Haemophilia severity classification on the basis of FVIII:C/FIX:C levels.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"5692",leadTitle:null,fullTitle:"Sustainable Home Design by Applying Control Science",title:"Sustainable Home Design by Applying Control Science",subtitle:null,reviewType:"peer-reviewed",abstract:'Today\'s homes must prepare for a progressing ageing population and an increasing risk caused by climate change, as well as to reduce CO2 emissions. How homes can be designed to meet all of these requirements? How such design can be promoted in the housing market? Sustainable Home Design by Applying Control Science answers these questions, by using a novel approach. Kazutoshi Fujihira, an innovative environmental scientist and sustainable housing award winner, demonstrates the "control system for promoting sustainable home design" with the "sustainable design guidelines" and "sustainability checklist". Moreover, the chapter of case study illustrates an actually designed and constructed house, which shows excellent sustainability and energy-saving performance.',isbn:"978-953-51-3658-3",printIsbn:"978-953-51-3657-6",pdfIsbn:"978-953-51-4586-8",doi:"10.5772/64660",price:119,priceEur:129,priceUsd:155,slug:"sustainable-home-design-by-applying-control-science",numberOfPages:108,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"83bab2850ca5c3aea1dd9c25cd2aee8c",bookSignature:"Kazutoshi Fujihira",publishedDate:"December 6th 2017",coverURL:"https://cdn.intechopen.com/books/images_new/5692.jpg",numberOfDownloads:7727,numberOfWosCitations:0,numberOfCrossrefCitations:13,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:13,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:26,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 21st 2016",dateEndSecondStepPublish:"December 12th 2016",dateEndThirdStepPublish:"March 10th 2017",dateEndFourthStepPublish:"June 8th 2017",dateEndFifthStepPublish:"August 7th 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Authored by",kuFlag:!1,featuredMarkup:null,editors:[{id:"69662",title:"BSc.",name:"Kazutoshi",middleName:null,surname:"Fujihira",slug:"kazutoshi-fujihira",fullName:"Kazutoshi Fujihira",profilePictureURL:"https://mts.intechopen.com/storage/users/69662/images/2068_n.jpg",biography:"Kazutoshi Fujihira, the founder and head of Institute of Environmentology, is an innovative scientist in the fields of environment and sustainability. His research started with clarifying causal relation between humans and environmental problems. After that, applying control science, he has been developing measures to control human activities towards sustainability. Recently, synthesizing these studies and his architectural background, he has produced a methodology for promoting sustainable home design. He is the author of several books, including Introduction to Environmentology and Complex Systems, Sustainability and Innovation and numerous research papers. He is also the recipient of the 2015 Japan Wooden Houses and Industry Association President Award and 2017 Albert Nelson Marquis Lifetime Achievement Award.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"11",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"852",title:"Sustainability",slug:"environmental-design-sustainability"}],chapters:[{id:"57469",title:"Requirements for Sustainable Housing Design",doi:"10.5772/intechopen.71322",slug:"requirements-for-sustainable-housing-design",totalDownloads:1457,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Buildings including homes are related to a variety of environmental, social, and economic problems. In the twenty-first century, especially two major problems, namely “climate change” and financial problems resulting from “aging population,” are expected to become more serious globally. In order to curb the progress of climate change, building sector has to strengthen “mitigation” measures, including improvement in energy efficiency of buildings and utilization of renewable energy. Building sector must also strengthen “adaptation” measures, aiming to reduce adverse effects caused by climate change. On the other hand, homes need to be transformed into those which contribute to reduce illnesses and injuries, which tend to increase in accordance with aging population. Taking accessible and universal design into homes is effective to increase mobility of occupants as well as to prevent injuries. Homes are used for a very long time; therefore, these considerations need to be comprehensively taken into homes from the beginning.",signatures:"Kazutoshi Fujihira",downloadPdfUrl:"/chapter/pdf-download/57469",previewPdfUrl:"/chapter/pdf-preview/57469",authors:[{id:"69662",title:"BSc.",name:"Kazutoshi",surname:"Fujihira",slug:"kazutoshi-fujihira",fullName:"Kazutoshi Fujihira"}],corrections:null},{id:"57403",title:"Background: Existing Japanese Systems Related to Sustainable Housing",doi:"10.5772/intechopen.71326",slug:"background-existing-japanese-systems-related-to-sustainable-housing",totalDownloads:1137,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In order to expand sustainable homes into the housing market, effective methods or systems for promoting sustainable housing design need to be widely disseminated in the society. In Japan, there are three important public systems related to sustainable housing design, namely the Housing Performance Indication System (HPIS), long-life quality housing (LQH) certification, and Comprehensive Assessment System for Built Environment Efficiency (CASBEE) for detached houses. The HPIS has stipulated the housing performance indication standards over 10 categories. The LQH system certifies houses that meet the criteria of long-life quality housing. CASBEE for detached houses comprehensively assesses and rates the sustainability of detached houses. However, there still remains room for further improvement in the set of these existing Japanese systems. First, the application of the systems to existing homes has been extremely limited until now. Second, CASBEE for detached houses, the one and only national comprehensive system, has not been used so often thus far. Moreover, readiness of the systems for emergent challenges, namely climate change and aging population, has also been insufficient.",signatures:"Kazutoshi Fujihira",downloadPdfUrl:"/chapter/pdf-download/57403",previewPdfUrl:"/chapter/pdf-preview/57403",authors:[{id:"69662",title:"BSc.",name:"Kazutoshi",surname:"Fujihira",slug:"kazutoshi-fujihira",fullName:"Kazutoshi Fujihira"}],corrections:null},{id:"57401",title:"Basic Schemes: Preparations for Applying Control Science to Sustainable Design",doi:"10.5772/intechopen.71325",slug:"basic-schemes-preparations-for-applying-control-science-to-sustainable-design",totalDownloads:1223,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"It is the ultimate goal for humankind to deal with various problems and achieve sustainability. Control science can be applied to all goal-oriented tasks and has already produced remarkable results. Accordingly, applying control science to the task of achieving sustainability is a rational and reliable approach. In order to apply control science to sustainability issues, our first study has shown the “basic control system for sustainability” as well as the “model of sustainability.” After that, in order to identify system components of practical control systems for promoting sustainable design, we have devised “two-step preparatory work for sustainable design.” The two steps of this preparatory work are “determining the relationships between the standard human activities and sustainability” and “sustainability checkup on human activities as an object.”",signatures:"Kazutoshi Fujihira",downloadPdfUrl:"/chapter/pdf-download/57401",previewPdfUrl:"/chapter/pdf-preview/57401",authors:[{id:"69662",title:"BSc.",name:"Kazutoshi",surname:"Fujihira",slug:"kazutoshi-fujihira",fullName:"Kazutoshi Fujihira"}],corrections:null},{id:"57412",title:"Methodology of Applying Control Science to Sustainable Housing Design",doi:"10.5772/intechopen.71324",slug:"methodology-of-applying-control-science-to-sustainable-housing-design",totalDownloads:1167,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"The previous chapter has demonstrated the “basic control system for sustainability”, “model of sustainability”, and “two-step preparatory work for sustainable design”. Based on these basic schemes, this chapter shows the methodology of applying control science to sustainable home design. First, using two factors, that is, “material” and “space”, we identify important elements of home. Next, we provide the two-step preparatory work for sustainable home design, namely, (1) determining the relationships between the standard home and sustainability and (2) sustainability checkup on a home as an object. After that, we derive “sustainable design guidelines” from step 1 and “sustainability checklist” from step 2, respectively. Finally, we compose the “control system for promoting sustainable home design” in which the sustainable design guidelines and sustainability checklist are incorporated. This practical control system demonstrates sustainable design processes for both new and existing homes.",signatures:"Kazutoshi Fujihira",downloadPdfUrl:"/chapter/pdf-download/57412",previewPdfUrl:"/chapter/pdf-preview/57412",authors:[{id:"69662",title:"BSc.",name:"Kazutoshi",surname:"Fujihira",slug:"kazutoshi-fujihira",fullName:"Kazutoshi Fujihira"}],corrections:null},{id:"57400",title:"Case Study: Detached House Designed by Following the Control System",doi:"10.5772/intechopen.71323",slug:"case-study-detached-house-designed-by-following-the-control-system",totalDownloads:1549,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The previous chapter has demonstrated the control system for promoting sustainable housing design in which the sustainable design guidelines and sustainability checklist are incorporated. Following this control system, we have actually designed and constructed a detached house. To be concrete, the homeowner and the architects of the housing manufacture have designed the home’s parts, or elements, so that as much as possible the elements’ variables meet their desired values. The sustainable design guidelines and sustainability checklist have been readily accepted because the material and spatial elements are equivalent to real parts of the home. After the home started to be used, we have obtained external evaluations of the home’s sustainability performance. For example, CASBEE for Detached Houses, a comprehensive assessment system, has readily ranked the house in the highest “S.” An energy-saving performance assessment has shown that this home has reduced energy consumption by over 70%, as compared with the average home. On the other hand, the reactions of the occupants and visitors have indicated the comfort, healthiness and safety of this house. Furthermore, this home has received a sustainable housing award, especially due to its extremely high sustainability and energy-saving performance.",signatures:"Kazutoshi Fujihira",downloadPdfUrl:"/chapter/pdf-download/57400",previewPdfUrl:"/chapter/pdf-preview/57400",authors:[{id:"69662",title:"BSc.",name:"Kazutoshi",surname:"Fujihira",slug:"kazutoshi-fujihira",fullName:"Kazutoshi Fujihira"}],corrections:null},{id:"57437",title:"Discussion and Conclusion: Effectiveness, Characteristics and Future Prospects of the Methodology",doi:"10.5772/intechopen.71321",slug:"discussion-and-conclusion-effectiveness-characteristics-and-future-prospects-of-the-methodology",totalDownloads:1194,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Following the control system for promoting sustainable home design, we have designed a home and built it. The quantitative evaluations and reactions of the occupants and visitors on the home indicate that if system users closely follow the methodology, they can comprehensively achieve sustainable homes, which have high environmental performance. Meanwhile, the results of the study have suggested that this methodology has several characteristics, besides comprehensiveness. First, the diagram of the control system itself is useful because it concisely explains the whole picture of the sustainable design processes on both new and existing homes. Second, the “sustainable design guidelines” and “sustainability checklist” are user-friendly since the material and spatial elements are equivalent to real parts of homes. Moreover, the “element – variable – desired value” structure in the guidelines and checklist is superior in “adaptability to regional differences” and “flexibility toward changes over time.” We expect that this methodology is widely used, in coordination with the existing methods for sustainable housing. Furthermore, it can be theoretically applied to other categories of human activities, which are regarded as the complex of material and spatial elements.",signatures:"Kazutoshi Fujihira",downloadPdfUrl:"/chapter/pdf-download/57437",previewPdfUrl:"/chapter/pdf-preview/57437",authors:[{id:"69662",title:"BSc.",name:"Kazutoshi",surname:"Fujihira",slug:"kazutoshi-fujihira",fullName:"Kazutoshi Fujihira"}],corrections:null}],productType:{id:"3",title:"Monograph",chapterContentType:"chapter",authoredCaption:"Authored by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"7650",title:"Different Strategies of Housing Design",subtitle:null,isOpenForSubmission:!1,hash:"a7228ca821b354d974a45eac0ca0eff8",slug:"different-strategies-of-housing-design",bookSignature:"Ayşem Berrin Çakmaklı",coverURL:"https://cdn.intechopen.com/books/images_new/7650.jpg",editedByType:"Edited by",editors:[{id:"220974",title:"Dr.",name:"Aysem",surname:"Cakmakli",slug:"aysem-cakmakli",fullName:"Aysem Cakmakli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9916",title:"Zero-Energy Buildings",subtitle:"New Approaches and Technologies",isOpenForSubmission:!1,hash:"03b533ca4c0a7f4f0307e4e4ec474594",slug:"zero-energy-buildings-new-approaches-and-technologies",bookSignature:"Jesús Alberto Pulido Arcas, Carlos Rubio-Bellido, Alexis Pérez-Fargallo and Ivan Oropeza-Perez",coverURL:"https://cdn.intechopen.com/books/images_new/9916.jpg",editedByType:"Edited by",editors:[{id:"172801",title:"Dr.",name:"Jesus Alberto",surname:"Pulido Arcas",slug:"jesus-alberto-pulido-arcas",fullName:"Jesus Alberto Pulido Arcas"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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A phenotype is defined as an observable characteristic which is expressed by an underlying genotype interacting with the environment [1]. Phenotype, in clinical scenario, hence represents the observable interface of the disease in terms of clinical features (laboratory findings, signs and symptoms) [2]. In contrast to genotype which is a stable entity, phenotype is dynamic and influenced by both the genotype and environment [3, 4]. Hence, in strict terms, the exact disease phenotype may be difficult to ascertain in many cases. This uncertainty usually underlies contemporary processes, directly or indirectly affecting the disease, with their own genetic and/or environmental influences [2]. Precise definition for a specific phenotype, therefore, needs development of a standardised comprehensive checklist of signs, symptoms and laboratory findings [3]. This is considerably convenient in case of monogenic disorders. Phenotypes for multigenic disorders or genetic diseases significantly influenced by environmental interactions are difficult to delineate [5].
