 | 6917 | 2990 | ||||
34 | 33 | 3150 | 4700 | 1520 | 765 | ||||
42 | 33 | 3800 | 4700 | 922 | 343 | ||||
17 | 15 | 1600 | 2200 | 108 | 47 | 48,550 | 40,200 | ||
31 | 24 | 2800 | 3300 | 84 | 65 | 37,500 | 55,400 | ||
12 | 10 | 1150 | 1450 | 4 | 3 | 2420 | 3450 | ||
40 | 33 | 3650 | 4500 | 155 | 100 | 86,350 | |||
6 | 5 | 550 | 650 | 12 | 7 | 6200 | 6600 | ||
39 | 35 | 3550 | 4900 | 90 | 77 | 40,300 | 65,700 | ||
19 | 18 | 1750 | 2600 | 4 | 4 | 2500 | 4650 | ||
65 | 67 | 5950 | 9500 | 14,325 | 5776 | ||||
82 | 88 | 7500 | 12,500 | 6920 | 4804 | ||||
31 | 26 | 2850 | 3650 | 105 | 70 | 47,000 | 60,000 | ||
3 | 3 | 300 | 450 | 6 | 3 | 2650 | 3250 | ||
40 | 28 | 3700 | 3900 | 110 | 72 | 49,600 | 61,400 | ||
22 | 16 | 2050 | 2250 | 17 | 16 | 7400 | 14,200 | ||
19 | 18 | 1750 | 2550 | NA | NA | NA | NA | ||
24 | 19 | 2200 | 2700 | NA | NA | NA | NA | ||
869 | 881 | NA | NA | NA | NA | ||||
1068 | 1162 | NA | NA | NA | NA |
Results for the optimization of the 2-D and 35-D test functions where
The number of cost function evaluations that the algorithm required to converge can also be calculated as a function of the algorithm’s average population size, average mating pool size and operator probabilities. For example, 2-D functions require four cost function evaluations for two level Taguchi crossover and nine cost function evaluations for three level Taguchi crossover. Therefore, the average number of cost function evaluations per algorithm iteration is
for two level Taguchi crossover and
for three level Taguchi crossover where
Similarly, for the 35-D functions, two level Taguchi crossover requires 40 cost function evaluations, and three level Taguchi crossover requires 81 cost function evaluations. Therefore, the average number of cost function evaluations per algorithm iteration is
for two level Taguchi crossover and
for three level Taguchi crossover.
Although no algorithm can solve all types of optimization problems [8, 9], the data in Table 2 shows that the algorithm converged below the specified
This chapter presents a hybrid genetic, differential evolution algorithm that represents the set of parameters being optimized in a vector. The algorithm uses an elitist, ranking, random selection method to generate a mating pool. Candidate solutions from the mating pool are randomly selected for two differential evolution operators, and two recombination operators. The new candidate solutions generated by these operators are added to the mating pool. Candidate solutions from this expanded mating pool are selected randomly for Taguchi crossover.
To evaluate this algorithm’s ability to solve optimization problems, the algorithm was applied to 13 commonly used global numerical optimization test functions, including a spherical, three hyper-ellipsoid, the sum of different powers, Rastrigin’s, Schwefel’s, Griewank’s, Rosenbrock’s valley, Styblinski-Tang, Ackley’s Path, Price-Rosenbrock, and Eggholder’s functions. The algorithm was evaluated using two and three level Taguchi crossover. For both two and three level Taguchi crossover, the algorithm converged below the specified
Although this algorithm required significantly more iterations to converge for Eggholder’s function and for 35-D Rosenbrock’s valley function, ref. [19] shows that this algorithm has been successfully used to design digital infinite impulse response (IIR) filters with arbitrary magnitude responses. As a result, it can be expected that the simple optimization algorithm described in this chapter can be used successfully for similar engineering optimization applications.
