Complication rates for Total Hip Arthroplasty
\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
\n'}],latestNews:[{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"},{slug:"intechopen-identified-as-one-of-the-most-significant-contributor-to-oa-book-growth-in-doab-20210809",title:"IntechOpen Identified as One of the Most Significant Contributors to OA Book Growth in DOAB"}]},book:{item:{type:"book",id:"6136",leadTitle:null,fullTitle:"Advances in Research on Down Syndrome",title:"Advances in Research on Down Syndrome",subtitle:null,reviewType:"peer-reviewed",abstract:"This book provides a concise yet comprehensive source of current information on Down syndrome. It focuses on exciting areas of research on chromosome editing, neurogenomics and diseases associated with Down syndrome. Research workers, scientists, medical graduates and physicians will find this book as an excellent source for consultation and references. Key features of this book are chromosome engineering in Down syndrome, mental retardation and cognitive disability, prenatal diagnosis and diseases associated with Down syndrome. Although aimed primarily for research workers on Down syndrome, we hope that the appeal of this book will extend beyond the narrow confines of academic interest and be exciting to wider audience, especially parents, relatives and health care providers who work with infants and children with Down syndrome.",isbn:"978-953-51-3763-4",printIsbn:"978-953-51-3762-7",pdfIsbn:"978-953-51-4041-2",doi:"10.5772/intechopen.68260",price:119,priceEur:129,priceUsd:155,slug:"advances-in-research-on-down-syndrome",numberOfPages:148,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"cb344b182e5c95b23d749f5ad1f2dcf3",bookSignature:"Subrata Dey",publishedDate:"January 31st 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6136.jpg",numberOfDownloads:10317,numberOfWosCitations:5,numberOfCrossrefCitations:5,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:12,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:22,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 16th 2017",dateEndSecondStepPublish:"June 6th 2017",dateEndThirdStepPublish:"September 2nd 2017",dateEndFourthStepPublish:"December 1st 2017",dateEndFifthStepPublish:"January 30th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"31178",title:"Prof.",name:"Subrata",middleName:"Kumar",surname:"Dey",slug:"subrata-dey",fullName:"Subrata Dey",profilePictureURL:"https://mts.intechopen.com/storage/users/31178/images/system/31178.jpeg",biography:"Prof. Subrata Kumar Dey, Ph.D, Vice Chancellor, Swami Vivekananda University, West Bengal, India has been associated with teaching and research for more than four decades and had visited different countries as invited speaker for delivering lectures. He joined as Professor of Biotechnology in Maulana Abul Kalam Azad University of Technology and was ex- Director of School of Biotechnology and Biological Sciences . His laboratory had long been involved in research on molecular genetics of Down syndrome, congenital heart disease and Alzheimer’s disease. He published more than hundred research papers, edited several books on Down syndrome and had completed eleven research projects. Several students obtained Ph.D under his supervision. Along with teaching and research , Prof. Dey handled a number of administrative assignments successfully and had made dedicated and innovative approaches with great integrity. His major administrative roles were Director of Centre for Genetic Studies, Pro-Vice Chancellor and Vice Chancellor, Maulana Abul Kalam Azad University of Technology, India.",institutionString:"West Bengal University of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"West Bengal University of Technology",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1048",title:"Clinical Genetics",slug:"clinical-genetics"}],chapters:[{id:"57905",title:"CRISPR/Cas9-Facilitated Chromosome Engineering to Model Human Chromosomal Alterations",doi:"10.5772/intechopen.70897",slug:"crispr-cas9-facilitated-chromosome-engineering-to-model-human-chromosomal-alterations",totalDownloads:1128,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Rodents, particularly the mouse, have been used extensively for genetic modeling and analysis of human chromosomal alterations based on the syntenic conservations between the human and rodent genomes. In this article, we will discuss the emergence of CRISPR/Cas9-facilitated chromosome engineering techniques, which may open up a new avenue to study human diseases associated with chromosomal abnormalities, such as Down syndrome and cancer.",signatures:"Zhuo Xing, Yichen Li, Annie Pao, Garrett Kaas and Y. Eugene Yu",downloadPdfUrl:"/chapter/pdf-download/57905",previewPdfUrl:"/chapter/pdf-preview/57905",authors:[{id:"30112",title:"Dr.",name:"Eugene",surname:"Yu",slug:"eugene-yu",fullName:"Eugene Yu"},{id:"220297",title:"Dr.",name:"Zhuo",surname:"Xing",slug:"zhuo-xing",fullName:"Zhuo Xing"},{id:"220298",title:"Mr.",name:"Yichen",surname:"Li",slug:"yichen-li",fullName:"Yichen Li"},{id:"220299",title:"Ms.",name:"Annie",surname:"Pao",slug:"annie-pao",fullName:"Annie Pao"},{id:"220300",title:"Dr.",name:"Garrett",surname:"Kaas",slug:"garrett-kaas",fullName:"Garrett Kaas"}],corrections:null},{id:"57240",title:"Psychopathology in Down Syndrome",doi:"10.5772/intechopen.71061",slug:"psychopathology-in-down-syndrome",totalDownloads:1581,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"The main aim of this section is to provide clinicians with a guide to the prevalence of psychopathologies, associated factors, and their treatment in children with Down syndrome (DS). Attention-deficit/hyperactivity disorder (ADHD), behavioral disorders, depression, and autism are more common in DS than the normal population. However, the incidence of psychopathology is generally lower in DS than in other diseases that cause mental retardation. While writing this chapter, approximately 200 articles in electronic databases were scanned using the keywords “Down Syndrome and Psychopathology,” “Down Syndrome and Mood Disorder,” “Down Syndrome and Autism,” “Down Syndrome and Anxiety,” “Down Syndrome and Catatonia,” and “Down Syndrome and Behavioral Disorder.” Psychopathologies in DS will be presented in eight subtitles beginning with the most often diagnosed. It is important to perform psychological evaluations of patients with DS during routine follow-ups. Comorbid diseases (obstructive sleep apnea, cardiac pathologies, etc.) should be taken into account when choosing drugs.",signatures:"Sevde Afife Ersoy, Hasan Ali Güler and Fatih Hilmi Çetin",downloadPdfUrl:"/chapter/pdf-download/57240",previewPdfUrl:"/chapter/pdf-preview/57240",authors:[{id:"205773",title:"Dr.",name:"Fatih Hilmi",surname:"Çetin",slug:"fatih-hilmi-cetin",fullName:"Fatih Hilmi Çetin"},{id:"211160",title:"Dr.",name:"Sevde Afife",surname:"Ersoy",slug:"sevde-afife-ersoy",fullName:"Sevde Afife Ersoy"},{id:"211161",title:"Dr.",name:"Hasan Ali",surname:"Güler",slug:"hasan-ali-guler",fullName:"Hasan Ali Güler"}],corrections:null},{id:"58014",title:"Functional Neurogenomics: A New Approach to Study Cognitive Disability in Down Syndrome Brain",doi:"10.5772/intechopen.71057",slug:"functional-neurogenomics-a-new-approach-to-study-cognitive-disability-in-down-syndrome-brain",totalDownloads:1226,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Functional neurogenomics is the interface between neurosciences knowledge and Omics sciences data. It characterizes, identifies, and analyzes expression of genes involved in the function of several structures of brain and cognition. Its major goal is to understand the main pathways of brain function, plasticity, and the etiopathogenesis of brain diseases. We have done an integrate analysis of global brain gene expression linked to cognitive disability in Down syndrome. It is a new approach to better understand the control of complex brain networks of gene expression involved in this syndrome. The objective of the chapter is to present computationally simulate data of global expression of 108 genes associated with cognitive disability and neuroplasticity from DNA microarray experiments of postmortem brain from normal controls and patients with Down syndrome. Some genes that were studied are involved in metabolic process and also promote hippocampal plasticity; interventions reawaken the neural plasticity may permit improved cognition. One of the striking findings was that some of the causes of dysregulation appear to result in the brain being trapped in an immature state of synaptic development. Understanding the functional neurogenomics of Down syndrome brain, emerge a new scenario to partially overcome cognitive disability through new prospective genomic therapies.",signatures:"Felipe García-Vallejo, Alejandra Rocío Rodríguez Ortiz, Camila\nAzcárate Gómez, Meliza Santiago Ospina, Julio César Montoya\nVillegas, Adalberto Sánchez Gómez and José María Satizábal Soto",downloadPdfUrl:"/chapter/pdf-download/58014",previewPdfUrl:"/chapter/pdf-preview/58014",authors:[{id:"139753",title:"Dr.",name:"Felipe",surname:"Garcia-Vallejo",slug:"felipe-garcia-vallejo",fullName:"Felipe Garcia-Vallejo"},{id:"211169",title:"Dr.",name:"Alejandra",surname:"Rodriguez",slug:"alejandra-rodriguez",fullName:"Alejandra Rodriguez"},{id:"211171",title:"BSc.",name:"Meliza",surname:"Santiago Ospina",slug:"meliza-santiago-ospina",fullName:"Meliza Santiago Ospina"},{id:"211173",title:"Dr.",name:"Julio Cesar",surname:"Montoya",slug:"julio-cesar-montoya",fullName:"Julio Cesar Montoya"},{id:"220850",title:"BSc.",name:"Camila",surname:"Azcarate",slug:"camila-azcarate",fullName:"Camila Azcarate"},{id:"220851",title:"Dr.",name:"Adalberto",surname:"Sanchez",slug:"adalberto-sanchez",fullName:"Adalberto Sanchez"},{id:"220852",title:"Dr.",name:"Jose Maria",surname:"Satizabal",slug:"jose-maria-satizabal",fullName:"Jose Maria Satizabal"}],corrections:null},{id:"57283",title:"Sleep in Down Syndrome",doi:"10.5772/intechopen.71065",slug:"sleep-in-down-syndrome",totalDownloads:1343,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Sleep disorders are common, often overlooked problem in Down syndrome, particularly during childhood. Comorbidities such as congenital heart disease often present early and management of these needs to take priority. However, this can result in the lack of early development of good sleep habits and may also lead to the perception that sleep issues are an expected problem in children with Down syndrome, which do not require intervention. Studies have shown that sleep problems continue to be under-reported by parents of children with Down syndrome, even though conditions such as obstructive sleep apnoea are up to six times more common in this population. Therefore an understanding of the nature of sleep problems in Down syndrome is important for anyone working with this group. In this chapter we provide an overview of this topic, highlighting the key sleep issues encountered by children with Down syndrome, as well as providing a general approach to evaluation and management.",signatures:"Jasneek Chawla and Helen Heussler",downloadPdfUrl:"/chapter/pdf-download/57283",previewPdfUrl:"/chapter/pdf-preview/57283",authors:[{id:"213284",title:"Dr.",name:"Honey",surname:"Heussler",slug:"honey-heussler",fullName:"Honey Heussler"},{id:"213285",title:"Dr.",name:"Jasneek",surname:"Chawla",slug:"jasneek-chawla",fullName:"Jasneek Chawla"}],corrections:null},{id:"57174",title:"Prenatal Diagnosis of Down Syndrome",doi:"10.5772/intechopen.71064",slug:"prenatal-diagnosis-of-down-syndrome-2018",totalDownloads:1674,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:0,abstract:"The chapter’s contribution to the book explores the prenatal modalities to diagnose Down syndrome (DS). The current knowledge in the field of genetic sonographic markers is presented, along the performance of current policies as well as the potential of new emerging genetic techniques. Besides the screening or testing pregnancy algorithms, the chapter describes the power of prenatal diagnostic techniques, namely, the advantages and the complications of the invasive genetic maneuvers. The progress in prenatal diagnosis of Down syndrome is one of the most important in prenatal medicine in the last decades. The methods vary in terms of detection rates, acceptability, costs, and potential complications. Although the early genetic screening was improved, ultrasound evaluation should not be dismissed, as the first-trimester sonography has the potential to diagnose the majority of