Haemophilia is known to mankind since ancient times with references from Babylonian history [6]. The first vague description of cases appeared in the tenth century [7]. The first modern description of the disease was made in the eighteenth century, and the term haemophilia was first used in 1828 by Johann Lukas Schönlein and his student Friedrich Hopff [6].
The two diseases, haemophilia A (HA) and haemophilia B (HB), were initially regarded as the same and attributed to fragility of vessels [8]. The idea later shifted to abnormalities in platelets in the 1930s. It was in 1937, when Patek and Taylor found the ‘anti-haemophilic globulin’, extracted from plasma, to be the factor responsible. The two diseases were, however, first discriminated in 1944 by Pavlosky of Buenos Aires [8].
In haemophilia, the phenotype is expressed at three distinct levels: the coagulation activity, the factor antigen level and the clinical outcome in terms of bleeding and its complications. Plasma procoagulant level, determined by coagulation activity, is the most important clinical entity determining severity of the disease. Employing this parameter, the Scientific and Standardisation Committee classified haemophilia A and haemophilia B into three major classes, that is, mild, moderate and severe [9]. Each phenotype has a distinct clinical impact (Table 1). Patients with severe phenotype (plasma factor level < 0.01 IU/ml; <1% of normal) commonly present with frequent (two to five bleeding episodes per month) spontaneous bleeding into the joints or deep muscles. Patients with moderate severity of the disease (plasma factor level 0.01–0.05 IU/ml; 1–5% of normal) would bleed following mild trauma; spontaneous bleeding is seen uncommonly. Diagnosis is usually established in the first 5–6 years of life. Bleeding frequency ranges from once a month to once a year. In mild severity of the disease (plasma factor level >0.05 to <0.40 IU/ml; >5 to <40% of normal), bleeding occurs as a result of major trauma, e.g., surgery or accident. Bleeding is infrequent in these patients [10, 11].
Severity | FVIII:C/FIX:C level (%) | Age at diagnosis | Bleeding and haemarthroses |
---|---|---|---|
Severe | ≤1 | ≤2 years | Spontaneous haemorrhages and haemarthroses since early childhood |
Moderate | 2–5 | <6 years | Haemorrhage are usually secondary to minor trauma or surgery; spontaneous haemarthrosis is unusual |
Mild | 6–40 | Subject to haemostatic challenge | Haemorrhage secondary to surgery or major trauma; spontaneous bleedings are rare |
Haemophilia severity classification on the basis of FVIII:C/FIX:C levels.
FVIII:C, factor VIII coagulation activity; FIX:C, factor IX coagulation activity.
This is, however, noteworthy that patients with a specific severity of the disease do not always behave as anticipated. Studies have reported a significant number of severe haemophilia cases with a milder phenotype [1, 12, 13]. In such cases, bleeding phenotype resembles that of moderate severity. These cases are hence treated like moderate haemophilia; prophylactic treatment is often not needed.
Haemophilia was previously regarded as a classical example of Mendelian inheritance, with mutation in only one gene (F8 or F9) causing the disease phenotype. The concept, however, has significantly evolved in the last couple of decades, and the two diseases are now recognised to have a heterogeneous spectrum of mutations. More than 2800 mutations are reported in F8, whereas more than 1200 mutations are reported in F9 [14]. These mutations, summarised in Table 2, include all the major types of mutations. Point mutations are the most frequent, followed by small indel mutations. Repeat variants are not yet reported to associate with the disease. In majority of the cases, specific mutations result in the same disease severity, a phenomenon referred to as genotype-phenotype correlation [13, 15].
Penetrance refers to the appearance of disease in affected individuals, whereas expressivity is the degree of severity of disease in patients [16]. Haemophilia is an X-linked recessive genetic disorder with complete penetrance in most of the cases, that is, male individuals with pathogenic variants in F8 or F9 are mostly fated to have haemophilia. This stands true particularly in case of F8. Patients from the same family have approximately the same severity status. However, the severity, as described earlier, is not the same in all patients. Cases with the same mutations exhibiting different levels of coagulation factor activity advocate variable expressivity for the specific genotype. This variation is believed to be the outcome factors including genetic alterations or polymorphisms in other genes (especially those related to haemostasis, inflammation and immune response) and environmental factors [17]. It has been established that the same genotype subjected to different environments expresses diverse phenotypes [18]. This interaction between genotype and environment is called gene–environment interaction [19, 20].
Large structural changes in the protein, by default, tend to generate a severe phenotype. Nonsense mutations, particularly those occurring in the early gene segments, have a similar tendency. Almost all the nonsense mutations reported within the initial part of the gene are associated with severe disease phenotype. Frameshift mutations in F8/F9 gene are again usually associated with an adverse phenotype [21].
Approximately 30% of the female individuals with heterozygous mutation have a coagulation factor activity less than 40% [22]. Increased bleeding tendency among the carriers, in comparison to normal females, is well documented [23, 24].
In case of F9 sequence variants, besides classical HB, four other phenotypes are reported. These are described in the following sections.
Haemophilia B Leyden is a specific type of HB in which the patient presents with decreased FIX:C levels in the early childhood, but the levels progressively increase after puberty. The disease is postulated to occur as a result of mutation in the 50 bp region that spans the transcriptional start site [25]. A total of 23 promoter region mutations have been identified until now (Table 3).
Mutation type | F8 | F9 |
---|---|---|
Missense/nonsense | 1674 | 748 |
Splicing | 193 | 101 |
Regulatory | 10 | 28 |
Small deletions | 489 | 161 |
Small insertions | 160 | 52 |
Small indels | 38 | 17 |
Gross deletions | 260 | 75 |
Gross insertions/duplications | 40 | 7 |
Complex rearrangements | 20 | 13 |
Repeat variations | 0 | 0 |
Total |
Frequency of different types of mutations reported in F8 and F9.
F8, factor VIII gene; F9, factor IX gene.
HGVS cDNA name | Legacy nucleotide no. | Nature of mutation | Disease severity | Reference |
---|---|---|---|---|
c.-55G>A | -26 | Substitution | Moderate | [26] |
c.-55G>C | -26 | Substitution | Severe | [27] |
c.-55G>T | -26 | Substitution | Severe | [28] |
c.-53A>G | -24 | Substitution | Not reported | [21] |
c.-52C>G | -23 | Substitution | Not reported | [21] |
c.-52C>T | -23 | Substitution | Not reported | [29] |
c.-50T>G | -21 | Substitution | Not reported | [30] |
c.-49T>A | -20 | Substitution | Moderate/mild | [31] |
c.-49T>C | -20 | Substitution | Mild | [32] |
c.-48G>C | -19 | Substitution | Moderate/mild | [29] |
c.-35G>A | -6 | Substitution | Mild | [33] |
c.-35G>C | -6 | Substitution | Mild | [34] |
c.-34A>G | -5 | Substitution | Mild | [26] |
c.-34A>T | -5 | Substitution | Moderate | [35] |
c.-24T>A | 6 | Substitution | Mild | [34] |
c.-23T>C | 7 | Substitution | Not reported | [21] |
c.-22T>C/c | 8 | Substitution | Mild | [36] |
c.-22delT | 8 | Deletion | Moderate | [21] |
c.-21C>G | 9 | Substitution | Not reported | [21] |
c.-18A>G | 12 | Substitution | Moderate | [21] |
c.-17A>C | 13 | Substitution | Severe | [26] |
c.-17A>G | 13 | Substitution | Mild | [37] |
c.-17delA | 13 | Deletion | Mild | [37] |
F9 promoter site mutations associated with HB Leyden (mutation c.-55G>C is an exception).
HGVS, Human Genome Variation Society; no., number.
The mutation at c.-55G>C (or c. -26G>C in legacy nucleotide numbering) found in the promoter region of F9 gene is also called the haemophilia B Brandenburg mutation [38]. Unlike HB Leyden this variant does not exhibit improvement in FIX:C levels with age. The promoter region sequence located at c.-34 to -10 of the F9 gene serves as a binding site for the hepatocyte nuclear factor 4 (HNF4). The liver-enriched HNF4 is a member of the steroid hormone receptor superfamily of transcription factors (also called the nuclear receptor superfamily). Mutation at HNF4 disrupts the binding site to variable extents of severity. The mutation c.-55G>C, however, occurs at a site which is overlapped by the HNF4 binding site and another regulatory region, the androgen-responsive element (ARE) [39].
The F9 mutation c.1151G>T is associated with several fold increase in FIX:C activity [40]. The mutant FIX has leucine substituted for arginine at p.Arg384Leu. This alteration increases the affinity for FX to bind at this site. Patients might present with thromboembolic complications. This variant was named ‘factor IX Padua’. Studies have also demonstrated that Arg-338 is part of an exosite (a secondary binding site) that binds factor X and heparin at the same time [41].
People with FIX:C levels more than 129 U/dL are 2–3 times more at risk of developing DVT in comparison to those with lower FIX:C levels. The risk is higher in females [42]. Variations in F9-associated single-nucleotide polymorphisms (SNPs) do not explain this raise in FIX antigen levels [43].
The Malmo polymorphism, c.580G>A (p. Ala194Thr), has an allele frequency of 0.32 in the Western population. It has been found that people with the G allele (F9 Malmo) have a 15–43% decreased risk of developing DVT in comparison to those with A allele [44]. This protective role of F9 Malmo has been extensively studied and confirmed [45]. The biochemical mechanisms behind this phenomenon are still obscure.
All vitamin K-dependent clotting factors [including FII, FVII, FIX, FX, protein C (PC), protein S (PS) and protein Z (PZ)] possess an 18 amino acid propeptide sequence which serves as a binding site for the γ-glutamyl carboxylase enzyme. This enzyme catalyses modification of certain glutamate residues in the amino terminus of the mentioned clotting factors [46]. It has been determined that mutations at this site reduce the affinity vitamin K-dependent γ-carboxylase for the proteins.
Phenotypic plasticity is defined as ‘the ability of individual genotypes to produce different phenotypes when exposed to different environmental conditions’ [47]. In the current scenario, this refers to presentation of the same mutation with different severities of the disease.
It has been found that the mutations with varying phenotypes (MVPs) mostly occur at the less conserved sites with Arg being the usual mutated residue. It is also noted that these mutations commonly occur at the CpG dinucleotides. In comparison, mutations with uniform phenotypes (MUPs) occur in more conserved sites, with cysteine as the most frequently mutated amino acid residue. Intrinsic protein structural changes have been reported with reduced severity in cases of MVPs. No significant structural variations are identified between the two groups. The phenomenon is hypothesised to be a function of multiple factors including modifier genes, epigenetic influences and environmental effects. These factors may act individually or in combination [48].
Tables 4 and 5 depict F8 and F9 mutations, respectively, reported with phenotypic plasticity [49, 50]. A total of 351 mutations are presented here with cases reported from at least two severity classes. The most significant are the 85 cases (32 from F8 and 53 from F9) wherein patients from both severe and mild categories are reported.
