\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"4651",leadTitle:null,fullTitle:"A Fresh Look at Anxiety Disorders",title:"A Fresh Look at Anxiety Disorders",subtitle:null,reviewType:"peer-reviewed",abstract:"This book, the ideal following of the previous New Insights into Anxiety Disorders, collects papers of a number of clinical psychiatrists all over the world, giving their contribution to the comprehension and clinical management of anxiety disorders. Following the previously edited book on anxiety, this new one will focus on some specific clinical issues such as PTSD, psychosomatics, and complementary approaches to anxiety management themes which were not discussed in the previous book.",isbn:null,printIsbn:"978-953-51-2149-7",pdfIsbn:"978-953-51-7254-3",doi:"10.5772/59525",price:139,priceEur:155,priceUsd:179,slug:"a-fresh-look-at-anxiety-disorders",numberOfPages:358,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"8f18ff3698fbd7584a3da8a3e4916fba",bookSignature:"Federico Durbano",publishedDate:"September 9th 2015",coverURL:"https://cdn.intechopen.com/books/images_new/4651.jpg",numberOfDownloads:42134,numberOfWosCitations:50,numberOfCrossrefCitations:57,numberOfCrossrefCitationsByBook:3,numberOfDimensionsCitations:97,numberOfDimensionsCitationsByBook:3,hasAltmetrics:1,numberOfTotalCitations:204,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 22nd 2014",dateEndSecondStepPublish:"November 12th 2014",dateEndThirdStepPublish:"February 16th 2015",dateEndFourthStepPublish:"May 17th 2015",dateEndFifthStepPublish:"June 16th 2015",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"157077",title:"Dr.",name:"Federico",middleName:null,surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano",profilePictureURL:"https://mts.intechopen.com/storage/users/157077/images/system/157077.jpeg",biography:"Dr. Federico Durbano received a degree in Medicine with a specialization in Psychiatry. He has worked at various hospitals, including Milan “Ospedale Maggiore Policlinico,” Treviglio, Melegnano, and Fatebenefratelli, where he achieved significant career milestones. He is currently the director of the Mental Health and Substance Abuse Department at ASST Melegnano e della Martesana. Dr. Durbano has had teaching assignments at the University of Milan (Nursing School) and the University of Castellanza (Master in Criminology). He has attended more than seventy local and national congresses and courses as an invited speaker and has published more than 180 papers. He is also a technical advisor to the court in the field of forensic psychiatry.",institutionString:"Mental Health and Substance Abuse Department in ASST Melegnano and Martesana",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"ASST Melegnano e della Martesana",institutionURL:null,country:{name:"Italy"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1061",title:"Psychiatry",slug:"mental-and-behavioural-disorders-and-diseases-of-the-nervous-system-psychiatry"}],chapters:[{id:"48919",title:"Risk Factors of Anxiety Disorders in Children",doi:"10.5772/61169",slug:"risk-factors-of-anxiety-disorders-in-children",totalDownloads:3107,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Anxiety disorders are common; lifetime prevalence for the group of disorders is estimated to be as high as 25%. The main question is What is the relative contribution of genetics and environment to etiology of anxiety disorders? The anxiety disorders are not, from a genetic perspective, etiologically homogeneous. Structural equation modeling provides estimates of variance in liability to a disorder that is attributable to additive genetic, common familial environmental, and individual-specific environmental factors. Familial aggregation that largely results from genetic risk factors has been documented for all of the major anxiety disorders. Genes predispose to two broad groups of disorders dichotomized as panic-generalized-agoraphobic anxiety versus specific phobias. The candidate genes are the ones encoding the central and peripheral nervous system receptors and transporters. Trauma in childhood disposes to further anxiety disorders through the hyperactivity of the HPA axis and the hypersecretion of CRF. Traumatic experience in developmental age leads to neurobiochemical changes in brain, typical for panic disorder or PTSD. Behavioral inhibition in early childhood is a predictor of further anxiety disorders. Some types of parental behaviors and family environment can lead to them, as well as improper