major fetal abnormalities.",signatures:"Iliescu Dominic-Gabriel and Drăgușin Roxana-Cristina",downloadPdfUrl:"/chapter/pdf-download/57174",previewPdfUrl:"/chapter/pdf-preview/57174",authors:[{id:"212459",title:"Dr.",name:"Dominic",surname:"Iliescu",slug:"dominic-iliescu",fullName:"Dominic Iliescu"},{id:"212490",title:"Dr.",name:"Dragusin",surname:"Roxana",slug:"dragusin-roxana",fullName:"Dragusin Roxana"}],corrections:null},{id:"57288",title:"Congenital Heart Disease in Down Syndrome",doi:"10.5772/intechopen.71060",slug:"congenital-heart-disease-in-down-syndrome",totalDownloads:1942,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Down syndrome remains the most common chromosomal abnormality in live-born infants in the world today. The association between Down syndrome and congenital heart disease (CHD) is well known, and it is widely recognized that CHD contributes significantly to the morbidity of children with Down syndrome. The reported incidence of CHD in Down syndrome patients is between 40 and 60%. The most commonly described defect is complete atrioventricular septal defect (AVSD), which comprises 30–40% of all cardiac defects. Complex genetic factors are involved. Routine cardiac screening of all newborn babies with Down syndrome is recommended. Expert groups suggest that the cardiac status of all children with Down syndrome should be established by 6 weeks of age to permit appropriate and timely treatment avoiding the establishment of irreversible pulmonary vascular disease that would make corrective surgery impossible.",signatures:"Margaret Louise Morrison and Colin J. McMahon",downloadPdfUrl:"/chapter/pdf-download/57288",previewPdfUrl:"/chapter/pdf-preview/57288",authors:[{id:"218141",title:"Prof.",name:"Colin",surname:"McMahon",slug:"colin-mcmahon",fullName:"Colin McMahon"},{id:"218161",title:"Dr.",name:"Louise",surname:"Morrison",slug:"louise-morrison",fullName:"Louise Morrison"},{id:"218162",title:"Dr.",name:"Sophie",surname:"Duignan",slug:"sophie-duignan",fullName:"Sophie Duignan"}],corrections:null},{id:"57817",title:"Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches",doi:"10.5772/intechopen.71059",slug:"mitochondrial-abnormalities-in-down-syndrome-pathogenesis-effects-and-therapeutic-approaches",totalDownloads:1427,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Down syndrome (DS) consists of a complex phenotype with constant features, such as mental retardation and hypotonia, and variable features, including heart defects and susceptibility to Alzheimer’s disease, type 2 diabetes, obesity and immune disorders. Overexpression of genes mapping to chromosome 21 (Hsa21) is directly or indirectly responsible for pathogenesis of DS phenotypic features, as overexpressed Hsa21 genes dysregulate several other genes mapping to different chromosomes. Many of these genes are involved in mitochondrial function. Recent studies highlight a link between mitochondrial dysfunction, consistently observed in DS subjects, and DS phenotype. In this review, we first provide a basic overview of mitochondrial alterations in DS in terms of mitochondrial bioenergetics, biogenesis and morphology. We then discuss how mitochondrial malfunction may contribute to the pathogenesis of clinical manifestations and how specific Hsa21 genes may cause the disruption of mitochondrial phenotype. Finally, we focus on drugs, which affect mitochondrial function and network to propose possible therapeutic approaches aimed at improving and/or preventing various aspects of the DS phenotype. Our working hypothesis is that correcting the mitochondrial defect might improve the neurological phenotype and prevent DS-associated pathologies, thus providing a better quality of life for DS individuals and their families.",signatures:"Antonella Izzo, Nunzia Mollo, Rita Cicatiello, Rita Genesio, Simona\nPaladino, Anna Conti and Lucio Nitsch",downloadPdfUrl:"/chapter/pdf-download/57817",previewPdfUrl:"/chapter/pdf-preview/57817",authors:[{id:"210932",title:"Dr.",name:"Anna",surname:"Conti",slug:"anna-conti",fullName:"Anna Conti"},{id:"211112",title:"Dr.",name:"Antonella",surname:"Izzo",slug:"antonella-izzo",fullName:"Antonella Izzo"},{id:"211113",title:"Dr.",name:"Nunzia",surname:"Mollo",slug:"nunzia-mollo",fullName:"Nunzia Mollo"},{id:"211114",title:"Prof.",name:"Lucio",surname:"Nitsch",slug:"lucio-nitsch",fullName:"Lucio Nitsch"},{id:"221127",title:"Dr.",name:"Rita",surname:"Cicatiello",slug:"rita-cicatiello",fullName:"Rita Cicatiello"},{id:"221128",title:"Dr.",name:"Rita",surname:"Genesio",slug:"rita-genesio",fullName:"Rita Genesio"},{id:"221129",title:"Prof.",name:"Simona",surname:"Paladino",slug:"simona-paladino",fullName:"Simona Paladino"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"211",title:"Genetics and Etiology of Down Syndrome",subtitle:null,isOpenForSubmission:!1,hash:"25b79c06f3fee34858efd200dd285ca6",slug:"genetics-and-etiology-of-down-syndrome",bookSignature:"Subrata Dey",coverURL:"https://cdn.intechopen.com/books/images_new/211.jpg",editedByType:"Edited by",editors:[{id:"31178",title:"Prof.",name:"Subrata",surname:"Dey",slug:"subrata-dey",fullName:"Subrata Dey"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"479",title:"Prenatal Diagnosis and 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Complications related to THA can be classified as either procedure specific or systemic. Advances in technology, anaesthesiology and surgical technique have resulted in an overall temporal decrease in complication rates despite the increasing incidence of co-morbidities in the patient population [4]. Table 1 highlights rates of complications most commonly encountered after THA.
Distal deep vein thrombosis (DVT) can range from being asymptomatic, to resulting in long term valvular damage resulting in chronic venous insufficiency. Proximal propagation can result in more serious pulmonary embolism. The overall incidence of DVT, including both radiologically diagnosed asymptomatic DVT and symptomatic DVT, post THA in early studies was reported to be as high as 70% without any form of prophylaxis [15]. Recent systematic review of several randomised control trials concerned with DVT prophylaxis has estimated this figure to be around 44% [16]. The recent FOTO study has shown a symptomatic DVT rate of 1.3% in THA patients with extended duration [36 day) chemical prophylaxis [8]. The overall combined incidence of asymptomatic and symptomatic DVT with prophylaxis has not declined with time, converse to the findings with knee arthroplasty in which the incidence has declined significantly [17]. This may be due to the increasing frequency of co morbidities within patients undergoing THA which act as risk factors for DVT.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t||
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Subclinical Fat Embolism | \n\t\t\t90%[5] | \n\t\t\tDislocation (Posterior approach with repair) | \n\t\t\t0.49%[6] | \n\t\t
Symptomatic Fat Embolism | \n\t\t\tUnknown | \n\t\t\tLeg length discrepancy (patient perceived) | \n\t\t\t30%[7] | \n\t\t
Symptomatic Deep Vein Thrombosis with prophylaxis | \n\t\t\t1.3%[8] | \n\t\t\tInfection | \n\t\t\t1.08%[9] | \n\t\t
Symptomatic Pulmonary Embolism with prophylaxis | \n\t\t\t0.5 – 0.6%[10] | \n\t\t\tAseptic Loosening | \n\t\t\t2% failure rate at 15 years (Corail uncemented stem)[11] 3.2% failure rate at 30 years (Exeter Cemented Stem)[12] | \n\t\t
Mortality | \n\t\t\t0.29 – 0.6%[4] | \n\t\t\tPeriprosthetic Fracture (Postoperative femoral) | \n\t\t\t1.1%[13] | \n\t\t
Myocardial Infarction | \n\t\t\t0.5%[10] | \n\t\t\tHeterotopic Ossification (Grade III/IV) | \n\t\t\t3 – 7%[14] | \n\t\t
Complication rates for Total Hip Arthroplasty
THA is thought to mainly affect 2 limbs of Virchow’s triad, namely hypercoagulability and venous stasis. Activation of the coagulation cascade begins during surgery, primarily during preparation and insertion of the femoral prosthesis, with cemented prostheses providing a greater stimulus than uncemented implants [18]. Whether this increases the incidence of DVT with cemented fixation is unclear as the evidence is inconclusive [15, 19]. Venous haemodynamics are also altered not only during surgery, but also for up to 6 weeks post operatively [20]. Significant reductions in venous capacitance and outflow are seen in both legs, with greater changes seen in the operated leg, and this has been shown to correlate directly with the incidence of postoperative DVT [20]. Complete femoral vein occlusion has also been noted during THA, particularly during the posterior approach when the limb is internally rotated and flexed for operation on the femur [18].
Numerous risk factors for postoperative DVT have been identified. Major risk factors in approximate order of importance include: hip fracture, malignancy, antiphospholipid syndrome, immobility, previous history of DVT, use of selective oestrogen receptor modulators, oral contraceptives, morbid obesity, stroke, atherosclerosis and a ASA greater than 3 [21]. However 50% of patients who develop DVT have no identifiable clinical risk factor [21]. Genetic predispositions include antithrombin III and protein C deficiency and prothrombin gene mutation [21]. In order to aid recognition of ‘at risk’ patients, the National Institute for Health and Clinical Excellence (NICE) has published a table of relevant patient related risk factors as shown in Table 2 [16].
Active cancer or cancer treatment | \n\t\t\tActive heart or respiratory failure | \n\t\t
Acute medical illness | \n\t\t\tAge over 60 years | \n\t\t
Antiphospholipid syndrome | \n\t\t\tBehcet’s disease | \n\t\t
Central venous catheter in situ | \n\t\t\tContinuous travel of more than 3hours approximately 4weeks before or after surgery | \n\t\t
Immobility (for example, paralysis or limb in plaster) | \n\t\t\tInflammatory bowel disease | \n\t\t
Myeloproliferative diseases | \n\t\t\tNephrotic syndrome | \n\t\t
Obesity (body mass index > 30kg/m2] | \n\tParaproteinaemia | \n
Paroxysmal nocturnal haemoglobinuria | \n\tPersonal or family history of VTE | \n
Pregnancy or puerperium | \n\tRecent myocardial infarction or stroke | \n
Severe infection | \n\tUse of oral contraceptives or hormonal replacement therapy | \n
Varicose veins with associated phlebitis | \n\t\n |
\n\t\t | \n\t\n |
High levels of coagulation factors (for example, Factor VIII) | \n\tHyperhomocysteinaemia | \n
Low activated protein C resistance (for example, Factor V Leiden) | \n\tProtein C, S and antithrombin deficiencies | \n
Prothrombin 2021A gene mutation | \n
Patient related risk factors for Venous Thromboembolism [16]
Prophylaxis against DVT begins with the type of anaesthesia used. Regional compared to general anaesthesia has been shown to reduce the risk of DVT post THA by over 50% [22, 23]. This is thought to be due to the relative hyperkinetic blood flow seen in the lower limbs during regional anaesthesia compared to general anaesthesia, and the stabilising effect of local anaesthetics on the cell membranes of vascular endothelium and platelets [24]. Mechanical and chemical prophylaxis remains a somewhat contentious issue, with various differing opinions existing regarding prophylaxis regimes. Numerous randomised controlled trials exist supporting the use of mechanical methods such as pneumatic compression devices (figure 1) and chemical methods such as low molecular weight heparins and fondaparinux, a factor Xa inhibitor [25-34].
Left: Thrombo-Embolic Deterrent Stockings, Right: Flotron pumps (Huntleigh Healthcare Ltd, Luton, UK)
There has been recent increasing interest in oral factor Xa inhibitors such as Rivaroxaban and Apixaban. The RECORD trial has demonstrated greater effectiveness for oral Rivaroxaban compared to subcutaneous Enoxaparin with equal side effect profiles [35, 36]. Pooled analysis of the ADVANCE-2 and ADVANCE-3 trials has also demonstrated greater efficacy for oral Apixaban compared to subcutaneous Enoxaparin [37]. There has been some recent concern however regarding the increased rate of wound complications, specifically with the use of Rivaroxaban [38]. A retrospective analysis by Jensen et al. demonstrated a greater return to theatre rate for wound complications such as prolonged drainage and haematoma associated with the use of Rivaroxaban compared to Tinzaparin [38]. The authors suggest that trial data to date has not fully evaluated the complications profile of Rivaroxaban, as only major bleeding was used as a primary outcome measure, and further randomised trials are necessary to examine rates of surgical complications.
