These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\n
Initially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"1428",leadTitle:null,fullTitle:"Cytokeratins - Tools in Oncology",title:"Cytokeratins",subtitle:"Tools in Oncology",reviewType:"peer-reviewed",abstract:'The first chapters of the volume "Cytokeratins - Tools in Oncology" discuss multiple functions of cytokeratins in organization of the intermediary filaments in normal intestine and liver as well as microfold L cells and the usability of cytokeratins 7, 8 and 20 in tumor diagnosis in detail. Epithelial to mesenchymal transition as a mechanism important in pathogenesis is touched in another chapter, followed by several articles dealing with the role of cytokeratins for detection of disseminated tumor cells and as response markers during chemotherapy. This book is therefore destined to all cancer researchers and therapists who want to understand the diagnostic application of cytokeratins in histology and, especially, the use of anti-cytokeratin antibodies to identify viable residual tumor cells accounting for a higher risk of tumor recurrence or cancer cells responding to chemotherapy, respectively.',isbn:null,printIsbn:"978-953-51-0047-8",pdfIsbn:"978-953-51-6818-8",doi:"10.5772/1888",price:119,priceEur:129,priceUsd:155,slug:"cytokeratins-tools-in-oncology",numberOfPages:172,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"43eb05ae5238aaf095c1344bce3b7ae1",bookSignature:"Gerhard Hamilton",publishedDate:"February 29th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/1428.jpg",numberOfDownloads:21840,numberOfWosCitations:16,numberOfCrossrefCitations:9,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:21,numberOfDimensionsCitationsByBook:1,hasAltmetrics:0,numberOfTotalCitations:46,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 12th 2011",dateEndSecondStepPublish:"May 10th 2011",dateEndThirdStepPublish:"September 14th 2011",dateEndFourthStepPublish:"October 14th 2011",dateEndFifthStepPublish:"February 13th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"96149",title:"Dr.",name:"Gerhard",middleName:null,surname:"Hamilton",slug:"gerhard-hamilton",fullName:"Gerhard Hamilton",profilePictureURL:"https://mts.intechopen.com/storage/users/96149/images/system/96149.jpg",biography:"Dr. Gerhard Hamilton studied biochemistry at the University of Vienna, Austria. 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\r\n\tDisplay technology is well known as an effective way of information communication. Nowadays, display technology is evolving at an exponential level. Consequently, an exciting future for generations of new displays can be guaranteed by the rapid-fire improvements in display technology. Major display technologies are well known as liquid crystal displays, organic light-emitting diodes, digital light processing technology, plasma displays, field emission displays, and electronic paper. Over the last decades, the human-machine interface (HMI) was improved by the achievement of display development. For example, it was demonstrated that OLED displays could replace LED-backlit displays in the not-too-distant future. The performance of this kind of display is equal to or better than LED or LCD screens. Or in the future, we expect new kinds of displays such as 3-D screens and holographic displays to be developed. In this book, we tried to review and introduce the received advances in display technology for readers.
",isbn:"978-1-83969-855-2",printIsbn:"978-1-83969-854-5",pdfIsbn:"978-1-83969-856-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"6b51a957a839ed3350b0785031c6343a",bookSignature:"Prof. Morteza Sasani Ghamsari",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11945.jpg",keywords:"Materials, Devices, Technology, Mini-LEDs, OLEDs, OD-OLEDs, Micro-LEDs, LCD, Passive and Active Technologies, Thin Film Transistor LCD, Phosphors, Large-Screen HDTV",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 29th 2022",dateEndSecondStepPublish:"May 27th 2022",dateEndThirdStepPublish:"July 26th 2022",dateEndFourthStepPublish:"October 14th 2022",dateEndFifthStepPublish:"December 13th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"6 hours",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in monophonic and quantum material, appointed head of the quantum technologies research group, and holder of two registered patents.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"64949",title:"Prof.",name:"Morteza",middleName:null,surname:"Sasani Ghamsari",slug:"morteza-sasani-ghamsari",fullName:"Morteza Sasani Ghamsari",profilePictureURL:"https://mts.intechopen.com/storage/users/64949/images/system/64949.jpg",biography:"Dr. Morteza Sasani Ghamsari is a senior researcher in the Photonics and Quantum Technologies Research School of Iranian Nuclear Science and Technology Research Institute. His research focuses on photonic materials including metamaterials, quantum\ndots, and plasmonic nanomaterials that can be used in a wide range of nanophotonics applications. His recent interests also include nano-bioimaging, 3D printing, nanostructures for tissue engineering (ZnO, TiO2, etc.) and biomaterials including carbon, graphene, and\ndiamond quantum dots. He is an editorial board member and reviewer for different\ninternational journals and has collaborated with local and international academics/\nresearchers on post-graduate research projects. He has edited four books and published four chapters and more than 105 articles in scientific journals and reviewed\nconference proceedings. His papers have been cited more than 2100 times with\nh-index 26 and i-10 index 46 (Google Scholar).",institutionString:"Photonics and Quantum Technologies Research School",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"4",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453623",firstName:"Silvia",lastName:"Sabo",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/453623/images/20396_n.jpg",email:"silvia@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"10198",title:"Response Surface Methodology in Engineering Science",subtitle:null,isOpenForSubmission:!1,hash:"1942bec30d40572f519327ca7a6d7aae",slug:"response-surface-methodology-in-engineering-science",bookSignature:"Palanikumar Kayaroganam",coverURL:"https://cdn.intechopen.com/books/images_new/10198.jpg",editedByType:"Edited by",editors:[{id:"321730",title:"Prof.",name:"Palanikumar",surname:"Kayaroganam",slug:"palanikumar-kayaroganam",fullName:"Palanikumar Kayaroganam"}],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"}],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"}],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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\n
1. Introduction
\n
Quantitative genetics result from the (connection) combination of statistics and the principles of animal and plant breeding. In quantitative genetics, selection for economically important traits refers to use of phenotypic values of the individual and pedigree information. Genomic is based on the use of dense markers through the whole genome to predict the breeding value of the individuals [1]. Linear models (univariate and multivariate) are of fundamental importance in applied and theoretical quantitative genetics [2]. In animal breeding, two major methods were particularly applied, restricted maximum likelihood (REML) and Bayesian methods. REML has emerged as the method of choice in animal breeding for variance component estimation [3]. Bayesian analysis is gaining popularity because of its more comprehensive assumptions than those of classical approaches and its flexibility in resolving a wide range of biological problems [4, 5]. In the Bayesian approach, the idea is to combine what is known about the statistical ensemble before the data are observed (prior probability distributions) with the information coming from the data, to obtain a posterior distribution from which inferences are made using the standard probability calculus techniques [2, 6]. In recent years, Bayesian methods were broadly used to solve many of the difficulties faced by conventional statistical methods and extend the applicability of statistics on animal and plant breeding data [7]. Furthermore, Markov chain Monte Carlo (MCMC) has an important impact in applied statistics, especially from Bayesian perspective for the estimation of genetic parameters in the linear mixed effect model [2, 5]. The specific objective of this chapter was to illustrate applications of Bayesian inference in quantitative genetics and genomics. First, Bayesian models in the quantitative genetics theory are examined. Second, and in the context of the genomic selection, we presented the details of statistical modeling, using BLUP and Bayesian analyses. Third, a critical review with a focus on the prior distributions is illustrated. Finally, genomic predictions from several methods used in many countries are discussed.
\n
\n
\n
2. A brief introduction to Bayesian analyses
\n
In Bayesian inference, the idea is to combine what is known about the statistical ensemble before the data are observed (prior probability distributions) with the information coming from the data, to obtain a posterior distribution from which inferences are made using the standard probability calculus techniques.
P(θ) is the prior distribution, which reflects the relative uncertainty about the possible values of θ before the data are seen. P(y/θ) is the likelihood function of observing the data given the parameter which represents the contribution of y to knowledge about the parameter θ. P(θ/y) is the posterior distribution of the parameter θ given the previous information on the data.
\n
\n
\n
3. Bayesian analyses of linear models
\n
\n
3.1. The mixed linear model
\n
The mixed linear model is of great importance in genetics and is one of the most used statistical models. Arguably, variance components and genetic parameters are important because they give an indication of the ability of species to respond to selection and thus the potential of that species to evolve. Mixed linear model is the simplest method for estimating the variance components for quantitative traits in population. In the “frequentist” view, mixed linear model is one included linearly the fixed and random effects. In the Bayesian context, there is no distinction between fixed and random effects. Detailed Bayesian analyses of models with two or more component variances will be discussed.
\n
\n
3.1.1. The univariate linear additive genetic model
\n
The mixed linear model is one that includes fixed and random effects.
y is a n×1 vector of records on a trait; β is the vector of fixed effects affecting records; a is the vector of additive genetic effects; e is a vector of residual effects. X and Z are incidence matrices relating records to fixed effects and additive genetic effects, respectively. Data are assumed to be generated from the following distribution:
where, I is an identity matrix of order n×n and \n\n\n\nσ\ne\n2\n\n\n\n is the residual variance. Independence of various effects was assumed for the sake of simplicity in implementation. We assume a genetic model in which genes act additively within and between loci, and there are effectively an infinite number of loci. Under this infinitesimal model, and assuming further initial Hardy-Weinberg and linkage equilibrium, the distribution of additive genetic values conditional on the additive genetic covariance is multivariate normal.
where \n\n\n\nv\ne\n\n,\n\n\n S\n\ne\n2\n\n\n\n and v\n\na\n\n,\n\n\nS\na\n2\n\n\n\n are interpreted as degrees of belief and a priori values for residual and additive genetic covariances. Posterior conditional distributions derived from the likelihood and the prior distributions for these parameters are,
\n
bi| b-i, a, \n\n\n\n\nσ\n\na\n2\n\n\n\n, \n\n\n\n\nσ\n\ne\n2\n\n\n\n, \n\n\n\ny\n\n∼\nN\n(\n\n\n\nb\n^\n\n\ni\n\n,\n\n\n(\n\nx\ni\n′\n\n\nx\ni\n\n)\n\n\n−\n1\n\n\n\nσ\ne\n2\n\n)\n\n\n, with (x′ixi) is the ith element of the diagonal of X′X
\n
\n
\n
3.1.2. The univariate linear additive genetic model with permanent and genetic group effects
\n
The model equation [8] used to estimate genetic parameters and genetic breeding value for milk yield was as follows:
where y is the vector of milk yield, b is the vector of fixed effects, a is the vector of additive genetic effects, g is the vector of genetic group effects, p is the vector of random permanent environmental effects, and e is the vector of residual effects. X, Z, W, and ZQ are incidence matrices relating a record to fixed environmental effects in b, to a random animal effects in a, to a random permanent environment effects in p, and to genetic groups in g, respectively. g* is the vector of genetic group effects, â is a vector of breeding values. A is the numerator relationship matrix. where \n\n\n\n\n\n\na\n^\n\n\n\n*\n\n=\nQ\n\n\n\n\ng\n^\n\n\n\n+\n\n\n\na\n^\n\n\n\n\n\n.
\n
The conditional distribution of observed yield is defined by:
with the assumption of P(b) being a constant; a*|A*, \n\n\n\n\nσ\n\na\n2\n\n∼\nN\n(\n\nQ\ng\n\n,\n\n\nA\n\n*\n\n\nσ\n\na\n\n2\n\n)\n\n\n;
\n
\n\n\n\n\np\n\n|\n\nσ\n\np\n\n2\n\n∼\nN\n(\n0\n,\n\nI\n\n\nσ\n\np\n\n2\n\n)\n;\n and \n\nP\n\n(\n\nσ\n\ni\n\n2\n\n|\n\nν\n\ni\n\n\n,\n\n\nS\n\n\ni\n\n2\n\n)\n∼\n\n\n(\n\nσ\n\ni\n\n2\n\n)\n\n\n(\n(\n\n\n\n\nν\n\ni\n\n\n\n2\n\n\n+\n1\n)\n)\n\n\nexp\n\n(\n\n−\n\n\n\nν\ni\n\n\nS\ni\n2\n\n\n\n2\n\nσ\ni\n2\n\n\n\n\n)\n\n\n\n\n\nE8
\n
where \n\n\n\nS\ni\n2\n\n\n\n are prior values for the variances, \n\n\n\nχ\n\n\nν\ni\n\n\n\n−\n2\n\n\n\n\n are inverted chi-square distributions, and νi are degrees of freedom of parameters.
with (x′ixi) \n\n\n\n\n\n\nb\n^\n\n\n\ni\n\n=\n\n\nx\n\n\'\n\ny\n−\n\n\nx\n\ni\n\'\n\n\n\nx\n\n\n−\ni\n\n\'\n\n\n\nb\n\n\n−\ni\n\n\n−\n\n\nx\n\ni\n\'\n\n\n\nw\n\np\n\n−\n\n\nx\n\ni\n\'\n\nz\n\n\na\n\n*\n\n,\n\n\n
\n
where (x′ixi) is the ith element of the diagonal of X′X
with \n\n\n(\n\nw\ni\n′\n\n\nw\ni\n\n+\nδ\n)\n\n\n\np\n^\n\n\ni\n\n=\n\n\nw\n′\n\ni\n\n\ny\n−\n\n\nw\n′\n\ni\n\n\nX\nb\n−\n(\n\nw\ni\n\n\nW\n\n−\ni\n\n\n+\nδ\n)\n\np\n\n−\ni\n\n\n−\n\nw\ni\n\n\nz\na\n\n\n\n\n*\n\n,\n\n\n
\n
where w′iwi is the ith element of the diagonal of W′W.
with \n\n\n\n\n\n(\nz\n\n\ni\n\'\n\n\n\nz\n\ni\n\n+\n\n\nA\n\n\ni\n,\ni\n\n\n*\n−\n1\n\n\nα\n)\n\n\n\n\na\n^\n\n\n\ni\n\n=\n\n\nz\n\ni\n\'\n\ny\n−\n\n\nz\n\ni\n\'\n\nX\nb\n−\n\n\nz\n\ni\n\'\n\n\n\nW\n\nP\n\n−\n\n\nA\n\n\ni\n,\ni\n\n\n*\n−\n1\n\n\nα\n\n\na\n\n\n−\ni\n\n*\n\n\n\n,
\n
where z′izi is the i th element of the diagonal of Z′Z.
with \n\n\n\n\n\n\nV\n˜\n\n\n\na\n\n=\n\n\nn\n\na\n\n+\n\n\nV\n\na\n\n\n\n, \n\n\n\n\n\n\nS\n˜\n\n\n\na\n2\n\n=\n\n\n\n(\na\n*\n\n\n\'\n\n\n\nA\n\n\n*\n−\n1\n\n\n\n\na\n\n*\n\n+\n\n\nV\n\na\n\n\n\nS\n\na\n2\n\n)\n/\n\n\n\n\nV\n˜\n\n\n\na\n\n\n\n, and np is the number of animals being evaluated.
\n
The variance of permanent environmental effects is given by:
with \n\n\n\n\n\n\nV\n˜\n\n\n\np\n\n=\n\n\nn\n\np\n\n+\n\n\nV\n\np\n\n\n\n, \n\n\n\n\n\nS\n˜\n\n\np\n2\n\n=\n(\n\np\n′\n\np\n+\n\nV\np\n\n\nS\np\n2\n\n)\n/\n\n\n\nV\n˜\n\n\np\n\n\n\n, and np is the number of animals being evaluated.
Comparing genetic value predictions based on polygenic model in Tunisian Holstein Population using BLUP and Bayesian analyses, Ref. [8] reported that the rankings of animals with Bayesian methods are similar to those obtained by BLUP method. Spearman’s rank correlation between genetic values estimated from Bayesian procedures and genetic values estimated from BLUP methods were high (0.99). Again, Bayesian and best linear unbiased estimator (BLUE) solutions of fixed effects (month of calving, herd-year, and age-parity) showed the same patterns. The same result is reported by Ref. [9]. However, Ref. [8] illustrated different correlation estimates between two methods (Bayesian and BLUP) for cow’s and bull’s breeding value.
\n
\n
\n
\n
\n
\n
4. Genomic selection
\n
A massive quantity of genomic data is now available in animal and plant breeding with the revolutionary development in sequencing and genotyping. The cost of genotyping is dramatically reduced. Consequently, practices of genomic selection are nowadays possible with the high number of single nucleotide polymorphism (SNP) markers available. Therefore, it is feasible to perform analysis of the genome at a level that was not possible before [10–13]. The concept of genomic selection was introduced by Ref. [1]. The latter suggested that a set of markers covering the whole genome explain the all genetic variances and each marker is likely to be associated with a quantitative trait locus (QTL), and each QTL is in linkage disequilibrium with the markers. The number of effects per QTL to be estimated is very small. The estimated effects of all markers are summed in order to obtain the genetic value of the individual. Using simulation, Ref. [1] showed in simulation that with a high-density SNP marker, it is possible to predict the breeding value with an accuracy of 0.85 (where accuracy is the correlation between the estimated breeding value and true breeding value). The challenge in genomic evaluation is to find the best prediction method to obtain accurate genetic values of candidates. Many genomic evaluation methods have been proposed [14, 15]. The main objective of this section is to compare Bayesian methods to other methods used in genomic selection based on their predictive abilities. The study reported by Ref. [1] was considered an influential paper on dairy cattle breeding programs. First, the methods suggested correspond well to the data structures where the number of SNPs substantially exceeds the number of observations. Second, the methods of Ref. [1] constitute a logical evolution of the BLUP methodology, which is the reference method in animal genetics by considering specific variances of SNPs in the different loci. Third, the Bayesian approaches used in Ref. [1] that take into account unknown effects (measuring prior uncertainty) in a model, and combined with the ability of the Monte Carlo Markov chain, can be used in the majority of parametric statistical models.
\n
\n
4.1. Genomic BLUP (GBLUP)
\n
The GBLUP method assumes that effects of all SNPs are sampled from the same normal distribution; the effects of all markers are assumed to be small with equal variance. Genomic BLUP was defined by the model:
\n
\n\n\n\ny\n=\n1\nμ\n+\nZ\ng\n+\ne\n\n\n\n\nE4
\n
where y is the data vector; μ is the overall mean; 1 is a vector of n ones; Z is a matrix of incidence, allocating records to the markers’ effects; g is a vector of SNP effects assumed to be normally distributed \n\n\ng\n∼\nN\n(\n0\n,\nG\n\nσ\ng\n2\n\n)\n\n\n, where \n\n\n\n\nσ\n\ng\n2\n\n\n\n is the additive genetic variance and G is the genomic relationship matrix; e is the vector of normal error, \n\n\ne\n∼\nN\n(\n0\n,\n\nσ\ne\n2\n\n)\n\n\n where \n\n\n\n\nσ\n\ne\n2\n\n\n\n is the error variance. The genomic relationship matrix was defined as \n\n\nG\n=\n\n\nX\n\'\nX\n\n\n\n\n\n∑\n\ni\n=\n1\n\nm\n\n\n\n\n\np\n\ni\n\n(\n1\n−\n\n\np\n\ni\n\n)\n\n\n\n\n\n\n, where X is matrix for specified SNP genotype coefficient at each locus, pi is the rare allele frequency for SNPi.
\n
\n
\n
4.2. Bayesian approaches
\n
In Bayesian estimation, the information from the data is combined with the information from the prior distribution of the variances of the markers. Several Bayesian statistical analyses have been used in genomic evaluation, which differ in the hypotheses of distributions of marker effects. At the level of the modeling of the variances of the effects of the markers, Meuwissen et al. [1] proposed different distributions a priori between the Bayes A and Bayes B methods.
\n
\n
4.2.1. Bayes A
\n
Bayes A method assumes that variance of marker effects differ among loci (e.g., \n\n\n\n\nσ\n\n\n\n\ng\n\nj\n\n\n2\n\n\n\n is different across the j) [16]. The variances are modeled according to the scaled inverted chi-square distribution: The a priori distribution of the variances of the SNP effects is written:
\n
\n\n\n\nP\n(\n\nσ\n\n\ng\nj\n\n\n2\n\n)\n∼\n\nχ\n\n−\n2\n\n\n(\nν\n,\nS\n)\n\n\n, where S is the scale parameter and ν is the number of degrees of freedom. This has the advantage, if we consider a normal distribution of the data, to lead to an a posteriori conditional distribution of χ−2.
where, nj is the number of marker effects at segment j. The posterior distribution combines both the information provided by the data and the a priori distribution.
\n
\n
\n
4.2.2. Bayes B
\n
In a genomic evaluation context, Bayes B method [1, 17] assumes different variances of SNP effects, with many SNP contribute per zero effects, and a few contribute per a large effects on the trait. Meuwissen et al. [1] propose a model in which a proportion π (arbitrarily fixed at 0.95) of the markers having zero effect. The a priori distribution of the variances of the effects to the markers is then written:
\n
\n\n\n\n\nσ\ng\n2\n\n=\n0\n\n\n with a probability π, \n\n\nP\n(\n\nσ\n\n\ng\nj\n\n\n2\n\n)\n∼\n\nχ\n\n−\n2\n\n\n(\nν\n,\nS\n)\n\n\n with a probability (1 − π), Gibbs sampling cannot be used to estimate the effects and variances of the Bayes B model because of the high probability on some markers of being of zero variance. We therefore use a Metropolis-Hastings algorithm which allows the simultaneous estimation of \n\n\n\n\nσ\n\n\n\n\ng\n\nj\n\n\n2\n\n\n\n and gj. On the basis of the results of Ref. [1] and many subsequent works, the Bayes B method is often considered the “benchmark” in terms of genomic prediction efficiency, but it is extremely costly in computational time. However, Meuwissen [18] propose an alternative to the Bayes B method which relies on a fast algorithm.