interactions between parents and child.",signatures:"Malgorzata Dabkowska and Agnieszka Dabkowska-Mika",downloadPdfUrl:"/chapter/pdf-download/48919",previewPdfUrl:"/chapter/pdf-preview/48919",authors:[{id:"48667",title:"Dr.",name:"Malgorzata",surname:"Dabkowska",slug:"malgorzata-dabkowska",fullName:"Malgorzata Dabkowska"},{id:"58055",title:"Dr.",name:"Agnieszka",surname:"Dabkowska-Mika",slug:"agnieszka-dabkowska-mika",fullName:"Agnieszka Dabkowska-Mika"}],corrections:null},{id:"48416",title:"Examining Sex and Gender Differences in Anxiety Disorders",doi:"10.5772/60662",slug:"examining-sex-and-gender-differences-in-anxiety-disorders",totalDownloads:3743,totalCrossrefCites:18,totalDimensionsCites:29,hasAltmetrics:1,abstract:"Several studies have examined sex differences in different anxiety disorders. Females are repeatedly found to be more likely than males to suffer from anxiety in general and to be diagnosed with most anxiety disorders, including agoraphobia (AG), panic disorder (PD), separation anxiety (SA), specific phobia (SP), social anxiety disorder (SAD), generalised anxiety disorder (GAD), obsessive-compulsive disorder (OCD), and acute and posttraumatic stress disorder (ASD and PTSD), although the latter three are technically no longer categorised as anxiety disorders according to DSM-5. This chapter provides an overview of research on sex and gender differences in anxiety disorders ranging from the well-established female preponderance in prevalence and severity to possible sex differences in the risk and protective factors associated with anxiety, sex differences in the clinical presentation of anxiety disorders, and potential sex differences in the effectiveness of different treatments. The chapter contains suggestions for future research, including important questions that remain to be answered.",signatures:"Dorte M. Christiansen",downloadPdfUrl:"/chapter/pdf-download/48416",previewPdfUrl:"/chapter/pdf-preview/48416",authors:[{id:"113525",title:"MSc.",name:"Dorte",surname:"M. Christiansen",slug:"dorte-m.-christiansen",fullName:"Dorte M. Christiansen"}],corrections:null},{id:"48428",title:"Psychobiological Aspects of Panic Disorder",doi:"10.5772/60663",slug:"psychobiological-aspects-of-panic-disorder",totalDownloads:2619,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Anxiety is a useful warning sign that helps an individual face potential or real danger. At appropriate levels, it serves as a warning for the presence of internal or external threats, causing a person to be alert and prepare to deal appropriately with such situations. Moreover, moderate levels of anxiety can lead to improved performance in several activities. However, anxiety becomes pathological when its duration is excessively long or its intensity is extremely high and leads to significant suffering and distress. In such cases, anxiety is appropriately described as part of a pathological response, characterizing an anxiety disorder. The historical concept of a unitary anxiety disorder has been replaced by a heterogeneous group of psychopathologies with different etiologies. Panic disorder is a complex anxiety disorder that involves both recurrent, unexpected panic attacks, and persistent concern about having additional attacks. The present chapter reviews current psychobiological perspectives in the etiology and treatment of panic disorder. The first section describes the current classification of this anxiety disorder. We then explore possible neural circuitry associated with panic disorder. Finally, the chapter addresses current treatment approaches, considering the efficacy of different forms of psychotherapy and pharmacological treatments.",signatures:"Daniel C. Mograbi, Vitor Castro-Gomes, Elie Cheniaux and J.\nLandeira-Fernandez",downloadPdfUrl:"/chapter/pdf-download/48428",previewPdfUrl:"/chapter/pdf-preview/48428",authors:[{id:"52728",title:"Dr.",name:"J.",surname:"Landeira-Fernandez",slug:"j.