Current recommendations by National Institute for Health and Clinical Excellence (NICE) in England state that, THA patients should be offered mechanical prophylaxis in the form of intermittent pneumatic compression devices or compression stockings, and chemical prophylaxis with either low molecular weight heparin, Fondaparinux, Rivaroxaban or Dabigatran. This should be continued for 28-35 days post operatively [39].
DVTs that propagate proximally have the potential embolise to the lungs resulting in pulmonary emboli (PE). Mild emboli can be asymptomatic, whereas massive embolism can be fatal, and PE is one of the leading causes of mortality post THA. Rates for symptomatic pulmonary embolism in recent large case series of primary THA in which chemical prophylaxis was used, has been between 0.51-0.6% [10, 40]. In the absence of prophylaxis this is estimated to be around 3%, with approximately 6% of symptomatic PEs post THA result in fatality [16].
As with DVT, both mechanical and chemical methods such as pneumatic compression pumps and low molecular weight heparins have been shown to provide effective prophylaxis against symptomatic PE [25, 41-44]. However due to the low rate of fatal PE, trials and even meta-analyses have failed to demonstrate statistically significant effects on the rate of fatal PE by using thromboembolic prophylaxis [45]. Power analysis indicates a trial involving 67,000 patients would be needed to demonstrate a statistically significant difference [46].
Vena Caval filters as shown in figure 2 can also be used to prevent migration of venous emboli into the pulmonary circulation. However no RCTs exist supporting their use in surgical patients and significant complications such as pneumothorax, air embolism and arteriovenous fistulae can develop either during their placement or post procedure [47]. UK NICE guidelines therefore recommend their use in patients with recent or existing thromboembolic disease in whom anticoagulation is contraindicated [39].
Retrievable Inferior Vena Caval Filter, courtesy of Cook Medical
During insertion of the femoral component, rises in intramedullary pressure can force medullary fat and marrow contents into the venous circulation via the metaphyseal vessels [48-50]. Fat and marrow embolus can then pass into and through the pulmonary circulation depending on the size of the emboli [51, 52]. Large emboli can lodge within the pulmonary circulation leading to pulmonary hypertension and haemodynamic instability. Trans-pulmonary passage of micro-emboli can result in cerebral embolism potentially causing neurological complications [51, 53].
Subclinical fat embolisation can been detected in up to 90% of patients undergoing THA [5]. However the exact incidence of fat embolism syndrome characterised by the classic triad of respiratory insufficiency, neurolgic symptoms and upper body petechiae is unknown [54].
Measures to reduce the risk of fat embolism include medullary lavage to reduce the fat load during cement pressurisation [55]. Vacuum cementation techniques using drainage cannulae have also been shown to be effective in reducing the intramedullary pressure rises during cementation therefore reducing the risk of emboli [56]. Treatment of established fat embolism syndrome is essentially supportive, frequently requiring intensive care unit admission for respiratory support.
Published rates for mortality following primary THA are low, ranging from between 0.29% to 0.6% [4, 10]. Mortality rates have declined slightly with time despite the increasing incidence of relevant co-morbidities [4]. Cardiovascular complications account for the most common cause of death [57].
Age has been identified as one of the strongest predictors of post operative mortality after joint arthroplasty [10]. Octegenarians have been shown to have a mortality rate 3.4 times higher than patients between 65-79 years of age and were 2.4 times more likely to suffer a post operative myocardial infarction [58]. Other significant risk factors for post operative mortality and morbidity include male sex, smoking and higher American Society of Anesthesiologists’ (ASA) grade which is representative of relevant significant co-morbidities such as artherosclerosis, diabetes, renal impairment and valvular disease [10, 59, 60]. Greenfield et al. found that the incidence of morbidity after THA varied from 3% to 41% when comparing those with the lowest and highest incidence of co-morbidities [61]. The role of anaesthesia is somewhat controversial. Some studies suggest regional compared to general anaesthesia may reduce the risk of thromboembolic and cardiorespiratory complications and short term mortality [62, 63]. Others have shown no difference between the 2 groups in terms of morbidity and mortality [64]. Therefore no conclusive evidence exists supporting one form of anaesthesia, but the overall consensus would appear to favour regional techniques [54].
Dislocation is the 3rd most common cause for revision after THA [65]. Published rates for dislocation after primary THA vary widely between 0.2% to 7% [66]. Up to 70% of dislocations occur early within 6 weeks [67]. Early dislocation carries a better prognosis compared to late dislocation which is defined as occurring after 3 months, as late dislocation usually has a multifactiorial aetiology including component wear and soft tissue laxity [68, 69]. Approximately a third of dislocating THAs managed conservatively after the first episode will go on to become recurrent dislocators [67]. Risk factors for dislocation can be classified as either patient, surgery or implant related.
Patients with neuromuscular and cognitive disorders such as cerebral palsy, muscular dystrophy and dementia, have been shown to have higher rates of dislocation [70]. Fracture as the primary indication for surgery is the indication most strongly linked with dislocation [71]. This is thought to be due to the lack of capsular hypertrophy normally seen with osteoarthritis which provides additional stability. Previous hip surgery of any sort has also been shown to double the risk of dislocation [68]. Factors such as height, weight, age and sex of the patient have not been conclusively shown to affect the rates of dislocation [67].
Surgical factors include surgical approach, soft tissue tension, component design and orientation, and surgeon experience. The majority of dislocations occur in a posterior direction and therefore the posterior approach has been deemed to be the approach with the highest risk of dislocation. Early data supported this theory with Woo et al reporting a rate of 5.8% for posterior approach compared to 2.3% for an antero-lateral approach [68]. However recent research investigating the role of posterior capsular and external rotator repair has shown comparable rates to other approaches [72, 73]. A recent meta-analysis has shown a reduction of the dislocation rate from 4.46% to 0.49% by carrying out a posterior soft tissue repair [6]. Therefore with meticulous soft tissue repair, surgical approach should have little effect on dislocation rates. Besides the posterior structures, the glutei and joint capsule also provide soft tissue tension reducing dislocation risk. Therefore following a transtrochanteric approach, trochanteric non union greater than 1cm can result in abductor insufficiency increasing the rates of dislocation by over 6 fold [68]. Inadequate offset is another factor affecting soft tissue tension and has been shown to increase dislocation risk [74].
Component positioning and design both play key roles in reducing dislocation risk. “Safe zones” for acetabular cup position are defined as an abduction angle of 40° ± 10° and anteversion of 20° ± 10° [75, 76]. With a posterior approach reduced cup anteversion has been shown to be a major risk factor for dislocation [77]. Archbold et al. have suggested the use of the transverse acetabular ligament as a landmark to judge cup anteversion [78]. Using this technique they reported a 0.6% dislocation rate using a posterior approach with soft tissue repair. How this relates to the traditionally defined safe zones is currently being examined. Femoral component positioning has been less well studied. Recent studies have suggested the use of a ‘combined anteversion’ technique in which the acetabular and stem combined anteversion should be 35° ± 10° [79, 80].
Femoral head size also affects stability. Larger heads provide more favourable head-neck ratios, reducing possible impingement, and seat deeper within the acetabulum requiring a greater ‘jump distance’ to cause dislocation as illustrated in figure 3. Such advantages have been validated using cadaveric and computer modelling [81-83]. Clinical data from both the Norwegian and Australian joint registries has also shown a reduction in rates of revision for dislocation with increasing head size [84, 85].
Surgeon experience is another factor that has been identified in influencing dislocation rates. Hedlundh et al. found that surgeons who had performed less than 30 THAs had a double rate of dislocation compared to more experienced surgeons [86]. A recent systematic review has also demonstrated reduced dislocation rates with increased surgical volume [87].
Jumping Distance highlighted by red arrow demonstrates distance the head needs to travel before dislocation occurs. Increasing head size increases this distance
Management of dislocation initially involves closed reduction which is usually successful in the majority of cases. This should be performed ideally under anaesthesia with muscle relaxation to reduce the chance of damage to the femoral head [88, 89]. Some surgeons advocate the use of an abduction brace after reduction but little evidence exists supporting their use.
Indications for operative intervention include recurrent or irreducible dislocation, component malposition, soft tissue laxity and dislocation due to impingement. Strategies during revision include component realignment, removal of osteophytes causing impingement, modular component exchange to increase head size and improve head-neck ratio, liner exchange if worn and addressing soft tissue laxity using capsulorrhaphy, trochanteric advancement or tendon allografts.
Selected patients unsuitable for major revision surgery can be treated with posterior lip augmentation devices (PLAD) as shown in figure 4. These consist of a C shaped piece of UHMWPE and a steel backing plate, and are applied to the posterior lip of the acetabulum and held in place with up to 5 screws. This constrains the head within the augmented socket. Contraindications to its use include gross component malalignment and loosening. McConway et al. reviewed 307 recurrently dislocating THAs treated with PLADs [90]. Persistent instability occurred in only 5 patients [1.6%) and there was no evidence of accelerated loosening affecting the acetabular component.
Salvage procedures for failed revision or uncorrectable aetiology include the use of constrained cups or conversion to bipolar hemiarthroplasty. However both of these procedures are associated with poor functional outcome and constrained cups can result in premature loosening [70]. Therefore their use is usually reserved for low demand patients. The final salvage option is Girdlestone resection for the unreconstructable hip.
Posterior Lip Augementation Device (PLAD, Depuy, UK)
Leg length discrepancy (LLD) is the most common cause of patient dissatisfaction and subsequent litigation after THA [91]. LLD can result in nerve palsies, abnormal gait, lower back pain and reduced functional outcome [92]. Wylde et al. showed up to 30% of patients after primary THA can have a perceived LLD, but only 36% of these had an anatomic LLD greater than 5mm [7].
Nerve palsies are potentially the most serious complications of LLD. Sciatic and peroneal nerve palsies have both been associated with limb lengthening. Edwards et al suggested sciatic and peroneal nerve palsies are associated with lengthening greater than 4 and 3.8cm respectively [93]. Farrell et al however found an average lengthening of only 1.7cm was a significant risk factor for nerve palsies [94]. Therefore safe limits for limb lengthening before traction nerve palsies develop are yet to be defined, and it may be that any minor degree of lengthening may make the nerve more susceptible to other trauma [94].
Minor LLD less than 1cm is usually well tolerated by patients. However LLD greater than 2cm has been shown to significantly affect the gait cycle, increasing physiological demand [95]. LLD greater than 3cm in the elderly was shown to cause significant increases in heart rate and quadriceps activity in the lengthened limb, which may be especially relevant in patients with cardio-respiratory co-morbidities [95].
Avoiding potential problems with LLD begins with patient history and examination. It is crucial to determine patient perceived leg length in order to counsel the patient effectively regarding likely outcomes. True leg length can then be determined, measuring from the ipsilateral anterior superior iliac spine to the medial malleolus, followed by apparent leg length by measuring from the umbilicus to the medial malleolus. Apparent leg length can be affected by pelvic obliquity secondary to either lumbar spine pathology or contractures about the hip. Significant LLD due to fixed pelvic obliquity secondary to chronic lumbar spine pathology cannot usually be corrected as it may involve significant shortening or lengthening. With pelvic obliquity secondary to contractures, the true length only needs to be corrected as after the THA the pelvis will balance with time [96].
Radiographs can also be used to determine leg length by referencing the position of the lesser trochanter in relation to a line drawn across the inferior aspect of the pelvis as shown in figure 5. Templating can then be carried out to determine the correct level of the neck cut for the femoral prosthesis and the position of the acetabular component in order to determine the new hip centre. Both of these directly affect leg length.