HGVS cDNA | HGVS protein | Mutation type | Mechanism | Exon | Domain | Severe (<1 U/dL) | Moderate (1–5 U/dL) | Mild (>5 U/dL) |
---|---|---|---|---|---|---|---|---|
c.1171C>T | p.Arg391Cys | Missense | Substitution | 8 | a1 | X | X | X |
c.1172G>A | p.Arg391His | Missense | Substitution | 8 | a1 | X | X | X |
c.1492G>A | p.Gly498Arg | Missense | Substitution | 10 | A2 | X | X | X |
c.396A>C | p.Glu132Asp | Missense | Substitution | 4 | A1 | X | X | X |
c.4380delT | p.Asn1460Lysfs*5 | Frameshift | Deletion | 14 | B | X | X | X |
c.5122C>T | p.Arg1708Cys | Missense | Substitution | 14 | a3 | X | X | X |
c.5219+3A>G | Splice site change | Substitution | Intron 14 | X | X | X | ||
c.5399G>A | p.Arg1800His | Missense | Substitution | 16 | A3 | X | X | X |
c.5663G>T | p.Arg1888Ile | Missense | Substitution | 17 | A3 | X | X | X |
c.590T>G | p.Val197Gly | Missense | Substitution | 4 | A1 | X | X | X |
c.6356A>G | p.Gln2119Arg | Missense | Substitution | 22 | C1 | X | X | X |
c.6371A>G | p.Tyr2124Cys | Missense | Substitution | 22 | C1 | X | X | X |
c.6506G>A | p.Arg2169His | Missense | Substitution | 23 | C1 | X | X | X |
c.6545G>A | p.Arg2182His | Missense | Substitution | 23 | C1 | X | X | X |
c.6683G>A | p.Arg2228Gln | Missense | Substitution | 24 | C2 | X | X | X |
c.6977G>A | p.Arg2326Gln | Missense | Substitution | 26 | C2 | X | X | X |
c.902G>A | p.Arg301His | Missense | Substitution | 7 | A1 | X | X | X |
c.1063C>T | p.Arg355* | Nonsense | Substitution | 8 | A1 | X | X | |
c.1226A>G | p.Glu409Gly | Missense | Substitution | 8 | A2 | X | X | |
c.1316G>T | p.Gly439Val | Missense | Substitution | 9 | A2 | X | X | |
c.143+1567A>G | Splice site change | Substitution | Intron 1 | X | X | |||
c.1475A>G | p.Tyr492Cys | Missense | Substitution | 10 | A2 | X | X | |
c.1639T>C | p.Cys547Arg | Missense | Substitution | 11 | A2 | X | X | |
c.1702G>A | p.Gly568Ser | Missense | Substitution | 11 | A2 | X | X | |
c.1754T>C | p.Ile585Thr | Missense | Substitution | 12 | A2 | X | X | |
c.1804C>T | p.Arg602* | Nonsense | Substitution | 12 | A2 | X | X | |
c.1809C>G | p.Ser603Arg | Missense | Substitution | 12 | A2 | X | X | |
c.2015_2017del | p.Phe672del | Small structural change (in-frame, <50 bp) | Deletion | 13 | A2 | X | X | |
c.2048A>G | p.Tyr683Cys | Missense | Substitution | 13 | A2 | X | X | |
c.206_212del | p.Leu69Glnfs*21 | Frameshift | Deletion | 2 | A1 | X | X | |
c.2090T>A | p.Val697Asp | Missense | Substitution | 13 | A2 | X | X | |
c.2114-?_5219+?del | Large structural change (>50 bp) | Deletion | 14 | A3 | X | X | ||
c.2159G>A | p.Gly720Asp | Missense | Substitution | 14 | A2 | X | X | |
c.2182delT | p.Ser728Leufs*23 | Frameshift | Deletion | 14 | A2 | X | X | |
c.2373G>A | p.Trp791* | Nonsense | Substitution | 14 | B | X | X | |
c.2440C>T | p.Arg814* | Nonsense | Substitution | 14 | B | X | X | |
c.266G>A | p.Gly89Asp | Missense | Substitution | 3 | A1 | X | X | |
c.2945dupA | p.Asn982Lysfs*9 | Frameshift | Duplication | 14 | B | X | X | |
c.296T>A | p.Val99Asp | Missense | Substitution | 3 | A1 | X | X | |
c.3143G>A | p.Trp1048* | Nonsense | Substitution | 14 | B | X | X | |
c.3300dupA | p.Glu1101Argfs*17 | Frameshift | Duplication | 14 | B | X | X | |
c.353A>G | p.His118Arg | Missense | Substitution | 3 | A1 | X | X | |
c.3637delA | p.Ile1213Phefs*5 | Frameshift | Deletion | 14 | B | X | X | |
c.3637dupA | p.Ile1213Asnfs*28 | Frameshift | Duplication | 14 | B | X | X | |
c.3702_3705del | p.His1234Glnfs*2 | Frameshift | Deletion | 14 | B | X | X | |
c.388G>C | p.Gly130Arg | Missense | Substitution | 3 | A1 | X | X | |
c.421G>A | p.Glu141Lys | Missense | Substitution | 4 | A1 | X | X | |
c.4296_4300del | p.His1434Serfs*6 | Frameshift | Deletion | 14 | B | X | X | |
c.4379dupA | p.Asn1460Lysfs*2 | Frameshift | Duplication | 14 | B | X | X | |
c.43C>T | p.Arg15* | Nonsense | Substitution | 1 | Signal | X | X | |
c.4796G>A | p.Trp1599* | Nonsense | Substitution | 14 | B | X | X | |
c.4825dupA | p.Thr1609Asnfs*4 | Frameshift | Duplication | 14 | B | X | X | |
c.491G>A | p.Gly164Asp | Missense | Substitution | 4 | A1 | X | X | |
c.5113C>T | p.Gln1705* | Nonsense | Substitution | 14 | a3 | X | X | |
c.515G>T | p.Cys172Phe | Missense | Substitution | 4 | A1 | X | X | |
c.5219G>T | p.Arg1740Met | Missense | Substitution | 14 | A3 | X | X | |
c.5471dupA | p.Asn1824Lysfs*6 | Frameshift | Duplication | 16 | A3 | X | X | |
c.5536A>T | p.Lys1846* | Nonsense | Substitution | 16 | A3 | X | X | |
c.556G>T | p.Asp186Tyr | Missense | Substitution | 4 | A1 | X | X | |
c.5606G>T | p.Gly1869Val | Missense | Substitution | 17 | A3 | X | X | |
c.5685delT | p.Phe1895Leufs*50 | Frameshift | Deletion | 17 | A3 | X | X | |
c.5719A>T | p.Ser1907Cys | Missense | Substitution | 17 | A3 | X | X | |
c.5878C>T | p.Arg1960* | Nonsense | Substitution | 18 | A3 | X | X | |
c.5953C>T | p.Arg1985* | Nonsense | Substitution | 18 | A3 | X | X | |
c.5973_5976del | p.Met1992Hisfs*37 | Frameshift | Deletion | 18 | A3 | X | X | |
c.5998+1G>A | Splice site change | Substitution | Intron 18 | X | X | |||
c.5999-?_6429+?dup | Large structural change (>50 bp) | Duplication | 19–22 | X | X | |||
c.602-?_787+?del | Large structural change (>50 bp) | Deletion | 5–6 | X | X | |||
c.6046C>T | p.Arg2016Trp | Missense | Substitution | 19 | A3 | X | X | |
c.6133G>A | p.Gly2045Arg | Missense | Substitution | 20 | C1 | X | X | |
c.6172G>C | p.Ala2058Pro | Missense | Substitution | 20 | C1 | X | X | |
c.6274-?_6429+?del | Large structural change (>50 bp) | Deletion | 22 | C1 | X | X | ||
c.6403C>T | p.Arg2135* | Nonsense | Substitution | 22 | C1 | X | X | |
c.6429+?_6430-?inv | Large structural change (>50 bp) | Inversion | Intron 22 | X | X | |||
c.6481C>T | p.Pro2161Ser | Missense | Substitution | 23 | C1 | X | X | |
c.6485C>T | p.Pro2162Leu | Missense | Substitution | 23 | C1 | X | X | |
c.6496C>T | p.Arg2166* | Nonsense | Substitution | 23 | C1 | X | X | |
c.6544C>T | p.Arg2182Cys | Missense | Substitution | 23 | C1 | X | X | |
c.6593G>T | p.Gly2198Val | Missense | Substitution | 24 | C2 | X | X | |
c.6682C>G | p.Arg2228Gly | Missense | Substitution | 24 | C2 | X | X | |
c.6682C>T | p.Arg2228* | Nonsense | Substitution | 24 | C2 | X | X | |
c.670+5G>A | Splice site change | Substitution | Intron 5 | X | X | |||
c.6742T>A | p.Trp2248Arg | Missense | Substitution | 25 | C2 | X | X | |
c.6875_6876del | p.Phe2294Serfs*90 | Frameshift | Deletion | 25 | C2 | X | X | |
c.6967C>T | p.Arg2323Cys | Missense | Substitution | 26 | C2 | X | X | |
c.6977G>T | p.Arg2326Leu | Missense | Substitution | 26 | C2 | X | X | |
c.6994T>C | p.Trp2332Arg | Missense | Substitution | 26 | C2 | X | X | |
c.764G>C | p.Gly255Ala | Missense | Substitution | 6 | A1 | X | X | |
c.785C>T | p.Pro262Leu | Missense | Substitution | 6 | A1 | X | X | |
c.787+3A>G | Splice site change | Substitution | Intron 6 | X | X | |||
c.822G>C | p.Trp274Cys | Missense | Substitution | 7 | A1 | X | X | |
c.901C>T | p.Arg301Cys | Missense | Substitution | 7 | A1 | X | X | |
c.954_955del | p.Leu319Aspfs*18 | Frameshift | Deletion | 7 | A1 | X | X | |
c.991_992del | p.Ile331Leufs*6 | Frameshift | Deletion | 7 | A1 | X | X | |
c.1043G>A | p.Cys348Tyr | Missense | Substitution | 8 | A1 | X | X | |
c.121G>T | p.Gly41Cys | Missense | Substitution | 1 | A1 | X | X | |
c.1409C>T | p.Pro470Leu | Missense | Substitution | 9 | A2 | X | X | |
c.1751A>G | p.Gln584Arg | Missense | Substitution | 11 | A2 | X | X | |
c.1910A>G | p.Asn637Ser | Missense | Substitution | 13 | A2 | X | X | |
c.3870dupA | p.Gly1291Argfs*29 | Frameshift | Duplication | 14 | B | X | X | |
c.437A>C | p.Lys146Thr | Missense | Substitution | 4 | A1 | X | X | |
c.5150A>G | p.Tyr1717Cys | Missense | Substitution | 14 | A3 | X | X | |
c.5183A>G | p.Tyr1728Cys | Missense | Substitution | 14 | A3 | X | X | |
c.6273+1G>T | Splice site change | Substitution | Intron 21 | X | X | |||
c.677G>T | p.Ser226Ile | Missense | Substitution | 6 | A1 | X | X | |
c.6967C>G | p.Arg2323Gly | Missense | Substitution | 26 | C2 | X | X | |
c.902G>T | p.Arg301Leu | Missense | Substitution | 7 | A1 | X | X | |
c.923C>T | p.Ser308Leu | Missense | Substitution | 7 | A1 | X | X | |
c.1293G>T | p.Leu431Phe | Missense | Substitution | 9 | A2 | X | X | |
c.1348T>A | p.Tyr450Asn | Missense | Substitution | 9 | A2 | X | X | |
c.1408C>A | p.Pro470Thr | Missense | Substitution | 9 | A2 | X | X | |
c.1569G>T | p.= | Synonymous | Substitution | 11 | A2 | X | X | |
c.1636C>T | p.Arg546Trp | Missense | Substitution | 11 | A2 | X | X | |
c.1648C>T | p.Arg550Cys | Missense | Substitution | 11 | A2 | X | X | |
c.1660A>G | p.Ser554Gly | Missense | Substitution | 11 | A2 | X | X | |
c.1834C>T | p.Arg612Cys | Missense | Substitution | 12 | A2 | X | X | |
c.2044G>T | p.Val682Phe | Missense | Substitution | 13 | A2 | X | X | |
c.2149C>T | p.Arg717Trp | Missense | Substitution | 14 | A2 | X | X | |
c.2167G>A | p.Ala723Thr | Missense | Substitution | 14 | A2 | X | X | |
c.274G>A | p.Gly92Ser | Missense | Substitution | 3 | A1 | X | X | |
c.311T>A | p.Val104Asp | Missense | Substitution | 3 | A1 | X | X | |
c.410C>T | p.Thr137Ile | Missense | Substitution | 4 | A1 | X | X | |
c.5096A>T | p.Tyr1699Phe | Missense | Substitution | 14 | a3 | X | X | |
c.5143C>G | p.Arg1715Gly | Missense | Substitution | 14 | A3 | X | X | |
c.5339C>A | p.Pro1780Gln | Missense | Substitution | 15 | A3 | X | X | |
c.5393C>T | p.Ala1798Val | Missense | Substitution | 16 | A3 | X | X | |
c.5398C>G | p.Arg1800Gly | Missense | Substitution | 16 | A3 | X | X | |
c.541G>A | p.Val181Met | Missense | Substitution | 4 | A1 | X | X | |
c.5428T>C | p.Ser1810Pro | Missense | Substitution | 16 | A3 | X | X | |
c.5526G>A | p.Met1842Ile | Missense | Substitution | 16 | A3 | X | X | |
c.5557G>A | p.Ala1853Thr | Missense | Substitution | 16 | A3 | X | X | |
c.5618C>T | p.Pro1873Leu | Missense | Substitution | 17 | A3 | X | X | |
c.5825G>C | p.Gly1942Ala | Missense | Substitution | 18 | A3 | X | X | |
c.5879G>A | p.Arg1960Gln | Missense | Substitution | 18 | A3 | X | X | |
c.5921C>T | p.Ser1974Phe | Missense | Substitution | 18 | A3 | X | X | |
c.5954G>A | p.Arg1985Gln | Missense | Substitution | 18 | A3 | X | X | |
c.601+1632G>A | Splice site change | Substitution | Intron 4 | X | X | |||
c.6113A>G | p.Asn2038Ser | Missense | Substitution | 19 | A3 | X | X | |
c.6119G>A | p.Cys2040Tyr | Missense | Substitution | 20 | C1 | X | X | |
c.6212G>C | p.Arg2071Thr | Missense | Substitution | 21 | C1 | X | X | |
c.6278A>G | p.Asp2093Gly | Missense | Substitution | 22 | C1 | X | X | |
c.6350T>G | p.Ile2117Ser | Missense | Substitution | 22 | C1 | X | X | |
c.6413C>A | p.Ser2138Tyr | Missense | Substitution | 22 | C1 | X | X | |
c.6443A>G | p.Asn2148Ser | Missense | Substitution | 23 | C1 | X | X | |
c.6520C>G | p.His2174Asp | Missense | Substitution | 23 | C1 | X | X | |
c.6532C>T | p.Arg2178Cys | Missense | Substitution | 23 | C1 | X | X | |
c.668A>C | p.Glu223Ala | Missense | Substitution | 5 | A1 | X | X | |
c.670+6T>C | Splice site change | Substitution | Intron 5 | X | X | |||
c.6744G>T | p.Trp2248Cys | Missense | Substitution | 25 | C2 | X | X | |
c.67A>G | p.Arg23Gly | Missense | Substitution | 1 | A1 | X | X | |
c.6915T>G | p.Asn2305Lys | Missense | Substitution | 26 | C2 | X | X | |
c.6920A>C | p.Asp2307Ala | Missense | Substitution | 26 | C2 | X | X | |
c.6956C>T | p.Pro2319Leu | Missense | Substitution | 26 | C2 | X | X | |
c.755C>T | p.Thr252Ile | Missense | Substitution | 6 | A1 | X | X | |
c.871G>A | p.Glu291Lys | Missense | Substitution | 7 | A1 | X | X |
List of F8 mutations reported with phenotypic plasticity.