\n
\n
\n
4.2.3. Bayesian lasso
\n
Legarra et al. [19] proposed a model of Bayesian lasso (BL) with different variances for residual and SNP effects which they termed BL2Var. It is therefore assumed that a large number of SNPs have an effect practically zero and that very few have large effects. Tibshirani [20] showed that the distribution of the lasso estimators can be written:
He suggests that the lasso estimators can be interpreted as an a posteriori mode of a model in which the regression parameters would be independent and identically distributed according to a prior double exponential distribution. Park and Casella [21] propose to use a complete Bayesian approach by assuming an a priori distribution of regression coefficients such as:
where σ2 represents the variance of residual effects of the model and the variance of the SNP effects. Applications of the Bayesian lasso to the genomic selection proposed by Refs. [22, 23] use the same variance σ2 to model both the distribution of effects of SNPs and residuals. De los Campos et al. [22] showed that the Bayesian lasso is close in terms of precision of prediction to the Bayes B method but with a significant reduction in the complexity of the calculations. In addition, these authors suggested using Bayesian lasso against the large number of markers included in regression models, which is typically larger than the number of records.
\n
\n
\n
4.2.4. The Bayes C method
\n
Bayesian methods such as Bayes A and Bayes B [1] have been widely used for genomic evaluation. Similar methods exist, with similar performances, developed in order to reduce computation times and to simplify statistical modeling. The Bayes C method [24] differs from Bayes B by assuming the variance associated with SNPs common to all markers. In Bayes C, as in Bayes B, the probability π that an SNP has a nonzero effect is assumed to be known. The model is similar to the Bayes B model but for a homogeneous variance of effects on all loci: \n\n\n\n\nσ\n\ng\n2\n\n=\n0\n\n\n with a probability 1 − π;\n\n\n(\n\n\nσ\n\ng\n2\n\n)\n∼\n\n\nχ\n\n\n−\n2\n\n\n(\nν\n,\n S)\n\n\n. The main problem with the Bayes C method is that SNPs with a nonzero effect is assumed to be known. With the Bayes A method, the parameter π is equal to 1, which implies that all the markers have an effect. For the Bayes B method, π is strictly less than 1 in order to take into account the hypothesis that some SNPs may have a zero effect but is fixed arbitrarily while the intensity of the selection of variables is controlled by this parameter. Habier et al. [25] propose to modify the Bayes C method by estimating the parameter π: the parameter π is assumed to be unknown. Thus, the a priori distribution of π becomes uniform over [0, 1]. SNP modeling is the same as with Bayes C. \n\n\nP\n(\n\ng\nj\n\n|\nπ\n,\n\nσ\ng\n2\n\n)\n=\n0\n\n\n with a probability 1 − π; \n\n\nP\n(\n\ng\nj\n\n|\nπ\n,\n\nσ\ng\n2\n\n)\n∼\nN\n(\n0\n,\n\nσ\ng\n2\n\n)\n\n\n where \n\n\nP\n\n\n\n(\nσ\n\n\ng\n2\n\n)\n∼\n\nχ\n\n−\n2\n\n\n(\nν\n,\nS\n)\n\n\n with a probability π. The various parameters of this model are estimated by MCMC methods, Markov Chain Monte Carlo [6, 26] as proposed by Ref. [25]. It is written as a function of the additive genetic variance \n\n\n\n\nσ\n\na\n2\n\n\n\n. \n\n\n\n\nσ\n\ng\n2\n\n=\n\n\n\n\nσ\n\na\n2\n\n\n\n(\n1\n−\nπ\n)\n\n\n\n∑\n\nj\n=\n1\n\np\n\n\n\n2\n\n\np\n\nj\n\n(\n1\n−\n\n\np\n\nj\n\n)\n\n\n\n\n\n\n, where pj is the allelic frequency of SNP j.
\n
\n
\n
\n
4.3. A critique
\n
The extreme speed with which events are running handicaps the process of linking new development to extant theory, and the understanding of statistical models suggested up until now [27]. The latter authors criticize the theoretical and statistical concepts followed by Ref. [1] in three levels. The first is the connection between parameters (additive genetic variances with Bayesian view) from infinitesimal models with those from marker-based models. The second is the relationship between molecular marker genotypes and similarity between relatives. The third is the connection between infinitesimal genetic models and marker-based regression models. Gianola et al. [27] argued that the methods Bayes A and Bayes B proposed by Ref. [18] require specifying parameters. The latter used formulas for obtaining the variance of SNP effects, based on some knowledge of the additive genetic variance in the population. Their development begins on the assumption that the effects of the markers are fixed and in other development, they consider them as random without a clear demonstration. Meuwissen et al. [1] explained that affecting a priori a value \n\n\n\n\nσ\n\ng\n2\n\n=\n0 \n\n\n with a probability π means that the specific SNP does not have an effect on the trait. By contrast, Ref. [27] illustrated that a parameter having zero variance does not obligatory imply that the parameter takes zero value. The parameter could have any value, but with certainty. Gianola et al. [27] suggested the use of a nonparametric method as developed by Refs. [22, 28] because these methods do not impose hypotheses about mode of inheritance as Bayesian A and Bayesian B methods.
\n
\n
\n
\n
5. Applications in genomics
\n
Major dairy breeding countries are now using genomic evaluation [27]. Several results have been reported around the world. Several authors reported that the reliabilities of genomic estimated breeding values (GEBV) were substantially greater than breeding values from estimated breeding values (EBV) based on pedigree information [29]. The accuracy of selection was different between countries [12]. The accuracy was dependent on the size of reference population, the heritability of the trait studied, the statistical models and approaches used for prediction of genetic values for quantitative traits, and the method achieved to estimate the accuracy [12, 27, 29]. Ref. [14] found the reliability of GEBV bulls of the Canadian and American Holstein population. A genotyping of 39,416 molecular markers of 3576 Holstein bulls was used to establish the prediction equations.
\n
The prediction methods contained a linear model, in which marker effects are assumed to be normal, and a nonlinear model with a heavier tailed prior distribution to account for major genes as described by [1]. VanRaden et al. [14] reported that the combination of the polygenic effects based on pedigree information with the genomic predictions can improve the reliability to 23% greater than the reliability of polygenic effects only. The same study showed that the nonlinear model had a little advantage in reliability over the linear model for all traits except for fat and protein percentages. Genomic breeding values of 25 traits in New Zealand dairy cattle were estimated by Ref. [30]. The reference population consisted of 4500 bulls genotyped using the BovineSNP50Beadchip, containing 44,146 SNPs. Harris and Johnson [31] reported an increase in accuracy was found by using Bayesian approaches compared to BLUP methods. In Ref. [31], genomic breeding values (GBVs) for young bulls with no daughter information had accuracies ranging from 50 to 67% for milk traits, live weight, fertility, somatic cell, and longevity, versus an average 34% for progeny test. Meuwissen et al. [1] compared least squares method with BLUP and two Bayesian methods (Bayesian A and Bayesian B). The latter authors estimated the effects of 50,000 marker haplotypes from a limited number of observations (2200). Using least squares method, it is not possible to estimate all effects simultaneously. For this reason, different steps have been adopted to incorporate the effects of markers. First, they performed regression on markers for every segment of 1 cm each. Second, they calculated a Log-likelihood, which assumed to be normal at every segment of chromosome. Third, they summed all segments corresponding to a likelihood peak into multiple regression models. Using BLUP analyses, Ref. [1] considered that all SNP effects were independent and identically distributed with a known variance. Bayes A method was as BLUP at the level of the data, but differs in the variance of the chromosome segments, which assumed to have an inverted chi-square distribution. A mixture prior distribution of genetic variances was used in Bayes B method. Table 1 shows the accuracy of selection obtained by Ref. [1] from the GBLUP methods, the least squares regression and the Bayes A and Bayes B approaches. The predictive abilities of the different methods are estimated by calculating the correlation (ρ) between true and estimated breeding values and the regression (b) of true on estimated breeding value.
\n
\n
\n
\n
\n\n
\n
Methods
\n
ρ
\n
b
\n
\n\n\n
\n
Least squares
\n
0.318
\n
0.285
\n
\n
\n
GBLUP
\n
0.732
\n
0.896
\n
\n
\n
Bayes A
\n
0.798
\n
0.827
\n
\n
\n
Bayes B
\n
0.848
\n
0.946
\n
\n\n
Table 1.
Comparing estimated versus the breeding value [1].
\n
The least squares method is the least efficient because it overestimates effects on QTL [32]. The Bayes B approach is the most accurate both in terms of correlation and regression. However, the regression coefficient obtained by the Bayesian methods was still less than 1, and probably due to the hypothesis of a priori distribution χ−2 for Bayes A and Bayes B being different from the simulated distribution of the variances. Goddard and Hayes [11] compared the correlation of 0.85 as reported by Ref. [1] to results obtained on real data by Refs. [14, 33, 34]. VanRaden et al. [14] produced a mean correlation over several characters of 0.71 from a reference population of more than 3500 bulls. Studies have shown the superiority of genomic evaluation [35] or marker-assisted selection in France [36] on classical infinitesimal model of quantitative genetics. Several authors have applied the first genomic evaluation methods described by Ref. [1] or their derived methods on real data. The Bayes A and Bayes B approaches have found results that are often similar or slightly superior to GBLUP in terms of accuracy of genetic value prediction for the Australian Holstein-Friesian cattle breed (+0.02 to +0.07 of correlation gain between predicted and observed values), for example [12] and New Zealand (+2% correlation gain, [31]). However, the GBLUP method required less computing time than the Bayes A method [32, 37]. Gredler et al. [38] demonstrated the superiority of the Bayes B method, in terms of the accuracy of genomic estimates, on a modified Bayes A method for integrating a polygenic effect [39]. Thus, although the Bayes B method seems slightly more efficient than the Bayes A method, numerous studies showed that the Bayes B method is not so much better in terms of accuracy of the genomic estimates than a GBLUP model [40]. Again, all researches indicate that the Bayesian approaches, which assume an a priori distribution of SNPs, increase the reliability of breeding values over traditional BLUP methods [1, 12, 14]. A common conclusion is that for most quantitative traits, the hypothesis of the traditional BLUP method, that all markers are associated with equal variances, is far from reality. By comparing the results obtained in the various populations around the world, clearly, the accuracies of GEBVs were greater than breeding values estimated from progeny test based on pedigree information. Several researches suggested combining the progeny test based on pedigree information with the breeding value from genomic to calculate the final GEBV [5, 25]. Accuracy based on modeling molecular marker and pedigree information was generally superior to that of the model including only genomic or pedigree information. Hayes et al. [12] reported that a main advantage of using the both sources of information coming from polygenic breeding values and genomic information is that any QTL not detected by the marker effects may be detected by the progeny test based on pedigree information. A significant reduction in posterior mean of residual variance component was reported by Ref. [22] when pedigree and markers were considered jointly compared to pedigree-based model. In the same study, Spearman’s rank correlation of estimated breeding value between model including marker information and pedigree-based model was close to 1.
\n
\n
\n
6. Conclusion
\n
Standard quantitative genetic model based on phenotypic and pedigree information has been very successful in term of genetic value prediction. Also, the availability of genome-wide dense markers leads researchers to be able to perform advanced genetic evaluation of quantitative traits with a high accuracy of prediction of genetic value. However, a main problem is how this information should be included into statistical genetic models. Bayesian MCMC methods appear to be convenient for genetic value prediction with a focus on the precision of the choice of prior distribution for the different parameters.
\n
\n\n',keywords:"accuracy of prediction, breeding value, Bayesian methods, BLUP, pedigree, markers",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/56457.pdf",chapterXML:"https://mts.intechopen.com/source/xml/56457.xml",downloadPdfUrl:"/chapter/pdf-download/56457",previewPdfUrl:"/chapter/pdf-preview/56457",totalDownloads:1477,totalViews:449,totalCrossrefCites:1,totalDimensionsCites:1,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:50,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"December 5th 2016",dateReviewed:"June 20th 2017",datePrePublished:null,datePublished:"November 2nd 2017",dateFinished:"July 14th 2017",readingETA:"0",abstract:"This chapter provides a critical review of statistical methods applied in animal and plant breeding programs, especially Bayesian methods. Classical and Bayesian procedures are presented in pedigree-based and marker-based models. The flexibility of the Bayesian approaches and their high accuracy of prediction of the breeding values are illustrated. We show a tendency of the superiority of Bayesian methods over best linear unbiased prediction (BLUP) in accuracy of selection, but some difficulties on elicitation of some complex prior distributions are investigated. Genetic models including marker and pedigree information are more accurate than statistical models based on markers or pedigree alone.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/56457",risUrl:"/chapter/ris/56457",book:{id:"5964",slug:"bayesian-inference"},signatures:"Hafedh Ben Zaabza, Abderrahmen Ben Gara and Boulbaba Rekik",authors:[{id:"203343",title:"Ph.D. Student",name:"Hafedh",middleName:null,surname:"Ben Zaabza",fullName:"Hafedh Ben Zaabza",slug:"hafedh-ben-zaabza",email:"hafedhbenzaabza@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Carthage",institutionURL:null,country:{name:"Tunisia"}}},{id:"204175",title:"Prof.",name:"Abderrahmen",middleName:null,surname:"Ben Gara",fullName:"Abderrahmen Ben Gara",slug:"abderrahmen-ben-gara",email:"bengara.abderrahmen@iresa.agrinet.tn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"207038",title:"Prof.",name:"Boulbaba",middleName:null,surname:"Rekik",fullName:"Boulbaba Rekik",slug:"boulbaba-rekik",email:"rekik.boulbaba@iresa.agrinet.tn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. A brief introduction to Bayesian analyses",level:"1"},{id:"sec_3",title:"3. Bayesian analyses of linear models",level:"1"},{id:"sec_3_2",title:"3.1. The mixed linear model",level:"2"},{id:"sec_3_3",title:"3.1.1. The univariate linear additive genetic model",level:"3"},{id:"sec_4_3",title:"3.1.2. The univariate linear additive genetic model with permanent and genetic group effects",level:"3"},{id:"sec_4_4",title:"3.1.2.1. Management and environmental effects",level:"4"},{id:"sec_5_4",title:"3.1.2.2. Permanent environmental effects",level:"4"},{id:"sec_6_4",title:"3.1.2.3. Breeding values",level:"4"},{id:"sec_7_4",title:"3.1.2.4. Variance components",level:"4"},{id:"sec_11",title:"4. Genomic selection",level:"1"},{id:"sec_11_2",title:"4.1. Genomic BLUP (GBLUP)",level:"2"},{id:"sec_12_2",title:"4.2. Bayesian approaches",level:"2"},{id:"sec_12_3",title:"4.2.1. Bayes A",level:"3"},{id:"sec_13_3",title:"4.2.2. Bayes B",level:"3"},{id:"sec_14_3",title:"4.2.3. Bayesian lasso",level:"3"},{id:"sec_15_3",title:"4.2.4. The Bayes C method",level:"3"},{id:"sec_17_2",title:"4.3. A critique",level:"2"},{id:"sec_19",title:"5. Applications in genomics",level:"1"},{id:"sec_20",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Meuwissen THE, Hayes BJ, Goddard ME. Prediction of total genetic value using genome-wide dense marker maps. Genetics. 2001;157:1819-1829\n'},{id:"B2",body:'Sorenson D, Gianola D. Likelihood, Bayesian, and MCMC Methods in Quantitative Genetics. 1st ed. New York: Springer-Verlag; 2002. p. 740\n'},{id:"B3",body:'Neumaier A, Groeneveld E. Restricted maximum likelihood estimation of covariances in sparse linear models. Genetics Selection Evolution. 1997;30(1):3-26\n'},{id:"B4",body:'Waldmann P. Easy and flexible Bayesian inference of quantitative genetic parameters. Evolution. 2009;63(6):1640-1643. 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Genetics. 2009;182:375-385. DOI: 10.1534/genetics.109.101501\n'},{id:"B23",body:'Weigel KA, De los Campos G, González-Recio O, Naya H, Wu XL, Long N, et al. Predictive ability of direct genomic values for lifetime net merit of Holstein sires using selected subsets of single nucleotide polymorphism markers. Journal of Dairy Science. 2009;92(10):5248-5257. DOI: 10.3168/jds.2009-2092\n'},{id:"B24",body:'Kizilkaya K, Fernando RL, Garrick DJ. Genomic prediction of simulated multi-breed and purebred performance using observed fifty thousand single nucleotide polymorphism genotypes. Journal of Animal Science. 2010;88(2):544-551. DOI: 10.2527/jas.2009-2064\n'},{id:"B25",body:'Habier D, Fernando RL, Kizilkaya K, Garrick DJ. Extension of the Bayesian alphabet for genomic selection. BMC Bioinformatics. 2011;12:12\n'},{id:"B26",body:'Metropolis N, Rosenbluth AW, Rosenbluth MN, Teller AH, Teller E. Equations of state calculations by fast computing machines. 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The 36th International Committee for Animal Recording (ICAR) Session, held June 16-20, in Niagara Falls; 2008\n'},{id:"B31",body:'Harris BL, Johnson DL. Genomic predictions for New Zealand dairy bulls and integration with national genetic evaluation. Journal of Dairy Science. 2009;93(3):1243-1252. DOI: 10.3168/jds.2009-2619\n'},{id:"B32",body:'Moser G, Tier B, Crump RE, Khatkar MS, Raadsma HM. A comparison of five methods to predict genomic breeding values of dairy bulls from genome-wide SNP markers. Genetics Selection Evolution. 2009;41(56). DOI: 10.1186/1297-9686-41-56\n'},{id:"B33",body:'Legarra A, Misztal I. Technical note: Computing strategies in genome-wide selection. Journal of Dairy Science. 2008;91(1):360-366. DOI: 10.3168/jds.2007-0403\n'},{id:"B34",body:'González-Recio O, Gianola G, Rosa GJM, Weigel KA, Kranis A. Genome-assisted prediction of a quantitative trait measured in parents and progeny: Application to food conversion rate in chickens. Genetics Selection Evolution. 2009;41(3):10. DOI: 10.1186/1297-9686-41-3\n'},{id:"B35",body:'VanRaden P. Efficient methods to compute genomic predictions. Journal of Dairy Science. 2008;91(11):4414-4423. DOI: 10.3168/jds.2007-0980\n'},{id:"B36",body:'Boichard D, Fritz S, Rossignol MN, Bosher MY, Malafosse A, Colleau JJ. Implementation of marker-assisted selection in French dairy cattle. In: 7th World Congress on Genetics Applied to Livestock Production; 19-23 August 2002; Montpellier, France. 2002. Session 22. Exploitation of molecular information in animal breeding. Electronic communication 22-03. p. 4\n'},{id:"B37",body:'Solberg TR, Sonesson AK, Woolliams JA, Meuwissen THE. Reducing dimensionality for prediction of genome-wide breeding values. Genetics Selection Evolution. 2009;41(29):8. DOI: 10.1186/1297-9686-41-29\n'},{id:"B38",body:'Gredler B, Nirea KG, Solberg TR, Egger-Danner C, Meuwissen THE, Solkner J. Genomic selection in Fleckvieh/Simmental—First results. In: Proceedings of the Interbull Meeting; 21-24 August 2009; Interbull Bulletin, Barcelone, Espagne; 2009;40:209-213\n'},{id:"B39",body:'Hayes BJ. Genomic selection in the era of the $1000 genome sequence. In: Symposium Statistical Genetics of Livestock for the Post-Genomic Era; USA: Wisconsin-Madison, USA; 2009\n'},{id:"B40",body:'Habier DJ, Tetens J, Seefried FR, Lichtner P, Thaller G. The impact of genetic relationship information on genomic breeding values in German Holstein cattle. Genetics Selection Evolution. 2010;42(5). DOI: 10.1186/1297-9686-42-5\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Hafedh Ben Zaabza",address:"hafedhbenzaabza@gmail.com",affiliation:'
Institut National Agronomique, Tunis-Mahrajène, Tunisie
'},{corresp:null,contributorFullName:"Abderrahmen Ben Gara",address:null,affiliation:'
Département des productions animales, Ecole supérieure d’Agriculture de Mateur, Mateur, Tunisie
Département des productions animales, Ecole supérieure d’Agriculture de Mateur, Mateur, Tunisie
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1. Introduction
Transplant recipients constitute a group of patients who are immunocompromised. Among them, hematopoietic stem cell transplant (HSCT) recipients suffer from the most severe immunosuppression, which may be prolonged. Many risk factors make these patients prone to fungal infections caused by yeast-like fungi or molds.
Filamentous fungi of the genus Aspergillus may cause many clinical forms of the disease in immunocompromised patients (including HSCT recipients and solid organ transplant recipients), but increasingly also in patients undergoing intensive care or even without any immune deficiencies [1]. Aspergillosis usually results from inhalation of spores, affecting primarily the respiratory system [1, 2, 3]. Humans are exposed daily to massive numbers of fungal spores; however, usually they are eliminated by various pulmonary defense mechanisms, for example, mucociliary function [1, 2]. With progress in molecular diagnostic methods, particularly next-generation sequencing (NGS) techniques, we have learned that molds and yeast-like fungi are present in the respiratory tract, even in healthy individuals [4]. Similar to microbiota composition in other parts of the body, the lung mycobiota also comprises numerous fungal species, which become less diverse in many diseases [4].
Aspergillosis may present in different forms, such as invasive aspergillosis (IA), allergic aspergillosis, chronic pulmonary aspergillosis, and as superficial disease in various anatomical locations (keratitis, otomycosis, and wound infections) [1, 4, 5, 6]. Allergic aspergillosis may present as allergic bronchopulmonary aspergillosis (ABPA) and allergic fungal rhinosinusitis (AFRS) [7].
Invasive aspergillosis is further divided into invasive pulmonary aspergillosis (IPA), sinusitis caused by Aspergillus spp., disseminated aspergillosis, and several types of invasive aspergillosis with the involvement of single organs [5, 6]. In transplant recipients and other immunocompromised patients, the most common clinical form of aspergillosis is invasive pulmonary aspergillosis, which untreated or unsuccessfully treated can lead to systemic dissemination to other organs and systems, for example, brain, heart, or the bones [1, 2]. In contrast, paranasal sinuses, larynx, eyes, ears, and the oral cavity are often involved in primary aspergillosis [2].