Radiographic estimation of LLD can be made by measuring vertically from the top of the lesser trochanter to a line drawn across the inferior margin of the pelvis
Intraoperative methods include the use of measurements taken from reference pins placed in the pelvis to a mark on the greater trochanter [97-99]. Mihalko et al described using a large fragment screw placed above the superior rim of the acetabulum and marking a point on the greater trochanter a fixed distance from this prior to dislocation. After insertion of the prostheses this distance was rechecked giving an indication of leg length changes [98]. Shiramizu et al used a similar method but with a steimann pin in the ilium and a custom calliper to measure the distances [99]. They found a mean LLD of only 2.1mm with this method.
Minor LLD postoperatively can be treated using a shoe raise. Prescription of such devices should be delayed for 3-6 months to allow any residual pelvic tilt secondary to contractures to resolve as the soft tissues can progressively relax. Failure of conservative measures and symptoms such as severe pain, nerve palsies and instability can necessitate surgical intervention. Shortening can be treated using soft tissue release and exchange of modular heads to give modest changes in leg length or more extensive surgery such as exchange of the femoral component to give greater neck length or offset. Lengthening can also be treated with component exchange but secondary procedures such as trochanteric advancement or the use of larger heads or stems with increased offset may be needed to maintain stability [100].
Infection post THA is potentially one of the most catastrophic and challenging to treat complications. During the early development of THA, Charnley reported a deep infection rate of 9.4% in unventilated operating theatres [101]. This initial unacceptably high deep infection rate stimulated the development of several prophylactic measures including ultraclean laminar air flow ventilation and peri-operative antibiotics. With the aid of such measures, infection rates in the UK between 1993 and 1996 fell to 1.08% [9].
Bacterial contamination of theatre air was initially recognized as a risk factor for post operative sepsis by Lister in 1867 [102]. Charnley later introduced the concept of ultraclean air flow ventilation that produces less than 10 colony forming units per cubic meter [103]. His reported infection rates in THA fell to 1% with the use of such enclosures. A MRC trial published in 1982 demonstrated a deep sepsis rate of 0.6% with ultraclean ventilation compared to 1.5% with conventional ventilation [104]. The use of ultraclean air ventilation during joint arthroplasty has subsequently become universally adopted practice within the UK [105].
The use of peri-operative antibiotics during THA is also a common prophylactic measure. Early trials using cloxacillin in THA found a 12% infection rate without prophylaxis compared to 0% with [106]. Currently cephalosporins are commonly used prophylaxis for THA. There is however a gradual move away from these due to the emergence of MRSA and problems with Clostridium difficile infection. Alternative regimens include flucloxacillin and gentamicin, or vancomycin and gentamicin. There is no conclusive evidence with regards to the optimal antibiotic regimen or duration of administration. However no benefit of extended prophylaxis beyond 24 hours has been demonstrated [107]. Therefore antibiotic regimes should be ideally guided by local microbiological knowledge so locally prevalent organisms can be targeted. Other measures shown to reduce rates of infection or bacterial load include the use of occlusive clothing, exhaust suits, pulsed wound lavage, preoperative showering and reducing theatre traffic [105].
Infection can arise by direct bacterial contamination at the time of surgery or later haematogenous spread. Staphylococcus aureus was the most common causative organism in an early series published by Charnley [108]. Coagulase negative staphylococci have become increasingly prevalent over the years with a recent series showing such organisms responsible for 58% of infections [109]. This is thought to be due to the effect of antibiotic use on bacterial flora [105]. Risk factors for periprosthetic infection include obesity, revision surgery, inflammatory arthritis, open skin lesions on the affected limb, blood transfusion, urinary infections and high ASA score [110].
Pathogenesis begins with bacterial adhesion. Primary adhesion occurs due to physical interactions (hydrophobic/electrostatic) between the bacteria and prosthetic surface. This is followed by bacterial aggregation through membrane adhesion molecules and generation of exopolysaccharides which form a glyocalyx or biofilm surrounding the bacteria [111]. This biofilm is thought to protect the bacteria from antibiotics and host defences [112].
Periprosthetic infections can be classified into 4 main catogeries [113]. Early postoperative infection is one that becomes apparent within one month of the procedure. Late chronic infection presents later than 1 month after operation and has an insidious course of gradual onset of pain and swelling with minimal systemic symptoms. Acute haematogenous spread results in an acute onset of symptoms associated with a documented or suspected bacteraemia. The final type is positive intra-operative culture, this is an occult infection diagnosed by positive cultures taken at time of revision surgery.
Diagnosis of peri-prosthetic infection can be extremely challenging. Hip pain is the most consistent symptom. Presence of systemic symptoms such as fevers or rigors can be very variable. Examination may reveal local wound tenderness, signs of inflammation, discharge, sinuses and a painful range of movement.
Plain radiographs may show evidence of osteopenia or osteolysis, periostiitis and endosteal scalloping. However none of these can reliably differentiate between infection and aseptic loosening. Radionucleotide scanning using technetium or gallium can also been used. Technetium uptake reflects active bone turnover and gallium binds to transferrin, accumulating in inflammatory foci. Technetium scanning has a greater sensitivity than gallium for infection but their inability to differentiate infection and aseptic loosening limits their application [114, 115]. However its relatively high negative predictive value can make technetium bone scanning a useful initial screening test [116]. 18F-Fluoro-deoxyglucose [18-FDG) PET scanning is a newer technique that has increased sensitivity and specificity for infection. Pooled data from recent studies demonstrate a sensitivity of 85.5% and a specificity of 92.6% for periprosthetic infection [117]. Availability of PET scanners however still remains poor. Using radio-labelled white cells or immunoglobulins is another technique which has shown improved sensitivity and specificity relative to traditional three phase bone scans. Their widespread availability combined with the lack of established diagnostic criteria for 18-FDG PET scans, makes labelled white cell scans the current nuclear medicine investigation of choice for periprosthetic infection [118].
Blood investigations include ESR, CRP and Interleukin-6. ESR and CRP are non specific inflammatory markers and therefore can be elevated by concurrent illnesses. In the absence of such conditions an ESR greater than 30 mm/hr has a sensitivity and specificity of 82 and 85% respectively for peri-prosthetic infection, and the values for a CRP greater than 10mg/l are 96% and 92% [119]. Elevated levels of interleukin-6 have also been associated with periprosthetic infection with a sensitivity and specificity of 100% and 95% in one study [120]. However other chronic inflammatory conditions such as rheumatoid arthritis and other illnesses such as AIDS and Multiple Sclerosis can also cause elevated levels.
Cytological and microbiological analysis of hip aspirate taken under sterile conditions can give useful information regarding not only the presence of infection but also the potential offending organism. Ali et al. have shown a sensitivity and specificity of 0.82 and 0.91 for radiologically guided guided hip aspiration. However recent antibiotics can affect cultures and therefore antibiotics must be stopped for at least 2 weeks prior to aspiration.
The aims of treatment of an infected prosthesis are eradication of infection and restoration of function. The classification by Tsukyama et al. can be used to help guide treatment [113]. Acute infections either presenting as early infection or acute haematogenous spread can be treated by component retention and thorough debridement, irrigation and intravenous antibiotics. However such treatment must be undertaken within 2 weeks of onset of symptoms [121]. Success rates between 50-74% have been reported with such a strategy [113].
Late chronic infection is best treated with full revision. This can be performed as a single stage exchange arthroplasty or a 2 stage exchange procedure. Originally described by Bucholz, a single stage procedure involves prosthesis removal, soft tissue debridement and lavage, followed by re-implantation of a new prosthesis if a clean uninfected bed is achieved, followed by appropriate antibiotic therapy [122]. Review of 1299 cases treated with single stage revision showed an 83% success rate at an average follow up of 4.8 years [123]. Factors associated with successful outcome were good general health of the patient, absence of wound complications after the primary procedure, methicillin sensitive organisms and infection with organisms sensitive to antibiotics within the cement [123]. Advantages of a single stage procedure include lower patient morbidity and lower incidence of complications such as fracture and dislocation. However 2 stage procedures have consistently demonstrated higher success rates compared to single stage procedures [124-128]. Thus 2 stage exchange still remains the most common strategy.
2 stage procedures involve initial prosthesis removal, soft tissue debridement and insertion of an antibiotic loaded cement spacer. This can be in the form of an articulating spacer allowing some range of movement and reducing soft tissue contracture. This is followed by appropriate antibiotic therapy and a usual interval of 6 weeks prior to reimplantation of the definite new prosthesis. Success rates of between 87 to 94% have been reported with cemented 2 stage revision [124, 125, 128].
The overall incidence of nerve injury after THA is estimated to be around 1% [129]. Sciatic nerve palsies account for 79% of all cases, followed by femoral nerve palsies (13%), combined femoral and sciatic nerve palsy (5.8%) and obturator nerve palsy (1.6%) [129]. In the majority of cases (47%) the aetiology is unknown. Other causes include traction (20%), contusion (19%), haematoma (11%) and dislocation (2%), with laceration only accounting for 1% of all nerve palsies [130]. Risk factors for nerve injury include female sex, revision surgery and developmental dysplasia of the acetabulum [129].
When the sciatic nerve is affected, it most commonly involves the common peroneal division. This is thought to be due to the lower amount of connective tissue present between the funiculi and its relatively tethered position at the sciatic notch compared to the tibial branch [129, 131]. These factors are thought to make the peroneal branch more susceptible to trauma and traction. The use of the posterior approach has traditionally been associated with increased risk of sciatic nerve damage. However a Cochrane review in 2006 found no difference in the incidence of nerve palsy between the posterior and direct lateral approaches [132]. Femoral nerve palsy is less common and is usually secondary to direct compression, usually due to a malpositioned retractor [130].
Indications for surgical intervention in a patient with nerve palsy include haematoma causing compression, palsy associated with excessive lengthening and palsy that can be definitely attributed to implanted metalwork. Electrodiagnostic studies can be helpful in determining the level of the lesion. Outcomes of nerve palsies are variable, with 40% of patients showing a good recovery, 45% of patients having mild residual motor or sensory symptoms and 15% left with a dense motor or sensory deficit [129]. Partial nerve lesions and maintenance of some motor function are good prognostic indicators, with recovery possible for up to 3 years after the initial insult [133].
Vascular injury during THA is extremely rare. Published incidence varies between 0.04 to 0.08% [134, 135]. As opposed to knee arthroplasty, vascular injury in THA is usually the result of direct trauma either during component insertion or removal [136]. Risk factors include revision surgery, previous vascular injury or surgery and pre-existing atherosclerosis [137]. The majority of vascular injuries are arterial but venous injury has been described [138]. Venous injuries however may be under diagnosed as they may run a relatively benign course remaining undetected.
The majority of vascular injuries are either the result direct trauma from acetabular retractors or acetabular screw insertion [130]. Wasielewski et al. have described an acetabular quadrant system to help guide safe screw insertion [139]. The postero-superior and poster-inferior quadrants are the safest zones for screw insertion as they have they areas of greatest bone stock [139].
Aseptic loosening is the most common cause for revision surgery, accounting for 75% of revision cases [140]. Aseptic failure occurs as a result of a chronic inflammatory reaction secondary to particulate wear debris eventually resulting in osteoclast activation, osteolysis and loosening [141].
The pathogenesis begins with the generation of wear particles from the bearing surface, and also non bearing surfaces such as the interface between acetabular shell and the liner insert, known as backside wear. The morphology of the wear debris is dependent on the type of implant used. Particles from polyethylene bearing surfaces can vary from submicron in size to several millimetres. The average size of polyethylene debris has been shown to be around 0.5 µm and it is this submicron sized particle that has been shown to have the most bio-reactivity [142, 143]. The rate of generation of the wear particles has also been shown to correlate with the degree of osteolysis [142]. Inadequate initial fixation can also contribute to loosening by generating micromotion and increasing the rate of generation of particulate debris [144]. This highlights the importance of good cementation techniques in reducing the risk of aseptic failure. Pressure within the joint fluid has also been suggested to contribute to osteolysis. Increased joint fluid pressure in animal models has been shown to induce bone loss at the prosthesis bone interface possibly by interfering with bone perfusion causing osteocyte death [145, 146]. Increased joint fluid pressures have been noted in THAs undergoing revision and pressure waves generated by load bearing have been demonstrated in retroacetabular lytic lesions [147, 148]. Thus increased fluid pressures may directly contribute to osteolysis and also perpetuate the dissemination of the wear debris throughout the prosthesis bone interface, enhancing the biological response.