HGVS cDNA name | HGVS protein name | Mutation type | Mechanism | Exon | Domain | Severe (< 1 U/dL) | Moderate (1–5 U/dL) | Mild (>5 U/dL) |
---|---|---|---|---|---|---|---|---|
c.87A>G | p.Thr29Thr | Synonymous | Substitution | 1 | PRO | X | X | X |
c.127C>T | p.Arg43Trp | Missense | Substitution | 2 | PRO | X | X | X |
c.128G>A | p.Arg43Gln | Missense | Substitution | 2 | PRO | X | X | X |
c.172G>A | p.Gly58Arg | Missense | Substitution | 2 | GLA | X | X | X |
c.173G>A | p.Gly58Glu | Missense | Substitution | 2 | GLA | X | X | X |
c.191G>A | p.Cys64Tyr | Missense | Substitution | 2 | GLA | X | X | X |
c.259T>G | p.Phe87Val | Missense | Substitution | 3 | GLA | X | X | X |
c.301C>G | p.Pro101Ala | Missense | Substitution | 4 | EGF1 | X | X | X |
c.316G>A | p.Gly106Ser | Missense | Substitution | 4 | EGF1 | X | X | X |
c.412A>C | p.Asn138His | Missense | Substitution | 5 | EGF2 | X | X | X |
c.415G>A | p.Gly139Ser | Missense | Substitution | 5 | EGF2 | X | X | X |
c.571C>T | p.Arg191Cys | Missense | Substitution | 6 | Linker | X | X | X |
c.572G>A | p.Arg191His | Missense | Substitution | 6 | Linker | X | X | X |
c.720G>T | p.Trp240Cys | Missense | Substitution | 6 | Protease | X | X | X |
c.755G>A | p.Cys252Tyr | Missense | Substitution | 7 | Protease | X | X | X |
c.797C>T | p.Ala266Val | Missense | Substitution | 7 | Protease | X | X | X |
c.835G>A | p.Ala279Thr | Missense | Substitution | 7 | Protease | X | X | X |
c.838G>C | p.Gly280Arg | Missense | Substitution | 7 | Protease | X | X | X |
c.881G>A | p.Arg294Gln | Missense | Substitution | 8 | Protease | X | X | X |
c.914A>G | p.Tyr305Cys | Missense | Substitution | 8 | Protease | X | X | X |
c.987C>G | p.Ser329Arg | Missense | Substitution | 8 | Protease | X | X | X |
c.1009G>A | p.Ala337Thr | Missense | Substitution | 8 | Protease | X | X | X |
c.1025C>T | p.Thr342Met | Missense | Substitution | 8 | Protease | X | X | X |
c.1135C>T | p.Arg379* | Nonsense | Substitution | 8 | Protease | X | X | X |
c.1136G>A | p.Arg379Gln | Missense | Substitution | 8 | Protease | X | X | X |
c.1187G>C | p.Cys396Ser | Missense | Substitution | 8 | Protease | X | X | X |
c.1235G>A | p.Gly412Glu | Missense | Substitution | 8 | Protease | X | X | X |
c.1240C>A | p.Pro414Thr | Missense | Substitution | 8 | Protease | X | X | X |
c.1275A>C | p.Leu425Phe | Missense | Substitution | 8 | Protease | X | X | X |
c.1304G>A | p.Cys435Tyr | Missense | Substitution | 8 | Protease | X | X | X |
c.1306G>A | p.Ala436Thr | Missense | Substitution | 8 | Protease | X | X | X |
c.1328T>C | p.Ile443Thr | Missense | Substitution | 8 | Protease | X | X | X |
c.*2545A>G | 3′UTR | Substitution | 3′UTR | X | X | X | ||
c.-17A>G | Promoter | Substitution | 1 | X | X | X | ||
c.-35G>A | Promoter | Substitution | 5′UTR | X | X | X | ||
c.-35G>C | Promoter | Substitution | 5′UTR | X | X | X | ||
c.50T>A | p.Ile17Asn | Missense | Substitution | 1 | Signal peptide | X | X | |
c.83G>A | p.Cys28Tyr | Missense | Substitution | 1 | Signal peptide | X | X | |
c.128G>T | p.Arg43Leu | Missense | Substitution | 2 | PRO | X | X | |
c.138G>T | p.Arg47Ser | Missense | Substitution | 2 | PRO | X | X | |
c.190T>C | p.Cys64Arg | Missense | Substitution | 2 | GLA | X | X | |
c.199G>A | p.Glu67Lys | Missense | Substitution | 2 | GLA | X | X | |
c.219A>C | p.Glu73Asp | Missense | Substitution | 2 | GLA | X | X | |
c.223C>T | p.Arg75Stop | Nonsense | Substitution | 2 | GLA | X | X | |
c.226G>A | p.Glu76Lys | Missense | Substitution | 2 | GLA | X | X | |
c.260T>G | p.Phe87Cys | Missense | Substitution | 3 | GLA | X | X | |
c.263G>A | p.Trp88* | Nonsense | Substitution | 3 | GLA | X | X | |
c.291T>G | p.Cys97Trp | Missense | Substitution | 4 | EGF1 | X | X | |
c.304T>C | p.Cys102Arg | Missense | Substitution | 4 | EGF1 | X | X | |
c.305G>A | p.Cys102Tyr | Missense | Substitution | 4 | EGF1 | X | X | |
c.350G>A | p.Cys117Tyr | Missense | Substitution | 4 | EGF1 | X | X | |
c.383G>A | p.Cys128Tyr | Missense | Substitution | 4 | EGF1 | X | X | |
c.392delA | p.Asp131fs | Frameshift | Deletion | 5 | EGF2 | X | X | |
c.414T>A | p.Asn138Lys | Missense | Substitution | 5 | EGF2 | X | X | |
c.422G>A | p.Cys141Tyr | Missense | Substitution | 5 | EGF2 | X | X | |
c.423C>A | p.Cys141* | Nonsense | Substitution | 5 | EGF2 | X | X | |
c.423C>G | p.Cys141Trp | Missense | Substitution | 5 | EGF2 | X | X | |
c.427C>G | p.Gln143Glu | Missense | Substitution | 5 | EGF2 | X | X | |
c.434G>A | p.Cys145Tyr | Missense | Substitution | 5 | EGF2 | X | X | |
c.464G>T | p.Cys155Phe | Missense | Substitution | 5 | EGF2 | X | X | |
c.470G>A | p.Cys157Tyr | Missense | Substitution | 5 | EGF2 | X | X | |
c.470G>C | p.Cys157Ser | Missense | Substitution | 5 | EGF2 | X | X | |
c.479G>T | p.Gly160Val | Missense | Substitution | 5 | EGF2 | X | X | |
c.482A>G | p.Tyr161Cys | Missense | Substitution | 5 | EGF2 | X | X | |
c.484C>T | p.Arg162* | Nonsense | Substitution | 5 | EGF2 | X | X | |
c.509G>A | p.Ser170Tyr | Missense | Substitution | 5 | EGF2 | X | X | |
c.520G>A | p.Val174Met | Missense | Substitution | 5 | EGF2 | X | X | |
c.532T>C | p.Cys178Arg | Missense | Substitution | 6 | Linker | X | X | |
c.535G>A | p.Gly179Arg | Missense | Substitution | 6 | Linker | X | X | |
c.545_546del | p.Ser182Cysfs*6 | Frameshift | Deletion | 6 | Linker | X | X | |
c.547delG | p.Val183fs | Frameshift | Deletion | 6 | Linker | X | X | |
c.676C>T | p.Arg226Trp | Missense | Substitution | 6 | Activation | X | X | |
c.677G>A | p.Arg226Gln | Missense | Substitution | 6 | Activation | X | X | |
c.677G>T | p.Arg226Leu | Missense | Substitution | 6 | Activation | X | X | |
c.688_690del | p.Gly230del | Small structural change (in-frame, <50 bp) | Deletion | 6 | Protease | X | X | |
c.706G>T | p.Gly236Cys | Missense | Substitution | 6 | Protease | X | X | |
c.707G>A | p.Gly236Asp | Missense | Substitution | 6 | Protease | X | X | |
c.711A>G | p.Gln237Gln | Synonymous | Substitution | 6 | Protease | X | X | |
c.719G>A | p.Trp240* | Nonsense | Substitution | 6 | Protease | X | X | |
c.719G>T | p.Trp240Leu | Missense | Substitution | 6 | Protease | X | X | |
c.721C>T | p.Gln241* | Nonsense | Substitution | 6 | Protease | X | X | |
c.723G>A | p.Gln241Gln | Synonymous | Substitution | 6 | Protease | X | X | |
c.727_728delinsA | p.Val243fs | Frameshift | Insertion/deletion | 7 | Protease | X | X | |
c.757G>A | p.Gly253Arg | Missense | Substitution | 7 | Protease | X | X | |
c.789_790InsT | p.Thr264fs | Frameshift | Insertion | 7 | Protease | X | X | |
c.799C>T | p.His267Tyr | Missense | Substitution | 7 | Protease | X | X | |
c.839G>T | p.Gly280Val | Missense | Substitution | 8 | Protease | X | X | |
c.871G>A | p.Glu291Lys | Missense | Substitution | 8 | Protease | X | X | |
c.880C>T | p.Arg294* | Nonsense | Substitution | 8 | Protease | X | X | |
c.881G>T | p.Arg294Leu | Missense | Substitution | 8 | Protease | X | X | |
c.892C>T | p.Arg298* | Nonsense | Substitution | 8 | Protease | X | X | |
c.946A>T | p.Ile316Phe | Missense | Substitution | 8 | Protease | X | X | |
c.990C>A | p.Tyr330* | Nonsense | Substitution | 8 | Protease | X | X | |
c.1004G>T | p.Cys335Tyr | Missense | Substitution | 8 | Protease | X | X | |
c.1009G>C | p.Ala337Pro | Missense | Substitution | 8 | Protease | X | X | |
c.1068G>C | p.Trp356Cys | Missense | Substitution | 8 | Protease | X | X | |
c.1069G>A | p.Gly357Arg | Missense | Substitution | 8 | Protease | X | X | |
c.1070G>A | p.Gly357Glu | Missense | Substitution | 8 | Protease | X | X | |
c.1076T>G | p.Val359Gly | Missense | Substitution | 8 | Protease | X | X | |
c.1097C>A | p.Ala366Asp | Missense | Substitution | 8 | Protease | X | X | |
c.1108C>T | p.Gln370* | Nonsense | Substitution | 8 | Protease | X | X | |
c.1113C>A | p.Tyr371* | Nonsense | Substitution | 8 | Protease | X | X | |
c.1120G>T | p.Val374Glu | Missense | Substitution | 8 | Protease | X | X | |
c.1135C>G | p.Arg379Gly | Missense | Substitution | 8 | Protease | X | X | |
c.1144T>C | p.Cys382Arg | Missense | Substitution | 8 | Protease | X | X | |
c.1147C>T | p.Leu383Phe | Missense | Substitution | 8 | Protease | X | X | |
c.1150C>T | p.Arg384* | Nonsense | Substitution | 8 | Protease | X | X | |
c.1168A>T | p.Ile390Phe | Missense | Substitution | 8 | Protease | X | X | |
c.1169T>G | p.Ile390Ser | Missense | Substitution | 8 | Protease | X | X | |
c.1181T>A | p.Met394Lys | Missense | Substitution | 8 | Protease | X | X | |
c.1204G>A | p.Gly402Arg | Missense | Substitution | 8 | Protease | X | X | |
c.1217C>G | p.Ser406* | Nonsense | Substitution | 8 | Protease | X | X | |
c.1217C>T | p.Ser406Leu | Missense | Substitution | 8 | Protease | X | X | |
c.1219T>C | p.Cys407Arg | Missense | Substitution | 8 | Protease | X | X | |
c.1226G>A | p.Gly409Glu | Missense | Substitution | 8 | Protease | X | X | |
c.1228G>A | p.Asp410Asn | Missense | Substitution | 8 | Protease | X | X | |
c.1228G>C | p.Asp410His | Missense | Substitution | 8 | Protease | X | X | |
c.1232G>A | p.Ser411Asn | Missense | Substitution | 8 | Protease | X | X | |
c.1237G>A | p.Gly413Arg | Missense | Substitution | 8 | Protease | X | X | |
c.1241C>T | p.Pro414Leu | Missense | Substitution | 8 | Protease | X | X | |
c.1245T>A | p.His415Gln | Missense | Substitution | 8 | Protease | X | X | |
c.1256T>A | p.Val419Glu | Missense | Substitution | 8 | Protease | X | X | |
c.1258G>T | p.Glu420* | Nonsense | Substitution | 8 | Protease | X | X | |