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",coverUrl:"https://cdn.intechopen.com/series/covers/3.jpg",latestPublicationDate:"August 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. 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Her main research interests are implant-soft tissue interface, zirconia implant, photofunctionalization, 3D-oral mucosal model and pulpal regeneration.",institutionString:null,institution:{name:"University of Malaya",institutionURL:null,country:{name:"Malaysia"}}},editorTwo:{id:"479686",title:"Dr.",name:"Ghee Seong",middleName:null,surname:"Lim",slug:"ghee-seong-lim",fullName:"Ghee Seong Lim",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003ScjLZQAZ/Profile_Picture_2022-06-08T14:17:06.png",biography:"Assoc. Prof Dr. Lim Ghee Seong graduated with a Bachelor of Dental Surgery from University of Malaya, Kuala Lumpur in 2008. He then pursued his Master in Clinical Dentistry, specializing in Restorative Dentistry at Newcastle University, Newcastle, UK, where he graduated with distinction. He has also been awarded the International Training Fellowship (Restorative Dentistry) from the Royal College of Surgeons. His passion for teaching then led him to join the faculty of dentistry at University Malaya and he has since became a valuable lecturer and clinical specialist in the Department of Restorative Dentistry. He is currently the removable prosthodontic undergraduate year 3 coordinator, head of the undergraduate module on occlusion and a member of the multidisciplinary team for the TMD clinic. He has previous membership in the British Society for Restorative Dentistry, the Malaysian Association of Aesthetic Dentistry and he is currently a lifetime member of the Malaysian Association for Prosthodontics. Currently, he is also the examiner for the Restorative Specialty Membership Examinations, Royal College of Surgeons, England. He has authored and co-authored handful of both local and international journal articles. 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He is an academic staff member of the Department of Reproduction and Artificial Insemination, Selçuk University, Turkey. He manages several studies on sperms and embryos and is an editorial board member for several international journals. His studies include sperm cryobiology, in vitro fertilization, and embryo production in animals.",institutionString:"Selçuk University, Faculty of Veterinary Medicine",institution:null},{id:"90846",title:"Prof.",name:"Yusuf",middleName:null,surname:"Bozkurt",slug:"yusuf-bozkurt",fullName:"Yusuf Bozkurt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/90846/images/system/90846.jpg",biography:"Yusuf Bozkurt has a BSc, MSc, and Ph.D. from Ankara University, Turkey. He is currently a Professor of Biotechnology of Reproduction in the field of Aquaculture, İskenderun Technical University, Turkey. His research interests include reproductive biology and biotechnology with an emphasis on cryo-conservation. He is on the editorial board of several international peer-reviewed journals and has published many papers. Additionally, he has participated in many international and national congresses, seminars, and workshops with oral and poster presentations. He is an active member of many local and international organizations.",institutionString:"İskenderun Technical University",institution:{name:"İskenderun Technical University",country:{name:"Turkey"}}},{id:"61139",title:"Dr.",name:"Sergey",middleName:null,surname:"Tkachev",slug:"sergey-tkachev",fullName:"Sergey Tkachev",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61139/images/system/61139.png",biography:"Dr. Sergey Tkachev is a senior research scientist at the Institute of Fundamental Medicine and Biology, Kazan Federal University, Russia, and at the Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia. He received his Ph.D. in Molecular Biology with his thesis “Genetic variability of the tick-borne encephalitis virus in natural foci of Novosibirsk city and its suburbs.” His primary field is molecular virology with research emphasis on vector-borne viruses, especially tick-borne encephalitis virus, Kemerovo virus and Omsk hemorrhagic fever virus, rabies virus, molecular genetics, biology, and epidemiology of virus pathogens.",institutionString:"Russian Academy of Sciences",institution:{name:"Russian Academy of Sciences",country:{name:"Russia"}}},{id:"310962",title:"Dr.",name:"Amlan",middleName:"Kumar",surname:"Patra",slug:"amlan-patra",fullName:"Amlan Patra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/310962/images/system/310962.jpg",biography:"Amlan K. Patra, FRSB, obtained a Ph.D. in Animal Nutrition from Indian Veterinary Research Institute, India, in 2002. He is currently an associate professor at West Bengal University of Animal and Fishery Sciences. He has more than twenty years of research and teaching experience. He held previous positions at the American Institute for Goat Research, The Ohio State University, Columbus, USA, and Free University of Berlin, Germany. His research focuses on animal nutrition, particularly ruminants and poultry nutrition, gastrointestinal electrophysiology, meta-analysis and modeling in nutrition, and livestock–environment interaction. He has authored around 175 articles in journals, book chapters, and proceedings. Dr. Patra serves on the editorial boards of several reputed journals.",institutionString:null,institution:{name:"West Bengal University of Animal and Fishery Sciences",country:{name:"India"}}},{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.png",biography:"László Babinszky is Professor Emeritus, Department