Invasive aspergillosis is the most common mold infection, particularly among immunocompromised patients. Patients subjected to allogeneic hematopoietic stem cell transplantation (alloHSCT) constitute a group of patients with the highest risk of systemic fungal infections, caused by both Candida spp., as well as Aspergillus spp. [5, 6]. Factors predisposing to the invasive aspergillosis are prolonged neutropenia (<500/μl for >10 days) and lymphopenia (mainly affecting CD4+ cells) [5, 8, 9, 10, 11, 12]. Frequency of invasive infections caused by Aspergillus spp. is on the increase in patients undergoing chemo- and/or radiotherapy, treated with corticosteroids or immunosuppressive agents, as well as in patients with acquired immune deficiency syndrome (AIDS) or congenital deficiencies of the immune system, such as chronic granulomatous disease [1, 8, 10, 12, 13, 14]. Patients at the extremes of age (>60 and neonates), persons with chronic malnutrition, and individuals on total parenteral nutrition have fungal infections more often than patients in other groups [8, 10, 13]. Surgical procedures, particularly thoracic or abdominal surgery and solid organ transplantation, and the use of central venous catheters or dialysis catheters are linked to endogenous and exogenous infections, including those caused by Aspergillus spp. [1, 5, 6, 8, 9, 10, 11]. Underlying diseases, such as diabetes, kidney, and/or liver failure, and chronic obstructive pulmonary disease (COPD) also predispose to invasive fungal infections [1, 8].
2. Etiology of invasive aspergillosis
Aspergillosis is caused by opportunistic molds of the genus Aspergillus, which contains more than 300 species; however, only relatively few of them are known to cause human diseases [12]. These fungi are ubiquitous in soil, plants, and decaying organic debris, as well as in household dust and building materials [1]. Hospitalized immunocompromised patients are at risk of aspergillosis during construction or renovation works at the hospital. Fungi Aspergillus spp. (like other molds), produce conidia that are easily aerosolized [12]. Inhaled conidia colonize the respiratory system of the host in whom—depending on the degree of immunosuppression—various clinical forms of aspergillosis may develop. Rarely, aspergillosis results from ingestion of the spores or their direct inoculation into the wounds [12].
The most common etiological agent of invasive aspergillosis with a high morality is A. fumigatus, responsible for the majority (up to 90%) of cases in humans [1, 12, 15, 16, 17, 18, 19]. It is followed by A. flavus, which causes up to 10% of cases of bronchoalveolar aspergillosis [18]. This species also is responsible for most cases of aspergillosis with sinus and skin involvement [1]. It appears that A. flavus survives better than other Aspergillus spp. in a dry and hot climate; therefore, it is mainly isolated in Asia, Middle East, and Africa [17]. Other species of the genus Aspergillus, such as A. niger, A. nidulans, A. terreus, A. versicolor, A. calidoustus, and A. ustus cause invasive infections less frequently; however, they are of importance in immunocompromised patients [12, 18, 20, 21]. Strains of A. niger colonize the respiratory tract and are etiological agents of most cases of external otitis [1]. According to the Prospective Antifungal Therapy Alliance® (PATH Alliance ®) registry, in a cohort study of 960 cases of proven/probable IA, A. fumigatus (72.6%) was the most predominant species, followed by A. flavus (9.9%), A. niger (8.7%), and A. terreus (4.3%) [12]. Recently, an increasing frequency of infections caused by environmental species of Aspergillus (of unknown significance in medicine) is being reported [21].
Apart from Aspergillus species other than A. fumigatus, recently attention is being focused on the strains classified in the section Fumigati (A. fumigatus complex), for example, Neosartorya udagawae (A. udagawae) [18, 22]. They may cause similar diseases as A. fumigatus sensu stricto; however, duration of illness may be prolonged (even sevenfold) [22]. It appears that actual prevalence of these cases may be underestimated, as these strains are often misidentified because they cannot be distinguished from A. fumigatus sensu stricto by conventional morphological tests [18]. Moreover, the outcome of treatment of these infections may be unfavorable, as strains belonging to A. fumigatus-related species (the section Fumigati) often show some level of intrinsic resistance to azoles and other antifungal drugs, with the minimum inhibitory concentrations (MICs) of various antifungals for these isolates higher than those for A. fumigatus, which is usually susceptible to azoles [22]. However, in a recent multicenter prospective study, the rate of azole resistance among A. fumigatus isolates was relatively high—3.2%, out of which 78% were A. fumigatus sensu stricto with a mutation of the cyp51A gene, while the remaining 22% were the related species (A. lentulus, A. thermomutatus, and A. udagawae) [23].
In clinical practice A. lentulus, A. udagawae, A. viridinutans, and A. thermomutatus (Neosartorya pseudofischeri), A. novofumigatus and A. hiratsukae have been linked etiologically to such refractory cases of IA [18]. These A. fumigatus complex strains are characterized by lower virulence ascribed to a lower thermotolerance and different profiles of secondary metabolites with decreased production of mycotoxins, such as gliotoxin [18]. Definitive identification of these cryptic species requires specific sequencing analyses of the beta-tubulin or calmodulin genes, which are not readily available. Clinical microbiologists should, therefore, be aware of such cryptic species of Aspergillus and the methods of their differentiation from A. fumigatus—defect in sporulation, unusual susceptibility profile to antifungals, as well as multiplex PCR assays and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) technique [18].
3. Clinical forms of invasive aspergillosis
Molds of the genus Aspergillus may cause a wide variety of clinical entities, ranging from asymptomatic colonization, allergic bronchopulmonary aspergillosis, and chronic pulmonary aspergillosis to severe (even fulminant) invasive infections in almost every organ or system in the body of the host, including (but not limited to) the lungs, heart, central nervous system, and the sinuses [5, 18, 19, 24]. The most common clinical form of invasive diseases caused by Aspergillus spp. is pulmonary aspergillosis, which in about 50% of cases spreads to other anatomical locations, including the brain, liver, kidneys, endocardium, bones, and gastrointestinal tract [8, 10, 13, 19, 25]. Aspergillosis may also affect the paranasal sinuses, the ear, or the eyeball [13].
The spectrum of aspergillosis is determined by the host’s immune status (particularly severe and prolonged neutropenia) and the virulence of Aspergillus strain causing the infection [5, 6, 12, 13]. In immunocompetent persons, molds of the genus Aspergillus mainly cause allergic symptoms and chronic pulmonary aspergillosis, without invasion and destruction of the host’s tissues [12]. In the chronic pulmonary aspergillosis, usually a preexisting pulmonary condition is observed, such as preformed cavity in the lung (resulting from tuberculosis, sarcoidosis, or other necrotising process), in which an aspergilloma (or a fungus ball) is being formed (chronic cavitary pulmonary aspergillosis) [12]. Allergic bronchopulmonary aspergillosis (ABPA) is a disease that arises from a hypersensitivity reaction to Aspergillus antigens and most often develops in patients who have asthma, atopy, or cystic fibrosis [8, 12, 26]. Another form of aspergillosis, characterized by a local invasion of the lung parenchyma; however, without invasion or dissemination to other organs, is called subacute invasive aspergillosis (or chronic necrotizing pulmonary aspergillosis) [12].
Invasive aspergillosis is a life-threatening infection and a major cause of death in immunocompromised patients, particularly hematopoietic stem cell transplant recipients, but may be fatal even in immunocompetent individuals, with the death rate of 40% for pulmonary disease, 90% for disseminated disease, and practically 100% for disseminated disease with the central nervous system (CNS) involvement [1, 19]. According to the literature, invasive aspergillosis occurs in 1–15% of the solid organ transplant recipients, in whom mortality rates due to this disease range from 65 to 92% [1]. However, currently these indices improve in these patients due to advances in immunosuppressive regimens and transplantation practices, as well as frequent use of antifungal prophylaxis.
Recent reports indicate that invasive aspergillosis is being increasingly diagnosed in patients without above-mentioned severe neutropenia—particularly in the lung transplant recipients, patients hospitalized in the intensive care unit or treated with corticosteroids [9, 11, 27]. Also, individuals with chronic obstructive pulmonary disease (COPD), liver failure, and other underlying diseases are listed in this group [8, 11, 20]. It has been reported that in ICU patients with invasive pulmonary aspergillosis 40–80% of them do not have any malignancy or other classical risk factors for this infection [8, 20]. Moreover, in contrast to patients with neutropenia, in ICU patients the symptoms of aspergillosis are atypical; therefore the diagnosis of this infection may be delayed or omitted, according to the autopsy studies [11, 15, 28]. Tejerina et al. showed that among 893 deceased patients, previously treated in ICU, only 40% (10 out of 25) had invasive aspergillosis diagnosed ante mortem [11]. Problems with proper diagnosis of invasive asergillosis, and therefore a delay in administration of effective antifungal therapy, are undoubtfully linked to a high mortality rate in this group of patients (30–40%), which may even exceed 90% despite lack of severe immunosuppression in these individuals [15, 27, 29].
3.1 Aspergillosis of the oral cavity and the upper respiratory tract
As mentioned earlier, aspergillosis affects mainly the lungs; however it may also be diagnosed in the upper respiratory tract and the oral cavity [2, 30]. Orofacial aspergillosis is relatively common in oncohematological patients undergoing chemotherapy [2].
Aspergillosis of the larynx is very rare, with only a few cases reported in the literature [31]. Usually, it is secondary form of this disease, while primary aspergillosis of the larynx is even rarer. Risk factors for aspergillosis of the larynx comprise the use of inhaled or systemic steroids, prolonged antibiotic therapy, and underlying immunosuppression [31]. It should be emphasized that these lesions may mimic malignancy or a premalignant condition, while proper diagnosis and administration of antifungal therapy, as well as elimination of the risk factors (if possible), are effective in the elimination of this condition [31].
It also appears that chronic tonsillitis may be caused by Aspergillus spp. In a study of 75 symptomatic children who underwent a tonsillectomy, in 9 (12%) of them Aspergillus was detected on histological examination of the removed tonsils [30].
Aspergillus spores may be deposited in the oral cavity upon inhalation or during dental procedures, for example, tooth extraction [3]. The fungus may then spread further into the sinuses as odontogenic infection [32, 33]. The infection may also become established in the oral cavity itself.
In oral aspergillosis, the lesions are usually located on the palate or posterior tongue [2]. They are yellow or black, with a necrotic ulcerated base. The hyphal elements of Aspergillus fungus may invade the oral mucosa through the release of various toxins, such as proteases, phospholipases, hemolysins, gliotoxin, aflatoxin, phthioic acid, and many others. Subsequently, they penetrate the blood vessels, producing thrombosis, infarction and necrosis, and then systemic spread follows [2].
3.2 Aspergillosis of the nose and paranasal sinuses
Paranasal sinuses may be colonized or infected by fungi, while infection can be invasive (acute or chronic) or noninvasive (allergic sinusitis and aspergilloma) [18]. In invasive aspergillosis of the sinuses, there are rapid (within a few days) destructions of the sinuses, the nasal cavity, and the adjacent structures, such as the orbit and the brain [18]. Aspergillus spp. may also cause allergic Aspergillus sinusitis (AAS), which results from a hypersensitivity reaction to the presence of the fungus in the sinus [26]. The hallmark of AAS is demonstration of fungal elements in the material obtained from the sinus [26].
It is estimated, that fungal sinusitis constitutes 6–9% of all cases of rhinosinusitis. Among fungi causing sinusitis, the most common is Aspergillus spp. [18]. Aspergillosis of the paranasal sinus should be suspected in patients with refractory or recurrent sinusitis. Apart from the sinuses, aspergillosis may also affect the nasal cavity, from which the infection can spread to the CNS (rhinocerebral aspergillosis).
The maxillary sinus is more often affected than other paranasal sinuses. However, it is frequently misdiagnosed, even as malignancy [3, 18, 34]. Untreated infection may spread to the other structures in the head [35]. Invasive aspergillosis of the maxillary sinus should be considered in patients with maxillary sinusitis which does not respond to standard therapy with antibiotics, even in immunocompetent patients [3].
From the paranasal sinuses, Aspergillus infection may spread locally into the vasculature and the brain, leading to cavernous sinus thrombosis and a variety of central nervous system manifestations and to other locations, for example, the orbit [36]. In these cases, computed tomography (CT) or magnetic resonance imaging (MRI) and biopsy of any lesion located in the sinuses or the nasal cavity in high-risk patients is mandatory [19]. Intracranial and intraorbital extension decreases the survival rate of these patients [3].
Factors which predispose immunocompetent individuals to fungal infections in the sinuses include polyps and blocked drainage of secretions [3]. Additional risk factors for fungal sinusitis, including Aspergillus, are reported in immunocompromised patients and individuals with various underlying diseases, such as neutropenia, immunosuppressive therapy, corticosteroids, uncontrolled diabetes mellitus, trauma, burns, and radiation therapy [3]. In these patients, particularly with hematological malignancies and in transplant recipients, Aspergillus may cause an invasive infection as aggressive in its clinical course as those caused by Zygomycetes [19]. Invasive fungal sinusitis is potentially fatal, with an extremely high mortality rate, particularly in immunocompromised patients [3]. Therefore invasive aspergillosis of the paranasal sinuses has to be recognized and treated to avoid significant mortality in immunocompromised patients, particularly in transplant recipients [3]. It should be suspected in cases of purulent rhinosinusitis not responding to repeated courses of antibiotics, and on the basis of radiological features.
Therapy of fungal sinusitis depends on its clinical form. In cases of Aspergillus fungal ball of the paranasal sinuses, surgical removal alone can be sufficient [5, 6]. Enlargement of the sinus opening may be needed to improve drainage and prevent further recurrence of sinusitis [5, 6]. In invasive aspergillosis apart from surgery, also systemic antifugal therapy is recommended.
3.3 Aspergillosis of the lower respiratory tract
Within the lower respiratory tract, Aspergillus infection may affect the larynx, trachea, and bronchi (tracheobronchitis), as well as lung parenchyma (pulmonary aspergillosis). In rare cases, Aspergillus pleuritis has been reported [19].
The lungs are affected in up to 92% of all cases of invasive aspergillosis [19]. Invasive pulmonary aspergillosis is a clinical entity characterized by invasion of the fungal hyphae into the blood vessels (angioinvasion), which subsequent hemoptysis. Other symptoms comprise nonproductive cough, pleuritic pain, low-grade fever, and dyspnea [19]. However, in the early stages of the disease, both clinical symptoms and radiological findings may be nonspecific, so proper diagnosis and treatment may be delayed, resulting in increased mortality in this group of patients.
The frequency of invasive pulmonary aspergillosis has significantly increased in recent years due to a growing number of immunocompromised patients [8, 37]. This clinical entity most often occurs in patients with different forms of immunosuppression, for example, hematological malignancies, profound and prolonged neutropenia, or corticosteroid therapy, as well as organ transplantation, autoimmune and inflammatory conditions, in critically ill patients, and those with chronic obstructive pulmonary disease (COPD) [8, 37]. In about 50% of patients with invasive pulmonary aspergillosis, the infection spreads to other anatomical sites, such as the brain, liver, kidneys, or the gastrointestinal tract [8, 10, 13, 19, 25].
An uncommon clinical form of IA is an isolated invasive Aspergillus tracheobronchitis (iIATB), in which fungal infection is limited predominantly or entirely to the tracheobronchial tree [19, 38]. It has been mainly reported in lung- and heart-lung transplant recipients. Wu et al. reviewed 19 cases of this disease and concluded that iIATB occurs in moderately or nonimmunocompromised patients with impaired airway structures or defense functions and it may be an early period of invasive pulmonary aspergillosis [38]. Early diagnosis and effective antifungal treatment were linked to a favorable prognosis; however, 5 out of 19 (26.3%) patients died.
Other forms of Aspergillus infection of the lungs comprise chronic necrotizing aspergillosis, which is described in patients with chronic lung disease or low degree immunodeficiency as a locally invasive disease, as well as aspergilloma usually found in individuals with previously formed cavities in the lungs [8, 12].
As mentioned earlier, symptoms of the pulmonary disease may result not from actual infection, but allergic reaction of the host to the presence of Aspergillus in the bronchial tree—allergic brochopulmonary aspergillosis (ABPA) [12, 26]. This immunologically mediated disease occurs predominantly in patients with asthma, atopy, and cystic fibrosis (CF) [8, 12, 26].
3.4 Aspergillosis of the central nervous system
Aspergillosis of the brain (cerebral aspergillosis) is usually a part of the disseminated disease after hematogenous spread of infection from the lungs, but rarely it may represent an isolated disease of the central nervous system (CNS) [19]. It is reported in 10–15% of patients with invasive pulmonary aspergillosis [39]. The most common risk factors comprise neutropenia and other forms of immunosuppression and transplantation surgery [19]. Cerebral aspergillosis usually presents as a single or multiple brain abscess, also as cerebral vasculitis and cerebral infarcts, while meningitis is rare [19]. Brain abscesses are common in HSCT recipients, while relatively rare in solid organ transplant (SOT) recipients [40, 41]. CT and MRI are recommended in patients in whom cerebral aspergillosis is suspected [42]. Among all types of IA, brain aspergillosis has the worst prognosis, with mortality rate usually exceeding 90% (up to 100%), however early and proper treatment improves the prognosis in these patients and significantly increases their survival rates [19].
Aspergillosis of the CNS may also present as rhinocerebral aspergillosis, particularly in patients with underlying malignancies and neutropenia, HSCT recipients, and patients with diabetic ketoacidosis [37]. Symptoms usually comprise fever, nasal or sinus congestion or pain, nasal discharge, unilateral facial swelling, and headaches [37]. Necrotic lesions may be seen on the hard palate and in the nasal cavity. The spread of infection may lead to ophthalmic complications, such as ptosis, proptosis, and vision disturbances [37].
3.5 Invasive cardiac aspergillosis
Invasive cardiac aspergillosis may present as endocarditis, myocarditis, pericarditis, mediastinitis, septic thrombophlebitis, and infections of aortic grafts—also in transplant recipients [5, 6, 43, 44].
Endocarditis caused by Aspergillus spp. is a severe form of fungal endocarditis [45, 46]. The mortality rate is high and surgery is usually required [19, 45, 46, 47]. It is very rare, but in recent years, the incidence of this form of aspergillosis is increasing, due to a rise in the frequency of its risk factors—the use of invasive procedures involving the heart, cardiac surgery with replacement of the heart valves, implantation of cardiac devices, organ transplantation, drug abuse, or administration of immunosuppressive therapy [19, 45]. Pierrotti and Baddour analyzed mold-related endocarditis in 3939 patients (the majority of cases were caused by Aspergillus spp.) and found the following risk factors: underlying cardiac abnormalities (41%), prosthetic heart valves (39%), malignancy (18%), solid-organ transplantation (18%), and bone marrow transplantation (18%) [47]. In a study by Paterson et al., 26% of cases of infective endocarditis occurring within a month of solid organ transplantation were caused by Aspergillus [48]. Woods et al. found that the most common predisposing factors for Aspergillus endocarditis in 29 patients were corticosteroid therapy (55%), prolonged antibiotic treatment (31%), hematological malignancy (28%), and chemotherapy and cytotoxic therapy (28%) [49].
In the course of Aspergillus endocarditis, mitral and bicuspid valves (native or prosthetic) are most often affected [19, 46, 50, 51]. Fungal vegetations may be formed on the heart valves, which subsequently may cause embolism blocking the arteries. Gumbo et al. reported that vegetations were revealed on the heart valves in 78% of the cases in which echocardiography was performed, while embolic episodes were seen in 69% of patients with Aspergillus endocarditis, and a new or changing heart murmur—in 41% of them [52]. In a recently published study, Meshaal et al. showed that aortic abscess or pseudoaneurysm was one of the strong predictors of Aspergillus endocarditis [45]. However, it should be noted that Aspergillus endocarditis may be difficult to diagnose because blood cultures are usually negative, while fever is absent in 26% of patients with this disease [19, 45]. Aspergillus endocarditis should, therefore, be suspected in patients with underlying immunosuppression, hematological malignancies, recent cardiothoracic surgery, intravenous drug use, systemic or pulmonary emboli with negative blood cultures, and vegetation on echocardiography [24]. Diagnosis should be confirmed by histology and mycological culture of tissue or vegetation samples [24]. Delayed or erroneous diagnosis of Aspergillus endocarditis contributes to incorrect management of patients. Early surgical replacement of an infected valve and prolonged administration of antifungal therapy (which may be lifelong) are recommended to prevent embolic complications, valvular decompensation, and further spread of the infection [5, 6, 24, 43, 44].
Heart muscle may be affected by Aspergillus infection in the form of myocarditis or cardiomyopathy [53, 54]. This form of disease usually results from hematogenous spread of infection and is characterized by the presence of abscesses. Pericarditis caused by Aspergillus spp. has been described, also in transplant recipients [43, 55].
3.6 Ocular aspergillosis
Aspergillosis of the eye may take a form of fungal keratitis, endophthalmitis, or invasive aspergillosis of the orbit. All structures of the eyeball may be affected—eyelids, conjunctivae, lacrimal apparatus, cornea, sclera, or uvea. Aspergillus dacryocystitis is a rare complication of aspergillosis of the paranasal sinuses [56]. Clinicians must be aware that the clinical course of ocular aspergillosis may range from asymptomatic infection or slowly developing disease to rapidly progressive infection, with a fulminant course and fatal outcome [56].
Fungal keratitis often presents as a corneal ulcer, which results from mechanical injury of the cornea, with subsequent necrosis. In a recent study, Manikandan et al. examined a total of 500 corneal scrapings, collected from patients in whom mycotic keratitis was suspected, out of which 68 (13.6%) were positive for Aspergillus spp. [57].