c.1291T>C | p.Trp431Arg | Missense | Substitution | 8 | Protease | X | X | |
c.1293G>T | p.Trp431Cys | Missense | Substitution | 8 | Protease | X | X | |
c.1294G>A | p.Gly432Ser | Missense | Substitution | 8 | Protease | X | X | |
c.1295G>A | p.Gly432Asp | Missense | Substitution | 8 | Protease | X | X | |
c.1295G>C | p.Gly432Ala | Missense | Substitution | 8 | Protease | X | X | |
c.1295G>T | p.Gly432Val | Missense | Substitution | 8 | Protease | X | X | |
c.1297G>A | p.Glu433Lys | Missense | Substitution | 8 | Protease | X | X | |
c.1298A>C | p.Glu433Ala | Missense | Substitution | 8 | Protease | X | X | |
c.1307C>T | p.Ala436Val | Missense | Substitution | 8 | Protease | X | X | |
c.1318A>G | p.Lys440Glu | Missense | Substitution | 8 | Protease | X | X | |
c.1324G>A | p.Gly442Arg | Missense | Substitution | 8 | Protease | X | X | |
c.1357T>C | p.Trp453Arg | Missense | Substitution | 8 | Protease | X | X | |
c.1361T>C | p.Ile454Thr | Missense | Substitution | 8 | Protease | X | X | |
c.*1157A>G | 3′UTR | Substitution | 3′UTR | X | X | |||
c.252+3_252+6del | Splice site change | Deletion | Intron 2 | X | X | |||
c.252+6T>C | Splice site change | Substitution | Intron 2 | X | X | |||
c.253-25A>G | Splice site change | Substitution | Intron 2 | X | X | |||
c.277+2T>C | Splice site change | Substitution | Intron 3 | X | X | |||
c.277+5G>A | Splice site change | Substitution | Intron 3 | X | X | |||
c.392-1G>C | Splice site change | Substitution | Intron 4 | X | X | |||
c.392-2A>G | Splice site change | Substitution | Intron 4 | X | X | |||
c.521-3T>G | Splice site change | Substitution | Intron 5 | X | X | |||
c.-55G>A | Promoter | Substitution | 5′UTR | X | X | |||
c.723+1G>A | Splice site change | Substitution | Intron 6 | X | X | |||
c.839-4A>G | Splice site change | Substitution | Intron 7 | X | X | |||
c.88+1_88+4del | Splice site change | Deletion | Intron 1 | X | X | |||
c.88+1G>T | Splice site change | Substitution | Intron 1 | X | X | |||
c.88+5G>C | Splice site change | Substitution | Intron 1 | X | X | |||
c.88+5G>T | Splice site change | Substitution | Intron 1 | X | X | |||
c.19A>T | p.Ile7Phe | Missense | Substitution | 1 | Signal peptide | X | X | |
c.164T>G | p.Phe55Cys | Missense | Substitution | 2 | GLA | X | X | |
c.339T>A | p.Asn113Lys | Missense | Substitution | 4 | EGF1 | X | X | |
c.466T>C | p.Ser156Phe | Missense | Substitution | 5 | EGF2 | X | X | |
c.676C>G | p.Arg226Gly | Missense | Substitution | 6 | Activation | X | X | |
c.685G>A | p.Gly229Ser | Missense | Substitution | 6 | Protease | X | X | |
c.907C>T | p.His303Tyr | Missense | Substitution | 8 | Protease | X | X | |
c.942T>G | p.His314Gln | Missense | Substitution | 8 | Protease | X | X | |
c.1045G>T | p.Gly349* | Nonsense | Substitution | 8 | Protease | X | X | |
c.1072A>G | p.Arg358Gly | Missense | Substitution | 8 | Protease | X | X | |
c.1079T>C | p.Phe360Ser | Missense | Substitution | 8 | Protease | X | X | |
c.1109A>C | p.Gln370Pro | Missense | Substitution | 8 | Protease | X | X | |
c.1174A>G | p.Asn392Asp | Missense | Substitution | 8 | Protease | X | X | |
c.1238G>A | p.Gly413Glu | Missense | Substitution | 8 | Protease | X | X | |
c.252+5G>A | Splice site change | Substitution | Intron 2 | X | X | |||
c.839-1G>A | Splice site change | Substitution | Intron 7 | X | X | |||
c.82T>C | p.Cys28Arg | Missense | Substitution | 1 | Signal peptide | X | X | |
c.151A>G | p.Lys51Glu | Missense | Substitution | 2 | GLA | X | X | |
c.163T>A | p.Phe55Ile | Missense | Substitution | 2 | GLA | X | X | |
c.279T>A | p.Asp93Glu | Missense | Substitution | 4 | EGF1 | X | X | |
c.335T>C | p.Ile112Thr | Missense | Substitution | 4 | EGF1 | X | X | |
c.479G>A | p.Gly160Glu | Missense | Substitution | 5 | EGF2 | X | X | |
c.479G>C | p.Gly160Ala | Missense | Substitution | 5 | EGF2 | X | X | |
c.484C>A | p.Arg162Arg | Synonymous | Substitution | 5 | EGF2 | X | X | |
c.572G>C | p.Arg191Pro | Missense | Substitution | 6 | Linker | X | X | |
c.785T>C | p.Ile262Thr | Missense | Substitution | 7 | Protease | X | X | |
c.786T>G | p.Ile262Met | Missense | Substitution | 7 | Protease | X | X | |
c.839G>C | p.Gly280Ala | Missense | Substitution | 8 | Protease | X | X | |
c.872A>G | p.Glu291Gly | Missense | Substitution | 8 | Protease | X | X | |
c.950C>T | p.Ala317Val | Missense | Substitution | 8 | Protease | X | X | |
c.997C>A | p.Pro333Thr | Missense | Substitution | 8 | Protease | X | X | |
c.1067G>T | p.Trp356Leu | Missense | Substitution | 8 | Protease | X | X | |
c.1097C>T | p.Ala366Val | Missense | Substitution | 8 | Protease | X | X | |
c.1127T>C | p.Leu376Pro | Missense | Substitution | 8 | Protease | X | X | |
c.1180A>G | p.Met394Val | Missense | Substitution | 8 | Protease | X | X | |
c.1187G>T | p.Cys396Phe | Missense | Substitution | 8 | Protease | X | X | |
c.1193G>C | p.Gly398Ala | Missense | Substitution | 8 | Protease | X | X | |
c.1348T>C | p.Tyr450His | Missense | Substitution | 8 | Protease | X | X | |
c.-48G>C | Promoter | Substitution | 5′UTR | X | X | |||
c.-49T>A | Promoter | Substitution | 5′UTR | X | X | |||
c.520+13A>G | Splice site change | Substitution | Intron 5 | X | X | |||
c.88+5G>A | Splice site change | Substitution | Intron 1 | X | X |
List of F9 mutations reported with phenotypic plasticity.
Taking into account the significant amount of phenotypic plasticity in haemophilia, researchers have proposed to recognise the disease phenotype, in terms of coagulation activity, a continuous variable and abandoning of the classical categorical classification [51]. With the evolving concepts of personalised medicine, this may prove realistic… and the future.
The two main methods of revascularization in coronary artery disease are percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG). In modern medicine, coronary artery bypass surgery is mostly reserved for the most severe or complex coronary artery disease. Patients who are status post-CABG can develop further coronary disease and myocardial ischemia in the years following surgery. As in any other patient who is suspected of having coronary artery disease, cardiac catheterization provides the definitive test (angiography) and is often the treatment modality of choice (PCI) in patients with prior CABG. This chapter aims to highlight the most important aspects of cardiac catheterization, coronary angiography, bypass graft angiography, and percutaneous coronary intervention in patients who are status post coronary artery bypass surgery.
The left internal mammary artery (LIMA) graft to the left anterior descending (LAD) coronary artery provides CABG with its primary benefit over PCI in multi-vessel disease. The LIMA is a branch of the left subclavian artery, which itself branches from the aortic arch. The LIMA arises from the inferior-anterior aspect of the subclavian artery and courses caudally down the left chest. This graft is generally used as an in situ graft with its free end anastomosed to a coronary artery (usually the LAD).
Other than the LIMA, other bypass graft options include the right internal mammary artery (RIMA), radial artery, and saphenous veins. Most often grafts to arteries other than the LAD utilize saphenous veins. These are harvested from the legs and an anastomosis is created most often from the ascending aorta to the target coronary artery. Rarely an in situ gastroepiploic artery is anastomosed to the right coronary artery or the inferior epigastric artery is harvested and used as a free graft anastomosed to the aorta.
Free arterial grafts are superior to saphenous vein grafts (SVGs) [1, 2] however their use is limited by several factors. Radial artery grafts must meet stringent requirements before harvesting for use in CABG. Rarely radial arteries cannot be used because they are too small, previously traumatized (i.e. prior transradial catheterizations), or supply all blood flow to the hand. The RIMA can also be used, either in situ or as a free graft, but the use of both the LIMA and the RIMA is associated with an increased risk of sternal wound infections [2]. For these reasons, SVGs remain the most frequently used graft other than the LIMA.
Most commonly grafts have a single origin and single terminal anastomosis. However, several variations are used by surgeons:
“Jump” or sequential grafts: Often a LIMA or SVG will be anastomosed side-to-side to an artery or branch and then the distal graft will be anastomosed end-to-side to a second artery or branch. For the LIMA it is typical to anastomose to a LAD-diagonal branch and terminate at the distal LAD. SVGs are often jumped from a first to a second obtuse marginal or from a right coronary artery (RCA) posterior descending branch to an RCA-posterolateral branch.
“Snake” or long circular grafts: In a technique that has fallen out of favor but still may be found occasionally, a single long saphenous vein graft is anastomosed to the aorta and then anastomosed side-to-side to the LAD and/or branches then to the circumflex branches and finally anastomosed end-to-side to the RCA.
Under unusual circumstances (e.g., a third CABG surgery) a surgeon may anastomose an SVG from the descending aorta to a coronary artery (usually the circumflex).
An in situ RIMA may be anastomosed to the circumflex, right coronary artery, or the right coronary posterior descending branch.