-landeira-fernandez",fullName:"J. Landeira-Fernandez"},{id:"52733",title:"Dr.",name:"Vitor",surname:"Castro-Gomes",slug:"vitor-castro-gomes",fullName:"Vitor Castro-Gomes"},{id:"174509",title:"Dr.",name:"Daniel",surname:"Mograbi",slug:"daniel-mograbi",fullName:"Daniel Mograbi"},{id:"175657",title:"Dr.",name:"Elie",surname:"Cheniaux",slug:"elie-cheniaux",fullName:"Elie Cheniaux"}],corrections:null},{id:"48437",title:"Genetics of Posttraumatic Stress Disorder — Candidate Genes and Their Implication in the Disease-Associated Molecular Pathomechanisms",doi:"10.5772/60443",slug:"genetics-of-posttraumatic-stress-disorder-candidate-genes-and-their-implication-in-the-disease-assoc",totalDownloads:1622,totalCrossrefCites:0,totalDimensionsCites:3,hasAltmetrics:1,abstract:"Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder (DSM-V code: 309.81; ICD-10 codes: F43.1). PTSD is an anxiety disorder developed in a person experiencing, witnessing, or learning about an extreme physically or/and psychologically distressing event. Its incidence and the number of this disease-affected people are threateningly increasing in contemporary society. Therefore, the development of prognostic strategies and novel efficient methods on early diagnostics and treatment of PTSD is currently considered as one of the most important healthcare problems worldwide.",signatures:"Boyajyan Anna, Avetyan Diana, Hovhannisyan Lilit and Mkrtchyan\nGohar",downloadPdfUrl:"/chapter/pdf-download/48437",previewPdfUrl:"/chapter/pdf-preview/48437",authors:[{id:"157186",title:"Prof.",name:"Anna",surname:"Boyajyan",slug:"anna-boyajyan",fullName:"Anna Boyajyan"},{id:"157188",title:"Dr.",name:"Gohar",surname:"Mkrtchyan",slug:"gohar-mkrtchyan",fullName:"Gohar Mkrtchyan"},{id:"174627",title:"M.Sc.",name:"Diana",surname:"Avetyan",slug:"diana-avetyan",fullName:"Diana Avetyan"},{id:"174628",title:"Dr.",name:"Lilit",surname:"Hovhannisyan",slug:"lilit-hovhannisyan",fullName:"Lilit Hovhannisyan"}],corrections:null},{id:"48867",title:"Posttraumatic Stress Disorder Biomarker — p11",doi:"10.5772/61073",slug:"posttraumatic-stress-disorder-biomarker-p11",totalDownloads:1535,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Post-traumatic stress disorder (PTSD) is a chronic and disabling anxiety disorder associated with a traumatic event [1]. It is linked to increased risk of suicide and deficits in social functioning [2, 3]. Despite extensive study in psychiatry, the underlying mechanisms of PTSD are still poorly understood [4, 5]. Currently, the diagnosis for PTSD is based on clinical observation and symptom checklist [4, 6-8] and no laboratory blood-based tests. Although biomarker discovery for PTSD is not easy [8], a reliable biomarker would significantly impact the diagnosis and therapeutic monitoring of PTSD. Developing interventions to identify and treat PTSD requires objective approaches to determining the presence of PTSD [8]. Substantial data indicate several potential biomarkers for PTSD. Of these candidate markers, p11 (S100A10) has been studied in PTSD animal models [7] and in human subjects with PTSD [6]. We found that p11 is over-expressed in both animal models and post-mortem brains of subjects with PTSD [7]. Incorporating testing of p11, a novel biomarker for PTSD, into clinical practice, along with more subjective measures, such as participants’ medical history, mental status, duration of symptoms, and symptom checklist or self-report, would provide additional power to predict impending PTSD. In this chapter, we discuss the biomarker concept and the potential clinical utility of PTSD biomarkers. We further discuss the potential of p11 as a PTSD biomarker and as a tool that may enhance PTSD diagnosis and intervention in health care practice.",signatures:"Lei Zhang, Xian-Zhang Hu, He Li, Xiaoxia Li, Stanley Smerin, Dale W.\nRussell, Angela Boutte, Berwin Yuan, Nora Wang, Ze Chen and\nRobert J. Ursano",downloadPdfUrl:"/chapter/pdf-download/48867",previewPdfUrl:"/chapter/pdf-preview/48867",authors:[{id:"30247",title:"Dr.",name:"Lei",surname:"Zhang",slug:"lei-zhang",fullName:"Lei Zhang"}],corrections:null},{id:"48385",title:"Anxiety Disorders and Suicide: Psychiatric Interventions",doi:"10.5772/60594",slug:"anxiety-disorders-and-suicide-psychiatric-interventions",totalDownloads:1872,totalCrossrefCites:0,totalDimensionsCites:3,hasAltmetrics:0,abstract:"A universal phenomenon equally ancient as the history of mankind, suicide is defined as the willful and intentional ending of one’s own life. Risk factors for suicidal behavior are traumatic childhood and adulthood experiences, negative interfamily interactions, social isolation, decreased social solidarity, financial troubles, losses, despair, impulsivity, and migration. Recognized as a critical public health problem, preliminary causes of suicide are financial, religious, political, social, cultural, and medical in addition to mental disorders like depression and alcohol addiction. It has been proven in a number of researches till today that there is a correlation between major depression, bipolar