Endophthalmitis may be a complication of surgical procedures or may result from hematogenous spread from other sites of infection. Endogenous Aspergillus endophthalmitis is mainly reported in severely immunocompromised patients, transplant organ recipients, patients after heart valve replacement, and in oncohematological patients [58, 59, 60].
Orbital invasive aspergillosis is a rare infection, which most often results from dissemination of the infection from the nose or paranasal sinuses. It may take an acute or chronic form. This form of IA usually presents with a severe orbital pain, paralysis of the oculomotor nerve and visual impairment. Ophthalmic complications, such as ptosis, proptosis, and vision disturbances may result from the spread of infection in rhinocerebral aspergillosis [37].
3.7 Aspergillosis of the genitourinary tract
Aspergillosis of the urinary tract is relatively rare. In immunocompromised patients, such as kidney transplant recipients, frequency of this form of aspergillosis amounts to only 0.5–2.2%, but is fatal in >88% of patients [61]. Urinary tract aspergillosis may also be a complication of surgical procedures, such as lithotripsy, urinary tract instrumentation, or ureteric stenting, particularly in immunocompromised patients [62, 63, 64, 65]. Renal aspergillosis is being occasionally reported with obstruction of one or both ureters [19]. Localized aspergillosis of the renal graft was reported in a child 5 months after kidney transplantation [61]. A case of urinary tract aspergillosis presenting as an aspergilloma of the urinary bladder has also been described [66].
Aspergillosis of the genital tract has been rarely reported [67, 68, 69]. In women, it may give the symptoms resembling a pelvic inflammatory disease.
3.8 Other clinical forms of aspergillosis
Other clinical forms of aspergillosis—apart from above-mentioned—are very rare and comprise gastrointestinal aspergillosis, cutaneous aspergillosis, Aspergillus peritonitis, osteomyelitis, and septic arthritis, as well as Aspergillus ear infections [5, 6, 19, 37].
Gastrointestinal aspergillosis is mainly reported in patients who are transplant recipients or severely malnourished [37]. It results from ingestion of Aspergillus spp. spores. The most commonly involved sites are the stomach, colon, and ileum.
Cutaneous aspergillosis is classified as primary or secondary [37]. Primary form of the disease is usually reported in patients with burn wounds or surgical wounds. This clinical entity is caused by direct inoculation of the fungus or its spores into the injured skin [37]. Primary cutaneous aspergillosis has been linked to leukemic patients, neonates, transplant recipients, as well as the use of occlusive dressings or permanent intravenous catheters [19]. Secondary cutaneous aspergillosis results from hematogenous spread of the fungus and therefore represents a disseminated form of Aspergillus infection. It may present as nodules or extensive necrotic lesions [19]. The mortality rate may be high.
Aspergillus peritonitis is seen in patients undergoing peritoneal dialysis [19]. It may be complicated by hemorrhage, perforation, or infarction.
Aspergillus ear infections may present as noninvasive otitis externa (otomycosis) or invasive aspergillosis of the ear. Examples of other forms of invasive aspergillosis comprise vertebral osteomyelitis (resulting from hematogenous spread, by contiguity or from direct inoculation), septic arthritis, cholangitis, and prosthetic vascular graft rejection [19].
Disseminated aspergillosis if defined as the involvement of at least two noncontiguous sites in the body, mainly in transplant recipients [19]. Disseminated disease has been reported in 9–36% of kidney transplant recipients, 15–20% of lung transplant recipients, 20–35% of heart transplant recipients, and 50–60% of liver transplant recipients with invasive aspergillosis [70].
4. Aspergillosis in transplant recipients
In patients with immune deficiencies and other risk factors, invasive aspergillosis (IA) is a life-threatening infection caused by the opportunistic molds of the genus Aspergillus, most often by A. fumigatus [5, 6, 14, 70, 71]. A cohort study of 960 cases of probable or proven IA reported in the Prospective Antifungal Therapy Alliance (PATH Alliance) registry, indicated that 48.3% of patients had hematologic malignancy, 29.2% were SOT recipients, 27.9% were HSCT recipients, and 33.8% were neutropenic [12]. In these patients, the most common clinical forms of IA are invasive pulmonary aspergillosis (IPA) and rhinocerebral aspergillosis [12].
In transplant recipients, particularly in hematopoietic stem cell transplant (HSCT) recipients who are severely immunocompromised, invasive aspergillosis is not only more common than in other groups of patients, but is also characterized by much more severe and rapidly progressive clinical course, and much higher mortality [12, 72].
Although prognosis has improved in recent years, IA still remains a significant post-transplant complication in solid organ transplant (SOT) recipients [43, 44]. It occurs in up to 30% of SOT recipients. Although in recent years the mortality rate in transplant recipients decreased from 65–92% to 22%, still an estimated 9.3–16.9% of all deaths in transplant recipients in the first year after transplantation can be attributed to IA [44].
The incidence of IA differs between different populations of transplant recipients, and unique risk factors for Aspergillus infections have been identified for various types of organ transplant recipients [43, 44]. However, regardless of the type of transplantation a major risk factor for the development of IA in SOT recipients is the net state of immunosuppression including the intensity of administered immunosuppressive therapy [44].
Regarding the risk of invasive fungal infections (particularly IA) in transplant recipients, at present routine antifungal prophylaxis or preemptive therapy is recommended in HSCT recipients with prolonged neutropenia or graft-versus-host disease (GVHD), and in lung transplant recipients, while targeted prophylaxis should be considered in liver and heart transplant recipients [5, 6, 44, 71].
Invasive aspergillosis remains a major complication following allogeneic HSCT (alloHSCT) [73]. The burden of IA has increased significantly in the last 30 years as a result of the increased number of patients undergoing immunosuppressive therapy for hematological malignancies and HSCT [14]. It is estimated that IA is a leading cause of fatal outcomes in HSCT patients, accounting for 10% of all deaths in this group of patients [14].
In the recipients of alloHSCT, IA can occur during the neutropenic pre-engraftment phase (early IA) or during the post-engraftment period (late IA) [14]. Although IA remains an important complication after allogeneic transplantation, regardless of the type of conditioning regimen, early IA is more common in patients undergoing myeloablative transplantation due to extensive chemotherapy and radiation used to destroy the native bone marrow, and prolonged neutropenia which results from this treatment [14, 74]. On the other hand, non-myeloablative HSCT comprises a shorter neutropenic period and therefore, a decrease in the incidence of early IA. However, a higher risk of GVHD in this group of patients and the therapies given for this condition caused a shift to late IA, diagnosed increasingly during the post-engraftment period [14]. It should be noted that the risk period for late IA, associated with GVHD, can last for months to years, so prophylactic and monitoring procedures must be implemented over a long period. Carvalho-Dias et al. analyzed 24 cases of proven and probable invasive aspergillosis among HSCT recipients and reported, that 83% of the patients died due to invasive fungal infection within 60 days of follow-up [72].
Kojima et al. compared the incidence of IA and mortality rates due to this disease in 664 recipients of alloHSCT—486 conventional stem cell transplantation (CST) patients and 178 reduced-intensity stem cell transplant (RIST) recipients. The overall incidence of IA in all 664 recipients of alloHSCT was 35 (5.3%) [74]. Despite significant differences in the estimated 3-year incidence of IA in CST group (4.5%) and RIST population (8.2%) (P = 0.045), the mortality rates were similar in both groups (76 and 86%, respectively). However, the median onset of IA after RIST was day 127, which was significantly later than that after CST—day 97 [74]. Furthermore, a multivariate analysis showed that IA was associated with age > 50 years and the presence of acute or chronic GVHD [74]. In another study, Labbe et al. analyzed the risk factors for IA in 125 alloHSCT recipients with nonmyeloablative (NMA) regimens, who received a 6/6 matched sibling NMA HSCT and were treated homogenously [73]. IA developed in 13 patients (5 proved, 6 probable, and 2 possible IA), at 44–791 days (median 229 days) after NMA HSCT. The risk of IA was calculated as 7% at 1 year, 11% at 2 years, and 15% at 3 years after NMA alloHSCT [73]. It was concluded that in NMA HSCT recipients the risk of IA increases over time and is significantly associated with intestinal GVHD, therefore these patients should be monitored for this complication and administration of antifungal prophylaxis with activity against molds should be considered [73].
4.2 Lung and heart-lung transplant recipients
In lung transplant recipients, invasive aspergillosis is the predominant fungal infection [44, 71, 75]. In the past, the incidence of IA in this group of patients was reported in the range of 4.0–23.3%, however, newer studies point to a lower frequency of this disease [44]. On the other hand, the time from lung transplantation to the onset of IA becomes longer due to the use of antifungal prophylaxis in the early post-transplant period. Therefore the median time to IA onset has increased from 120 days post-transplant to 483 or 508 days post-transplant reported in recent studies [44].
The most common species linked to the etiology of IA in lung transplant recipients is Aspergillus fumigatus. In an international, multicenter, retrospective cohort study of 900 consecutive adult lung transplant recipients with 4 years of follow-up, 79 patients developed 115 episodes of IA [75]. Aspergillus fumigatus was isolated in 72 of 115 (63%) episodes [75]. In a retrospective study of 251 lung transplant recipients, Aspergillus was isolated from 86 (33%) cases including 50 patients colonized with Aspergillus spp., 17 recipients with tracheobronchitis, and 19 cases of IA [76]. These authors reported that isolation of Aspergillus spp. from respiratory samples preceded acute rejection of the graft, therefore it may be a marker of threatening graft rejection and/or inflammation of the airways [76].
The significance of the patient’s airway colonization with Aspergillus spp. before lung transplantation remains controversial. Some authors indicate its importance within the first year after lung transplantation, if the recipient was colonized in the period of 6 months before lung transplantation, while others did not find any significant link between Aspergillus pre-transplant colonization and occurrence of IA in the post-transplant period [44, 75, 76, 77]. Other risk factors for IA, which are unique to lung transplant recipients, comprise bronchial anastomotic leaks and other complications within the surgical site, airway narrowing, allograft dysfunction and/or graft ischaemia, reperfusion injury, CMV infection, bronchiolitis, and requirement for more intensive immunosuppressive therapy to prevent graft rejection [44, 76]. In lung transplant recipients, recovery of Aspergillus spp. from a respiratory tract sample warrants bronchoscopy to exclude the presence of tracheobronchitis [44].
It should be beared in mind that in lung transplant recipients there is a continuous exposure of the graft to the external environment through the airways, with impaired defense mechanisms (decreased mucociliary function, weakened cough reflex) in the early postransplant period [44].
In lung transplant recipients, there is a transient devascularization of the bronchial anastomotic site, which may contribute to ischemic injury and necrosis. This is a risk factor for development of ulcerative tracheobronchitis—a locally invasive form of IA involving the anastomotic site, the trachea, and the bronchi [44, 78]. In these patients, bronchovascular fistulas may develop, with a potentially fatal hemorrhage.
In the literature reports, the mortality rate of lung transplant recipients with IA ranges from 23 to 29% in individuals with tracheobronchitis to as high as 67–82% in patients with invasive pulmonary aspergillosis, but according to some estimates at present, it could be as low as 20% [44]. In a follow-up study of 251 lung transplant recipients, Aspergillus infection was associated with a reduced 5-year survival rate of these patients [76]. Prognosis is worse in patients with aspergillosis of the central nervous system or with disseminated disease [71].
4.3 Heart transplant recipients
According to the literature, the incidence of invasive aspergillosis in heart transplant recipients ranges from 1 to 14% [44, 79]. In this population, the risk factors for IA comprise isolation of Aspergillus fumigatus from bronchoalveolar lavage fluid, disease caused by cytomegalovirus, reoperation, and post-transplant hemodialysis [44]. The mortality rate in heart transplant recipients with invasive aspergillosis remains high—in the range of 66–88% [44, 79, 80, 81].
Invasive pulmonary aspergillosis remains the most common clinical presentation of this disease, particularly in early-onset IA (≤3 months after transplantation), while in late-onset IA, there is a higher frequency of disseminated disease and involvement of the central nervous system and other extrapulmonary sites [79, 80]. In an analysis of 455 heart transplant recipients, in whom 8 cases of IA have been diagnosed, all had invasive pulmonary form of the disease [79]. Risk factors for early-onset IA (within ≤3 months after heart transplantation), comprised hemodialysis, thoracic reoperation, and the presence of another case in the institution within the preceding 3 months [79]. For late-onset IA in this population of heart transplant recipients, hemodialysis and augmented immunosuppression were identified as risk factors [79]. In the clinical course of these cases, predominated septic shock and multiple organ dysfunction syndrome (MODS), nonspecific clinical and radiographic findings, as well as rapid (at a median of 11 days after diagnosis) mortality despite administration of antifungal therapy with activity against molds [79]. In a study by Montoya et al., none of the heart transplant recipients with either invasive pulmonary aspergillosis or invasive extrapulmonary aspergillosis had neutropenia [81]. Therefore, even in the absence of neutropenia invasive pulmonary aspergillosis should be suspected, particularly within the first 3 months of transplantation in heart transplant recipients who have fever and respiratory symptoms, a positive result of culture of respiratory secretions, and abnormal radiological findings (particularly nodules) [81].
A study of 479 consecutive heart transplant recipients in a single institution revealed a decrease in the incidence of IA from 8.7% (24/277) in the period 1988–2000 to 3.5% (7/202) in 2001–2011 [80]. Overall the incidence of IA in the studied group of heart transplant recipients was 6.5% (31 of 479). However, the authors report that four of seven cases were diagnosed as an outbreak, which indicates that favorable conditions for an infection with Aspergillus spp. may be present in a hospital [80]. Over the study period, there was a decrease in the mortality rate among the heart transplant recipients with IA from 46 to 0% (p = 0.04) [80]. The authors also noted a higher mortality rate in late-onset IA cases (63%) in comparison to early-onset IA (26%, p = 0.09) [80].
4.4 Liver transplant recipients
Invasive aspergillosis is reported in 1.0–9.2% of the liver transplant recipients. Mortality rates have decreased from 83–88% in earlier studies to 33–65% in more recent reports [44]. However, they remain very high in patients who develop invasive aspergillosis after liver retransplantation (82.4%), particularly in those undergoing surgery later than 30 days after primary liver transplantation (100%) [44].
Risk factors for invasive fungal infections, including aspergillosis, in these patients, comprise retransplantation (30-fold higher risk) and renal dysfunction, particularly requiring any form of renal replacement therapy (15- to 25-fold higher risk) [44]. Furthermore, transplantation for fulminant hepatic failure, pretransplant corticosteroid therapy, cytomegalovirus (CMV) infection, and prolonged intensive unit care stay are other risk factors associated with invasive aspergillosis in liver transplant recipients [44]. It is underlined that liver transplant recipients are particularly susceptible to disseminated and central nervous system invasive aspergillosis [44].
Previously most invasive fungal infections in liver transplant recipients occurred within the first month after transplantation (the median time to onset was reported as 16–17 days), however, in recent years, they are usually diagnosed in the late period (>90 days) after liver transplantation. After renal replacement therapy and retransplantation, the median time to onset of IA was reported as 13 and 28 days, respectively [44].
4.5 Kidney transplant recipients
Invasive aspergillosis has been reported in 0.7–4.0% of the renal transplant recipients [44]. It should be emphasized that despite a relatively low overall incidence of IA in comparison to other solid organ transplant (SOT) recipients, the mortality rate is high in these patients—in the range of 67–75% [44]. Risk factors for invasive aspergillosis in kidney transplant recipients are the following: potent immunosuppressive therapy, leukopenia, prolonged and/or high dose corticosteroid therapy, longer duration of renal replacement therapy in the pretransplant period, and graft failure requiring hemodialysis [44, 82].
In a recent study, Desbois et al. analyzed the outcome of IA in kidney transplant recipients in the era of voriconazole availability [83]. Unfortunately, they concluded that the prognosis of patients with IA after renal transplantation is still poor, and even if the patients survive, the risk of graft loss is high [83].
5. Mycological diagnostics
The diagnosis of invasive aspergillosis remains a significant challenge [19]. It is usually based on a histopathological evidence of tissue invasion, in conjunction with an isolation of Aspergillus spp. in culture of the biopsy material or other clinically relevant specimen, as well as compatible clinical signs and symptoms in a patient with recognized risk factors. Imaging examinations (radiographic, computed tomography, and magnetic resonance), as well as serological tests (detection of fungal antigens and antifungal antibodies), provide only additional information and should be interpreted in conjunction with the clinical picture and the results of additional laboratory tests [13, 19, 48].
It should be emphasized that fast detection and identification of the etiological agent of infection is of utmost importance as it allows an early start of an effective antimicrobial therapy, which improves the patient’s chances to survive.
In mycological diagnostics, the culture of the fungus from the site of infection and in vitro susceptibility testing of the isolate remain the “gold” standard. A diagnosis of invasive pulmonary aspergillosis comprises detection of the fungal mycelium with histopathological (with the use of different staining techniques) tests and/or positive culture of the relevant material obtained from the lower respiratory tract [5, 6, 13, 15, 19]. In a patient in whom invasive pulmonary aspergillosis is suspected, it is recommended to culture a sample of bronchoalveolar lavage fluid (BALF), obtained as early as possible during the course of infection [5, 6, 13, 19]. It should be emphasized that the result of sputum culture is not an unequivocal proof of invasive infection of the lung parenchyma, because it may represent only colonization of the respiratory tract by the isolated microorganism. It has been reported that among 66 elderly patients in whom Aspergillus spp. was cultured from sputum, only 3 individuals had invasive pulmonary aspergillosis [84]. In another study, no Aspergillus spp. was cultured from the sputum of 70% of patients with invasive pulmonary aspergillosis confirmed with other reliable methods [8].
Blood cultures are rarely positive in patients with invasive pulmonary aspergillosis [8, 19, 45]. In patients with pulmonary aspergillosis, Aspergillus fungaemia was detected in 10.1% (9/89) of them, at a median of 5 days from the onset of clinical symptoms [19]. The diagnostic role of Aspergillus fungaemia in patients with an invasive form of infection is limited because blood cultures become positive (if at all) in the late stage of the disease when a microbiological or clinical diagnosis has already been made [19].
In laboratory diagnostics of this form of aspergillosis, detection of Aspergillus spp. antigen—galactomannan (GM)—in BALF or in serum, may be useful; however, it should be remembered that it could represent a false positive result [10, 13, 15, 19, 29]. Detection of another fungal antigen which is a constituent of the fungal cell wall—(1–3)-β-D-glucan (BDG)—is a nonspecific marker of fungal infection, being positive in many fungal infections apart from aspergillosis [13]. Molecular methods (e.g. detection of DNA of the strains classified in the genus Aspergillus in blood or BALF using PCR technique) are promising, however at present, they are not routinely available in clinical microbiology laboratories, and interpretation of their results requires further analyses [13, 19, 85]. Research is ongoing on the usefulness of serum interleukin-8 concentration as an auxiliary marker in laboratory diagnostics of invasive pulmonary aspergillosis [86]. Therefore, it should be emphasized that diagnosis of invasive pulmonary aspergillosis requires evaluation of the patient’s clinical status in conjunction with the results of various examinations—imaging, histological, and mycological, as well as biochemical markers [1, 8, 13, 15, 86].
Laboratory methods currently used in diagnosis of invasive aspergillosis comprise three groups of techniques: detection of fungal invasion in histopathological examination of tissue sections; direct microscopy and isolation of Aspergillus spp. in culture of the clinically relevant samples; and noninvasive methods such as serological detection of antigens or nucleic material of Aspergillus spp., or detection of antibodies [19, 87].
5.1 Histopathological examination of tissue sections
Histopathological examination of biopsy or autopsy tissue sections confirms the fungal etiology of invasive infections [1, 5, 6, 13, 15, 19]. Tissue sections are usually stained with hematoxylin and eosin, but other staining techniques are also used in practice (e.g. Gomori-Grocott methenamine silver stain, periodic acid-Schiff stain) [2, 88, 89]. Histopathological tissue sections from a patient with invasive easpergillosis of the heart and lung are shown in Sulik-Tyszka et al. [89].
In tissue sections, Aspergillus appears as septate hyphae, with dichotomous branching at 45° angles suggestive of Aspergillus spp. [2, 19]. Conidiophores and fruiting bodies are rarely seen, except in areas exposed to air, for example, bronchi [19]. Invasive lesions are characterized by an area of necrosis and non-caseating granulomatous inflammation. A characteristic feature of invasive aspergillosis is trespassing of the the fungus into the blood vessels, with subsequent infarction and tissue necrosis.
5.2 Direct microscopic examination, culture, and identification of Aspergillus spp.
Clinical samples for isolation of Aspergillus spp. in culture depend on the clinical symptoms and suspected localization of infection. In the diagnosis of invasive pulmonary aspergillosis, a lung biopsy or a sample of BALF is recommended. Other specimens, such as bronchial or endotracheal aspirates, pleural fluid, and also sputum may be cultured as well [5, 6, 19]. Blood cultures can be done, but are usually negative. In fact, any suspicious lesion (e.g. cutaneous or skeletal) should be biopsied and cultured for fungi [19].
The direct microscopic examination allows not only rapid detection of the fungus directly in the specimen, but also its preliminary identification.
A universal solid medium for culturing fungi is Sabouraud agar. When culturing a sample obtained from a site which is primarily nonsterile, Sabouraud agar supplemented with chloramphenicol and gentamicin is used. Czapek-Dox agar and 2% malt extract agar are also used, as well as liquid media [19]. Commercially available media are recommended in order to standardize the culture methods.
Identification of the isolates belonging to the genus Aspergillus relies on evaluation of the colony morphology and color (both on the upper and reverse sides of the agar plate), and diffusion of the pigment into the medium (Figure 1). Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) technique may be used in the identification of Aspergillus spp. and is a promising tool, particularly for the identification of rare species of Aspergillus [90, 91]. This method allows a rapid and reliable identification of the isolate and therefore, an early start of effective antifungal therapy.