The primary response to wear debris is predominantly macrophage mediated. The exact mechanism of macrophage activation is still unclear. Macrophages can be activated as a result of either phagocytosis of particulate matter and also possibly through cell membrane interactions with particulate matter [149]. Macrophage activation causes the release of pro-inflammatory cytokines and growth factors including TNF-α, Interleukin-1, TGF-β and RANKL [150]. This results in the production of a pseudomembrane at the bone cement prosthesis interface consisting of macrophages, fibroblasts and lymphocytes within a connective tissue matrix [151]. TNF-α and Interleukin-1 both promote osteoclastic differentiation and activation, but it is the up regulation of the RANK/RANKL pathway that is the key to activating osteoclastogenesis and subsequent osteolysis [143]. Recent studies have suggested individual genetic susceptibility to osteolysis may exist via single nucleotide polymorphisms in the implicated cytokine genes, possibly by altering the magnitude of the biological response [152-155].
Alternative bearing surfaces can be used to reduce wear rates, debris generation and subsequent osteolysis. Highly crosslinked polyethylene, ceramic on ceramic and metal on metal bearings have all been shown to have reduced wear rates compared to standard ultra-high molecular weight polyethylene (UHWPE) [156-164]. However there are concerns regarding the increased bioreactivity of crosslinked polyethylene debris compared to standard UHWPE which may offset the benefits of reduced volumetric wear [165, 166]. Volumetric wear is also lower with metal on metal bearings. However as the particle size is much smaller, usually between 20-90nm, the overall surface area is much larger compared to UHWPE raising concerns of possible increased bioreactivity.
Pain is usually the primary presenting symptom of aseptic failure. Gross acetabular loosening can cause groin pain whereas thigh pain can indicate femoral loosening [167]. Early loosening however may also be asymptomatic merely detected on routine follow up radiographs. Clinical signs may include inability to straight leg raise, shortening of the leg due to subsidence and increasing external rotation of the leg if the femoral stem twists into retroversion. Investigations for aseptic loosening are similar to those for infection discussed earlier. Blood inflammatory markers such as CRP are usually normal with aseptic loosening [168]. Radiological tests include plain radiography, subtraction and nuclear arthrography and bone scintigraphy. Meta-analysis has shown similar diagnostic performance for all of these tests and therefore suggests plain radiographs and bone scintigraphy as the tests of choice due to their lower risk of patient morbidity [169]. CT 3D imaging is also useful for the evaluation of lytic lesions as plain 2 dimensional radiographs can underestimate the size of the lesion as demonstrated in figure 1 [170, 171].
Treatment of aseptic loosening is guided by the severity of the patient’s symptoms and the rate and volume of osteolysis. Indications for surgical treatment in asymptomatic patients are progressive osteolysis and risk of catastrophic mechanical failure such as periprosthetic fracture. Nonsurgical treatment using bisphosphonates and anti cytokine therapy such as anti-TNF-α to prevent progression of osteolysis has been suggested. However their efficacy is yet to be determined [172]. Goals of surgical treatment include removal of wear debris and also the wear generator, reconstruction of the osseous lesion and restoration of mechanical stability [173]. This can involve exchange of bearing surfaces, bone grafting of lytic lesions and revision of loose components.
Ceramic articulations have become increasingly popular due to their low wear profile and good biocompatibility. However potential complications of ceramic bearings include chipping and incomplete seating of ceramic liners during insertion, fracture and bearing generated noise.
Currently all ceramic acetabular bearings consist of a modular ceramic liner which is inserted into a metal shell implanted into the acetabulum. Incomplete seating of the liner due to soft tissue interposition or deformation of the metal shell has been reported [174, 175]. Thus extra care and good visualisation of the acetabulum is imperative when inserting a modular ceramic liner. Chipping during impaction has also been reported and this can also be secondary to deformation of the metal shell [176]. Using titanium sleeved or recessed ceramic liners has been shown to reduce such risks [177].
Risk of fracture for modern 3rd generation ceramic bearings is extremely low. Willman et al. found a fracture rate of 0.004% for femoral heads manufactured after 1994 [178]. Fracture of both the liner and femoral head have however been reported [179, 180]. Head fracture has been associated with improper handling during implantation. Contamination of the stem-ball interface with blood or soft tissue has been shown to significantly reduce the load required for inducing fracture [181]. Impingement of the femoral neck on the edge of ceramics liner is thought to be a major risk factor for liner fracture [179, 182]. Therefore correct positioning of the acetabular component is especially important for ceramic bearings.
Noise generated from ceramic bearings is a recently described phenomenon. Published rates of “squeaky” ceramic bearings range from 2.7% to 20.9% [183, 184]. Component malposition has been implicated [185]. However recent studies have found no association between cup inclination and version and the incidence of squeaking [183, 184]. Short neck length is the only factor that has been associated with squeaking, possibly due to impingement or microseperation to due increased joint laxity [184]. Revision of squeaking hips has revealed evidence of stripe wear but there is currently no evidence to suggest squeaking is a precursor for ceramic fracture [186, 187].
Metal on metal bearings also have superior wear rates compared to standard UHMWPE [161, 163, 164]. However there is increasing concern regarding metal ion toxicity and hypersensitivity type reactions. Volumetric wear is considerably lower for metal bearings compared to UHMWPE, but the absolute number of particles generated is estimated to be 13500 times higher [188]. Therefore the total surface area is considerably higher. Thus the bioreactivity of metal wear particles may be higher than polyethylene or ceramic debris, and the nanometre scale of the particles and dissolution of metal ions allows distant transport, raising concerns of systemic toxicity.
The possibility of systemic toxicity has raised interest in serum metal ion levels in patients with modern metal on metal bearings. Recent studies using standardised measurement techniques have reported mean serum chromium levels of between 0.86 – 17.7 µg/L [189-192]. Safe levels of serum metal ion levels have however yet to be determined [193]. Concerns regarding carcinogenesis and immune suppression secondary to raised blood metal ion levels have been raised [194, 195]. Teratogenicity is also another potential concern as transplacental crossage of metal ions has been demonstrated [196]. However, currently no conclusive evidence exists supporting these theories [197, 198]. A positive correlation between cup inclination and blood metal ion levels has been demonstrated with metal on metal bearings [191, 199]. This is probably due to increased edge loading with increasing cup inclination and serum metal ion levels have been suggested as a tool to monitor the performance of metal on metal bearings [190]. Therefore metal ion exposure can be minimised with proper cup orientation.
Local tissue reactions to metal on metal articulations have also been reported [200-202]. Metal ions are thought to induce an immune reaction leading to tissue necrosis and osteolysis. This is in contrast to UHMWPE which induces a macrophage reaction to particulate wear debris. Willert et al. has called this unique reaction, aseptic lymphocytic vasculitic associated lesions (ALVAL) [200]. Histologically this reaction is characterised by perivascular lymphocytic infiltration and plasma cells. Clinical presentation can vary between chronic groin pain to extensive tissue necrosis forming pseudotumours [201]. Exact incidence of such tissue reactions is unknown but is estimated to be around 1% [201]. Risk factors associated with the development of these adverse reactions include small component size and component malposition [203]. Stemmed metal on metal hip replacements also appear to have a higher rate of revision and their use has now been discouraged [204].
Periprosthetic fractures can occur either intraoperatively or in the postoperative period. Overall, periprosthetic fractures more commonly affect the femoral component of the THA. Data from the largest published series by Berry et al. reports the incidence of intra- and postoperative femoral fracture as 1% and 1.1% respectively [13]. Rates of intraoperative fracture after cementless fixation are higher, 5.4% for primary THAs and 21% for revision surgery [13].
The treatment of unstable postoperative periprosthetic femoral fractures is now almost always operative. Loosening, non-union, varus malunion and morbidity associated with prolonged immobility have made conservative management unpopular [205]. Treatment can be guided by using the Vancouver classification which is the most widely accepted system for classifying such fractures [206]. This system takes into account three main factors, site of the fracture, stability of the implant and quality of the surrounding bone. Type A fractures occur in the trochanteric region and are subdivided into type AG and AL fractures. AG fractures involve the greater trochanter and usually stable and can therefore be treated conservatively with protected weightbearing. AL fractures involve the lesser trochanter, and are also usually insignificant unless a large portion of the calcar is involved potentially affecting implant stability, in which case revision THA may be necessary. Type B fractures occur around or just distal to the stem and are subdivided into type B1, B2 and B3 fractures. B1 fractures have a well fixed stem and can be treated with open reduction and internal fixation. Combined plate and cerclage wire systems are commonly used for such fractures. Type B2 fractures have a loose stem but good bone stock. These are usually revised with long stem implants bypassing the fracture, and can be augmented by plates, cables and strut allografts to improve stability. Type B3 fractures have a loose stem and poor stock stock. These are the most difficult to treat and require either revision THA with structural allografts to reconstitute the proximal femur, distally fixed long stemmed implants of custom proximal femoral replacement. Type C fractures occur distal to the stem. The stem can therefore essentially be ignored and the fracture treated with standard open reduction and internal fixation.
Acetabular fractures are somewhat less common with reported intraoperative rates ranging between 0.02-0.4% [207, 208]. Data regarding postoperative fractures is currently not available [13]. The majority of intraoperative acetabular fractures occur during acetabular insertion especially during impaction of pressfit cementless components [209]. Underreaming by greater than 2mm has been suggested to significantly increase fracture risk [210].
The aims of treatment of intraoperative acetabular fractures include stabilizing the fracture and preventing further propagation and maintaining component stability [209]. Techniques include plating the anterior and posterior columns and using bone graft and jumbo revision cups if there is marked bone loss. Treatment of postoperative fractures follows similar principles. Early postoperative fractures with stable cups and minimally displaced fractures, especially around uncemented implants with supplemental screw fixation, can be treated conservatively. Unstable cups require revision with fixation of the fracture. Late presenting fractures are frequently associated with osteolysis and therefore usually require revision with bone grafting [211].
Heterotopic ossification (HO) is the abnormal formation of mature lamellar bone within extraskeletal soft tissues. HO is most commonly asymptomatic, merely detected on follow up radiology. When symptomatic, stiffness is the most common presentation. Pain and soft tissue signs such as localised warmth, mild oedema and erythema are uncommon but can cause confusion raising concerns over infection [212].
Early changes of HO within the soft tissues can be detected after 3 weeks on bone scan and plain radiographic changes can take 6 weeks to become apparent [212]. Extensive bone deposition can occur within 3 months, but full maturation takes up to one year [213]. The abductor compartment is most commonly affected. HO is most commonly classified using the Brooker classification [214]. This is based upon plain anteroposterior radiographs of the pelvis and is outlined in figure 7.
Brooker classification showing a) grade 1: islands of bone within the soft tissues about the hip, b) grade 2: bony spurs from either the femur or the pelvis, with a gap of more than 1 cm between opposing bony ends, c) grade 3: the gaps between the spurs are less than 1 cm and d) grade 4: apparent ankylosis of the hip due to the heterotopic ossification.
The pathophysiology is believed to involve inappropriate differentiation of pluripotent mesenchymal stem cells into osteoblasts, causing the excess bone formation [215]. Overexpression of bone morphogenetic protein-4 has been implicated [216, 217].
Incidence of clinically significant HO is reported to be between 3 – 7% [218, 219]. Risk factors include male gender, previous history of HO, pre-existing hip fusion, hypertrophic osteoarthritis, ankylosing spondylitis, diffuse idiopathic skeletal hyperostosis, Paget’s disease, post traumatic osteoarthritis, osteonecrosis and rheumatoid arthritis [14]. Surgical factors include extensive soft tissue dissection, haematoma and persistence of bone debris. Evidence implicating the role of surgical approach is debatable [14].