disorder, schizophrenia, borderline personality disorder, alcohol-drug use, and suicidal behavior. Nonetheless, the relation between anxiety disorders and suicidal behavior has not been clearly defined to date. The evidences gathered so far reveal that panic disorder is only an independent risk factor for suicide attempt. The limited number of studies on this domain provided nonhomogenous results. It is however a point to keep in mind that if anxiety disorders are codiagnosed with mental disorders, they pose risk for suicidal behavior. In different studies with a wider sampling in this domain, analyzing the effect of specific anxiety disorders on suicidal behavior might be useful for suicide prevention programs.",signatures:"Cicek Hocaoglu",downloadPdfUrl:"/chapter/pdf-download/48385",previewPdfUrl:"/chapter/pdf-preview/48385",authors:[{id:"28322",title:"Prof.",name:"Cicek",surname:"Hocaoglu",slug:"cicek-hocaoglu",fullName:"Cicek Hocaoglu"}],corrections:null},{id:"48400",title:"Comorbid Anxiety in Schizophrenia and Schizoaffective Disorder",doi:"10.5772/60643",slug:"comorbid-anxiety-in-schizophrenia-and-schizoaffective-disorder",totalDownloads:1531,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"There is some evidence that antipsychotic medication (Quetiapine) is somewhat efficient in reducing anxiety in schizophrenic patients.",signatures:"Delia M. Podea, Aurora I. Sabau and Karol J. Wild",downloadPdfUrl:"/chapter/pdf-download/48400",previewPdfUrl:"/chapter/pdf-preview/48400",authors:[{id:"30327",title:"Prof.",name:"Delia",surname:"Podea",slug:"delia-podea",fullName:"Delia Podea"},{id:"174601",title:"Dr.",name:"Aurora",surname:"Sabau",slug:"aurora-sabau",fullName:"Aurora Sabau"},{id:"174602",title:"Ms.",name:"Karol Julien",surname:"Wild",slug:"karol-julien-wild",fullName:"Karol Julien Wild"}],corrections:null},{id:"48398",title:"Joint Hypermobility, Anxiety, and Psychosomatics — The New Neuroconnective Phenotype",doi:"10.5772/60607",slug:"joint-hypermobility-anxiety-and-psychosomatics-the-new-neuroconnective-phenotype",totalDownloads:9353,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,abstract:"In this chapter, after summarizing the concept and diagnosis of the Joint Hypermobility (Hyperlaxity), we review case control studies in two directions: Anxiety in Joint Hypermobility and Joint Hypermobility in Anxiety disorders, studies in nonclinical samples, review papers, and one incidence study. Collected evidence tends to confirm the strength of the association described two and a half decades ago. Common mechanisms involved include genetics, autonomic nervous system dysfunctions, and interoceptive and exteroceptive processes. Considering clinical and nonclinical data, pathophysiological mechanisms, and present nosological status, we suggest a new Neuroconnective phenotype in which together around a common core Anxiety-Collagen hyperlaxity, it includes five dimensions: behavioral, psychopathology, somatic symptoms, somatosensory symptoms, and somatic illnesses. Somatic illnesses include irritable bowel, dysfunctional esophagus, multiple chemical sensitivity, dizziness or unsteadiness (central vestibular pattern), chronic fatigue, fibromyalgia, glossodynia, vulvodynia, hypothyroidism, asthma, migraine, temporomandibular dysfunction, and intolerances or food and drug hypersensitivity. It is envisaged that new descriptions of anxiety disorders and also of some psychosomatic conditions will emerge and different nosological approaches will be required.",signatures:"Guillem Pailhez, Juan Castaño, Silvia Rosado, Maria Del Mar\nBallester, Cristina Vendrell, Núria Mallorquí-Bagué, Carolina Baeza-\nVelasco and Antonio Bulbena",downloadPdfUrl:"/chapter/pdf-download/48398",previewPdfUrl:"/chapter/pdf-preview/48398",authors:[{id:"53824",title:"Prof.",name:"Guillem",surname:"Pailhez",slug:"guillem-pailhez",fullName:"Guillem Pailhez"},{id:"174181",title:"Prof.",name:"Antonio",surname:"Bulbena",slug:"antonio-bulbena",fullName:"Antonio Bulbena"},{id:"174182",title:"Dr.",name:"Juan",surname:"Castaño",slug:"juan-castano",fullName:"Juan Castaño"},{id:"174191",title:"Dr.",name:"Cristina",surname:"Vendrell",slug:"cristina-vendrell",fullName:"Cristina Vendrell"},{id:"174192",title:"Dr.",name:"Maria Del Mar",surname:"Ballester",slug:"maria-del-mar-ballester",fullName:"Maria Del Mar Ballester"},{id:"174193",title:"Mrs.",name:"Silvia",surname:"Rosado",slug:"silvia-rosado",fullName:"Silvia Rosado"},{id:"174194",title:"Dr.",name:"Núria",surname:"Mallorquí",slug:"nuria-mallorqui",fullName:"Núria