Interpretation of the mycological culture results is important and depends on the clinical picture [19]. In a routine microbiology laboratory work, most of the isolates of Aspergillus fumigatus do not indicate proven or probable infection. However, cultures positive for Aspergillus fumigatus, in the appropriate epidemiological and clinical setting, such as highly immunocompromised transplant recipients, are strongly associated with the presence or risk of IA and therefore should not be disregarded [19]. Also, the isolation of Aspergillus fumigatus in hematological patients, even from nonsterile samples, is generally regarded as potentially significant [19]. It has been reported that in heart transplant recipients with suspicion of invasive aspergillosis, a culture positive for Aspergillus has a positive predictive value (PPV) of 60–70% [92]. Higher PPV (78–91%) was linked to the isolation of Aspergillus fumigatus, with a further increase to 88–100% when Aspergillus fumigatus is recovered from a respiratory specimen other than sputum [92].
It should be emphasized that in transplant recipient’s fungal cultures may be negative, despite disseminated infection, and in invasive aspergillosis, blood cultures are usually negative, even in patients with Aspergillus endocarditis [19].
5.3 Serological testing in the diagnosis of aspergillosis
Serological tests are widely used in the laboratory diagnostics of aspergillosis. Conventional methods, such as culture of clinical samples and direct microscopy of the specimens, have low sensitivity and may give positive results in the late stages of the disease [19]. Furthermore, suitable specimens for these methods may be difficult to obtain in severely ill, immunocompromised patients. In recent years, serological techniques are being used increasingly on such specimens, like serum or BALF, for detection of fungal antigens (e.g. galactomannan, (1,3)-ß-d-glucan) and anti-galactomannan antibodies against Aspergilllus [44]. Detection of galactomannan in BALF or serum is at present recommended in the American and European guidelines on laboratory diagnosis of invasive aspergillosis in immunocompromised patients [5, 6, 13].
Duration of antifungal therapy may be guided not only by monitoring of galactomannan levels, but also by the clinical status of the patient and radiological findings.
5.3.1 Galactomannan (GM)
Galactomannan (GM) is a cell wall component of Aspergillus spp., released from Aspergillus hyphae, while they invade the host tissue, and therefore, it is a specific marker of this fungus [19]. This test may be helpful in early diagnosis of IA (median of 6 days before the symptoms appear) before the infection becomes disseminated [19]. Galactomannan can be detected with the use of latex tests (detection level 15 ng/ml) or more sensitive immunoenzymatic assays, in which 1 ng/ml of GM can be detected. Variation in sensitivity of these tests is being reported, which may due to the different cut-off values for a positive GM result in Europe (1.5 ng/mL) and the USA (0.5 ng/mL) [19].
Galactomannan concentration in the bronchoalveolar lavage fluid, in combination with other diagnostic tests (e.g. chest CT scan or mycological culture) is recommended as a test for the diagnosis of IA in lung and nonlung transplant recipients [71]. Galactomannan in BALF sample has proven superior to serum testing with high sensitivity (67–100%) and specificity rates (91–100%) for the diagnosis of invasive aspergillosis in lung transplant recipients [44]. In patients with prolonged neutropenia and allogeneic stem cell transplant recipients during the early engraftment phase, GM detection is commonly used, and serial screening for GM in serum has a high sensitivity and a negative predictive value for IA [13, 14]. However, serial screening for GM is not recommended in patients receiving antifungal prophylaxis with anti-Aspergillus spectrum of activity [13].
False-positive results of galactomannan detection have been documented in up to 13–29% of the liver transplant recipients and in 20% of the lung transplant recipients [44]. In the liver transplant recipients, false-positive results of galactomannan tests were more often seen in patients with transplantation for autoimmune liver disease, perioperative prophylaxis with β-lactam antibiotics, and requirement of dialysis. Most false-positive tests after lung transplantation occurred in the early post-transplant period: that is, in 43% within 3 days, in 64% within 7 days, and in 79% within 14 days of surgery. False-positive results of galactomannan detection are linked to several factors, such as antibiotic therapy with specific groups of antibacterials (such as some cephalosporins, carbapenems, amoxicillin-clavulanate, ampicillin/sulbactam, and piperacillin/tazobactam), cyclophosphamide therapy, as well as administration of blood products, albumin or immunoglobulins, or the use of cellulose hemodialysis membranes [93, 94].
5.3.2 (1,3)-ß-d-glucan
Detection of (1,3)-ß-d-glucan is a nonspecific test for fungal infection, as it is one of the main cell wall polysaccharide components of many fungi [19]. Available diagnostic tests are characterized by a high sensitivity and specificity and enable detection of (1,3)-ß-d-glucan at the concentration of >1 pg/ml. It has been reported that in living-donor, liver allograft recipients, detection of (1,3)-ß-d-glucan was useful for the diagnosis of invasive aspergillosis [95]. Several factors have been linked to false-positive results of the tests for (1,3)-ß-d-glucan, which are similar to those for galactomannan detection [19].
5.4 Molecular methods
At present, molecular diagnostic tests for Aspergillus spp. are not available in routine clinical microbiology laboratories, however, in the near future, they will be used increasingly, particularly for identification of unusual species, with specific profiles of susceptibility or resistance to antifungals [19, 44, 96]. Recently, PCR technique for detection of Aspergillus spp. has been extensively validated and will be included in the diagnostic criteria in the revised European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC-MSG) definitions [97]. A comprehensive review of the molecular diagnosis of invasive aspergillosis has recently been published [85].
The majority of molecular methods which can be used in the clinical microbiology laboratories are based on PCR technique. These methods are particularly useful for testing of lung specimens. It has been reported, that quantitative PCR test used for diagnosis of IA with a sample of bronchoalveolar lavage fluid was characterized by 67% sensitivity and 100% specificity [98]. Perhaps in the future, quantitative PCR tests will also be used to monitor the response to antifungal treatment in patients with IA [19].
Fluorescence in situ hybridization-based molecular method is a promising approach in the A. fumigatus detection in the tissues [87]. Species identification of Aspergillus isolates may be made by β-tubulin and calmodulin gene sequencing [91]. Further analyses are needed to evaluate the significance of the results of molecular tests in immunocompromised patients suspected of invasive aspergillosis.
6. Treatment of invasive aspergillosis
Successful treatment of invasive aspergillosis comprises early diagnosis of the disease, selection of an appropriate antifungal agent active against fungi of the genus Aspergillus, and prompt initiation of antifungal therapy, as well as surgical debridement, particularly in immunocompromised patients, such as HSCT and SOT recipients [3, 44]. Proper pharmacokinetics, pharmacoeconomics, and no interactions with other medications (e.g. immunosuppressants) administered to the patient are further factors which determine the choice of a proper antifungal agent.
At present, there are three groups of antifungal agents, which can be used in the therapy of aspergillosis: azoles, polyenes, and echinocandins [99]. The choice of treatment regimen depends on several factors, including the host’s immune status, liver, and kidney functions, and prior antifungal therapies [99]. Treatment regimens of invasive aspergillosis are shown in Figure 2.
Figure 2.
Treatment of invasive aspergillosis.
It should be emphasized that in the choice of proper antifungal therapy, susceptibility testing of the cultured isolate is important in view of an emerging resistance of some Aspergillus strains to azoles, as well as identification to the species level, as resistance to antifungals is more likely with certain species of Aspergillus other than Aspergillus fumigatus [99]. For example, A. terreus has a high minimum inhibitory concentration (MIC) to amphotericin B, while A. calidoustus has to numerous antifungals [99]. The role of a combination antifungal treatment for primary therapy of IA remains controversial; however, it may be considered (e.g. voriconazole with an echinocandin) for treatment of infection caused by these species [71, 99].
Apart from antifungal therapy, surgery may be indicated in patients with invasive aspergillosis. It applies to the cases in which the disease is localized and infection site is easily accessible to debridement (e.g. invasive fungal sinusitis or localized cutaneous lesions) [5, 6]. Surgical excision or debridement may be used for both diagnostic and therapeutic purposes [44].
Surgery of the sinuses may involve removal of the granulation tissue and necrotic bone [3]. Surgery may also be required in patients with endocarditis, osteomyelitis, or focal lesions in the central nervous system [5, 6]. Surgery is particularly indicated for persistent, or a life-threatening hemoptysis, lesions in the proximity of great vessels or pericardium, nasal and sinus infections, single cavitary lesion in the lung, intracranial abscesses, as well as lesions invading the pericardium, bone, the subcutaneous, or thoracic tissue [100].
6.1 Triazoles
According to the newest guidelines of ECIL-6 (the European Conference on Infections in Leukemia), recommendations of Infectious Diseases Society of America (IDSA) and European Society of Clinical Microbiology and Infectious Diseases, European Confederation of Medical Mycology, European Respiratory Society (ESCMID/ECMM/ERS) as well as expert groups, the drugs of first choice in therapy of invasive aspergillosis are triazoles—voriconazole or isavuconazole in monotherapy [5, 6, 13, 20, 71].
Isavuconazole is as effective as voriconazole, and in addition, it is characterized by a better safety profile, therefore in the newest guidelines, it has been granted AI recommendation equally with voriconazole [5, 6]. In patients who do not tolerate voriconazole, therapy with itraconazole or posaconazole may be considered; however, cross-resistance between azoles may be a problem [5]. An alternative antifungal agent used in the therapy of this disease is liposomal amphotericin B [5, 6, 13, 71]. It is emphasized that the chosen agent should be implemented as quickly as possible after fungal etiology of the infection has been suspected [5, 15]. At present, the routine use of combination therapy is neither recommended as a first line treatment, nor the use of echinocandins as the primary treatment [5].
In recent years, an increase in the percentage of strains of Aspergillus fumigatus resistant to azoles (including voriconazole) is being observed, which may pose a therapeutic problem [20, 101, 102, 103]. Resistance is mainly due to mutations in the gene cyp51A and/or overexpression of the efflux pumps in the cells of these fungi [101, 102, 103, 104, 105, 106]. Lestrade et al. showed that among 196 patients with IA, in 37 (19%) infection was caused by a strain of A. fumigatus resistant to voriconazole, which was linked to >20% increase in the mortality rate in this group of patients in comparison to individuals who received proper antifungal treatment [107]. In 2006–2016, Borman et al. analyzed 2501 clinical strains of Aspergillus fumigatus, among which 3.1% were resistant to voriconazole and 12.5% were resistant to amphotericin B [108]. The range of MIC values for these strains to voriconazole was 0.03–16.0 μg/ml and to amphotericin B was 0.06–4.0 μg/ml [108]. In a study comprising 105 clinical strains of Aspergillus fumigatus, a significant difference was reported in the percentage of strains resistant to triazoles among the isolates cultured from samples obtained from hematological patients (15.9%), in comparison with the group of patients treated in the ICU (4.5% strains) [101].
Voriconazole has emerged as the preferred agent for primary therapy of IA. Its efficacy has been confirmed in many studies, including hematopoietic stem cell transplant recipients and patients with hematological malignancies, as well as SOT recipients [44]. Voriconazole was effective in heart transplant recipients, in SOT recipients with central nervous system aspergillosis. In a lung transplant patient with Aspergillus endophthalmitis, voriconazole has been used in the form of an intravitreal injection [44].
6.2 Liposomal amphotericin B
An alternative antifungal agent recommended in therapy of IA is liposomal amphotericin B (L-AmB), which is active in vitro against the majority of strains of Aspergillus [5, 6, 13, 44, 71, 99]. However, it should be remembered that some species of Aspergillus (e.g. A. terreus) neutropaenic patients may be resistant to this antifungal agent.
6.3 Echinocandins
Echinocandins (caspofungin, micafungin, or anidulafungin) are not recommended as first-line therapy of invasive aspergillosis, as they exhibit only fungistatic (not fungicidal) activity against the isolates of Aspergillus spp. They can be considered in salvage therapy; however, in combination with voriconazole, isavuconazole, or liposomal amphotericin B [44, 99, 109].
6.4 Salvage therapy
In patients not responding to monotherapy with antifungal agents recommended as first-line therapy, such as voriconazole, isavuconazole, or liposomal amphotericin B, a salvage therapy must be considered, with the use of a combination antifungal regimen [99]. In these cases, it is suggested to combine an echinocandin (caspofungin, micafungin, or anidulafungin) with voriconazole, isavuconazole, or liposomal amphotericin B, while there are no clinical data to support the use of triazoles in combination with amphotericin B [99]. Apart from salvage antifungal therapy, reduction of the doses of immunosuppressive agents (if feasible), as well as surgery should be considered in these patients.
6.5 Duration of antifungal therapy
The duration of therapy for IA is usually 12 weeks, but may range from 3 to >50 weeks or may be even lifelong [5, 6, 13, 44]. Many factors may influence it, such as the response to administered therapy, the patient’s immune status and underlying diseases [44]. It is recommended to continue therapy until all clinical and radiographic abnormalities have resolved, and cultures are negative for Aspergillus. In transplant recipients, it is important to lower the doses of immunosuppressive agents, as well as to monitor an allograft function [44]. Patterson et al. and other expert groups recommend that therapy of invasive pulmonary aspergillosis should be continued for at least 6–12 weeks, depending on the site of disease, degree and duration of immunosuppression, and evidence of improvement of the patient’s clinical status [5, 6]. In patients with stable and pharmacokinetically predictable status, physicians should consider switching from intravenous to oral therapy [13]. If immunosuppression has to be continued after successful therapy of invasive aspergillosis, secondary prophylaxis should be initiated to prevent recurrence of the infection [5, 6].
6.6 Prophylaxis of invasive aspergillosis in transplant recipients
Antifungal prophylaxis against aspergillosis should be used in patients at high risk of IA during prolonged neutropenia [5, 6]. It is recommended to administer posaconazole, voriconazole, or micafungin (caspofungin is also probably effective) [5, 6]. Prophylaxis with itraconazole is effective, but absorption and tolerability of this drug may be a problem.
For allogeneic HSCT recipients with graft-versus-host disease (GVHD), who are at high risk for IA, prophylaxis with posaconazole is recommended, but other azoles active against Aspergillus may also be used [5, 6]. In patients with chronic immunosuppression associated with GVHD antifungal prophylaxis should be continued throughout the duration of immunosuppression [5, 6].
According to the ECIL-6 and other recommendations, antifungal prophylaxis with either a systemic triazole (voriconazole or itraconazole) or an inhaled AmB product is recommended for 3–4 months after lung transplantation [5, 6]. Aerosolized amphotericin B is an option which allows the direct administration of the antifungal agent into the transplanted lung, with avoidance of systemic unwanted effects and drug–drug interactions [44]. However, for certain groups of lung transplant recipients (single lung transplant recipients, mold colonization before or after lung transplantation, mold infections detected in explanted lungs, and fungal infections of the sinus) systemic voriconazole or itraconazole is recommended rather than inhaled AmB. Patterson et al. and other experts recommend reinitiation of antifungal prophylaxis in lung transplant recipients who receive immunosuppression augmentation with thymoglobulin, alemtuzumab, or high-dose corticosteroids [5, 6].
For other SOT recipients, antifungal prophylaxis against IA is not routinely recommended and should be based on the institutional epidemiology of aspergillosis and assessment of the patient’s risk factors [5, 6, 44]. A common approach to antifungal prophylaxis in liver transplant recipients is to target high-risk patients (fulminant hepatic failure, reoperation, retransplantation, or with renal failure), and it is administered during pre-transplant hospitalization and for the first-month posttransplant. Risk factors for IA have also been identified in heart transplant recipients, such as pretransplant colonization with Aspergillus spp., reoperation, cytomegalovirus (CMV) infection, and renal dysfunction. Other risk factors for IA, which may justify antifungal prophylaxis are institutional outbreaks and prolonged or high-dose corticosteroid therapy; however, the optimal duration of such prophylaxis has not been determined [5, 6].
6.7 Immunomodulatory agents and new therapeutic options
At present, it is recommended to reduce the doses of immunosuppressive therapy administered to the patient (or eliminate it, if possible), as this improves the outcome of anti-Aspergillus therapy [5, 6]. Other approaches can be considered in cases not responding to standard antifungal therapy, such as granulocyte transfusions in neutropenic patients with IA, or recombinant interferon-γ as prophylaxis in patients with chronic granulomatous disease (CGD) [5, 6].
A relatively new approach to the therapy of invasive aspergillosis in immunocompromised patients involves the use of immunomodulatory agents which would enhance the host’s immune system [44]. There is a potential for clinical use of selected cytokines or colony-stimulating factors (e.g. granulocyte colony-stimulating factor, G-CSF; granulocyte-macrophage colony-stimulating factor, GM-CSF; interferon-γ) with immunomodulatory effect [44, 110].
There is an ongoing search for new, more effective antifungals, which will be active also against drug-resistant isolates of Aspergillus spp. Currently, there are new classes of antifungal drugs under development—two agents in phase 2 study for the therapy of systemic invasive fungal infections and one drug in phase 1 [111]. Among them are agents which show activity against resistant to azoles cyp51A mutants of Aspergillus spp.
7. Summary
Diagnosis of invasive aspergillosis remains a challenge for clinicians and microbiologists. Progress in modern diagnostic methods and imaging techniques may contribute to an early and reliable diagnosis of infections caused by Aspergillus spp. This is particularly important in immunocompromised patients, such as HSCT and SOT recipients. Proper choice and early commencement of antifungal therapy increase the chances for survival and recovery of these patients from invasive aspergillosis.