An in situ gastroepiploic artery may be anastomosed to the right coronary artery. This can be easily cannulated using a Judkins right (JR4) catheter to identify the hepato-splenic trunk, advancing the catheter over the wire into the hepatic artery and then the gastro-epiploic artery.
Y grafts: Surgeons may anastomose a free radial artery to a LIMA with the radial graft going to a diagonal branch of the left anterior descending and the LIMA ending at the LAD. Rarely surgeons will anastomose a SVG segment to an SVG in a similar fashion.
Common aortic “hoods” or “buttons”. Occasionally surgeons will anastomose two SVGs to a single spot on the aorta so that both arise from the same point.
Arterial grafts are more durable than venous grafts. When grafted to the LAD, the LIMA graft has a five-year patency rate of 91%, whereas vein grafts had a five-year patency rate of 78% [3, 4]. In patients who underwent CABG between 1995 and 2010, at a 7-year follow-up the patency of the LIMA was 87%, the patency of a radial artery graft to the RCA or LCx was 82%, and the patency of saphenous vein grafts was 58% [5].
Three processes lead to SVG failure, and the mechanism of failure can be predicted by the timing of failure. A useful rule of thumb is that about 10% of grafts occlude in under 1 month due to thrombosis or surgical issues, about 10% occlude between 1 month and 1 year due to intimal proliferation, in about 2–3% more occlude per year due to accelerated atherosclerosis. Within the first month after CABG, thrombosis (i.e. due to hypercoagulability) and technical failure (i.e. damage to or defects of the graft) are the predominant mechanisms. From the first month to the first year after CABG intimal hyperplasia is the predominant mechanism, a process in which smooth muscle cells proliferate and fibroblasts lay down extracellular matrix (also known as “arterialization” of the graft) in response to exposure to arterial pressures. And beyond the first year of CABG atherosclerosis is the predominant mechanism, a process that is accelerated in SVGs as compared to native arteries and in which unstable plaques often form [6].
The 2012 Appropriate Use Criteria for Diagnostic Catheterization provide indications for cardiac catheterization in patients with prior CABG [7]. Common indications include acute coronary syndromes or electrical instability. Emergent coronary angiography may be indicated for postoperative CABG patients who have clear signs of ischemia, unexplained hemodynamic instability, low cardiac output syndrome, electrical instability, diffuse electrocardiogram changes, new ischemic wall motion abnormalities, or very large troponin elevations after CABG. Troponin elevations of >10x the upper limits of normal qualify as type 5 myocardial infarction (MI) in the Fourth Universal Definition of Myocardial Infarction [6, 8, 9].
For stable patients, the indications are more limited. In general, asymptomatic patients should not undergo catheterization unless there is other evidence of extensive ischemia. Specifically, a small or even moderate-sized ischemic abnormality on stress testing would not warrant catheterization in a patient with no symptoms or atypical symptoms. The indication for catheterization strengthens as symptoms increase despite guideline-directed medical therapy or as the evidence for extensive ischemia increases. Consideration of catheterization in patients after CABG must balance the risks of catheterization (which are about twice those of diagnostic coronary arteriography in non-CABG patients) and the risks of subsequent PCI against the benefits of symptom relief or of diagnosing atypical symptoms. To our knowledge, no study has demonstrated improved survival from repeat PCI or CABG in any sub-group of post-CABG patients.
The approach to cardiac catheterization in a patient with prior CABG is the same as the approach to cardiac catheterization in patients without CABG for a right heart catheterization, left heart catheterization, and native coronary angiography. Graft arterography includes finding and selectively engaging each graft, usually one LIMA graft and one or more grafts arising from the ascending aorta.
It is critically important for the operator to know the details of the CABG surgery before starting catheterization, in order to plan access. For example, the best access for a patient with LIMA and RIMA grafts, or with the left radial used for CABG, may be femoral access. It is critically important for the operator to review the operative report because this is the only reliable roadmap to finding grafts. Downstream descriptions of the surgery become progressively unreliable. Specifically, the discharge summary is usually written by an advanced practice provider who may misinterpret the operative report, and subsequent summaries by cardiologists or primary care providers are routinely misleading. For example, a LIMA to the LAD with radial Y-graft to the diagonal and an SVG jumping from the second obtuse marginal to the RCA postero-lateral branch will be recorded in subsequent clinic notes as a 4-vessel CABG. But without details, the operator will not know how many anastomoses from the aorta to look for, or whether a graft will be arising from the right side of the aorta as is typical of grafts to the RCA. When the allowable contrast dose is limited by kidney disease it is particularly important to know details of coronary anatomy to prevent excessive test injections while searching for grafts.
When details of the surgery are unavailable, patients are usually reliable sources of the number of distal anastomoses. Usually, when patients are told the results of their surgery by the surgical team, they are told the number of distal anastomoses, which may exceed the number of proximal anastomoses. The wise operator will make sure all distal anastomoses are accounted for before ending a procedure.
Radial access decreases vascular complications compared to femoral access in patients without prior CABG. The same is true for patients after CABG, but left radial artery access is preferred since it offers easy access to the origin of the LIMA. In patients with the left radial artery harvested for use as a bypass graft, femoral access is usually used although experienced operators can non-selectively (and occasionally selectively) cannulate the LIMA using right radial access. With left radial access, the left arm can be pulled across the abdomen so the operator does not have to reach across the table. The use of the distal radial access site (“snuffbox approach”) can bring the access point even closer to the operator standing on the right side of the table. The RADIAL-CABG randomized trial compared femoral access to left radial access at a single center and demonstrated higher radiation doses, contrast volumes, and longer procedure times with left radial access as compared to femoral access; though radial access was associated with higher patient satisfaction. The crossover rate was higher (17%) in the transradial group compared to the transfemoral group [0%] [10]. A meta-analysis found fewer vascular complications with radial access [11].
Graft markers are used or not used variably by cardiac surgeons. Common varieties include a small disk usually placed above the aortic anastomosis, a horseshoe or wire ring around the proximal part of the graft, or occasionally just a clip by the aortic anastomosis. Often SVGs or in situ LIMA grafts will have clips where side branch veins were cut; these can lead like breadcrumbs along the course of the graft and give a hint as to the location of its terminus.
A typical patient will have a LIMA graft arising from the left subclavian anastomosing distally to the LAD and two or three free grafts, usually SVGs, with anastomoses from the aorta to the target vessel in the LCX system, RCA system, or a diagonal branch of the LAD. Our general approach is described in Table 1.
Graft | LIMA to LAD | SVG/radial to RCA | SVG/radial to LCX | SVG/radial to Diagonal | RIMA to LCX | In-situ GEA |
---|---|---|---|---|---|---|
Catheters | 1: JR4 2: IMA 3: VB1 | 1: Multi A 2: AL1/2 3: BG right | 1: JR4 2: AL2 3: Multi 4: BG left | 1: JR4 2: AL2 3: Multi 4: BG left | 1: JR4 2: IMA 3: VB1 | JR4 engages through the hepato-splenic artery |
View | AP cranial RAO Left lateral | LAO RAO RAO cranial LAO cranial | LAO RAO AP caudal | LAO cranial LAO RAO | LAO RAO | (Depends on anastomosed artery) |
An approach to bypass graft angiography.
The LIMA is engaged by finding its ostium in the subclavian artery. It may arise on the more proximal vertical section or on the more distal horizontal section of the subclavian. We use the anterior–posterior view although occasionally the right anterior oblique view will better separate the proximal LIMA from the subclavian. From left radial access, the JR4 catheter is advanced over a wire retrograde in the left subclavian to the LIMA ostium. From femoral access, the JR is advanced retrograde through the transverse aorta. Counter-clockwise rotation allows the operator to place the catheter sequentially in the right innominate, then the left carotid, and finally into the left subclavian. The JR4 catheter can be advanced over a wire distally into the subclavian. From either access point, the JR4 can be gently maneuvered proximally in the subclavian with gentle counter-clockwise rotation and test injections. If the origin of the LIMA is acute the JR4 can be exchanged over a wire for an IMA catheter and maneuvered similarly. For a severely angulated LIMA origin, a VB-1 or similar catheter with a pigtail-like curve can be positioned beyond the ostium and pulled back to engage the LIMA ostium (Table 2).
Name | Type | Study |
---|---|---|
GuardWire | Distal balloon | SAFER demonstrated improved rates of periprocedural MI and no-reflow as compared to usual therapy |
TriActiv | Distal balloon | PRIDE demonstrated noninferiority to the GuardWire and FilterWire |
FilterWire* | Distal filter | FIRE demonstrated noninferiorty to the GuardWire |
SpideRx* | Distal filter | SPIDER demonstrated noninferiority to the GuardWire and FilterWire |
CardioShield | Distal filter | CAPTIVE failed to demonstrate noninferiority to the GuardWire |
Proxis | Proximal balloon | PROXIMAL demonstrated noninferiority to the GuardWire and FilterWire |
Free grafts to the other coronary arteries (i.e. SVGs or radial grafts) are found in the proximal ascending aorta. The grafts are found by selecting a catheter and searching the aorta above the level of the coronary arteries. Right coronary artery grafts will be located on the right side of the aorta whereas left circumflex and diagonal grafts will be located on the left or posterior aspects of the aorta. Generally, grafts are arranged in the following ascending position in the aorta: RCA grafts lowest in the aorta, followed by LAD grafts (if there is SVG to LAD) located a little higher, followed by diagonal branch, then left circumflex first obtuse marginal, second obtuse marginal, and circumflex posterolateral grafts highest in the aorta. We favor multi-purpose shapes (or right bypass graft shape) for grafts to the RCA (which usually have a downward takeoff). Grafts to diagonal branches or circumflex branches may be cannulated with the JR or multi-shaped catheter, but if necessary Amplatz-shaped catheters or left bypass graft catheters can be used. For all of these, we use a clockwise rotation of the catheter with frequent test injections to engage grafts.
On occasion, it can be hard to find all of the grafts. When searching for grafts, start with a specific catheter for the suspected graft as described above. A proximally occluded graft may be demonstrated by test injections showing a short stump in a side view or a circle in an end-on view. Occasionally grafts are flush occluded at the aorta and cannot be identified. For RCA grafts it is important to point the catheter downward in the graft using a slight counter-clockwise torque since injection in the proximal graft orthogonal to its direction can mimic a total occlusion. Consider that a graft may arise from an unusual location on the ascending aorta or even from the descending aorta [13], or that a RIMA or gastroepiploic artery may have been used. When all else fails, non-selective aortography can be performed although it does not reliably demonstrate all patent grafts. The last option for finding a graft would be a CT or MRI angiogram.
It may be helpful to identify native vessels that appear to have been grafted. Occasionally the stump of the graft where it is terminally anastomosed to the vessel may be seen. In other cases where the graft has flush-occluded, a characteristic upward omega-bend of the native vessel caused by scarring/retraction of the graft after surgery may reveal where the graft was anastomosed to the native vessel. Occasionally a segment of a jump graft between two native branches will remain patent even after the graft from the aorta to the first anastomosis has occluded.
PCI in patients who are post-CABG is common. Data published from the NCDR CathPCI registry in 2011 show that PCI in prior CABG patients represents 17.5% of all PCIs. Native arteries were targeted alone in 62.5% of PCI in prior CABG patients, saphenous vein grafts were the target in 34.9%, and arterial grafts were the target in 2.5% [14]. A similar observational analysis from VA medical centers in 2016 showed overall similar data (73.4% of PCI was in a native artery, 25.0% in an SVG, and 1.5% in an arterial graft). The VA analysis demonstrated that procedure-related complications were more frequent in bypass PCI patients compared to those without, including in-hospital mortality, procedural complications, peri-procedural MI, no-reflow, and dissection. The patients who received PCI to graft lesions were also noted to have higher mortality, MI, and revascularization at 1 and 5 years of follow-up [15].
Indications for PCI in post-CABG patients are similar to those without prior CABG. Graft lesions causing acute coronary syndromes may undergo PCI or may be used as conduits for retrograde PCI of the native vessel to which they anastomose. In stable patients, PCI is generally not indicated for asymptomatic patients. The strength of indication for PCI increases as the severity of symptoms despite guideline medical therapy increases.
There are several issues with intervention on SVGs, and as such, the operator must carefully consider their options before embarking on SVG intervention. SVG intervention carries a high risk of distal embolization, no-reflow, and peri-procedural MI. Degenerated vein grafts are noted in both the ACC/AHA and SCAI classification schemes to be high-risk lesions and to have worse outcomes as compared to low-to-intermediate risk native vessel lesions [16]. Several principles affect decisions regarding SVG intervention.