Mallorquí"},{id:"174195",title:"Dr.",name:"Carolina",surname:"Baeza",slug:"carolina-baeza",fullName:"Carolina Baeza"}],corrections:null},{id:"48395",title:"Anxiety in Natural and Surgical Menopause — Physiologic and Therapeutic Bases",doi:"10.5772/60621",slug:"anxiety-in-natural-and-surgical-menopause-physiologic-and-therapeutic-bases",totalDownloads:1999,totalCrossrefCites:7,totalDimensionsCites:13,hasAltmetrics:0,abstract:"Generalized anxiety disorder is one of the most common psychiatric disorders, affecting a high percentage of human beings around the world. This emotional disorder possesses marked gender differences and occurs more often in women than in men, in a proportion of 2:1. Accompanying the reproductive cycle of women are significant fluctuations in plasma and brain steroid hormone concentrations, including oestradiol, progesterone, and allopregnanolone, among others. These hormonal changes are related to some illnesses and with the development of anxiety and mood swings occurring in the premenstrual and postpartum period, and particularly during the menopause. Menopause is a clinical term used to indicate the cessation of the woman's reproductive ability that occurs naturally, but also may be surgically induced by bilateral oophorectomy, with or without the removal of the Fallopian tubes and uterus. Natural menopause includes specific periods related to the physiological and hormonal changes produced by ovarian failure, it is usually a natural stage that occurs to women in midlife, during their late 40s or early 50s, indicating the end of the reproductive period in the woman. During the menopause transition years, women experience changes in the production of ovarian hormones, which are associated with significant changes in the physiological, emotional, and affective processes. Unfortunately, surgical menopause occurs at an early age, and produces similar physiological and psychiatric disorders, but they are more severe in this instance. In both cases, typical symptoms associated with menopause critically deteriorate the mental health of the women. In this way, the therapeutic management of clinical symptoms of menopause include replacement hormone therapy, the use of anxiolytic and antidepressant drugs, and other natural alternatives based on the use of chemical compounds obtained from plants such as soya. However, a general effective treatment for menopause symptoms does not yet exist. For this reason, experimental studies have proposed ovariectomy in rats as a potential tool to study the effects of a long-term absence of ovarian hormones associated with surgical menopause, which also allowed the study of substances with potential therapeutic application to ameliorate typical symptoms associated with surgical menopause. The aim of this chapter is to review the participation of ovarian hormones in the regulation of emotional and affective disorders in women with natural or surgical menopause; particularly their anatomical pathways, neurotransmission systems, and the resulting behavioural patterns. Finally, preclinical and clinical research suggested that long-term absence of ovarian hormones associated with natural or surgical menopause is the principal cause of physiological and psychiatric disorder in the women; therefore, oestrogenic compounds seem to play an important role in the maintenance of the brain structures that regulate anxiety, mood, memory, and cognitive functions in menopausal women.",signatures:"Juan Francisco Rodríguez-Landa, Abraham Puga-Olguín, León Jesús\nGermán-Ponciano, Rosa-Isela García-Ríos and Cesar Soria-Fregozo",downloadPdfUrl:"/chapter/pdf-download/48395",previewPdfUrl:"/chapter/pdf-preview/48395",authors:[{id:"45702",title:"Dr.",name:"Juan Francisco",surname:"Rodríguez-Landa",slug:"juan-francisco-rodriguez-landa",fullName:"Juan Francisco Rodríguez-Landa"},{id:"174651",title:"Dr.",name:"Abraham",surname:"Puga-Olguín",slug:"abraham-puga-olguin",fullName:"Abraham Puga-Olguín"},{id:"174652",title:"MSc.",name:"León Jesús",surname:"Germán-Ponciano",slug:"leon-jesus-german-ponciano",fullName:"León Jesús Germán-Ponciano"},{id:"174653",title:"Dr.",name:"Rosa Isela",surname:"García-Ríos",slug:"rosa-isela-garcia-rios",fullName:"Rosa Isela García-Ríos"},{id:"174654",title:"Dr.",name:"Cesar",surname:"Soria-Fregozo",slug:"cesar-soria-fregozo",fullName:"Cesar Soria-Fregozo"}],corrections:null},{id:"48578",title:"A Systematic Review of Anxiety Disorders following Mild, Moderate and