\n',keywords:"Aspergillus fumigatus, invasive fungal infection, risk factors, antifungal therapy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/69995.pdf",chapterXML:"https://mts.intechopen.com/source/xml/69995.xml",downloadPdfUrl:"/chapter/pdf-download/69995",previewPdfUrl:"/chapter/pdf-preview/69995",totalDownloads:749,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 2nd 2019",dateReviewed:"September 23rd 2019",datePrePublished:"November 15th 2019",datePublished:"October 7th 2020",dateFinished:"November 8th 2019",readingETA:"0",abstract:"Patients with hematological malignancies and recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) as well as solid organ transplant recipients are the groups of patients with the highest risk of invasive fungal infections (IFI). Neutropenia, lymphopenia, chemotherapy of malignancies, radiation therapy, immunosuppressive therapy, administration of glucocorticosteroids, use of central venous catheters, dialysis therapy, liver and kidney failure, and diabetes are diseases and medical conditions which foster invasive fungal infections. In recent years, it has been observed that the most common etiological agents of these infections are yeast-like fungi of the genus Candida, and the second most common is moulds Aspergillus spp. Antifungal agent recommended for therapy of IFI caused by Aspergillus is voriconazole, according to the present guidelines. A combined therapy using voriconazole and caspofungin may not be effective. According to numerous publications, in case of infections caused by strains resistant to voriconazole, a therapeutic success is possible after a switch to the liposomal form of amphotericin B. Due to nonspecific clinical symptoms of IFI caused by Aspergillus spp., histopathological as well as mycological and serological tests, echocardiographic examination, magnetic resonance imaging (MRI) and computer tomography (CT) may contribute to an early and reliable diagnosis of invasive aspergillosis.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/69995",risUrl:"/chapter/ris/69995",signatures:"Marta Wróblewska, Beata Sulik-Tyszka, Wojciech Figiel, Grzegorz Niewiński and Krzysztof Zieniewicz",book:{id:"7936",type:"book",title:"Surgical Recovery",subtitle:null,fullTitle:"Surgical Recovery",slug:"surgical-recovery",publishedDate:"October 7th 2020",bookSignature:"Selim Sozen",coverURL:"https://cdn.intechopen.com/books/images_new/7936.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83880-892-1",printIsbn:"978-1-83880-891-4",pdfIsbn:"978-1-83880-893-8",isAvailableForWebshopOrdering:!0,editors:[{id:"90616",title:"Associate Prof.",name:"Selim",middleName:null,surname:"Sözen",slug:"selim-sozen",fullName:"Selim Sözen"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"303801",title:"Prof.",name:"Marta",middleName:null,surname:"Wroblewska",fullName:"Marta Wroblewska",slug:"marta-wroblewska",email:"martamwroblewska@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"303802",title:"Dr.",name:"Beata",middleName:null,surname:"Sulik-Tyszka",fullName:"Beata Sulik-Tyszka",slug:"beata-sulik-tyszka",email:"beata.sulik-tyszka@wum.edu.pl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Medical University of Warsaw",institutionURL:null,country:{name:"Poland"}}},{id:"303803",title:"Dr.",name:"Wojciech",middleName:null,surname:"Figiel",fullName:"Wojciech Figiel",slug:"wojciech-figiel",email:"wojciech.figiel@wum.edu.pl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Medical University of Warsaw",institutionURL:null,country:{name:"Poland"}}},{id:"303804",title:"Prof.",name:"Krzysztof",middleName:null,surname:"Zieniewicz",fullName:"Krzysztof Zieniewicz",slug:"krzysztof-zieniewicz",email:"krzysztof.zieniewicz@wum.edu.pl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Medical University of Warsaw",institutionURL:null,country:{name:"Poland"}}},{id:"310186",title:"Prof.",name:"Marta",middleName:null,surname:"Wróblewska",fullName:"Marta Wróblewska",slug:"marta-wroblewska",email:"marta.wroblewska@wum.edu.pl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Medical University of Warsaw",institutionURL:null,country:{name:"Poland"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Etiology of invasive aspergillosis",level:"1"},{id:"sec_3",title:"3. Clinical forms of invasive aspergillosis",level:"1"},{id:"sec_3_2",title:"3.1 Aspergillosis of the oral cavity and the upper respiratory tract",level:"2"},{id:"sec_4_2",title:"3.2 Aspergillosis of the nose and paranasal sinuses",level:"2"},{id:"sec_5_2",title:"3.3 Aspergillosis of the lower respiratory tract",level:"2"},{id:"sec_6_2",title:"3.4 Aspergillosis of the central nervous system",level:"2"},{id:"sec_7_2",title:"3.5 Invasive cardiac aspergillosis",level:"2"},{id:"sec_8_2",title:"3.6 Ocular aspergillosis",level:"2"},{id:"sec_9_2",title:"3.7 Aspergillosis of the genitourinary tract",level:"2"},{id:"sec_10_2",title:"3.8 Other clinical forms of aspergillosis",level:"2"},{id:"sec_12",title:"4. Aspergillosis in transplant recipients",level:"1"},{id:"sec_12_2",title:"4.1 Hematopoietic stem cell transplant (HSCT) recipients",level:"2"},{id:"sec_13_2",title:"4.2 Lung and heart-lung transplant recipients",level:"2"},{id:"sec_14_2",title:"4.3 Heart transplant recipients",level:"2"},{id:"sec_15_2",title:"4.4 Liver transplant recipients",level:"2"},{id:"sec_16_2",title:"4.5 Kidney transplant recipients",level:"2"},{id:"sec_18",title:"5. Mycological diagnostics",level:"1"},{id:"sec_18_2",title:"5.1 Histopathological examination of tissue sections",level:"2"},{id:"sec_19_2",title:"5.2 Direct microscopic examination, culture, and identification of Aspergillus spp.",level:"2"},{id:"sec_20_2",title:"5.3 Serological testing in the diagnosis of aspergillosis",level:"2"},{id:"sec_20_3",title:"5.3.1 Galactomannan (GM)",level:"3"},{id:"sec_21_3",title:"5.3.2 (1,3)-ß-d-glucan",level:"3"},{id:"sec_23_2",title:"5.4 Molecular methods",level:"2"},{id:"sec_25",title:"6. Treatment of invasive aspergillosis",level:"1"},{id:"sec_25_2",title:"6.1 Triazoles",level:"2"},{id:"sec_26_2",title:"6.2 Liposomal amphotericin B",level:"2"},{id:"sec_27_2",title:"6.3 Echinocandins",level:"2"},{id:"sec_28_2",title:"6.4 Salvage therapy",level:"2"},{id:"sec_29_2",title:"6.5 Duration of antifungal therapy",level:"2"},{id:"sec_30_2",title:"6.6 Prophylaxis of invasive aspergillosis in transplant recipients",level:"2"},{id:"sec_31_2",title:"6.7 Immunomodulatory agents and new therapeutic options",level:"2"},{id:"sec_33",title:"7. Summary",level:"1"}],chapterReferences:[{id:"B1",body:'Davies S, Guidry C, Politano A, Rosenberger L, McLeod M, Hranjec T, et al. Aspergillus infections in transplant and non-transplant surgical patients. Surgical Infections. 2014;15(3):207-212'},{id:"B2",body:'Deepa AG, Nair BJ, Sivakumar TT, Joseph AP. Uncommon opportunistic fungal infections of oral cavity: A review. 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Treatment of aspergillosis: Clinical practice guidelines of the Infectious Diseases Society of America. Clinical Infectious Diseases. 2008;46:327-360'},{id:"B101",body:'Fuhren J, Voskuil WS, Boel CH, Haas PJ, Hagen F, Meis JF, et al. High prevalence of azole resistance in Aspergillus fumigatus isolates from high-risk patients. The Journal of Antimicrobial Chemotherapy. 2015;70(10):2894-2898'},{id:"B102",body:'Nawrot U, Sulik-Tyszka B, Kurzyk E, Mroczyńska M, Włodarczyk K, Wróblewska M, et al. Relation of the polymorphism of cyp51A sequence and the susceptibility of Aspergillus fumigatus isolates to triazoles determined by commercial gradient test (E-test) and by reference methods. Acta Biochimica Polonica. 2017;64(4):631-663'},{id:"B103",body:'Nawrot U, Kurzyk E, Arendrup MC, Mroczynska M, Wlodarczyk K, Sulik-Tyszka B, et al. Detection of polish clinical Aspergillus fumigatus isolates resistant to triazoles. Medical Mycology. 2018;56(1):121-124'},{id:"B104",body:'Spiess B, Postina P, Reinwald M, Cornely OA, Hamprecht A, Hoenigl M, et al. Incidence of Cyp51 A key mutations in Aspergillus fumigatus—A study on primary clinical samples of immunocompromised patients in the period of 1995-2013. PLoS One. 2014;9(7):e103113'},{id:"B105",body:'Howard SJ, Arendrup MC. Acquired antifungal drug resistance in Aspergillus fumigatus: Epidemiology and detection. Medical Mycology. 2011;49:90-95'},{id:"B106",body:'Rajendran R, Mowat E, McCulloch E, Lappin DF, Jones B, Lang S, et al. Azole resistance of Aspergillus fumigatus biofilms is partly associated with efflux pump activity. Antimicrobial Agents and Chemotherapy. 2011;55(5):2092-2097'},{id:"B107",body:'Lestrade PP, Bentvelsen RG, Schauwvlieghe AFAD, Schalekamp S, van der Velden WJFM, Kuiper EJ, et al. Voriconazole resistance and mortality in invasive aspergillosis: A multicenter retrospective cohort study. Clinical Infectious Diseases. 2019;68:1463'},{id:"B108",body:'Borman AM, Fraser M, Palmer MD, Szekely A, Houldsworth M, Patterson Z, et al. MIC distributions and evaluation of fungicidal activity for amphotericin B, itraconazole, voriconazole, posaconazole and caspofungin and 20 species of pathogenic filamentous fungi determined using the CLSI broth microdilution method. J Fungi. 2017;3(2):E27'},{id:"B109",body:'Panackal AA. Combination antifungal therapy for invasive aspergillosis revisited. Medical Mycology: Open Access. 2016;2(2):12'},{id:"B110",body:'Delsing CE, Gresnigt MS, Leentjens J, Preijers F, Frager FA, Kox M, et al. Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: A case series. BMC Infectious Diseases. 2014;14:166'},{id:"B111",body:'Sanguinetti M, Posteraro B, Beigelman-Aubry C, Lamoth F, Dunet V, Slavin M, et al. Diagnosis and treatment of invasive fungal infections: Looking ahead. The Journal of Antimicrobial Chemotherapy. 2019;74(Suppl 2):ii27-ii37'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Marta Wróblewska",address:"marta.wroblewska@wum.edu.pl",affiliation:'
Department of Dental Microbiology, Medical University of Warsaw, Poland
Department of Microbiology, Central Clinical Hospital, University Clinical Centre, Medical University of Warsaw, Poland
Department of General, Transplantation and Liver Surgery, Medical University of Warsaw, Poland
'}],corrections:null},book:{id:"7936",type:"book",title:"Surgical Recovery",subtitle:null,fullTitle:"Surgical Recovery",slug:"surgical-recovery",publishedDate:"October 7th 2020",bookSignature:"Selim Sozen",coverURL:"https://cdn.intechopen.com/books/images_new/7936.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83880-892-1",printIsbn:"978-1-83880-891-4",pdfIsbn:"978-1-83880-893-8",isAvailableForWebshopOrdering:!0,editors:[{id:"90616",title:"Associate Prof.",name:"Selim",middleName:null,surname:"Sözen",slug:"selim-sozen",fullName:"Selim Sözen"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"136647",title:"Dr.",name:"N.K.",middleName:null,surname:"Agrawal",email:"drnkavns@gmail.com",fullName:"N.K. Agrawal",slug:"n.k.-agrawal",position:null,biography:'Prof. Neeraj Kumar Agrawal, DM (Endocrinology), is a professor at the Department of Endocrinology and Metabolism, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India. He has clinical and research training in endocrinology and metabolism. He completed his DM course in 2000 and is since actively involved in teaching and training. He has keen interest in reproductive endocrinology and adolescent endocrinology, diabetes, and thyroid disorders. He has published over 100 scientific publications in peer-reviewed journals and conference proceedings, and has edited books on "Thyroid Hormone" and "Debatable topics in PCOS patients". He acts as an examiner in endocrinology training centres, is actively involved in the Endocrine Society of India, and is a speaker at annual conferences.',institutionString:"Banaras Hindu University",profilePictureURL:"https://mts.intechopen.com/storage/users/136647/images/system/136647.jpeg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"3",totalEditedBooks:"3",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:{name:"Banaras Hindu University",institutionURL:null,country:{name:"India"}}},booksEdited:[{id:"9077",type:"book",slug:"goiter-causes-and-treatment",title:"Goiter",subtitle:"Causes and Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/9077.jpg",abstract:"The thyroid gland is a commonly diseased endocrine organ of human body. The disorders affecting the thyroid gland are varied but are very much amenable to treatment. The enlargement of the thyroid is termed goiter. It can affect the whole gland or only part of it. The disease is perplexing but in-depth knowledge of the pathophysiology helps in elucidating causes and thereby treating the disease. In this book, the diffuse and nodular goiter has been addressed as well as the functional abnormalities of the gland and its implications on the body are discussed in various chapters. The relevant updated information is included. To address a few of these current issues and recent updated information, authors have put in a lot of effort to organize the book.",editors:[{id:"136647",title:"Dr.",name:"N.K.",surname:"Agrawal",slug:"n.k.-agrawal",fullName:"N.K. Agrawal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",title:"Edited Volume"}},{id:"6152",type:"book",slug:"debatable-topics-in-pcos-patients",title:"Debatable Topics in PCOS Patients",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6152.jpg",abstract:"The book deliberates a wide range of the latest research issues on polycystic ovary syndrome (PCOS). The topics discussed include the diagnosis and management of PCOS, dwelling in more depth into the pathophysiology of the syndrome and its genetic and epigenetic basis. The book covers a contemplative discussion on the influence of changing lifestyle patterns on PCOS. The book also includes a number of chapters defining a detailed description of the associated morbidities of PCOS and its long-term sequelae. Since PCOS is quite prevalent globally, the book is also of great interest to the public. Providing detailed information suitable for patients and clinicians, it provides information about the various treatment regimens and screening recommendations for women having this condition.",editors:[{id:"136647",title:"Dr.",name:"N.K.",surname:"Agrawal",slug:"n.k.-agrawal",fullName:"N.K. Agrawal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",title:"Edited Volume"}},{id:"2589",type:"book",slug:"thyroid-hormone",title:"Thyroid Hormone",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/2589.jpg",abstract:"Thyroid hormone is important for controlling metabolism and many other body functions. Changes in thyroid hormone physiology, its regulation and diseases thereof have been a concern for the mankind.\nUnderstanding of the thyroid hormone(s) has been continuously updated and revised. The contributions from different authors have been incorporated in this book for this purpose. The original work of these contributors will be especially useful in furthering the knowledge on thyroid and help in creating new vistas of research.",editors:[{id:"136647",title:"Dr.",name:"N.K.",surname:"Agrawal",slug:"n.k.-agrawal",fullName:"N.K. Agrawal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",title:"Edited Volume"}}],chaptersAuthored:[{id:"37914",title:"Thyroid Hormone Excess: Graves’ Disease",slug:"thyroid-hormone-excess-graves-disease",abstract:null,signatures:"N.K. Agrawal, Ved Prakash and Manuj Sharma",authors:[{id:"136647",title:"Dr.",name:"N.K.",surname:"Agrawal",fullName:"N.K. Agrawal",slug:"n.k.-agrawal",email:"drnkavns@gmail.com"}],book:{id:"2589",title:"Thyroid Hormone",slug:"thyroid-hormone",productType:{id:"1",title:"Edited Volume"}}},{id:"58554",title:"Introductory Chapter: Polycystic Ovarian Disease: The Rainbow Without Color (SPECTRUM)",slug:"introductory-chapter-polycystic-ovarian-disease-the-rainbow-without-color-spectrum-",abstract:null,signatures:"Abha Kiran, Uma Pandey and Neeraj Kumar Agarwal",authors:[{id:"136647",title:"Dr.",name:"N.K.",surname:"Agrawal",fullName:"N.K. Agrawal",slug:"n.k.-agrawal",email:"drnkavns@gmail.com"}],book:{id:"6152",title:"Debatable Topics in PCOS Patients",slug:"debatable-topics-in-pcos-patients",productType:{id:"1",title:"Edited Volume"}}},{id:"69905",title:"Goiter: Overview of Aetiopathogenesis and Therapy",slug:"goiter-overview-of-aetiopathogenesis-and-therapy",abstract:"The goiter was described in history for long time. Many luminaries suffered from it. The enlargement of thyroid is known as goiter, it can arise from various causes and each has separate aetiopathogenesis and treatment. As an overview for the book, this chapter delves into each aspect, whereas the details are in separate chapter.",signatures:"Dhananjaya Melkunte Shanthaiah, Piyush Gupta and Neeraj Kumar Agrawal",authors:[{id:"136647",title:"Dr.",name:"N.K.",surname:"Agrawal",fullName:"N.K. Agrawal",slug:"n.k.-agrawal",email:"drnkavns@gmail.com"},{id:"307498",title:"Dr.",name:"Dhananjay",surname:"Ms",fullName:"Dhananjay Ms",slug:"dhananjay-ms",email:"djmsbmc@gmail.com"},{id:"307499",title:"Dr.",name:"Piyush",surname:"Gupta",fullName:"Piyush Gupta",slug:"piyush-gupta",email:"piyushesama@gmail.com"}],book:{id:"9077",title:"Goiter",slug:"goiter-causes-and-treatment",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"80280",title:"Dr.",name:"Giuseppe",surname:"Pasqualetti",slug:"giuseppe-pasqualetti",fullName:"Giuseppe Pasqualetti",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Pisa",institutionURL:null,country:{name:"Italy"}}},{id:"106019",title:"Prof.",name:"Fabio",surname:"Monzani",slug:"fabio-monzani",fullName:"Fabio Monzani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"EDUCATION\n\n• 1977 University of Pisa Medical School; Degree: MD, Magna cum Laude. \n• 1980 University of Pisa, School of Medicine; Degree: Specialist in Endocrinology and Metabolism, Magna cum Laude. \n• 1977-1980 Resident in Endocrinology at University of Pisa; \n• 1980-2000 Researcher at the Institute of Clinical Medicine, University of Pisa; \n• 2001-present Associate Professor of Internal Medicine, University of Pisa.\n• 1991-present Professor at postgraduate Schools of Internal Medicine, Geriatrics and Gerontology, Endocrinology and Metabolism, Environmental and Working Health, Gastroenterology, Neurology, Nephrology, Pneumology, Clinical Pathology, Thermal Medicine University of Pisa.\n• 2001-present Professor of Internal Medicine, School of Medicine, University of Pisa; \n• 2001-present Professor of Internal Medicine, School of Odontology, University of Pisa; \n• 2007-present Director of postgraduate School of Thermal Medicine, University of Pisa;\n• 2007-present Professor at the PhD School “Clinical and Experimental Pharmacologyâ€, University of Pisa.\n• 2007-present Deputy President of the Educational Board, School of Medicine, University of Pisa; \n• 2008-present Director Master in Thalassotherapy, University of Pisa; \n• 2009-present Director of postgraduate School of Geriatrics, University of Pisa;\n• 2009-present Director of Molecular Biology and Cell Culture Lab. of the Centre for Biological and Pathological Research in Geriatrics, University of Pisa\n• 2010-present member of the Scientific Board of the PhD School “ Biomedical Technology in Internal Medicine†University of Rome “La Sapienzaâ€\n\nCLINIC\n• 1998-2007 - Deputy Chief of the Endocrinology and Metabolism Unit, Department of Internal Medicine, University of Pisa.\n• Currently - Director, Geriatrics and Gerontology Unit, Department of Internal Medicine, University of Pisa\n\nRESEARCH\n\n• Referee for the following international scientific journals: Journal of Clinical Endocrinology and Metabolism, Clinical and Experimental Rheumatology, Multiple Sclerosis, Thyroid, Clinical Endocrinology, Diabetologia, Journal of Endocrinological Investigation, Circulation, Diabetologia, Endocrinology, European Journal of Internal Medicine, BioMed Central Endocrine Disorders, European Journal of Endocrinology, European Journal of Neurology, Journal of Postgraduate Medicine, Clinical and Experimental Medicine, Journal of The American Geriatrics Society, Translational Research, The Open Autoimmunity Journal, Journal of The American Geriatrics Society, Maturitas. \n\n• Member of the Editorial Board of: “European Journal of Internal Medicine†(the official Journal of the European Federation of Internal Medicine); “Journal of Clinical Endocrinology and Metabolism†(the official clinical Journal of the Endocrine Society); “The Open Autoimmunity Journalâ€; “Recent Patents on Endocrine, Metabolic & Immune Drug Discoveryâ€; “Acta Medica Labronicaâ€.\n\n• Ordinary Member: Italian Society of Endocrinology, Italian Thyroid Association (member of the Group for coordination of “Scientific Research Protocolsâ€); European Thyroid Association; Endocrine Society. \n\n• Member of the Scientific Board of “Centro di Area Vasta Nord Ovest per la Farmacovigilanzaâ€.\n\n• Member of the Scientific Board of the PhD School of “Medical and Pharmacological Physiopathology“, University of Pisa and of “Biomedical Technology in Clinical Medicine†University of “La Sapienzaâ€, Rome.\n\n• Coordinator of several national research projects, supported by Ministero dell’Università e della Ricerca Scientifica, Rome, Italy. \n\n• Main scientific fields of interest: physiopathology of endocrine disorders, thyroid autoimmune disorders, metabolic, cardiovascular and neuromuscular dysfunction in thyroid dysfunction, immunological and endocrine complications of cytokine therapy for multiple sclerosis, diagnosis and treatment of thyroid nodules, physiopathology of Purinergic receptors (P2) in normal thyroid cells and thyroid cancer. \n\n• His scientific production includes more than 100 original papers published in Italian and International peer reviewed scientific journals and more than 500 abstracts and full text proceedings of presentations at Italian and International scientific meetings.",institutionString:null,institution:{name:"University of Pisa",institutionURL:null,country:{name:"Italy"}}},{id:"112945",title:"Dr.",name:"Angela",surname:"Dardano",slug:"angela-dardano",fullName:"Angela Dardano",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Pisa",institutionURL:null,country:{name:"Italy"}}},{id:"139547",title:"Ph.D.",name:"Emina",surname:"Kasumagic-Halilovic",slug:"emina-kasumagic-halilovic",fullName:"Emina Kasumagic-Halilovic",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Sarajevo",institutionURL:null,country:{name:"Bosnia and Herzegovina"}}},{id:"140409",title:"Prof.",name:"Clara",surname:"Spinel",slug:"clara-spinel",fullName:"Clara Spinel",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"140928",title:"BSc.",name:"Magnolia",surname:"Herrera",slug:"magnolia-herrera",fullName:"Magnolia Herrera",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"141884",title:"Prof.",name:"Jun",surname:"Kitano",slug:"jun-kitano",fullName:"Jun Kitano",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"141959",title:"Dr.",name:"Asano",surname:"Ishikawa",slug:"asano-ishikawa",fullName:"Asano Ishikawa",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"150698",title:"Dr.",name:"Sara",surname:"Tognini",slug:"sara-tognini",fullName:"Sara Tognini",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"150699",title:"Dr.",name:"Antonio",surname:"Polini",slug:"antonio-polini",fullName:"Antonio Polini",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"scientific-advisors",title:"Scientific Advisory Boards",intro:"
IntechOpen’s team of Scientific Advisors supports the publishing team by providing editorial and academic input and ensuring the highest quality output of free peer-reviewed articles. The Boards consist of independent external collaborators who assist us on a voluntary basis. Their input includes advising on new topics within their field, proposing potential expert collaborators and reviewing book publishing proposals if required. Board members are experts who cover major STEM and HSS fields. All are trusted IntechOpen collaborators and Academic Editors, ensuring that the needs of the scientific community are met.