A first principle of vein graft intervention is that PCI in vein grafts is less reliable than PCI of native coronary arteries. Observational data suggest that PCI to SVGs is associated with worse outcomes than PCI to native coronary arteries [15, 17, 18]. For this reason, when reasonable, restoration of blood flow by performing PCI to the native vessel is preferred to PCI of the SVG. Preferencing PCI to the native artery where possible is given a Class 2a recommendation in the updated 2021 ACC/AHA Coronary Artery Revascularization guidelines [19]. It should be noted that this strategy is complicated by the high rate of CTOs in bypassed native arteries, and referral to a physician with experience in complex coronary disease and CTO may be necessary [20, 21]. A strategy of PCI to the SVG followed by staged PCI to the native artery, especially in the setting of acute MI, may be useful [22]. Intentional iatrogenic occlusion of the SVG after native vessel PCI may be beneficial to reduce competitive flow [23, 24].
A second principle is that intermediate lesions should in general be treated medically. Two trials, VELETI and VELETI II studied the utility of stenting intermediate SVG lesions. While there was a trend in the VELETI pilot study towards improved outcomes with stenting, the larger VELETI II study showed no benefit [25, 26, 27]. Additionally, the use of FFR has been studied in intermediate lesions. While there may be benefit to the use of FFR in arterial grafts, no benefit was seen in SVG lesions and should probably not be used in this setting [28].
A third principle is that PCI to CTOs of SVGs is not of benefit and should not be performed. Chronic total occlusions of SVGs were studied in a retrospective study published in 2010 that found success rate of PCI of SVG CTO was 68%. In the successful PCI group, the ISR rate was 68% and TVR rate was 61% with a median follow-up of 18 months [29]. Due to the low success rates and high rate of revascularization, current guidelines give PCI of SVG CTOs a Class 3: No Benefit designation [19].
Bare-metal stenting was clearly an improvement over balloon angioplasty for SVG lesions. The Saphenous Vein in De Novo (SAVED) trial compared bare-metal stents to balloon angioplasty for focal, de-novo SVGs lesions. Stenting increased the procedural success, demonstrating 92% success with BMS versus 69% for angioplasty [30]. This benefit of BMS as compared to balloon angioplasty alone was reinforced with data from the Venestent trial [31].
Several studies have examined the use of bare-metal versus drug-eluting stents in SVG PCI. The RRISC trial initially demonstrated improved outcomes of DES as compared to BMS [32], however the DELAYED RRISC study (a post hoc analysis of the RRISC trial) appeared to support increased mortality of patients treated with DES as compared to BMS [33]. Subsequent randomized controlled trials and meta-analyses have however demonstrated the safety of DES in SVGs [34, 35]. In addition to some smaller trials, two larger RCTs compared DES to BMS: ISAR-CABG and DIVA. While ISAR-CABG did demonstrate lower target lesion revascularization with DES as compared to BMS at 12 months [36], by follow-up at 5 years no difference between DES and BMS was observed [34]. The DIVA trial showed no difference at 12 months between DES and BMS [37]. A meta-analysis of the available RCTs done in 2018 showed no difference between DES and BMS [35]. Of note, in the ISAR-CABG trial, most stents were first-generation, while in the DIVA trial most stents were second-generation indicating that neither first nor second-generation DES stents are an improvement over BMS [35]. Two retrospective studies have found no difference between first- and second-generation DES [38, 39].
Directly stenting SVG lesions (as opposed to performing pre-dilation) might prevent distal embolization. One observational study done in 2003 indicated that direct stenting decreased post-procedural MB-CK elevation, and the one-year composite endpoint of death, Q-wave MI, and target lesion revascularization [40].
Under-sizing stents may improve outcomes in SVG PCI. Hong et al. in 2010 examined a series of patients who underwent SVG PCI with IVUS. They compared patients based on the ratio of stent diameter to vessel diameter and found that patients with relatively under-sized stents had fewer post-procedural CK-MB elevations without worse outcomes at 1 year [41].
SAFER was a trial in which a distal balloon device called the GuardWire demonstrated a significant decrease in peri-procedural MI and a decrease in no-reflow [42]. The GuardWire is a distal balloon embolic protection device wherein the balloon is inflated distal to the PCI target. The operator then stents the lesion and aspirates the blood containing post-PCI embolic debris out of the vessel before deflating the balloon [42]. The FIRE trial compared a device called the FilterWire, a distal filter-based device, against the GuardWire and showed non-inferiority [43]. Numerous other trials have been investigated (see table below), but all of these trials were in some way compared their device to the GuardWire to show non-inferiority as opposed to a comparison against usual therapy. The TRAP trial would have been a second RCT but was ended due to lack of enrollment and was therefore under-powered; the trend however was of findings consistent with SAFER (decreased peri-procedural MI) [44].
There have been multiple analyses since these trials in the early 2000s looking at EPDs. Iqbal et al. examined the British Columbia Cardiac Registry and showed that patients undergoing SVG PCI had improved post-procedural TIMI flow after EPD use, however had no difference in TVR or mortality at 2 years [45]. Brennan et al. examined the Cath PCI database and showed no difference in rates of death, MI, or TVR with the use of EPDs but did show increased rates of no-reflow, vessel dissection, perforation, and periprocedural MI with the use of EPDs [4]. Paul et al. performed a meta-analysis and review in 2017, which suggested no benefit to EPD use in SVG intervention [46].
The 2011 ACC/AHA guidelines on PCI gave the use of embolic protection devices (EPDs) a Class I recommendation based upon strong randomized control trial evidence from the SAFER trial. However, with the subsequent data described above, current guidelines downgrade the recommendation for use of EPDs from Class I (in 2011) to Class IIa (in 2021) [19, 47]. Despite the data supporting EDP use, estimates of usage rates in SVG lesions based on large registry data range from 14–22% [48, 49]. EPD use may be discouraged by the technical difficulty of using these somewhat bulky devices [49].
In summary, the only randomized trial data available shows the benefit to use of EPD. Multiple other EPDs have shown non-inferiority to the GuardWire. EPDs can be difficult to use which significantly limits their use in clinical practice. And while significant observational data have called into question the findings of the SAFER trial, guideline recommendations are unlikely to change significantly until further RCTs are performed.
In general, antiplatelet drugs are used in the same way post SVG PCI as they would be used post native vessel PCI. The PLATO trial demonstrated the efficacy of ticagrelor over clopidogrel in ACS patients. A post hoc analysis of PLATO showed that ticagrelor was as effective for post-CABG patients as it was for no-CABG patients [50]. In addition, SVG lesions are high-risk lesions and may benefit from more intensive antiplatelet therapy than some native vessel lesions. The DAPT trial showed that in patients who had SVG PCI, there was less stent thrombosis with 30 months of DAPT as compared to 12 months of DAPT [51]. An analysis of the DAPT study developed and validated a prediction rule intended to determine patients who would benefit most from prolonged DAPT. In the generated scoring system, the presence of a vein graft stent was one of the strongest predictors of deriving benefit from prolonged DAPT [24].
The use of GP IIb/IIIa inhibitors does not appear to be of benefit. A meta-analysis of five randomized trials published in 2002 showed that the use of GP IIb/IIIa inhibitors in graft interventions provided no benefit and had an association with worse outcomes [52].
The use of anticoagulants is similar in SVG PCI as in native-vessel PCI. Heparin is the dominant drug used, however, bivalirudin has been shown to be safe and effective [53].
Vasodilator drugs may decrease the rate of no-reflow in SVG PCI. Adenosine, nitroprusside, and the calcium channel blockers verapamil and nicardipine have been investigated. Overall, the quality of the evidence is low however all the studies show some degree of improvement in no-reflow, post-procedural CK-MB elevation, or both in association with the use of vasodilators [54, 55, 56, 57]. Nicardipine is often preferred as it causes less hypotension and a longer duration of action [58].
The CORAL trial examined the use of excimer laser coronary atherectomy before stenting. The study failed to enroll enough patients and so they compared laser atherectomy with a stent to the SAFER data (control and EPD groups). The rate of MACE, driven by peri-procedural MI, was lower in the SAFER GuardWire group [59]. One case–control registry indicated that ELCA showed better angiographic outcomes and lower rates of Type IVa MI as compared to distal embolic protection devices [60].
The VeGAS 2 trial compared the AngioJet rheolytic thrombectomy device to urokinase infusion for SVG thrombus. The AngioJet creates a local vacuum using high-velocity water jets, with the intention of sucking thrombus into the catheter for degradation and removal. AngioJet did show some improvements over urokinase infusion, especially in the rates of procedural success, non-Q-wave MI, and vascular complications [61].
Arterial grafts are significantly more durable and significantly fewer in number than venous grafts, and they are therefore significantly less likely to be the targets of PCI. PCI in arterial grafts is generally more successful and with lower complication rates than in PCI of vein grafts [14, 15].
The IMA is the most important arterial graft, and there are a few relevant points regarding PCI in these arteries. The risk of complication is not negligible. The most common cause of unsuccessful PCI in an IMA graft is excessive vessel tortuosity. Straightening a tortuous LIMA can cause pseudolesions which may cause ischemia; this effect must be distinguished from vasospasm (as it will not improve with vasodilators) and dissection. Removal of the guidewire should resolve a pseudolesion [58]. Tortuous subclavian arteries may be an issue as well – ipsilateral (usually meaning left) radial access can help in this case. On occasion, coronary ischemia in the distribution of the IMA can be caused by a stenosis of the subclavian artery proximal to the IMA graft, and PCI of the subclavian artery (by an experienced peripheral operator) can relieve the ischemia [62].
Ostial dissections can occur in IMA PCI and therefore the ostium should be evaluated at the end of an IMA PCI procedure. PCI of distal anastomotic IMA lesions has been shown to have better outcomes (less restenosis) with balloon angioplasty as compared to stenting; stents are typically used in lesions of the ostium and the body of IMA grafts [63, 64].
Indications for catheterization and PCI in post-CABG patients are similar to those for patients without CABG. Graft anatomy (taken from the source CABG operative report) should be known before starting a diagnostic procedure. Diagnostic procedures involving grafts are more difficult, require more time, contrast, and catheters, and produce more complications than procedures in patients without prior CABG. A set of unique “tricks” is required to selectively cannulate all grafts known to be present. PCI of grafts, particularly of SVGs, produces frequent complications and is often followed by restenosis. PCI of the native vessel supplying the grafted territory, either antegrade or retrograde, which may be preferred over graft arteriography. As the incidence of CABG is decreasing over recent decades, the number of post-CABG patients undergoing catheterization is decreasing. However, the ability to perform angiography of post-CABG patients will continue as a required skill of invasive interventional cardiologists.