of Animal Nutrition Physiology, University of Debrecen, Hungary. He has also worked in the Department of Animal Nutrition, University of Wageningen, Netherlands; the Institute for Livestock Feeding and Nutrition (IVVO), Lelystad, Netherlands; the Agricultural University of Vienna (BOKU); the Institute for Animal Breeding and Nutrition, Austria; and the Oscar Kellner Research Institute for Animal Nutrition, Rostock, Germany. In 1992, Dr. Babinszky obtained a Ph.D. in Animal Nutrition from the University of Wageningen. His main research areas are swine and poultry nutrition. He has authored more than 300 publications (papers, book chapters) and edited four books and fourteen international conference proceedings.",institutionString:"University of Debrecen",institution:{name:"University of Debrecen",country:{name:"Hungary"}}},{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201830/images/5017_n.jpg",biography:"I am a professor at UANL since 1988. My research lines are the development of reproductive techniques in small ruminants. We also conducted research on sexual and social behavior in males.\nI am Mexican and study my professional career as an engineer in agriculture and animal science at UANL. Then take a masters degree in science in Germany (Animal breeding). Take a doctorate in animal science at the UANL.",institutionString:null,institution:{name:"Universidad Autónoma de Nuevo León",country:{name:"Mexico"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",slug:"miguel-quaresma",fullName:"Miguel Quaresma",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309250/images/9059_n.jpg",biography:"Miguel Nuno Pinheiro Quaresma was born on May 26, 1974 in Dili, Timor Island. He is married with two children: a boy and a girl, and he is a resident in Vila Real, Portugal. He graduated in Veterinary Medicine in August 1998 and obtained his Ph.D. degree in Veterinary Sciences -Clinical Area in February 2015, both from the University of Trás-os-Montes e Alto Douro. He is currently enrolled in the Alternative Residency of the European College of Animal Reproduction. He works as a Senior Clinician at the Veterinary Teaching Hospital of UTAD (HVUTAD) with a role in clinical activity in the area of livestock and equine species as well as to support teaching and research in related areas. He teaches as an Invited Professor in Reproduction Medicine I and II of the Master\\'s in Veterinary Medicine degree at UTAD. Currently, he holds the position of Chairman of the Portuguese Buiatrics Association. He is a member of the Consultive Group on Production Animals of the OMV. He has 19 publications in indexed international journals (ISIS), as well as over 60 publications and oral presentations in both Portuguese and international journals and congresses.",institutionString:"University of Trás-os-Montes and Alto Douro",institution:{name:"University of Trás-os-Montes and Alto Douro",country:{name:"Portugal"}}},{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón Poggi",slug:"juan-carlos-gardon-poggi",fullName:"Juan Carlos Gardón Poggi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:null,institution:{name:"Valencia Catholic University Saint Vincent Martyr",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",country:{name:"United Kingdom"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",biography:"Samir El-Gendy is a Professor of anatomy and embryology at the faculty of veterinary medicine, Alexandria University, Egypt. Samir obtained his PhD in veterinary science in 2007 from the faculty of veterinary medicine, Alexandria University and has been a professor since 2017. Samir is an author on 24 articles at Scopus and 12 articles within local journals and 2 books/book chapters. His research focuses on applied anatomy, imaging techniques and computed tomography. Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",biography:"Dr. Fonseca-Alves earned his DVM from Federal University of Goias – UFG in 2008. He completed an internship in small animal internal medicine at UPIS university in 2011, earned his MSc in 2013 and PhD in 2015 both in Veterinary Medicine at Sao Paulo State University – UNESP. Dr. Fonseca-Alves currently serves as an Assistant Professor at Paulista University – UNIP teaching small animal internal medicine.",institutionString:null,institution:{name:"Universidade Paulista",country:{name:"Brazil"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",biography:"María de la Luz García Pardo is an agricultural engineer from Universitat Politècnica de València, Spain. She has a Ph.D. in Animal Genetics. Currently, she is a lecturer at the Agrofood Technology Department of Miguel Hernández University, Spain. Her research is focused on genetics and reproduction in rabbits. The major goal of her research is the genetics of litter size through novel methods such as selection by the environmental sensibility of litter size, with forays into the field of animal welfare by analysing the impact on the susceptibility to diseases and stress of the does. Details of her publications can be found at https://orcid.org/0000-0001-9504-8290.",institutionString:null,institution:{name:"Miguel Hernandez University",country:{name:"Spain"}}},{id:"350704",title:"M.Sc.",name:"Camila",middleName:"Silva Costa",surname:"Ferreira",slug:"camila-ferreira",fullName:"Camila Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/350704/images/17280_n.jpg",biography:"Graduated in Veterinary Medicine at the Fluminense Federal University, specialist in Equine Reproduction at the Brazilian Veterinary Institute (IBVET) and Master in Clinical Veterinary Medicine and Animal