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Physical Sciences, Technology and Engineering Board
\\n\\n
Chemistry
\\n\\n
\\n\\t
Ayben Kilislioglu - Department of Chemical Engineering Istanbul University, İstanbul, Turkey
\\n\\t
Goran Nikolic - Faculty of Technology, University of Nis, Leskovac, Serbia
\\n\\t
Mark T. Stauffer - Associate Professor of Chemistry, The University of Pittsburgh, USA
\\n\\t
Margarita Stoytcheva - Autonomous University of Baja California Engineering Institute Mexicali, Baja California, Mexico
Joao Luis Garcia Rosa - Associate Professor Bio-inspired Computing Laboratory (BioCom) Department of Computer Science University of Sao Paulo (USP) at Sao Carlos, Brazil
\\n\\t
Jan Valdman - Institute of Mathematics and Biomathematics, University of South Bohemia, České Budějovice, Czech Republic Institute of Information Theory and Automation of the ASCR, Prague, Czech Republic
\\n
\\n\\n
Earth and Planetary Science
\\n\\n
\\n\\t
Jill S. M. Coleman - Department of Geography, Ball State University, Muncie, IN, USA
\\n\\t
İbrahim Küçük Erciyes - Üniversitesi Department of Astronomy and Space Sciences Melikgazi, Kayseri, Turkey
\\n\\t
Pasquale Imperatore - Electromagnetic Environmental Sensing (IREA), Italian National Council of Research (CNR), Naples, Italy
\\n\\t
Mohammad Mokhtari - Director of National Center for Earthquake Prediction International Institute of Earthquake Engineering and Seismology (IIEES), Tehran, Iran
\\n
\\n\\n
Engineering
\\n\\n
\\n\\t
Narottam Das - University of Southern Queensland, Australia
\\n\\t
Jose Ignacio Huertas - Energy and Climate Change Research Group; Instituto Tecnológico y Estudios Superiores de Monterrey, Mexico
Likun Pan - Engineering Research Center for Nanophotonics and Advanced Instrument, Ministry of Education, Department of Physics, East China Normal University, China
\\n\\t
Mukul Chandra Paul - Central Glass & Ceramic Research Institute Jadavpur, Kolkata, India
\\n\\t
Stephen E. Saddow - Electrical Engineering Department, University of South Florida, USA
\\n\\t
Ali Demir Sezer - Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, İstanbul, Turkey
\\n\\t
Krzysztof Zboinski - Warsaw University of Technology, Faculty of Transport, Warsaw, Poland
\\n
\\n\\n
Materials Science
\\n\\n
\\n\\t
Vadim Glebovsky - Senior Researcher, Institute of Solid State Physics, Chernogolovka, Russia Expert of the Russian Fund for Basic Research, Moscow, Russia
\\n\\t
Jianjun Liu - State Key Laboratory of High Performance Ceramics and Superfine Microstructure of Shanghai Institute of Ceramics, Chinese Academy of Sciences, China
\\n\\t
Pietro Mandracci - Department of Applied Science and Technology, Politecnico di Torino, Italy
\\n\\t
Waldemar Alfredo Monteiro - Instituto de Pesquisas Energéticas e Nucleares Materials Science and Technology Center (MSTC) São Paulo, SP, Brazil
Toshio Ogawa - Department of Electrical and Electronic Engineering, Shizuoka Institute of Science and Technology, Toyosawa, Fukuroi, Shizuoka, Japan
\\n
\\n\\n
Mathematics
\\n\\n
\\n\\t
Paul Bracken - Department of Mathematics University of Texas, Edinburg, TX, USA
\\n
\\n\\n
Nanotechnology and Nanomaterials
\\n\\n
\\n\\t
Muhammad Akhyar - Farrukh Nano-Chemistry Lab. Registrar, GC University Lahore, Pakistan
\\n\\t
Khan Maaz - Chinese Academy of Sciences, China & The Pakistan Institute of Nuclear Science and Technology, Pakistan
\\n
\\n\\n
Physics
\\n\\n
\\n\\t
Izabela Naydenova - Lecturer, School of Physics Principal Investigator, IEO Centre College of Sciences and Health Dublin Institute of Technology Dublin, Ireland
\\n\\t
Mitsuru Nenoi - National Institute of Radiological Sciences, Japan
\\n\\t
Christos Volos - Physics Department, Aristotle University of Thessaloniki, Greece
\\n
\\n\\n
Robotics
\\n\\n
\\n\\t
Alejandra Barrera - Instituto Tecnológico Autónomo de México, México
\\n\\t
Dusan M. Stipanovic - Department of Industrial and Enterprise Systems Engineering, University of Illinois at Urbana-Champaign
\\n\\t
Andrzej Zak - Polish Naval Academy Faculty of Navigation and Naval Weapons Institute of Naval Weapons and Computer Science, Gdynia, Poland
Petr Konvalina - Faculty of Agriculture, University of South Bohemia in České Budějovice, Czech Republic
\\n
\\n\\n
Biochemistry, Genetics and Molecular Biology
\\n\\n
\\n\\t
Chunfa Huang - Saint Louis University, Saint Louis, USA
\\n\\t
Michael Kormann - University Children's Clinic Department of Pediatrics I, Pediatric Infectiology & Immunology, Translational Genomics and Gene Therapy in Pediatrics, University of Tübingen, Tübingen, Germany
\\n\\t
Bin WU - Ph.D. HCLD Scientific Laboratory Director, Assisted Reproductive Technology Arizona Center for Reproductive Endocrinology and Infertility Tucson, Arizona , USA
\\n
\\n\\n
Environmental Sciences
\\n\\n
\\n\\t
Juan A. Blanco - Senior Researcher & Marie Curie Research Fellow Dep. Ciencias del Medio Natural, Universidad Publica de Navarra Campus de Arrosadia, Pamplona, Navarra, Spain
\\n\\t
Mikkola Heimo - University of Eastern Finland, Kuopio, Finland
\\n\\t
Bernardo Llamas Moya - Politechnical University of Madrid, Spain
\\n\\t
Toonika Rinken - Department of Environmental Chemistry, University of Tartu, Estonia
\\n
\\n\\n
Immunology and Microbiology
\\n\\n
\\n\\t
Dharumadurai Dhanasekaran - Department of Microbiology, School of Life Sciences, Bharathidasan University, India
Isabel Gigli - Facultad de Agronomia-UNLPam, Argentina
\\n\\t
Milad Manafi - Department of Animal Science, Faculty of Agricultural Sciences, Malayer University, Malayer, Iran
\\n\\t
Rita Payan-Carreira - Universidade de Trás-os-Montes e Alto Douro, Departamento de Zootecnia, Portugal
\\n
\\n\\n
Medicine
\\n\\n
\\n\\t
Mazen Almasri - King Abdulaziz University, Faculty of Dentistry Jeddah, Saudi Arabia Dentistry
\\n\\t
Craig Atwood - University of Wisconsin-Madison, USA Stem Cell Research, Tissue Engineering and Regenerative Medicine
\\n\\t
Oreste Capelli - Clinical Governance, Local Health Authority, Modena, Italy Public Health
\\n\\t
Michael Firstenberg - Assistant Professor of Surgery and Integrative Medicine NorthEast Ohio Medical University, USA & Akron City Hospital - Summa Health System, USA Surgery
\\n\\t
Parul Ichhpujani - MD Government Medical College & Hospital, Department of Ophthalmology, India
Amidou Samie - University of Venda, SA Infectious Diseases
\\n\\t
Shailendra K. Saxena - CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India Infectious Diseases
\\n\\t
Dan T. Simionescu - Department of Bioengineering, Clemson University, Clemson SC, USA Stem Cell Research, Tissue Engineering and Regenerative Medicine
\\n\\t
Ke Xu - Tianjin Lung Cancer Institute Tianjin Medical University General Hospital Tianjin, China Oncology
\\n
\\n\\n
Ophthalmology
\\n\\n
\\n\\t
Hojjat Ahmadzadehfar - University Hospital Bonn Department of Nuclear Medicine Bonn, Germany Medical Diagnostics, Engineering Technology and Telemedicine
\\n\\t
Miroslav Blumenberg - Department of Ronald O. Perelman Department of Dermatology; Department of Biochemistry and Molecular Pharmacology, Dermatology, NYU School of Medicine, NY, USA Dermatology
\\n\\t
Wilfred Bonney - University of Dundee, Scotland, UK Medical Diagnostics, Engineering Technology and Telemedicine
\\n\\t
Christakis Constantinides - Department of Cardiovascular Medicine University of Oxford, Oxford, UK Medical Diagnostics, Engineering Technology and Telemedicine
\\n\\t
Atef Mohamed Mostafa Darwish - Department of Obstetrics and Gynecology , Faculty of Medicine, Assiut University, Egypt Gynecology
\\n\\t
Ana Polona Mivšek - University of Ljubljana, Ljubljana, Slovenia Midwifery
\\n\\t
Gyula Mozsik - First Department of Medicine, Medical and Health Centre, University of Pécs, Hungary
\\n\\t
Shimon Rumelt - Western Galilee-Nahariya Medical Center, Nahariya, Israel Ophthalmology
\\n\\t
Marcelo Saad - S. Paulo Medical College of Acupuncture, SP, Brazil Complementary and Alternative Medicine
\\n\\t
Minoru Tomizawa - National Hospital Organization Shimoshizu Hospital, Japan Gastroenterology
\\n\\t
Pierre Vereecken - Centre Hospitalier Valida and Cliniques Universitaires Saint-Luc, Belgium Dermatology
\\n
\\n\\n
Gastroenterology
\\n\\n
\\n\\t
Hany Aly - Director, Division of Newborn Services The George Washington University Hospital Washington, USA Pediatrics
\\n\\t
Yannis Dionyssiotis - National and Kapodistrian University of Athens, Greece Orthopedics, Rehabilitation and Physical Medicine
\\n\\t
Alina Gonzales- Quevedo Instituto de Neurología y Neurocirugía Havana, Cuba Mental and Behavioural Disorders and Diseases of the Nervous System
\\n\\t
Margarita Guenova - National Specialized Hospital for Active Treatment of Haematological Diseases, Bulgaria
\\n\\t
Eliska Potlukova - Clinic of Medicine, University Hospital Basel, Switzerland Edocrinology
\\n\\t
Raymond L. Rosales -The Royal and Pontifical University of Santo Tomas, Manila, Philippines & Metropolitan Medical Center, Manila, Philippines & St. Luke's Medical Center International Institute in Neuroscience, Quezon City, Philippines Mental and Behavioural Disorders and Diseases of the Nervous System
\\n\\t
Alessandro Rozim - Zorzi University of Campinas, Departamento de Ortopedia e Traumatologia, Campinas, SP, Brazil Orthopedics, Rehabilitation and Physical Medicine
\\n\\t
Dieter Schoepf - University of Bonn, Germany Mental and Behavioural Disorders and Diseases of the Nervous System
\\n
\\n\\n
Hematology
\\n\\n
\\n\\t
Hesham Abd El-Dayem - National Liver Institute, Menoufeyia University, Egypt Hepatology
\\n\\t
Fayez Bahmad - Health Science Faculty of the University of Brasilia Instructor of Otology at Brasilia University Hospital Brasilia, Brazil Otorhinolaryngology
\\n\\t
Peter A. Clark - Saint Joseph's University Philadelphia, Pennsylvania, USA Bioethics
\\n\\t
Celso Pereira - Coimbra University, Coimbra, Portugal Immunology, Allergology and Rheumatology
\\n\\t
Luis Rodrigo - Asturias Central University Hospital (HUCA) School of Medicine, University of Oviedo, Oviedo, Spain Hepatology & Gastroenterology
\\n\\t
Dennis Wat - Liverpool Heart and Chest Hospital NHS Foundation Trust, UK Pulmonology
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\\n\\n
Social Sciences and Humanities Board
\\n\\n
Business, Management and Economics
\\n\\n
\\n\\t
Vito Bobek - University of Applied Sciences, FH Joanneum, Graz, Austria
Joao Luis Garcia Rosa - Associate Professor Bio-inspired Computing Laboratory (BioCom) Department of Computer Science University of Sao Paulo (USP) at Sao Carlos, Brazil
\n\t
Jan Valdman - Institute of Mathematics and Biomathematics, University of South Bohemia, České Budějovice, Czech Republic Institute of Information Theory and Automation of the ASCR, Prague, Czech Republic
\n
\n\n
Earth and Planetary Science
\n\n
\n\t
Jill S. M. Coleman - Department of Geography, Ball State University, Muncie, IN, USA
\n\t
İbrahim Küçük Erciyes - Üniversitesi Department of Astronomy and Space Sciences Melikgazi, Kayseri, Turkey
\n\t
Pasquale Imperatore - Electromagnetic Environmental Sensing (IREA), Italian National Council of Research (CNR), Naples, Italy
\n\t
Mohammad Mokhtari - Director of National Center for Earthquake Prediction International Institute of Earthquake Engineering and Seismology (IIEES), Tehran, Iran
\n
\n\n
Engineering
\n\n
\n\t
Narottam Das - University of Southern Queensland, Australia
\n\t
Jose Ignacio Huertas - Energy and Climate Change Research Group; Instituto Tecnológico y Estudios Superiores de Monterrey, Mexico
Likun Pan - Engineering Research Center for Nanophotonics and Advanced Instrument, Ministry of Education, Department of Physics, East China Normal University, China
\n\t
Mukul Chandra Paul - Central Glass & Ceramic Research Institute Jadavpur, Kolkata, India
\n\t
Stephen E. Saddow - Electrical Engineering Department, University of South Florida, USA
\n\t
Ali Demir Sezer - Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, İstanbul, Turkey
\n\t
Krzysztof Zboinski - Warsaw University of Technology, Faculty of Transport, Warsaw, Poland
\n
\n\n
Materials Science
\n\n
\n\t
Vadim Glebovsky - Senior Researcher, Institute of Solid State Physics, Chernogolovka, Russia Expert of the Russian Fund for Basic Research, Moscow, Russia
\n\t
Jianjun Liu - State Key Laboratory of High Performance Ceramics and Superfine Microstructure of Shanghai Institute of Ceramics, Chinese Academy of Sciences, China
\n\t
Pietro Mandracci - Department of Applied Science and Technology, Politecnico di Torino, Italy
\n\t
Waldemar Alfredo Monteiro - Instituto de Pesquisas Energéticas e Nucleares Materials Science and Technology Center (MSTC) São Paulo, SP, Brazil
Toshio Ogawa - Department of Electrical and Electronic Engineering, Shizuoka Institute of Science and Technology, Toyosawa, Fukuroi, Shizuoka, Japan
\n
\n\n
Mathematics
\n\n
\n\t
Paul Bracken - Department of Mathematics University of Texas, Edinburg, TX, USA
\n
\n\n
Nanotechnology and Nanomaterials
\n\n
\n\t
Muhammad Akhyar - Farrukh Nano-Chemistry Lab. Registrar, GC University Lahore, Pakistan
\n\t
Khan Maaz - Chinese Academy of Sciences, China & The Pakistan Institute of Nuclear Science and Technology, Pakistan
\n
\n\n
Physics
\n\n
\n\t
Izabela Naydenova - Lecturer, School of Physics Principal Investigator, IEO Centre College of Sciences and Health Dublin Institute of Technology Dublin, Ireland
\n\t
Mitsuru Nenoi - National Institute of Radiological Sciences, Japan
\n\t
Christos Volos - Physics Department, Aristotle University of Thessaloniki, Greece
\n
\n\n
Robotics
\n\n
\n\t
Alejandra Barrera - Instituto Tecnológico Autónomo de México, México
\n\t
Dusan M. Stipanovic - Department of Industrial and Enterprise Systems Engineering, University of Illinois at Urbana-Champaign
\n\t
Andrzej Zak - Polish Naval Academy Faculty of Navigation and Naval Weapons Institute of Naval Weapons and Computer Science, Gdynia, Poland
Petr Konvalina - Faculty of Agriculture, University of South Bohemia in České Budějovice, Czech Republic
\n
\n\n
Biochemistry, Genetics and Molecular Biology
\n\n
\n\t
Chunfa Huang - Saint Louis University, Saint Louis, USA
\n\t
Michael Kormann - University Children's Clinic Department of Pediatrics I, Pediatric Infectiology & Immunology, Translational Genomics and Gene Therapy in Pediatrics, University of Tübingen, Tübingen, Germany
\n\t
Bin WU - Ph.D. HCLD Scientific Laboratory Director, Assisted Reproductive Technology Arizona Center for Reproductive Endocrinology and Infertility Tucson, Arizona , USA
\n
\n\n
Environmental Sciences
\n\n
\n\t
Juan A. Blanco - Senior Researcher & Marie Curie Research Fellow Dep. Ciencias del Medio Natural, Universidad Publica de Navarra Campus de Arrosadia, Pamplona, Navarra, Spain
\n\t
Mikkola Heimo - University of Eastern Finland, Kuopio, Finland
\n\t
Bernardo Llamas Moya - Politechnical University of Madrid, Spain
\n\t
Toonika Rinken - Department of Environmental Chemistry, University of Tartu, Estonia
\n
\n\n
Immunology and Microbiology
\n\n
\n\t
Dharumadurai Dhanasekaran - Department of Microbiology, School of Life Sciences, Bharathidasan University, India
Isabel Gigli - Facultad de Agronomia-UNLPam, Argentina
\n\t
Milad Manafi - Department of Animal Science, Faculty of Agricultural Sciences, Malayer University, Malayer, Iran
\n\t
Rita Payan-Carreira - Universidade de Trás-os-Montes e Alto Douro, Departamento de Zootecnia, Portugal
\n
\n\n
Medicine
\n\n
\n\t
Mazen Almasri - King Abdulaziz University, Faculty of Dentistry Jeddah, Saudi Arabia Dentistry
\n\t
Craig Atwood - University of Wisconsin-Madison, USA Stem Cell Research, Tissue Engineering and Regenerative Medicine
\n\t
Oreste Capelli - Clinical Governance, Local Health Authority, Modena, Italy Public Health
\n\t
Michael Firstenberg - Assistant Professor of Surgery and Integrative Medicine NorthEast Ohio Medical University, USA & Akron City Hospital - Summa Health System, USA Surgery
\n\t
Parul Ichhpujani - MD Government Medical College & Hospital, Department of Ophthalmology, India
Amidou Samie - University of Venda, SA Infectious Diseases
\n\t
Shailendra K. Saxena - CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India Infectious Diseases
\n\t
Dan T. Simionescu - Department of Bioengineering, Clemson University, Clemson SC, USA Stem Cell Research, Tissue Engineering and Regenerative Medicine
\n\t
Ke Xu - Tianjin Lung Cancer Institute Tianjin Medical University General Hospital Tianjin, China Oncology
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\n\n
Ophthalmology
\n\n
\n\t
Hojjat Ahmadzadehfar - University Hospital Bonn Department of Nuclear Medicine Bonn, Germany Medical Diagnostics, Engineering Technology and Telemedicine
\n\t
Miroslav Blumenberg - Department of Ronald O. Perelman Department of Dermatology; Department of Biochemistry and Molecular Pharmacology, Dermatology, NYU School of Medicine, NY, USA Dermatology
\n\t
Wilfred Bonney - University of Dundee, Scotland, UK Medical Diagnostics, Engineering Technology and Telemedicine
\n\t
Christakis Constantinides - Department of Cardiovascular Medicine University of Oxford, Oxford, UK Medical Diagnostics, Engineering Technology and Telemedicine
\n\t
Atef Mohamed Mostafa Darwish - Department of Obstetrics and Gynecology , Faculty of Medicine, Assiut University, Egypt Gynecology
\n\t
Ana Polona Mivšek - University of Ljubljana, Ljubljana, Slovenia Midwifery
\n\t
Gyula Mozsik - First Department of Medicine, Medical and Health Centre, University of Pécs, Hungary
\n\t
Shimon Rumelt - Western Galilee-Nahariya Medical Center, Nahariya, Israel Ophthalmology
\n\t
Marcelo Saad - S. Paulo Medical College of Acupuncture, SP, Brazil Complementary and Alternative Medicine
\n\t
Minoru Tomizawa - National Hospital Organization Shimoshizu Hospital, Japan Gastroenterology
\n\t
Pierre Vereecken - Centre Hospitalier Valida and Cliniques Universitaires Saint-Luc, Belgium Dermatology
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Gastroenterology
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\n\t
Hany Aly - Director, Division of Newborn Services The George Washington University Hospital Washington, USA Pediatrics
\n\t
Yannis Dionyssiotis - National and Kapodistrian University of Athens, Greece Orthopedics, Rehabilitation and Physical Medicine
\n\t
Alina Gonzales- Quevedo Instituto de Neurología y Neurocirugía Havana, Cuba Mental and Behavioural Disorders and Diseases of the Nervous System
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Margarita Guenova - National Specialized Hospital for Active Treatment of Haematological Diseases, Bulgaria
\n\t
Eliska Potlukova - Clinic of Medicine, University Hospital Basel, Switzerland Edocrinology
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Raymond L. Rosales -The Royal and Pontifical University of Santo Tomas, Manila, Philippines & Metropolitan Medical Center, Manila, Philippines & St. Luke's Medical Center International Institute in Neuroscience, Quezon City, Philippines Mental and Behavioural Disorders and Diseases of the Nervous System
\n\t
Alessandro Rozim - Zorzi University of Campinas, Departamento de Ortopedia e Traumatologia, Campinas, SP, Brazil Orthopedics, Rehabilitation and Physical Medicine
\n\t
Dieter Schoepf - University of Bonn, Germany Mental and Behavioural Disorders and Diseases of the Nervous System
\n
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\n\n
\n\t
Hesham Abd El-Dayem - National Liver Institute, Menoufeyia University, Egypt Hepatology
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Fayez Bahmad - Health Science Faculty of the University of Brasilia Instructor of Otology at Brasilia University Hospital Brasilia, Brazil Otorhinolaryngology
\n\t
Peter A. Clark - Saint Joseph's University Philadelphia, Pennsylvania, USA Bioethics
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\n\t
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Dennis Wat - Liverpool Heart and Chest Hospital NHS Foundation Trust, UK Pulmonology
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Social Sciences and Humanities Board
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Business, Management and Economics
\n\n
\n\t
Vito Bobek - University of Applied Sciences, FH Joanneum, Graz, Austria
Denis Erasga - De La Salle University, Phillippines
\n\t
Rosario Laratta - Associate Professor of Social Policy and Development Graduate School of Governance Studies, Meiji University, Japan