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",metaTitle:"IntechOpen events",metaDescription:"In our mission to support the dissemination of knowledge, we travel worldwide to present our publications, authors and editors at international symposia, conferences, and workshops, as well as attend business meetings with science, academia and publishing professionals. We are always happy to host our scientists in our office to discuss further collaborations. Take a look at where we’ve been, who we’ve met and where we’re going.",metaKeywords:null,canonicalURL:"/page/events",contentRaw:'[{"type":"htmlEditorComponent","content":"May 18, 2022 | 1:00 PM - 2:00 PM CEST
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This book chapter is prepared to evaluate the effects of occupational risks on health and decrease the exposure to occupational risks of health professionals by searching national and international literatüre. Thus, awareness can be raised to define occupational risks and help planning services for health professionals. American National Institute for Occupational Safety and Health (NIOSH) has reported 29 kinds of physical, 25 kinds of chemical, biological 24 varieties, 10 and six kinds of ergonomic and psycho‐social hazards and risks. According to ILO, it has been reported that there is 1.25 trillion dollars loss each year due to the OHS problems. In Turkey, the loss of only social security systems has been reported as approximately 4 million Turkish Liras per year. Health professionals have work stress, and they suffer from the inconvenient design and the hazards within the workplace. The health of the health professionals affects the health of the community. Thus, it is important to decrease the exposure to occupational risks of health professionals and diligently work on this issue.",book:{id:"5528",slug:"occupational-health",title:"Occupational Health",fullTitle:"Occupational Health"},signatures:"Nilgun Ulutasdemir and Ferdi Tanir",authors:[{id:"191796",title:"Associate Prof.",name:"Nilgun",middleName:null,surname:"Ulutasdemir",slug:"nilgun-ulutasdemir",fullName:"Nilgun Ulutasdemir"},{id:"195566",title:"Prof.",name:"Ferdi",middleName:null,surname:"Tanır",slug:"ferdi-tanir",fullName:"Ferdi Tanır"}]},{id:"52610",doi:"10.5772/65687",title:"Working in Cold Environment: Clothing and Thermophysiological Comfort",slug:"working-in-cold-environment-clothing-and-thermophysiological-comfort",totalDownloads:1783,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"The chapter presents an in-depth discussion over the occupational activities in a cold environment, which can be performed both outdoors and indoors. It explores the differences between working in natural and artificial cold environment. The thermophysiological comfort, the reactions of the thermoregulatory system during cold exposure, and cold-related injuries are presented and discussed in detail. Clothing as the only insulating barrier between the body and the cold environment is discussed, and hi-tech solutions for development of cold protective clothing are presented. The particular application of standards for the indoor environment is presented, and their input for the proper management of the occupational activities in the cold is analyzed.",book:{id:"5528",slug:"occupational-health",title:"Occupational Health",fullTitle:"Occupational Health"},signatures:"Radostina A. Angelova",authors:[{id:"175795",title:"Associate Prof.",name:"Radostina",middleName:"A.",surname:"Angelova",slug:"radostina-angelova",fullName:"Radostina Angelova"}]},{id:"53519",doi:"10.5772/66479",title:"Understanding the Stakeholders as a Success Factor for Effective Occupational Health Care",slug:"understanding-the-stakeholders-as-a-success-factor-for-effective-occupational-health-care",totalDownloads:2550,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Effective occupational health care at the workplace requires collaboration, partnerships and alliances with internal, interface and external stakeholders. Essential steps for solid work with various stakeholders are identification of key stakeholders, systematic analysis of their views and positions, and development of stakeholder participation and involvement. Stakeholder analysis aims to evaluate and understand stakeholders from the perspective of an organization. Stakeholder analysis starts with identifying and classifying the key stakeholders. After their identification, questions are asked about their position, interest, influence, inter-relations, networks and other characteristics of stakeholders, with reference to their past and present positions, and future potential. The results are presented as stakeholder maps as well as by the power-interest matrix of the stakeholders. Stakeholder analysis serves an organization and its various actors as a guideline in identifying, planning and implementing strategies for managing stakeholder relationships and utilizing the full potential of various stakeholders in developing occupational health care.",book:{id:"5528",slug:"occupational-health",title:"Occupational Health",fullTitle:"Occupational Health"},signatures:"Ari-Matti Auvinen",authors:[{id:"193252",title:"M.A.",name:"Ari-Matti",middleName:null,surname:"Auvinen",slug:"ari-matti-auvinen",fullName:"Ari-Matti Auvinen"}]},{id:"52842",doi:"10.5772/66120",title:"Gene-Environment Interactions: The Case of Asbestosis",slug:"gene-environment-interactions-the-case-of-asbestosis",totalDownloads:1386,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"It is becoming evident that both environmental/lifestyle and genetic factors may influence the development of many diseases. This chapter highlights the importance of considering gene-environment interactions, which is shown on the example of our studies into asbestosis, one of the most frequent asbestos-related diseases. Asbestos fibres induce generation of reactive oxygen and nitric species (ROS and RNS), and it is generally accepted that ROS and RNS are involved in the pathogenesis of asbestos-related diseases. Human tissues contain specific enzymes that metabolise ROS and RNS, such as superoxide dismutases (SODs), catalase (CAT), glutathione-S-transferases (GSTs) and inducible nitric oxide synthase (iNOS). As these enzymes are encoded by polymorphic genes, genetic variability in an individual’s capacity to detoxify these reactive species may modify the risk for disease. Our previous studies into asbestosis showed that the associations between the risk of asbestosis and MnSOD Ala-9Val polymorphism and between asbestosis and iNOS genotypes were modified by CAT −262C>T polymorphism. A strong interaction was also found between smoking (lifestyle factor) and GSTM1-null polymorphism, between smoking and iNOS (CCTTT)n polymorphism and between cumulative asbestos exposure (environmental factor) and iNOS (CCTTT)n polymorphism. The findings of our studies and other studies indicate that in addition to environmental and/or occupational exposure to different hazards and lifestyle factors, genetic factors as well as the interactions between different genotypes, between genotypes and lifestyle factors and between genotypes and environmental/occupational exposure to hazards may also have an important role on the development of diseases and should be further investigated.",book:{id:"5528",slug:"occupational-health",title:"Occupational Health",fullTitle:"Occupational Health"},signatures:"Vita Dolzan, Metoda Dodic-Fikfak and Alenka Franko",authors:[{id:"60449",title:"Prof.",name:"Vita",middleName:null,surname:"Dolžan",slug:"vita-dolzan",fullName:"Vita Dolžan"},{id:"195632",title:"Prof.",name:"Alenka",middleName:null,surname:"Franko",slug:"alenka-franko",fullName:"Alenka Franko"},{id:"195633",title:"Prof.",name:"Metoda",middleName:null,surname:"Dodic-Fikfak",slug:"metoda-dodic-fikfak",fullName:"Metoda Dodic-Fikfak"}]},{id:"53365",doi:"10.5772/66480",title:"Ibuprofen as a Treatment for Work-Related Musculoskeletal Disorders: Effectiveness versus Caveats",slug:"ibuprofen-as-a-treatment-for-work-related-musculoskeletal-disorders-effectiveness-versus-caveats",totalDownloads:1682,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Work-related upper limb disorders (WMSDs), also known as repetitive strain injuries, affect a large subsection of the US population. These disorders are a significant source of injury, morbidity, loss of work, and pain. We have developed a rat model of upper extremity repetitive work at high forces, and observed exposure-dependent increased inflammatory responses in all tissues involved in performing the task. A 2- to 8-week regimen of oral ibuprofen provided to rats while they continued to perform a high-repetition high-force task ameliorated these inflammatory responses as well as several motor declines. Ibuprofen treatment also attenuated task-induced tissue fibrosis, cartilage degeneration, and bone osteopenia, indicating their link to inflammatory processes. However, ibuprofen did not significantly attenuate persistent nocifensive pain behaviors (reflexive grip strength results are presented) likely because of persistent increases in inflammatory cytokines in the spinal cord, suggestive of central sensitization. Since long-term ibuprofen use can induce a number of negative side effects, such as gastritis, multi-pronged approaches should be considered with anti-inflammatory drugs included for only short time periods.",book:{id:"5528",slug:"occupational-health",title:"Occupational Health",fullTitle:"Occupational Health"},signatures:"Mary F. Barbe and Ann E. Barr-Gillespsie",authors:[{id:"197229",title:"Dr.",name:"Mary F",middleName:null,surname:"Barbe",slug:"mary-f-barbe",fullName:"Mary F Barbe"},{id:"197459",title:"Dr.",name:"Ann",middleName:"E",surname:"Barr-Gillespie",slug:"ann-barr-gillespie",fullName:"Ann Barr-Gillespie"}]}],mostDownloadedChaptersLast30Days:[{id:"53716",title:"Occupational Risks of Health Professionals",slug:"occupational-risks-of-health-professionals",totalDownloads:2580,totalCrossrefCites:4,totalDimensionsCites:7,abstract:"Health service is an important work area which can lead to important risks related to occupational health and safety (OHS) of employees. This book chapter is prepared to evaluate the effects of occupational risks on health and decrease the exposure to occupational risks of health professionals by searching national and international literatüre. Thus, awareness can be raised to define occupational risks and help planning services for health professionals. American National Institute for Occupational Safety and Health (NIOSH) has reported 29 kinds of physical, 25 kinds of chemical, biological 24 varieties, 10 and six kinds of ergonomic and psycho‐social hazards and risks. According to ILO, it has been reported that there is 1.25 trillion dollars loss each year due to the OHS problems. In Turkey, the loss of only social security systems has been reported as approximately 4 million Turkish Liras per year. Health professionals have work stress, and they suffer from the inconvenient design and the hazards within the workplace. The health of the health professionals affects the health of the community. Thus, it is important to decrease the exposure to occupational risks of health professionals and diligently work on this issue.",book:{id:"5528",slug:"occupational-health",title:"Occupational Health",fullTitle:"Occupational Health"},signatures:"Nilgun Ulutasdemir and Ferdi Tanir",authors:[{id:"191796",title:"Associate Prof.",name:"Nilgun",middleName:null,surname:"Ulutasdemir",slug:"nilgun-ulutasdemir",fullName:"Nilgun Ulutasdemir"},{id:"195566",title:"Prof.",name:"Ferdi",middleName:null,surname:"Tanır",slug:"ferdi-tanir",fullName:"Ferdi Tanır"}]},{id:"53383",title:"New Paradigms in Ergonomics: The Positive Ergonomics",slug:"new-paradigms-in-ergonomics-the-positive-ergonomics",totalDownloads:2170,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"This chapter aims look at ergonomics from a positive point of view. According to International Ergonomics Association, ergonomics is “the scientific discipline concerned with the understanding of interactions among humans and other elements of a system, and the profession that applies theory, principles, data and methods to design in order to optimize human well-being and overall system performance”. The major types of ergonomics. Some of them are physical, cognitive, and positive ergonomics. Positive ergonomics: Positive ergonomics refers to a new type of ergonomics that stresses the positive aspects of the man-machine system. Its major interest is to make “human-machine system” enjoyable where the human feels pleasant. Emotional ergonomics: Similar to positive ergonomics, emotional ergonomics refers to a type of ergonomics that pays attention to the emotional aspects of the man-machine system. Spiritual ergonomics: Spiritual ergonomics is based on the idea that spirit is a key factor which determines the employee’s health and success in the man machine system, no matter what he/she is doing in that system. New approach to Occupational health: When considering the legacy of occupational health, we find that two approaches were adopted throughout of its history. These are: professional harmonization and ergonomics approaches.",book:{id:"5528",slug:"occupational-health",title:"Occupational Health",fullTitle:"Occupational Health"},signatures:"Mohamed Mokdad and Tawfik Abdel-Moniem",authors:[{id:"104865",title:"Prof.",name:"Mohamed",middleName:null,surname:"Mokdad",slug:"mohamed-mokdad",fullName:"Mohamed Mokdad"},{id:"194579",title:"Prof.",name:"Tawfik",middleName:null,surname:"Abdel Moniem",slug:"tawfik-abdel-moniem",fullName:"Tawfik Abdel Moniem"}]},{id:"53519",title:"Understanding the Stakeholders as a Success Factor for Effective Occupational Health Care",slug:"understanding-the-stakeholders-as-a-success-factor-for-effective-occupational-health-care",totalDownloads:2550,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Effective occupational health care at the workplace requires collaboration, partnerships and alliances with internal, interface and external stakeholders. Essential steps for solid work with various stakeholders are identification of key stakeholders, systematic analysis of their views and positions, and development of stakeholder participation and involvement. Stakeholder analysis aims to evaluate and understand stakeholders from the perspective of an organization. Stakeholder analysis starts with identifying and classifying the key stakeholders. After their identification, questions are asked about their position, interest, influence, inter-relations, networks and other characteristics of stakeholders, with reference to their past and present positions, and future potential. The results are presented as stakeholder maps as well as by the power-interest matrix of the stakeholders. Stakeholder analysis serves an organization and its various actors as a guideline in identifying, planning and implementing strategies for managing stakeholder relationships and utilizing the full potential of various stakeholders in developing occupational health care.",book:{id:"5528",slug:"occupational-health",title:"Occupational Health",fullTitle:"Occupational Health"},signatures:"Ari-Matti Auvinen",authors:[{id:"193252",title:"M.A.",name:"Ari-Matti",middleName:null,surname:"Auvinen",slug:"ari-matti-auvinen",fullName:"Ari-Matti Auvinen"}]},{id:"52643",title:"Health‐Promoting Leadership Culture and its Role in Workplace Health Promotion",slug:"health-promoting-leadership-culture-and-its-role-in-workplace-health-promotion",totalDownloads:1804,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Purpose: The law on health and safety at work was implemented in Slovenia in 2011. On this basis, Slovenian organizations started preparation and implementation of workplace health promotion (WHP) programs. The article reports on research of the Slovenian leaders’ leadership style concerning their employees’ health following the new legislation.",book:{id:"5528",slug:"occupational-health",title:"Occupational Health",fullTitle:"Occupational Health"},signatures:"Simona Šarotar Žižek, Matjaž Mulej and Vesna Čančer",authors:[{id:"192730",title:"Associate Prof.",name:"Simona",middleName:null,surname:"Šarotar Žižek",slug:"simona-sarotar-zizek",fullName:"Simona Šarotar Žižek"}]},{id:"53481",title:"HSE Management for a Sound Work Environment: Strategies for Improving Health Safety and Environmental Indicators through Ergonomic Design Thinking",slug:"hse-management-for-a-sound-work-environment-strategies-for-improving-health-safety-and-environmental",totalDownloads:1670,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Ergonomic Design Thinking (EDT) is a project management methodology that takes advantage of two important concepts or themes in carrying out project actions. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. 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She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. 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