Treatment of symptomatic patients can initially involve intensive physiotherapy during the maturation phase. The efficacy of this treatment is however yet to be determined. Surgical management involves excision of the HO after maturation of the bone is allowed, followed by appropriate prophylaxis. Improvements in range of motion in all planes has been reported with surgical excision [220].
Patients at high risk of HO should be given prophylaxis either in the form of non steroidal anti-inflammatory medication (NSAIDs) or radiotherapy. Preoperative radiotherapy, 4 hours before, or post operative radiotherapy within 72 hours has been shown to be the most effective method of prophylaxis [221-223]. This involves a single dose of between 7 – 8 Gy. Combination therapy with NSAIDs and radiotherapy can be considered in patients at highest risk of HO such as patients undergoing excision of symptomatic HO [14].
Complications following total hip arthroplasty can be classified into procedure specific or systemic. On the whole complication rates have fallen with time due to improved surgical and anaesthetic technique.
The most common symptomatic systemic complication is DVT and data suggests that DVT rates post THA have not fallen with time.
The most common cause for revision is aseptic loosening. Registry data suggests up to 75% of revision surgery may be due to aseptic loosening.
Infection is one of the most feared complications. Rates with prophylactic measures such as antibiotics and clean air enclosures have however dropped significantly to below 1%.
Leg length discrepancy is one of the most common causes of patient dissatisfaction and is the most common cause of litigation in the USA.
Despite the potential wide range of complication that can occur after THA, it remains one of the most successful orthopaedic interventions
THA: Total Hip Arthroplasty
DVT: Deep Vein Thrombosis
PE: Pulmonary Embolism
THA: Total Hip Arthroplasty
PLAD: Posterior Lip Augmentation Device
UHMWPE: Ultra High Molecular Weight Polyehtylene
LLD: Limb Length Discrepancy
TGF-β: Transforming Growth Factor – Beta
RANKL: Receptor activator of nuclear factor kappa-B ligand
UHMWPE: Ultra High Molecular Weight Polyethylene
TNF-α: Tumour Necrosis Factor – Alpha
ALVAL: aseptic lymphocytic vasculitic associated lesions
HO: Heterotopic Ossification
Spatial competence is essential in everyday life for numerous human activities, as it entails the ability to understand and internalize the representation of the structure, entities, and relations of space with respect to one’s own body [1, 2]. Despite the fact that spatial competence encompasses a diverse set of skills, research in the field has generally focused on identifying the developmental steps that are necessary to acquire from an early age the ability to reason about spatial properties of the environment.
\nThere is a general consensus on the crucial role of visual experience in guiding the maturation of spatial competence [3]. Vision takes advantages respect to other senses in encoding spatial information because it ensures the simultaneous perception of multiple stimuli in the environment despite the apparent motion of the array on the retina during locomotion enabling us to extract more invariant spatial properties from the surrounding layout [4, 5]. Indeed psychophysical data indicate that when sensorial conflict occurs, audition and touch are strongly biased by simultaneously presented visuospatial information, suggesting that sighted people tend to organize spatial information according to a visual frame of reference [6, 7, 8, 9, 10, 11, 12]. Neurophysiological data further confirm the view by suggesting that the visual feedback is fundamental for spatial learning [13, 14, 15, 16, 17, 18], i.e., visual experience allows the alignment and thus the integration of auditory and visuospatial cortical maps [19, 20, 21, 22]. Thus, research on sighted individuals suggests that vision typically provides the most accurate and reliable information about the spatial properties of the external world, therefore it dominates spatial perception. Consequently, if visual experience is necessary to adequately represent spatial information, we would expect blind people to perform worse than sighted people in spatial tasks. This would be especially true if the visual impairment emerges at birth, when multisensory communication is fundamental for the sensorimotor feedback loop that contributes to the development of spatial representations [23, 24].
\nDespite valuable insights into the important guiding role of vision on spatial development, contrasting results indicate that visually impaired people can manifest or enhanced either impaired skills depending on the spatial aspects investigated, leading to the hypothesis that vision could have an essential or facilitating role depending on the nature of the spatial task that individuals carry out [14]. A clearer definition of the underlying processes involved in spatial competence enhancements and deficits caused by visual loss is important not only to quantify to what extent the perceptual consequences of early blindness translate to real-world settings but also to develop effective rehabilitation tools and technologies to improve their spatial skills [25]. Indeed, scientific findings related to spatial competence development in the absence of visual experience have important implications for clinical outcomes and for the design of new rehabilitation activities meant to activate compensatory strategies since an early age.
\nThe first developmental theory of spatial competence was proposed by Jean Piaget and his colleagues [26, 27, 28], who hypothesized that spatial understanding gradually improves with age thanks to a progressively more conscious interaction with the external world that permits to accumulate sensorimotor experiences such as reaching. Nonetheless, the identification of the starting points for spatial development remains one of the most debated topics within the literature of spatial competence.
\nWhile some researchers argue for innate knowledge of spatial understanding in humans [29] by reporting impressive spatial abilities in infants, other researchers advocate for a gradual acquisition of spatial competence during childhood [30] by reporting significant limitation of early spatial skills during infancy. For instance, several studies have demonstrated that already at 3 months infants are able to represent categorical spatial information by distinguishing between above vs. below and left vs. right [31, 32] and that by 5 months of age babies are sensitive to metric properties of space being able to code spatial object dimensions such as height [33, 34, 35], distance location [36], and angles [37]. Conversely, other studies indicate that while sensitivity to spatial properties appears in early infancy, further refinement of spatial accuracy emerges later during development. For instance, coding of categorical and metrical information improves through the primary school years [38, 39, 40] as well as capabilities of estimating and reproducing object size and location [41, 42].
\nThe question of whether spatial capabilities are innate or acquired is of central importance to understand if an early sensory deprivation can negatively impact on the acquisition of adult-like competences. In the case of blindness, a key developmental acquisition is the ability to code auditory and tactile spatial properties of the environment in order to independently orient and navigate in space. Research on auditory spatial perception has shown that sighted infants already possess the ability to differentiate acoustic information and perform adequate actions in different dimensions [43]. Indeed they can turn their heads toward a sound from the moment they are born [44, 45] and at the age of 4–5 months, head-orientation movements become even faster and more precise than in the neonatal period. Further improvements in the ability to code the location of sonorous objects in space manifest at 6 months of age, when infants are sensitive to changes in the location of sounds as small as 13–19 degrees [46, 47]. Nonetheless, this reflexive orientation to sound sources is present at birth but disappears during the first month if large movements of the head are required [48] to appear again at 4–5 months of age: for this reason, it has been hypothesized that the early orientation reflex represents the activity of lower brain stem and provides an initial stage to acquire spatial competence [49] that is later consolidated through concrete experience.
\nIn the spatial cognition domain, two main distinctions can be made about spatial representations of the environment [50]. The first distinction is between the egocentric and allocentric frame of reference which indicates the strategy to code location of objects, respectively, in a viewer-dependent or a viewer-independent manner. While the egocentric representation is tied to the observer and can be used either when the observer remains stationary or when the observer moves keeping track of the movement (dead reckoning or path integration), the allocentric representation does not depend on the viewer’s current position but on external landmarks that can be adjacent (cue learning) or distal (place learning). Although early spatial representations were originally described as purely egocentric [51], several studies indicated that infants can make use of both intrinsic and external features of the environment to locate objects. There is evidence that infants can update egocentric representations by keeping track of their movement and thus locate objects from novel positions within the first year of life: indeed by 9 months, infants can compensate for simple changes in their position, such as translation along a straight line [52] or rotational movements [53]. Nonetheless, for more complex displacements, infants manifest a general difficulty in keeping track of their changing relation to target location. For example, at 12 months of age, they start to solve complex problems involving both translation and rotation but they perform better when they can make use of adjacent landmarks embedded in the environment [54], and this ability seems to show little improvement between 16 and 36 months [55]. Moreover, previous research has shown that sighted infants reach for sounding objects in the absence of visual clues [47, 56, 57, 58, 59], implying that a sense of auditory space is well consolidated at this stage since sounding objects are localized in relation to one’s body. The allocentric strategy seems to emerge quite early in the development together with the egocentric strategy, but with different maturational rates for cue learning and place learning types of coding. Indeed, studies employing paradigms where the direction of looking from a novel position indicate where infants expect to see an engaging stimulus demonstrate that by 8.5 months of age, infants use an adjacent salient landmark to locate the stimulus, whereas only at 12 months of age, they consistently use relational information of distal landmarks [54]. Several studies confirm the idea that egocentric and allocentric strategies continue to refine during childhood by showing that at 18–24 months of age, toddlers become able to use geometrical cues such as shape to orient themselves [60, 61]. Nonetheless, an important milestone such as the ability to integrate different reference frames within a common system of spatial representation in order to increase accuracy and reduce the variability of spatial judgments emerge only later during the development. Indeed, children aged between 4 and 8 years old are not able to use both self-motion and external landmarks as egocentric and allocentric information, respectively, to reproduce object location because they alternated both strategies instead of combining them as adults usually do [62].
\nThe second distinction in the spatial cognition domain is between categorical and metric spatial representations, which, respectively, represent the coding of spatial information in a relative manner by means of comparisons among entities in space and the coding of spatial information in external coordinates by means of metric cues such as distance or length. It has been shown that at 7 months of age, infants spontaneously show categorical dichotomous discrimination of auditory space by differentiating objects within and beyond reach [57, 58] and by distinguishing spatial categories such as above vs. below and left vs. right [32, 63]. Early sensitivity to metric cues has been observed in 4.5–6.5 months old infants for the dimension of objects [64] and distance [36]. Nonetheless, methodological issues have been raised for the interpretation of such results since experimental paradigms typically used with infants employ observational measures of the infant’s behavior that may reveal more low-level perceptual rather than conceptual representation. Indeed, it has been shown that at the age of 2 years, children are able to match objects by height when these objects are presented in containers of a fixed height, but not when they are presented without containers, indicating that toddlers make use of distance cues only when they can rely on relative cues [65]. A considerable improvement in the ability to code object size and location can be observed between the ages of 4 and 12 [40, 41, 42, 66], for example, in tasks that require to use a configuration of distal landmarks to infer object location [67]. This could be due to the development of a hierarchical coding system, which integrates metrics and categorical information [68]. Given the time course of spatial cognition development and the discrepancy between early and later acquisition of spatial skills, an interactionist approach has been proposed that acknowledges strong potentiality and tries to identify underlying mechanisms implicated in the transformation of early abilities into mature competence [69]. The underlying mechanisms responsible for the refinement of spontaneous spatial orientation skills might be found both in the biological and environmental experiences. Within the biological context, many improvements in spatial functioning have been associated with the maturation of specific brain regions such as the hippocampus. For instance, the maturation of the hippocampus-mediated ability to encode relations among multiple objects may determine an increase in the number of stimuli that children rely on during reorientation and navigation tasks [70]. Within the environmental context, experience involves interactions with objects in the physical world and learning conventional information about symbolic spatial representations, such as maps and models. Spatial competence is strictly dependent on experiential factors such as exploratory activities which are in turn related to the development of locomotor activities. For example, it has been suggested that the emergence of allocentric coding in the form of cue learning might derive from the onset of crawling around 8–9 months, while further locomotor experiences may facilitate place learning by stimulating children to observe and approach object arrays from different directions. Indeed, locomotion is not simply a maturational precursor to psychological changes, but it plays a crucial role in their genesis [71]. For example, crawling provides the infant with concrete experiences that may change his coding strategy, for example, permitting the infant to abandon an egocentric body-oriented localization of objects to one based on the use of environmental landmarks. Recent findings suggest that sighted children acquire spatial capabilities thanks to the reciprocal influence between visual perception and execution of movements [72]: children monitor the success of action through a sensory-motor feedback by matching expected and observed changes of visual information. Indeed, self-generated movements commonly help to perceive the space acoustically because they convey the proprioceptive sensation corresponding to the movement of the ears toward sound sources [73]. In other words, using the dichotomy between the body and its exterior, an individual acquires spatial competence through observation of the body’s actions and the resulting sensory consequences: through self-generated movements, the nervous system learns sensorimotor contingencies [74], which reveal the spatial properties of the auditory space. Moreover, acting successfully entails affordances for action: since affordances change according to action capabilities and bodily characteristics, experiential factors are necessary especially during infancy when new skills are constantly appearing and bodily dimensions are changing rapidly [75].