Reproduction at the Fluminense Federal University. She has experience in analyzing zootechnical indices in dairy cattle and organizing events related to Veterinary Medicine through extension grants. I have experience in the field of diagnostic imaging and animal reproduction in veterinary medicine through monitoring and scientific initiation scholarships. I worked at the Equus Central Reproduction Equine located in Santo Antônio de Jesus – BA in the 2016/2017 breeding season. I am currently a doctoral student with a scholarship from CAPES of the Postgraduate Program in Veterinary Medicine (Pathology and Clinical Sciences) at the Federal Rural University of Rio de Janeiro (UFRRJ) with a research project with an emphasis on equine endometritis.",institutionString:null,institution:null},{id:"41319",title:"Prof.",name:"Lung-Kwang",middleName:null,surname:"Pan",slug:"lung-kwang-pan",fullName:"Lung-Kwang Pan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41319/images/84_n.jpg",biography:null,institutionString:null,institution:null},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain.Dr. Satué is accredited as a Private University Doctor Professor, Doctor Assistant, and Contracted Doctor by AVAP (Agència Valenciana d'Avaluació i Prospectiva) and currently, as a full professor by ANECA (since January 2022). To date, Katy has taught 22 years in the Department of Animal Medicine and Surgery at the CEU-Cardenal Herrera University in undergraduate courses in Veterinary Medicine (General Pathology, integrated into the Applied Basis of Veterinary Medicine module of the 2nd year, Clinical Equine I of 3rd year, and Equine Clinic II of 4th year). Dr. Satué research activity is in the field of Endocrinology, Hematology, Biochemistry, and Immunology in the Spanish Purebred mare. She has directed 5 Doctoral Theses and 5 Diplomas of Advanced Studies, and participated in 11 research projects as a collaborating researcher. She has written 2 books and 14 book chapters in international publishers related to the area, and 68 scientific publications in international journals. Dr. Satué has attended 63 congresses, participating with 132 communications in international congresses and 19 in national congresses related to the area. Dr. Satué is a scientific reviewer for various prestigious international journals such as Animals, American Journal of Obstetrics and Gynecology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology, among others. Since 2014 she has been responsible for the Clinical Analysis Laboratory of the CEU-Cardenal Herrera University Veterinary Clinical Hospital.",institutionString:null,institution:null},{id:"201721",title:"Dr.",name:"Beatrice",middleName:null,surname:"Funiciello",slug:"beatrice-funiciello",fullName:"Beatrice Funiciello",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201721/images/11089_n.jpg",biography:"Graduated from the University of Milan in 2011, my post-graduate education included CertAVP modules mainly on equines (dermatology and internal medicine) and a few on small animal (dermatology and anaesthesia) at the University of Liverpool. After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". Master\\\'s degree in Ecology and Biodiversity Conservation at Federal University of Mato Grosso with a scholarship by CAPES/REUNI program: Project \\"Reproductive biology of Melanorivulus punctatus\\". PhD\\\'s degree in Science (Cell and Tissue Biology Area) \n at University of Sao Paulo with scholarship granted by FAPESP; Project \\"Development of morphofunctional changes in ovary of Astyanax altiparanae Garutti & Britski, 2000 (Teleostei, Characidae)\\". She has experience in Reproduction of vertebrates and Morphology, with emphasis in Cellular Biology and Histology. She is currently a teacher in the medium / technical level courses at IFMT-Alta Floresta, as well as in the Bachelor\\\'s degree in Animal Science and in the Bachelor\\\'s degree in Business.',institutionString:null,institution:null},{id:"442807",title:"Dr.",name:"Busani",middleName:null,surname:"Moyo",slug:"busani-moyo",fullName:"Busani Moyo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Gwanda State University",country:{name:"Zimbabwe"}}},{id:"439435",title:"Dr.",name:"Feda S.",middleName:null,surname:"Aljaser",slug:"feda-s.-aljaser",fullName:"Feda S. Aljaser",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"423023",title:"Dr.",name:"Yosra",middleName:null,surname:"Soltan",slug:"yosra-soltan",fullName:"Yosra Soltan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"349788",title:"Dr.",name:"Florencia Nery",middleName:null,surname:"Sompie",slug:"florencia-nery-sompie",fullName:"Florencia Nery Sompie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sam Ratulangi University",country:{name:"Indonesia"}}},{id:"428600",title:"MSc.",name:"Adriana",middleName:null,surname:"García-Alarcón",slug:"adriana-garcia-alarcon",fullName:"Adriana García-Alarcón",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428599",title:"MSc.",name:"Gabino",middleName:null,surname:"De La Rosa-Cruz",slug:"gabino-de-la-rosa-cruz",fullName:"Gabino De La Rosa-Cruz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428601",title:"MSc.",name:"Juan Carlos",middleName:null,surname:"Campuzano-Caballero",slug:"juan-carlos-campuzano-caballero",fullName:"Juan Carlos Campuzano-Caballero",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}}]}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular Economy, Contingency Planning and Response to Disasters, Ecosystem Services, Integrated Urban Water Management, Nature-based Solutions, Sustainable Urban Development, Urban Green Spaces",scope:"