Severe TBI in Children and Adolescents",doi:"10.5772/60426",slug:"a-systematic-review-of-anxiety-disorders-following-mild-moderate-and-severe-tbi-in-children-and-adol",totalDownloads:1562,totalCrossrefCites:9,totalDimensionsCites:15,hasAltmetrics:0,abstract:"The aim of this chapter is to systematically review the research exploring the relationship between TBI and anxiety disorders in children and adolescents. A literature search was conducted using Google Scholar, Ovid Medline (1946 - Dec 2013), PsycINFO (1806 - Dec 2013), CINAHL plus (1937 - Dec 2013), Cochrane database (2005 – Dec 2013) and Embase (1946 – Dec 2013). The search returned 346 articles, and 11 of these met the inclusion criteria. Anxiety disorders were often found to be a negative outcome following childhood TBI, with a higher incidence of disorders including GAD, ASD, PTSD, PD, OCD, simple/specific phobia, social phobia and SAD found in children following their injury. In most cases, this relationship was strongest for children with severe TBI who sustained their injury at a younger age. Psychosocial adversity was found to be a consistently significant predictor for the likelihood of children developing anxiety following TBI. It is concluded that children who have suffered from a TBI (mild, moderate or severe), are at a higher risk of developing subsequent anxiety disorders, even 1 year following the injury event, and children with more severe injuries, greater psychosocial adversity, and younger age at injury are considered to be the most vulnerable.",signatures:"Michelle Albicini and Audrey McKinlay",downloadPdfUrl:"/chapter/pdf-download/48578",previewPdfUrl:"/chapter/pdf-preview/48578",authors:[{id:"169771",title:"BSc.",name:"Michelle",surname:"Albicini",slug:"michelle-albicini",fullName:"Michelle Albicini"},{id:"169982",title:"Dr.",name:"Audrey",surname:"McKinlay",slug:"audrey-mckinlay",fullName:"Audrey McKinlay"}],corrections:null},{id:"48585",title:"Impact of Anxiety and Depression Symptoms on Scholar Performance in High School and University Students",doi:"10.5772/60711",slug:"impact-of-anxiety-and-depression-symptoms-on-scholar-performance-in-high-school-and-university-stude",totalDownloads:4417,totalCrossrefCites:17,totalDimensionsCites:20,hasAltmetrics:1,abstract:"Emotional processes are important to survive. The Darwinian adaptive concept of stress refers to natural selection since evolved individuals have acquired effective strategies to adapt to the environment and to unavoidable changes. If demands are abrupt and intense, there might be insufficient time to successful responses. Usually, stress produces a cognitive or perceptual evaluation (emotional memory) which motivates to make a plan, to take a decision and to perform an action to face successfully the demand. Between several kinds of stresses, there are psychosocial and emotional stresses with cultural, social and political influences. The cultural changes have modified the way in which individuals socially interact. Deficits in familiar relationships and social isolation alter physical and mental health in young students, producing reduction of their capacities of facing stressors in school. Adolescence is characterized by significant physiological, anatomical, and psychological changes in boys and girls, who become vulnerable to psychiatric disorders. In particular for young adult students, anxiety and depression symptoms could interfere in their academic performance. In this chapter, we reviewed approaches to the study of anxiety and depression symptoms related with the academic performance in adolescent and graduate students. Results from available published studies in academic journals are reviewed to discuss the importance to detect information about academic performance, which leads to discover in many cases the very commonly subdiagnosed psychiatric disorders in adolescents, that is, anxiety and depression. With the reviewed evidence of how anxiety and depression in young adult students may alter their main activity in life (studying and academic performance), we discussed data in order to show a way in which professionals involved in schools could support students and stablish a routine of intervention in any case.",signatures:"Blandina Bernal-Morales, Juan Francisco Rodríguez-Landa and\nFrank Pulido-Criollo",downloadPdfUrl:"/chapter/pdf-download/48585",previewPdfUrl:"/chapter/pdf-preview/48585",authors:[{id:"45702",title:"Dr.",name:"Juan Francisco",surname:"Rodríguez-Landa",slug:"juan-francisco-rodriguez-landa",fullName:"Juan