\nThese results suggest that early interaction between the visual input and other sensory and motor signals provides a powerful background to shape the development of spatial cognition in sighted children. But if vision is so important, how spatial development changes when the visual input is missing?
\nWhile the development of spatial cognition has been extensively studied in sighted individuals [50], less effort has been spent in understanding how the sense of space changes during development in children with visual impairment. Specifically, scientific research on the development of auditory localization skills in visually impaired children has provided contrasting results. For example, it has been shown that children with visual disabilities have an excellent spatial hearing, measured as the ability to discriminate differences in sound localization in the horizontal and vertical plane as well as the ability to reach or walk toward the sound source position [76]. On the contrary, several studies suggested that infants and children with severe congenital blindness have a developmental delay in sound localization abilities [23, 77, 78, 79] and motor responses to sound [80, 81]. For example, blind children do not reach for objects that produced sounds until the end of the first year, while sighted children start around 5 months [82]. Similarly, blind children show worse performances than sighted children in auditory bisection, minimum audible angle tasks [23], and audio depth tasks [78]. Other studies show mixed results, indicating that children with congenital visual disabilities show an initial neuromotor developmental delay but compensate for the lack of vision developing good manipulatory and walking skills thanks to the exploration of sounding objects in the environment [83]. Studies of proprioceptive localization of immediate and memorized targets have been used to compare the proprioceptive performance of sighted and blind individuals. For instance, it has been shown that early visual deprivation does not necessarily prevent the development of spatial representations in both early blind children [84] and adults [85]. Considering that spatial competence emerges gradually thanks to the reciprocal influence between visual perception and execution of movements [72], it is evident that visually impaired children not only lack the visual input necessary to establish the sensorimotor feedback that typically promotes spatial development, but also manifests a general delay in the acquisition of important locomotor and proprioceptive skills, which may cause them to accumulate much less spatial experience compared to their sighted peers [79, 86, 87]. It has long been known that the development of blind infants is delayed in self-initiated postures and locomotion [79, 88, 89]. While sighted children typically start to perform first individual actions and navigation from the first year of age, blind children without cognitive and motor impairments start to walk at about 30–32 months of age [90]. Moreover, from the first month of life, blind infants show delays in the vestibular and proprioceptive functions due to the lack of integration with the visual inputs typically provided during the development [91]. Finally, since visual feedback represents the most important incentive for actions and thus for the development of locomotion and mobility skills, the onset of several motor milestones (e.g., rolling, crawling, standing, and balancing) can be delayed in visually impaired infants [92, 93], suggesting that the visual feedback of the body is fundamental for the development of self-concept.
\nTo perceive space, visually impaired children typically use hearing and touch. Despite the haptic sense provides essential information about the spatial layout of peripersonal space, such as the size, shape, position, and orientation of objects within reach, it typically conveys information only within the scope of the body. The case of hearing is particularly interesting because the auditory sense is not only the main channel for providing distal information but also it might be superior to all other sensory alternatives because it provides spatial information in both active and passive conditions and it does not necessarily involve direct contact with objects [94, 95]. At the same time, the use of hearing to perceive distal information might be particularly difficult for visually impaired children because in this case, they do not have any sensory feedback about sonorous objects in the far space. On the contrary, the haptic-proprioceptive system can provide accurate spatial data only within the scope of the body itself [96], and therefore a blind person must actively move in the environment to sequentially touch all the stimuli embedded in space. Several factors may contribute to increasing the difficulty in interpreting such contrasting results. For example, many studies on spatial hearing have been conducted within the framework of broader research on cognitive and motor skills development [87, 97] and reaching mixing the motor and the perceptual component of the observed behavior [83, 98]. In addition, different methodological approaches and stimuli have been used to assess similar aspects of auditory spatial perception: for instance, studies performed on visually impaired children under 3 years of age do not employ psychophysical procedures but they frequently use the sound of familiar voices or toys to gather information about auditory localization abilities in blind children [97]. In addition, in some cases, sighted and blind groups of children are not perfectly matched for age range and sometimes use also adults as comparison [76]. Finally, the difference between early and later loss of vision has not been often considered: many studies mix data from children with no visual experience with those of children with partial visual experience in the first period of life [76]. Instead, it has been demonstrated that the onset of blindness has a strong impact on spatial performance in adulthood: for example, late blind individuals who lost vision later in life after a normal visual experience during the first year of life perform equally or even better than sighted participants in several auditory spatial tasks (1, 50, 83, and 300). To summarize, although compensatory mechanisms for spatial perception have been demonstrated in blind adults, it is not clear whether an early visual impairment might delay the development of special auditory spatial skills. The development of spatial cognition is strictly related to the development of social cognition: the ability to independently navigate and orient ourselves in space facilitates engagement in social interactions. Indeed, a delay in the acquisition of language, motor or cognitive skills can have a direct impact on a child’s social competence (106, 109, and 246). More recent works highlighted that preschool-age children with visual impairments often have difficulties engaging in positive social interactions, making their assimilation into preschool programs difficult. In fact, many do not display a full range of play behaviors [99, 100, 101, 102, 103] and spend more time engaging in solitary play interacting more with adults than with their sighted peers [81, 87, 89, 102, 103, 104, 105, 106, 107]. Considering that the interaction among peers is essential for the development of cognitive, linguistic, social, and playing skills [108], the aforementioned delay in the acquisition of social competence in visually impaired children gives rise to feelings of frustration, rather than self-efficacy and independence which characterize the social experience of typical children. Indeed, the lack of visual information during early infancy often constitutes a risk for the development of the personality and emotional competence [89]. Nonetheless, when assessing social competence in visually impaired people, some other factors resulting from the loss of vision should be taken into account. For example, it has been shown that parenting style influences the socio-emotional development of sighted children [109, 110, 111, 112, 113] because parents represent the first influential setting that can produce appreciable differences in developmental outcomes in terms of psychological functions [114, 115]. Inconsistent, hostile and nonsensitive parenting behaviors have been associated with adjustment problems and social adversity during childhood [116, 117] and also with anxiety, depression, and other stress-related illnesses during adolescence [118, 119] and adulthood [120]. We speculate that a similar influence of parenting style holds also for blind children, especially because families of children with visual disabilities are more prone to experience various stressors such as concerns about the social acceptance of the child [121] and to face difficulties in initiating and sustaining social interactions [122], thus they might easily develop an overprotective behavior that negatively influences the social development of the visually impaired child. The negative effects of blindness on socio-emotional competence can be observed also in adulthood, with the impoverishment of the ability to perform everyday activities both in private settings like home and in public settings like workplace. Importantly, the decrease of functional abilities has been linked to the emergence of serious psychological problems in the blind population [123]. Indeed adults with visual impairments tend to feel more socially isolated and not properly supported compared to sighted individuals [123, 124, 125, 126] and are at higher risk of developing depressive symptoms [105, 125, 127, 128, 129, 130, 131], principally because social competence depends on the ability to utilize visual cues [132]. Overall, several scientific findings suggest that visual impairments, especially if acquired later in life, can have profound consequences for the physical functioning, psychological well-being, and health service needs of older adults [133]. Consequently, early therapeutic interventions specifically focused on activities fostering the development of perceptual and motor abilities would improve the quality of life of children and adults with visual impairments. In the next section, we will present some tools developed to improve perceptual skills of visually impaired individuals and propose a new solution we recently developed for early intervention in visually impaired children.
\nThe acquisition of spatial competence is typically a good indicator of the future ability to independently navigate in the environment and engage in positive social interaction with peers. While for sighted individuals, the visual feedback represents the most important incentive for actions and thus for the development of mobility and social skills, visually impaired individuals strongly rely on auditory and tactile landmarks to encode spatial and social information. Thus, the creation of technological devices to support visually impaired children in their spatial and social development would be a need. Nonetheless, despite the huge recent advancements in technological industry, most of the devices developed so far to address visually impaired population’s needs are not widely accepted by adults and not easily adaptable to children [134].
\nAs reported in the previous sections, visual impairments can determine spatial and social impairments during development. Technological support for the blind should fulfill two different but complementary tasks: the first is to substitute the absent sensory information (vision) with other sensory signals (audition and touch) for daily activities, and the second is to support the rehabilitation of impaired functions following sensory loss. This latter aspect is particularly important when the visual impairment occurs during the first year of life, because technological devices might represent an opportunity for children to develop perceptual and cognitive abilities by compensating for the sensory deprivation. Most of the technological supports developed to date have fulfilled mainly the first task, namely the substitution of vision with other modalities for everyday tasks such as object recognition.
\nSensory substitution devices (SSDs) convert the stimuli, normally accessed through one sensory modality, into stimuli accessible to another sensory modality. Specifically, sensory substitution devices for visually impaired individuals aim at supplying the missing visual information with visual-to-tactile or visual-to-auditory conversion systems [135]. Typically, substitution systems based on visual-to-tactile conversion transforms images captured by a camera into tactile stimulations directed to users. From the first device developed in the mid-1960s by Bach-y-Rita (Tactile-Visual Sensory Substitution device or TVSS), that converts signals from a video camera into tactile stimulation applied to the back of the subject allowing for the recognition of lines and shapes [136], recent technological progress allowed the development of much smaller, portable, and wearable devices. For instance, wristbands, vests, belts, and shoes which allow hands-free interactions [137] and devices that can be placed on various body surfaces (e.g., fingers, wrist, head, abdomen, and feet) [138, 139]. Conversely, systems based on visual-to-auditory conversion transform the images captured by a camera into sounds transmitted to users via headphones. One of the most famous visual-to-auditory devices is the vOICe developed by Meijer [140] that associates height with pitch and brightness with loudness in a left-to-right scan of the visual image.
\nIn our recent review, we listed the SSDs designed for visually impaired individuals by highlighting their main features and limitations for daily use [134]. In particular, we identified six main limitations that might determine low acceptance rate in adults and low adaptability in children:
Invasiveness: SSDs can be physically invasive in the sense that in order to be used, they must be positioned on crucial body parts (e.g., ears or mouth), thus limiting perceptual functions in users or they must be transported (e.g., in backpacks), thus limiting users’ navigation for weight and size;
Extensive training: SSDs typically require long periods of training in order to be used because users need to learn how to interpret the output of the device, which is typically not immediate (e.g., sound loudness corresponds to pixel brightness in the vOICe [141]);
High cognitive load: SSDs usually require high attentional resources, which makes it difficult for the user to focus on the main task they are performing when using the device;
No clinical validation: SSDs frequently remain prototypes and do not reach the blind users market, principally because they are not validated on large sample patients through standardized clinical trials;
Artificiality: SSDs are generally based on the idea that users can understand the properties of visual stimulus by listening (in the case of visual-to-auditory SSDs) or feeling (in the case of visual-to-tactile SSDs) a stimulus resulting from an artificial transformation code, missing an important aspect of the learning process, which is the association of action and perception.
Therefore, while sensory substitution devices have been shown to provide support for specific perceptual tasks in adults [142], they have never been tested in children principally because their use might too overwhelming for children. Nonetheless, technological development should be addressed especially to visually impaired children needs because cortical plasticity is maximal during the first year of life, therefore the benefit deriving from early interventions should be higher. Moreover, technological development should lead to multimodal stimulation whose benefits have been repeatedly reported compared to unimodal stimulation [143, 144, 145], while most of the SSDs developed so far substitute the visual function with either the auditory or the tactile modality alone.
\nWith this in mind, we developed a new device for visually impaired children (Audio Bracelet for Blind Interaction, ABBI, [146]), which is an audio bracelet that produces an auditory feedback of body movements when positioned on a main effector such as the wrist in order to provide a sensorimotor signal similar to that used by sighted children to construct a sense of space. Indeed, several reports indicate that sighted children typically acquire spatial competence by experiencing visuomotor correspondences [72]. In this sense, our device could be used to align the spatial understanding between one’s own body and the external space through coupling auditory feedback with intentional motor actions. The audio movement created by the bracelet conveys spatial information and allows the blind user to build a representation of the movement in space in an intuitive and direct manner.