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It is a cofactor for enzymes involved in regulating photosynthesis, hormone biosynthesis, and regenerating other antioxidants; which also regulates cell division and growth, is involved in signal transduction, and has roles in several physiological processes, such as immune stimulation, synthesis of collagen, hormones, neurotransmitters, and iron absorption, has also roles in detoxifying the body of heavy metals. Severe deficiency of vitamin C causes scurvy, whereas limited vitamin C intake causes symptoms, such as increased susceptibility to infections, loosening of teeth, dryness of the mouth and eyes, loss of hair, dry itchy skin, fatigue, and insomnia. In contrast, vitamin C can also act as a prooxidant, especially in the presence of transition metals, such as iron and copper, starting different hazardous radical reactions. Vitamin C can both act as a strong, efficient, and cheap antioxidant agent and, at the same time, behave as a radical promoter. Further investigations are needed to illuminate the dual roles of vitamin C",book:{id:"5940",slug:"vitamin-c",title:"Vitamin C",fullTitle:"Vitamin C"},signatures:"Fadime Eryılmaz Pehlivan",authors:[{id:"200567",title:"Dr.",name:"Fadime",middleName:null,surname:"Eryılmaz Pehlivan",slug:"fadime-eryilmaz-pehlivan",fullName:"Fadime Eryılmaz Pehlivan"}]},{id:"56440",doi:"10.5772/intechopen.70162",title:"Vitamin C: Sources, Functions, Sensing and Analysis",slug:"vitamin-c-sources-functions-sensing-and-analysis",totalDownloads:6338,totalCrossrefCites:13,totalDimensionsCites:25,abstract:"Vitamin C is a water-soluble compound found in living organisms. It is an essential nutrient for various metabolism in our body and also serves as a reagent for the preparation of many materials in the pharmaceutical and food industry. In this perspective, this chapter can develop interest and curiosity among all practicing scientists and technologists by expounding the details of its sources, chemistry, multifunctional properties and applications.",book:{id:"5940",slug:"vitamin-c",title:"Vitamin C",fullTitle:"Vitamin C"},signatures:"Sudha J. Devaki and Reshma Lali Raveendran",authors:[{id:"187911",title:"Associate Prof.",name:"Sudha",middleName:null,surname:"J Devaki",slug:"sudha-j-devaki",fullName:"Sudha J Devaki"},{id:"204937",title:"Mrs.",name:"Reshma",middleName:null,surname:"Laly Ravindran",slug:"reshma-laly-ravindran",fullName:"Reshma Laly Ravindran"}]},{id:"50921",doi:"10.5772/63712",title:"Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet",slug:"menaquinones-bacteria-and-foods-vitamin-k2-in-the-diet",totalDownloads:3272,totalCrossrefCites:10,totalDimensionsCites:21,abstract:"Vitamin K2 is a collection of isoprenologues that mostly originate from bacterial synthesis, also called menaquinones (MKs). Multiple bacterial species used as starter cultures for food fermentation are known to synthesize MK. Therefore, fermented food is the best source of vitamin K2. In the Western diet, dairy products are one of the best known and most commonly consumed group of fermented products.",book:{id:"5169",slug:"vitamin-k2-vital-for-health-and-wellbeing",title:"Vitamin K2",fullTitle:"Vitamin K2 - Vital for Health and Wellbeing"},signatures:"Barbara Walther and Magali Chollet",authors:[{id:"184784",title:"Dr.",name:"Barbara",middleName:null,surname:"Walther",slug:"barbara-walther",fullName:"Barbara Walther"},{id:"188194",title:"Mrs.",name:"Magali",middleName:null,surname:"Chollet",slug:"magali-chollet",fullName:"Magali Chollet"}]},{id:"66098",doi:"10.5772/intechopen.84445",title:"Golden Rice: To Combat Vitamin A Deficiency for Public Health",slug:"golden-rice-to-combat-vitamin-a-deficiency-for-public-health",totalDownloads:3307,totalCrossrefCites:12,totalDimensionsCites:17,abstract:"Vitamin A deficiency (VAD) has been recognised as a significant public health problem continuously for more than 30 years, despite current interventions. The problem is particularly severe in populations where rice is the staple food and diversity of diet is limited, as white rice contains no micronutrients. Golden Rice is a public-sector product designed as an additional intervention for VAD. There will be no charge for the nutritional trait, which has been donated by its inventors for use in public-sector rice varieties to assist the resource poor, and no limitations on what small farmers can do with the crop—saving and replanting seed, selling seed and selling grain are all possible. Because Golden Rice had to be created by introducing two new genes—one from maize and the other from a very commonly ingested soil bacterium—it has taken a long time to get from the laboratory to the field. Now it has been formally registered as safe as food, feed, or in processed form by four industrialised counties, and applications are pending in developing countries. The data are summarised here, and criticisms addressed, for a public health professional audience: is it needed, will it work, is it safe and is it economic? Adoption of Golden Rice, the next step after in-country registration, requires strategic and tactical cooperation across professions, non-governmental organisations (NGOs) and government departments often not used to working together. Public health professionals need to play a prominent role.",book:{id:"7978",slug:"vitamin-a",title:"Vitamin A",fullTitle:"Vitamin A"},signatures:"Adrian Dubock",authors:[{id:"273220",title:"Ph.D.",name:"Adrian",middleName:null,surname:"Dubock",slug:"adrian-dubock",fullName:"Adrian Dubock"}]},{id:"62836",doi:"10.5772/intechopen.79350",title:"The Role of Thiamine in Plants and Current Perspectives in Crop Improvement",slug:"the-role-of-thiamine-in-plants-and-current-perspectives-in-crop-improvement",totalDownloads:1534,totalCrossrefCites:7,totalDimensionsCites:11,abstract:"Current research is focusing on selecting potential genes that can alleviate stress and produce disease-tolerant crop variety. The novel paradigm is to investigate the potential of thiamine as a crop protection molecule in plants. Thiamine or vitamin B1 is important for primary metabolism for all living organisms. The active form, thiamine pyrophosphate (TPP), is a cofactor for the enzymes involved in the synthesis of amino acids, tricarboxylic acid cycle and pentose phosphate pathway. Recently, thiamine is shown to have a role in the processes underlying protection of plants against biotic and abiotic stresses. The aim of this chapter is to review the role of thiamine in plant growth and disease protection and also to highlight that TPP and its intermediates are involved in management of stress. The perspectives on its potential for manipulating the biosynthesis pathway in crop improvement will also be discussed.",book:{id:"6709",slug:"b-group-vitamins-current-uses-and-perspectives",title:"B Group Vitamins",fullTitle:"B Group Vitamins - Current Uses and Perspectives"},signatures:"Atiqah Subki, Aisamuddin Ardi Zainal Abidin and Zetty Norhana\nBalia Yusof",authors:[{id:"240031",title:"Dr.",name:"Zetty-Norhana Balia",middleName:null,surname:"Yusof",slug:"zetty-norhana-balia-yusof",fullName:"Zetty-Norhana Balia Yusof"},{id:"261167",title:"Mr.",name:"Aisamuddin Ardi",middleName:null,surname:"Zainal Abidin",slug:"aisamuddin-ardi-zainal-abidin",fullName:"Aisamuddin Ardi Zainal Abidin"},{id:"261169",title:"Ms.",name:"Atiqah",middleName:null,surname:"Subki",slug:"atiqah-subki",fullName:"Atiqah Subki"}]}],mostDownloadedChaptersLast30Days:[{id:"56440",title:"Vitamin C: Sources, Functions, Sensing and Analysis",slug:"vitamin-c-sources-functions-sensing-and-analysis",totalDownloads:6340,totalCrossrefCites:13,totalDimensionsCites:25,abstract:"Vitamin C is a water-soluble compound found in living organisms. It is an essential nutrient for various metabolism in our body and also serves as a reagent for the preparation of many materials in the pharmaceutical and food industry. In this perspective, this chapter can develop interest and curiosity among all practicing scientists and technologists by expounding the details of its sources, chemistry, multifunctional properties and applications.",book:{id:"5940",slug:"vitamin-c",title:"Vitamin C",fullTitle:"Vitamin C"},signatures:"Sudha J. Devaki and Reshma Lali Raveendran",authors:[{id:"187911",title:"Associate Prof.",name:"Sudha",middleName:null,surname:"J Devaki",slug:"sudha-j-devaki",fullName:"Sudha J Devaki"},{id:"204937",title:"Mrs.",name:"Reshma",middleName:null,surname:"Laly Ravindran",slug:"reshma-laly-ravindran",fullName:"Reshma Laly Ravindran"}]},{id:"56013",title:"Vitamin C: An Antioxidant Agent",slug:"vitamin-c-an-antioxidant-agent",totalDownloads:7749,totalCrossrefCites:24,totalDimensionsCites:52,abstract:"Vitamin C or ascorbic acid (AsA) is a naturally occurring organic compound with antioxidant properties, found in both animals and plants. It functions as a redox buffer which can reduce, and thereby neutralize, reactive oxygen species. It is a cofactor for enzymes involved in regulating photosynthesis, hormone biosynthesis, and regenerating other antioxidants; which also regulates cell division and growth, is involved in signal transduction, and has roles in several physiological processes, such as immune stimulation, synthesis of collagen, hormones, neurotransmitters, and iron absorption, has also roles in detoxifying the body of heavy metals. Severe deficiency of vitamin C causes scurvy, whereas limited vitamin C intake causes symptoms, such as increased susceptibility to infections, loosening of teeth, dryness of the mouth and eyes, loss of hair, dry itchy skin, fatigue, and insomnia. In contrast, vitamin C can also act as a prooxidant, especially in the presence of transition metals, such as iron and copper, starting different hazardous radical reactions. Vitamin C can both act as a strong, efficient, and cheap antioxidant agent and, at the same time, behave as a radical promoter. Further investigations are needed to illuminate the dual roles of vitamin C",book:{id:"5940",slug:"vitamin-c",title:"Vitamin C",fullTitle:"Vitamin C"},signatures:"Fadime Eryılmaz Pehlivan",authors:[{id:"200567",title:"Dr.",name:"Fadime",middleName:null,surname:"Eryılmaz Pehlivan",slug:"fadime-eryilmaz-pehlivan",fullName:"Fadime Eryılmaz Pehlivan"}]},{id:"69402",title:"Vitamin D Deficiency and Diabetes Mellitus",slug:"vitamin-d-deficiency-and-diabetes-mellitus",totalDownloads:1545,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Vitamin D (VD) is a molecule that can be synthesized directly in the humans’ body or enter the organism with food in the form of inactive precursors. To exert its biological action, VD undergoes two-stage hydroxylation (at the 25th and 1st position) catalyzed by cytochromes P450, the presence of which has already been shown in almost all tissues of the human body. The product of hydroxylation is hormone-active form of vitamin D–1,25(OH)2D. 1,25(OH)2D binds to specific vitamin D receptor (VDR) and regulates the expression of genes involved in bone remodeling (classical function) and genes that control immune response, hormone secretion, cell proliferation, and differentiation (nonclassical functions). VD deficiency is prevalent around the globe and may be one of the key factors for diabetes development. The direct association between vitamin D deficiency and type 1 (T1D) and type 2 (T2D) diabetes has been proven. Detection of VDR in pancreas and adipose tissue, skeletal muscles, and immune cells allowed implying the antidiabetic role of vitamin D by enhancing insulin synthesis and exocytosis, increasing the expression of the insulin receptor, and modulating immune cells’ functions. This chapter summarizes data about relationship between VD insufficiency/deficiency and development of T1D and T2D, and their complications.",book:{id:"7038",slug:"vitamin-d-deficiency",title:"Vitamin D Deficiency",fullTitle:"Vitamin D Deficiency"},signatures:"Ihor Shymanskyi, Olha Lisakovska, Anna Mazanova and Mykola Veliky",authors:null},{id:"76108",title:"Vitamin D Metabolism",slug:"vitamin-d-metabolism",totalDownloads:424,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Vitamin D plays an important role in bone metabolism. Vitamin D is a group of biologically inactive, fat-soluble prohormones that exist in two major forms: ergocalciferol (vitamin D2) produced by plants in response to ultraviolet irradiation and cholecalciferol (vitamin D3) derived from animal tissues or 7-dehydrocholesterol in human skin by the action of ultraviolet rays present in sunlight. Vitamin D, which is biologically inactive, needs two-step hydroxylation for activation. All of these steps are of crucial for Vitamin D to show its effect properly. In this section, we will present vitamin D synthesis and its action steps in detail.",book:{id:"10631",slug:"vitamin-d",title:"Vitamin D",fullTitle:"Vitamin D"},signatures:"Sezer Acar and Behzat Özkan",authors:[{id:"29878",title:"Dr.",name:"Behzat",middleName:null,surname:"Özkan",slug:"behzat-ozkan",fullName:"Behzat Özkan"},{id:"348287",title:"Dr.",name:"Sezer",middleName:null,surname:"Acar",slug:"sezer-acar",fullName:"Sezer Acar"}]},{id:"50754",title:"Medicinal Chemistry of Vitamin K Derivatives and Metabolites",slug:"medicinal-chemistry-of-vitamin-k-derivatives-and-metabolites",totalDownloads:1875,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Vitamin K acts as a cofactor for γ‐glutamyl carboxylase. Recently, various biological activities of vitamin K have been reported. Anti‐proliferative activities of vitamin K, especially in vitamin K3, are well known. In addition, various physiological and pharmacological functions of vitamin K2, such as transcription modulators as nuclear steroid and xenobiotic receptor (SXR) ligands and anti‐inflammatory effects, have been revealed in the past decade. Characterization of vitamin K metabolites is also important for clinical application of vitamin K and its derivatives. In this chapter, recent progress on the medicinal chemistry of vitamin K derivatives and metabolites is discussed.",book:{id:"5169",slug:"vitamin-k2-vital-for-health-and-wellbeing",title:"Vitamin K2",fullTitle:"Vitamin K2 - Vital for Health and Wellbeing"},signatures:"Shinya Fujii and Hiroyuki Kagechika",authors:[{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika"},{id:"180529",title:"Dr.",name:"Shinya",middleName:null,surname:"Fujii",slug:"shinya-fujii",fullName:"Shinya Fujii"}]}],onlineFirstChaptersFilter:{topicId:"42",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81286",title:"Potassium Derangements: A Pathophysiological Review, Diagnostic Approach, and Clinical Management",slug:"potassium-derangements-a-pathophysiological-review-diagnostic-approach-and-clinical-management",totalDownloads:25,totalDimensionsCites:0,doi:"10.5772/intechopen.103016",abstract:"Potassium is an essential cation critical in fluid and electrolyte balance, acid–base regulation, and neuromuscular functions. The normal serum potassium is kept within a narrow range of 3.5–5.2 meq/L while the intracellular concentration is approximately 140–150 meq/L. The total body potassium is about 45–55 mmol/kg; thus, a 70 kg male has an estimated ~136 g and 60 kg female has ~117 g of potassium. In total, 98% of the total body potassium is intracellular. Skeletal muscle contains ~80% of body potassium stores. The ratio of intracellular to extracellular potassium concentration (Ki/Ke) maintained by Na+/K+ ATPase determines the resting membrane potential. Disturbances of potassium homeostasis lead to hypo- and hyperkalemia, which if severe, can be life-threatening. Prompt diagnosis and management of these problems are important.",book:{id:"10794",title:"Potassium in Human Health",coverURL:"https://cdn.intechopen.com/books/images_new/10794.jpg"},signatures:"Sairah Sharif and Jie Tang"},{id:"79194",title:"Potassium in Solid Cancers",slug:"potassium-in-solid-cancers",totalDownloads:121,totalDimensionsCites:0,doi:"10.5772/intechopen.101108",abstract:"Electrolyte disorders are a frequent finding in cancer patients. In the majority of cases the etiologies of such disorders are common to all cancer types (i.e. diuretic-induced hyponatremia or hypokalemia). Sometimes, electrolyte disorders are caused by paraneoplastic syndromes or are due to cancer therapy. Potassium is one of the most important electrolytes of the human body since it is involved in the regulation of muscle contraction, maintenance of the integrity of the skeleton, blood pressure and nerve transmission as well as in the normal function of cells. Potassium homeostasis is strictly regulated since the gap between the recommended daily dietary intake (120 mEq/day) and the levels stored in the extracellular fluid (around 70 mEq) is huge. Alterations of potassium homeostasis are frequent in cancer patients as well alterations in potassium channels, the transmembrane proteins that mediate potassium fluxes within the cells. The present chapter is focused on the clinical significance of potassium homeostasis and potassium channels in patients with solid tumors.",book:{id:"10794",title:"Potassium in Human Health",coverURL:"https://cdn.intechopen.com/books/images_new/10794.jpg"},signatures:"Jessica Iorio, Lisa Lastraioli and Elena Lastraioli"},{id:"78820",title:"Potassium Homeostasis",slug:"potassium-homeostasis",totalDownloads:109,totalDimensionsCites:0,doi:"10.5772/intechopen.100368",abstract:"The average potassium intake in the United States population ranges from 90 to 120 mEq/day. About 98% of the total body’s potassium is intracellular, and only 2% is present in the extracellular compartment. This distributional proportion is essential for cellular metabolic reactions and maintaining a gradient for resting membrane potential. A loss of this gradient results in hyper- or hypopolarization of the cell membrane, especially in cardiac muscles leading to life-threatening arrhythmias. Multiple mechanisms in human maintain homeostasis. Transient initial changes are due to transcellular shifts activating sodium-potassium ATPase pumps on the cell membrane. The kidneys essentially take part in excess potassium excretion, maintaining total body stores constant within normal range. Gastrointestinal secretion of potassium is insignificant in individuals with normal renal function, however plays an essential role in individuals with compromised renal function. So far, a classic feedback mechanism was thought to maintain potassium homeostasis; however, a recently recognized feedforward mechanism acting independently also helps preserve potassium homeostasis. Hence, potassium homeostasis is vital for humans to function at a normal level.",book:{id:"10794",title:"Potassium in Human Health",coverURL:"https://cdn.intechopen.com/books/images_new/10794.jpg"},signatures:"Shakuntala S. Patil and Sachin M. Patil"},{id:"78193",title:"Potassium and Cardiac Surgery",slug:"potassium-and-cardiac-surgery",totalDownloads:181,totalDimensionsCites:0,doi:"10.5772/intechopen.99735",abstract:"Potassium homeostasis affects cardiac rhythm and contractility, along with vascular reactivity and vascular smooth muscle proliferation. This chapter will focus on potassium dynamics during and after cardiac surgery involving cardioplegic arrest and cardiopulmonary bypass (CPB). Hyperkalemic, hypothermic solutions are frequently used to induce cardioplegic arrest and protect the heart during cardiac surgery involving CPB. Common consequences of hyperkalemic cardioplegic arrest and reperfusion include microvascular dysfunction involving several organ systems and myocardial dysfunction. Immediately after CPB, blood potassium levels often drop precipitously due to a variety of factors, including CPB -induced electrolyte depletion and frequent, long-term administration of insulin during and after surgery. Meanwhile, some patients with pre-existing kidney dysfunction may experience postoperative hyperkalemia following cardioplegia. Any degree of postoperative hyper/hypokalemia significantly elevates the risk of cardiac arrythmias and subsequent myocardial failure. Therefore, proper management of blood potassium levels during and after cardioplegia/CPB is crucial for optimizing patient outcomes following cardiac surgery.",book:{id:"10794",title:"Potassium in Human Health",coverURL:"https://cdn.intechopen.com/books/images_new/10794.jpg"},signatures:"Shawn Kant, Frank W. Sellke and Jun Feng"}],onlineFirstChaptersTotal:4},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],testimonialsList:[]},series:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"
\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems. \r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.
",coverUrl:"https://cdn.intechopen.com/series/covers/25.jpg",latestPublicationDate:"April 13th, 2022",hasOnlineFirst:!1,numberOfPublishedBooks:1,editor:{id:"197485",title:"Dr.",name:"J. Kevin",middleName:null,surname:"Summers",slug:"j.-kevin-summers",fullName:"J. Kevin Summers",profilePictureURL:"https://mts.intechopen.com/storage/users/197485/images/system/197485.jpg",biography:"J. Kevin Summers is a Senior Research Ecologist at the Environmental Protection Agency’s (EPA) Gulf Ecosystem Measurement and Modeling Division. He is currently working with colleagues in the Sustainable and Healthy Communities Program to develop an index of community resilience to natural hazards, an index of human well-being that can be linked to changes in the ecosystem, social and economic services, and a community sustainability tool for communities with populations under 40,000. He leads research efforts for indicator and indices development. Dr. Summers is a systems ecologist and began his career at the EPA in 1989 and has worked in various programs and capacities. This includes leading the National Coastal Assessment in collaboration with the Office of Water which culminated in the award-winning National Coastal Condition Report series (four volumes between 2001 and 2012), and which integrates water quality, sediment quality, habitat, and biological data to assess the ecosystem condition of the United States estuaries. He was acting National Program Director for Ecology for the EPA between 2004 and 2006. He has authored approximately 150 peer-reviewed journal articles, book chapters, and reports and has received many awards for technical accomplishments from the EPA and from outside of the agency. Dr. Summers holds a BA in Zoology and Psychology, an MA in Ecology, and Ph.D. in Systems Ecology/Biology.",institutionString:null,institution:{name:"Environmental Protection Agency",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:0,paginationItems:[]},overviewPageOFChapters:{paginationCount:0,paginationItems:[]},overviewPagePublishedBooks:{paginationCount:0,paginationItems:[]},openForSubmissionBooks:{},onlineFirstChapters:{paginationCount:0,paginationItems:[]},subseriesFiltersForOFChapters:[],publishedBooks:{},subseriesFiltersForPublishedBooks:[],publicationYearFilters:[],authors:{}},subseries:{item:{id:"25",type:"subseries",title:"Evolutionary Computation",keywords:"Genetic Algorithms, Genetic Programming, Evolutionary Programming, Evolution Strategies, Hybrid Algorithms, Bioinspired Metaheuristics, Ant Colony Optimization, Evolutionary Learning, Hyperparameter Optimization",scope:"Evolutionary computing is a paradigm that has grown dramatically in recent years. This group of bio-inspired metaheuristics solves multiple optimization problems by applying the metaphor of natural selection. It so far has solved problems such as resource allocation, routing, schedule planning, and engineering design. Moreover, in the field of machine learning, evolutionary computation has carved out a significant niche both in the generation of learning models and in the automatic design and optimization of hyperparameters in deep learning models. This collection aims to include quality volumes on various topics related to evolutionary algorithms and, alternatively, other metaheuristics of interest inspired by nature. For example, some of the issues of interest could be the following: Advances in evolutionary computation (Genetic algorithms, Genetic programming, Bio-inspired metaheuristics, Hybrid metaheuristics, Parallel ECs); Applications of evolutionary algorithms (Machine learning and Data Mining with EAs, Search-Based Software Engineering, Scheduling, and Planning Applications, Smart Transport Applications, Applications to Games, Image Analysis, Signal Processing and Pattern Recognition, Applications to Sustainability).",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11421,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"111683",title:"Prof.",name:"Elmer P.",middleName:"P.",surname:"Dadios",slug:"elmer-p.-dadios",fullName:"Elmer P. 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