Francisco Rodríguez-Landa"},{id:"45701",title:"Dr.",name:"Blandina",surname:"Bernal-Morales",slug:"blandina-bernal-morales",fullName:"Blandina Bernal-Morales"},{id:"175891",title:"MSc.",name:"Frank",surname:"Pulido-Criollo",slug:"frank-pulido-criollo",fullName:"Frank Pulido-Criollo"}],corrections:null},{id:"48481",title:"The Role of Expectations in Treatment Outcome and Symptom Development in Anxiety Disorders",doi:"10.5772/60668",slug:"the-role-of-expectations-in-treatment-outcome-and-symptom-development-in-anxiety-disorders",totalDownloads:2078,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:0,abstract:"For more than 60 years, researchers have been interested in determining the impact of expectations on treatment outcome. Earlier studies mostly focused on two types of expectations: prognostic and process expectations. Aims: To review how four different types of expectations (prognostic, process, anxiety expectancy and anxiety sensitivity) contribute to psychotherapy outcome, and to the development of clinical disorders, especially anxiety. Conclusions: First, the role of process and prognostic expectancies in clinical disorders and psychotherapy outcome should be clarified by addressing the methodological flaws of the earlier expectancy studies. Second, studies, especially those on anxiety disorders, may benefit from evaluating the four different types of expectations to determine their relative impact on outcome, and on the development and maintenance of these disorders. Third, possible links with other clinical disorders should be further explored. Finally, expectancies should be assessed prior to treatment and after several sessions to determine the extent to which the treatment's failure in modifying initial low expectancies contribute to a poor outcome.",signatures:"Theodora E. Katerelos, Claude Bélanger, Marie-Christine Payette,\nGhassan El-Baalbaki, André Marchand and Michel Perreault",downloadPdfUrl:"/chapter/pdf-download/48481",previewPdfUrl:"/chapter/pdf-preview/48481",authors:[{id:"57536",title:"Prof.",name:"Claude",surname:"Belanger",slug:"claude-belanger",fullName:"Claude Belanger"},{id:"57551",title:"Dr.",name:"Michel",surname:"Perreault",slug:"michel-perreault",fullName:"Michel Perreault"},{id:"157412",title:"Prof.",name:"Ghassan",surname:"El-Baalbaki",slug:"ghassan-el-baalbaki",fullName:"Ghassan El-Baalbaki"},{id:"174810",title:"Dr.",name:"Theodora",surname:"Katerelos",slug:"theodora-katerelos",fullName:"Theodora Katerelos"},{id:"175625",title:"MSc.",name:"Marie-Christine",surname:"Payette",slug:"marie-christine-payette",fullName:"Marie-Christine Payette"},{id:"175626",title:"Prof.",name:"André",surname:"Marchand",slug:"andre-marchand",fullName:"André Marchand"}],corrections:null},{id:"48868",title:"Practical Applications of Complementary and Alternative Therapies in Adults and Youth with Anxiety Disorders",doi:"10.5772/61046",slug:"practical-applications-of-complementary-and-alternative-therapies-in-adults-and-youth-with-anxiety-d",totalDownloads:1563,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The use of complementary and alternative medicine (CAM) therapies is becoming an increasingly popular treatment option for anxiety disorders in adults and youth. Parents often are reluctant to use antidepressants due to fear of potential side effects. Youth are often unwilling to participate in cognitive behaviour therapy (CBT) or it is not readily available. Practitioners are not always knowledgeable or open to considering CAM therapies for their patients. This chapter will review the definition of CAM, prevalence of CAM use, its safety and effectiveness and finally its practical applications. Four case studies are discussed in which practitioners were open to the use of CAM and collaborated successfully with parents of youth with anxiety disorders. Literature review is presented for use of vitamin D, melatonin, acupuncture, acupressure and craniosacral therapy.",signatures:"Sarosh Khalid-Khan, Faiza Khalid-Khan and David Gratzer",downloadPdfUrl:"/chapter/pdf-download/48868",previewPdfUrl:"/chapter/pdf-preview/48868",authors:[{id:"174558",title:"Dr.",name:"Sarosh",surname:"Khalid-Khan",slug:"sarosh-khalid-khan",fullName:"Sarosh Khalid-Khan"}],corrections:null},{id:"48492",title:"Yoga for Anxiety Management in the Workplace",doi:"10.5772/60633",slug:"yoga-for-anxiety-management-in-the-workplace",totalDownloads:1848,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:'Anxiety is a potential