\nWe validated the ABBI device with a clinical trial on an Italian sample of 44 visually impaired children aged 6–17 years old assigned to an experimental (ABBI training) or a control (classical training) rehabilitation condition. The experimental training group followed an intensive but entertaining rehabilitation for 12 weeks during which children performed ad-hoc developed audio-spatial exercises with the Audio Bracelet for Blind Interaction (ABBI). The clinical trial consisted of three sessions: pre-evaluation, training, and post-evaluation. Pre- and post-evaluation sessions lasted 60 min during which a battery of spatial and motor tests were performed [147]. The BSP (Blind Spatial Perception) battery comprised six tests: (1) auditory localization: the child listens to the sound produced by a set of loudspeakers positioned horizontally in front of him/her and localizes the sound source by pointing to it with a white cane; (2) auditory bisection: the child listens to a sequence of three sounds presented successively by a set of loudspeakers positioned horizontally in front of him/her and verbally reports whether the second sound is closer in space to the first or to the third one presented; (3) auditory distance: the child listens to two consecutive sounds produced by a set of loudspeakers positioned vertically in front of him/her in depth and verbally reports which of the two stimuli presented is closer in space to his/her own body; (4) auditory reaching: the child listens to a static sound positioned in far space and reaches the position of the sound by walking toward it; (5) proprioceptive reaching: the child repeats a movement trajectory after being presented with it by an external operator; (6) general mobility: the child walks straight on for three meters and then back to the starting position at his/her own pace. The training session lasted 12 weeks and children were assigned to the experimental training condition based on activities with the use of ABBI or to the classical training condition based on psychomotor lessons not necessarily involving sound localization activities. All children enrolled in the ABBI training group performed weekly training exercises with a trained rehabilitator for 45 min (9 h over 12 weeks) and weekly training sessions with a relative at home for 5 h (60 h over 12 weeks) for a total training period of 69 h. All training exercises were developed to train children’ ability to recognize and localize sounds in space according to different levels of difficulty: (a) recognize and localize simple sound movements, such as a straight motion flow performed along the horizontal or sagittal planes in the front peri-personal space (first level); (b) recognize and localize complex sound movements, such as a motion flow performed randomly in space in the front peri-personal space, e.g., composite geometrical and nongeometrical figures (second level); (c) recognize and localize simple and complex sound movements in the back peri-personal space (third level); (d) recognize and localize simple and complex sound movements in the front and back in the extra-personal space (fourth level). The comparison of overall spatial performance before and after the training with a dedicated assessment battery indicated that the ABBI device is effective in improving spatial skills in an intuitive manner (see Table 1 for a summary of results), confirming that in the case of blindness perceptual development can be enhanced with naturally associated auditory feedbacks to body movements [148]. Moreover, the validation of the ABBI device demonstrated that the early introduction of a tailored audio-motor training could potentially prevent spatial developmental delays in visually impaired children [149].
\nScore difference (Δ) after 12 weeks training (T1-T0).
One year follow-up of the ABBI group (T2-T0). In order to evaluate the effects within groups, two-tailed t-tests assuming equal variances were performed between groups at baseline (T0) and post-training period (T1). Changes in the outcome measures were then calculated between baseline (T0) and post-training period (T1) in the ABBI training and classical training group (ΔΑ and ΔC), and between baseline (T0) and follow-up period (T2) in the ABBI training group (ΔΑ2). Data are presented as mean and standard deviation. The stars indicate the statistical significance of the corresponding t-test of the score difference (*p < 0.05; **p < 0.01; ***p < 0.001). Table readapted from [148].
Visual experience is deemed to be fundamental for the acquisition of spatial competence; indeed, visually impaired children tend to manifest impairments in spatial and locomotor skills, causing a general developmental delay. The hearing sense can be boosted since an early age to foster compensatory mechanisms for the development of spatial perception, principally because compared to touch it can provide distal information [150]. There is evidence that multisensory training based on the action-perception link can improve spatial abilities in visually impaired children and prevent the risk of developmental delays and social exclusion [148, 149, 151].
\nWe would like to thank all the children and parents for their willing participation in our studies and the Unit for Visually Impaired People (UVIP) members for their passionate work on visually impaired individuals.
\nThe authors declare no conflict of interest.
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His research interest focuses on computational chemistry and molecular modeling of diverse systems of pharmacological, food, and alternative energy interests by resorting to DFT and Conceptual DFT. He has authored a coauthored more than 255 peer-reviewed papers, 32 book chapters, and 2 edited books. He has delivered speeches at many international and domestic conferences. He serves as a reviewer for more than eighty international journals, books, and research proposals as well as an editor for special issues of renowned scientific journals.",institutionString:"Centro de Investigación en Materiales Avanzados",institution:{name:"Centro de Investigación en Materiales Avanzados",country:{name:"Mexico"}}},{id:"76477",title:"Prof.",name:"Mirza",middleName:null,surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/76477/images/system/76477.png",biography:"Dr. Mirza Hasanuzzaman is a Professor of Agronomy at Sher-e-Bangla Agricultural University, Bangladesh. He received his Ph.D. in Plant Stress Physiology and Antioxidant Metabolism from Ehime University, Japan, with a scholarship from the Japanese Government (MEXT). Later, he completed his postdoctoral research at the Center of Molecular Biosciences, University of the Ryukyus, Japan, as a recipient of the Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. He was also the recipient of the Australian Government Endeavour Research Fellowship for postdoctoral research as an adjunct senior researcher at the University of Tasmania, Australia. Dr. Hasanuzzaman’s current work is focused on the physiological and molecular mechanisms of environmental stress tolerance. Dr. Hasanuzzaman has published more than 150 articles in peer-reviewed journals. He has edited ten books and written more than forty book chapters on important aspects of plant physiology, plant stress tolerance, and crop production. According to Scopus, Dr. Hasanuzzaman’s publications have received more than 10,500 citations with an h-index of 53. He has been named a Highly Cited Researcher by Clarivate. He is an editor and reviewer for more than fifty peer-reviewed international journals and was a recipient of the “Publons Peer Review Award” in 2017, 2018, and 2019. He has been honored by different authorities for his outstanding performance in various fields like research and education, and he has received the World Academy of Science Young Scientist Award (2014) and the University Grants Commission (UGC) Award 2018. He is a fellow of the Bangladesh Academy of Sciences (BAS) and the Royal Society of Biology.",institutionString:"Sher-e-Bangla Agricultural University",institution:{name:"Sher-e-Bangla Agricultural University",country:{name:"Bangladesh"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",biography:"Kusal K. Das is a Distinguished Chair Professor of Physiology, Shri B. M. Patil Medical College and Director, Centre for Advanced Medical Research (CAMR), BLDE (Deemed to be University), Vijayapur, Karnataka, India. Dr. Das did his M.S. and Ph.D. in Human Physiology from the University of Calcutta, Kolkata. His area of research is focused on understanding of molecular mechanisms of heavy metal activated low oxygen sensing pathways in vascular pathophysiology. He has invented a new method of estimation of serum vitamin E. His expertise in critical experimental protocols on vascular functions in experimental animals was well documented by his quality of publications. He was a Visiting Professor of Medicine at University of Leeds, United Kingdom (2014-2016) and Tulane University, New Orleans, USA (2017). For his immense contribution in medical research Ministry of Science and Technology, Government of India conferred him 'G.P. Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke as a postdoctoral fellow where he worked on the interaction of ATP with the phosphoenzyme of the Na+/K+-ATPase and dual mechanisms of allosteric acceleration of the Na+/K+-ATPase by ATP; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. Pakistan Institute of Nuclear Science & Technology (PINSTECH) Islamabad, Punjab Institute of Nuclear Medicine (PINM), Faisalabad and Institute of Nuclear Medicine and Radiology (INOR) Abbottabad are the main collaborating institutes.",institutionString:"Government College University",institution:{name:"Government College University, Faisalabad",country:{name:"Pakistan"}}},{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",country:{name:"Hungary"}}},{id:"277367",title:"M.Sc.",name:"Daniel",middleName:"Martin",surname:"Márquez López",slug:"daniel-marquez-lopez",fullName:"Daniel Márquez López",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/277367/images/7909_n.jpg",biography:"Msc Daniel Martin Márquez López has a bachelor degree in Industrial Chemical Engineering, a Master of science degree in the same área and he is a PhD candidate for the Instituto Politécnico Nacional. His Works are realted to the Green chemistry field, biolubricants, biodiesel, transesterification reactions for biodiesel production and the manipulation of oils for therapeutic purposes.",institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",country:{name:"Argentina"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",biography:"Francisco Javier Martín-Romero (Javier) is a Professor of Biochemistry and Molecular Biology at the University of Extremadura, Spain. He is also a group leader at the Biomarkers Institute of Molecular Pathology. Javier received his Ph.D. in 1998 in Biochemistry and Biophysics. At the National Cancer Institute (National Institute of Health, Bethesda, MD) he worked as a research associate on the molecular biology of selenium and its role in health and disease. After postdoctoral collaborations with Carlos Gutierrez-Merino (University of Extremadura, Spain) and Dario Alessi (University of Dundee, UK), he established his own laboratory in 2008. The interest of Javier's lab is the study of cell signaling with a special focus on Ca2+ signaling, and how Ca2+ transport modulates the cytoskeleton, migration, differentiation, cell death, etc. He is especially interested in the study of Ca2+ channels, and the role of STIM1 in the initiation of pathological events.",institutionString:null,institution:{name:"University of Extremadura",country:{name:"Spain"}}},{id:"217323",title:"Prof.",name:"Guang-Jer",middleName:null,surname:"Wu",slug:"guang-jer-wu",fullName:"Guang-Jer Wu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217323/images/8027_n.jpg",biography:null,institutionString:null,institution:null},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/148546/images/4640_n.jpg",biography:null,institutionString:null,institution:null},{id:"272889",title:"Dr.",name:"Narendra",middleName:null,surname:"Maddu",slug:"narendra-maddu",fullName:"Narendra Maddu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272889/images/10758_n.jpg",biography:null,institutionString:null,institution:null},{id:"242491",title:"Prof.",name:"Angelica",middleName:null,surname:"Rueda",slug:"angelica-rueda",fullName:"Angelica Rueda",position:"Investigador Cinvestav 3B",profilePictureURL:"https://mts.intechopen.com/storage/users/242491/images/6765_n.jpg",biography:null,institutionString:null,institution:null},{id:"88631",title:"Dr.",name:"Ivan",middleName:null,surname:"Petyaev",slug:"ivan-petyaev",fullName:"Ivan Petyaev",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Lycotec (United Kingdom)",country:{name:"United Kingdom"}}},{id:"423869",title:"Ms.",name:"Smita",middleName:null,surname:"Rai",slug:"smita-rai",fullName:"Smita Rai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424024",title:"Prof.",name:"Swati",middleName:null,surname:"Sharma",slug:"swati-sharma",fullName:"Swati Sharma",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"439112",title:"MSc.",name:"Touseef",middleName:null,surname:"Fatima",slug:"touseef-fatima",fullName:"Touseef Fatima",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424836",title:"Dr.",name:"Orsolya",middleName:null,surname:"Borsai",slug:"orsolya-borsai",fullName:"Orsolya Borsai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",country:{name:"Romania"}}},{id:"422262",title:"Ph.D.",name:"Paola Andrea",middleName:null,surname:"Palmeros-Suárez",slug:"paola-andrea-palmeros-suarez",fullName:"Paola Andrea Palmeros-Suárez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Guadalajara",country:{name:"Mexico"}}}]}},subseries:{item:{id:"26",type:"subseries",title:"Machine Learning and Data Mining",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence",scope:"The scope of machine learning and data mining is immense and is growing every day. It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. It is not limited to any particular applications, but contributions are encouraged from all disciplines.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11422,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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