cause of serious influence in a person\'s daily life. This chapter is focused specifically on the effects of the work environment factors in disease development and progression. Working environments are places of significant sources of stress: they put us in connection with our duties and expectations (often not coincide with reality) and with a "forced socialization." Especially forced socialization is to be considered a main source of stress in work places, inducing negative outcomes in work and social relationships. The psychosocial risks of work places can so be defined according to design, organization and management of work as well as to social and environmental contexts that may lead to damage of physical, social and psychological domains. Stress can then be defined as a pattern of emotional, cognitive, behavioral, and physiological reactions to adverse and noxious aspects perceived as the contents of the working environment. Thanks to the beginning of psychosocial research on the working environment, the impact of some aspects of the work environment on health has become an object of study, as the interventions to mitigate it. Yoga, meditation, and mantra techniques, as described in this work (presenting others’ experiences and two of own current projects, used in a hospital workplace to control the condition of occupational stress but also in a clinical sample), showed the potential in considerably reducing anxiety and mood symptoms.',signatures:"S. Doria, F. Irtelli, R. Sanlorenzo and F. Durbano",downloadPdfUrl:"/chapter/pdf-download/48492",previewPdfUrl:"/chapter/pdf-preview/48492",authors:[{id:"157077",title:"Dr.",name:"Federico",surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano"},{id:"174641",title:"Dr.",name:"Floriana",surname:"Irtelli",slug:"floriana-irtelli",fullName:"Floriana Irtelli"},{id:"174682",title:"Dr.",name:"Stefania",surname:"Doria",slug:"stefania-doria",fullName:"Stefania Doria"},{id:"174683",title:"Dr.",name:"Roberto",surname:"Sanlorenzo",slug:"roberto-sanlorenzo",fullName:"Roberto Sanlorenzo"}],corrections:null},{id:"48516",title:"Mindfulness — New Research and Treatment Directions in Post-traumatic Stress Disorder",doi:"10.5772/60635",slug:"mindfulness-new-research-and-treatment-directions-in-post-traumatic-stress-disorder",totalDownloads:1720,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Combining mindfulness to strengthen emotion regulation with existing empirically supported post-traumatic stress disorder (PTSD) treatments may improve outcomes through increasing (a) engagement, (b) compliance, and (c) decreasing the level of ruminations in PTSD. Several psychotherapeutic interventions incorporating training in mindfulness are clinically relevant to traumatic stress. In order to see how far PTSD treatment could benefit from including mindfulness into the therapeutic process, we analyzed researches regarding: (a) the neuroscience of mindfulness, (b) assessment instruments for mindfulness, (c) mechanism of mindfulness, respective, and (d) the relation between mindfulness and other techniques. Based on this analysis, we can conclude that mindfulness may improve the therapeutic results and the outcome of PTSD patients. Mindfulness can be used in two ways: (a) as an emotion regulation support technique for existing empirically supported PTSD treatments and (b) as a standalone treatment- mindfulness-based cognitive behavior psychotherapies.",signatures:"Delia M. Podea and Karol J. Wild",downloadPdfUrl:"/chapter/pdf-download/48516",previewPdfUrl:"/chapter/pdf-preview/48516",authors:[{id:"30327",title:"Prof.",name:"Delia",surname:"Podea",slug:"delia-podea",fullName:"Delia Podea"},{id:"174602",title:"Ms.",name:"Karol Julien",surname:"Wild",slug:"karol-julien-wild",fullName:"Karol Julien Wild"}],corrections:null},{id:"49059",title:"Anxiety — Is There an App for That? Considering Technology, Psychiatry, and Internet-Assisted Cognitive Behavioral Therapy",doi:"10.5772/60816",slug:"anxiety-is-there-an-app-for-that-considering-technology-psychiatry-and-internet-assisted-cognitive-b",totalDownloads:1565,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Across Western countries, more than a third of people will have a mental health disorder over their lifetime; mood and anxiety disorders are the most common. The effectiveness of psychological interventions is well established. Cognitive Behavioural Therapy (CBT), for example, is as effective for mild and moderate anxiety as medications; combined psychopharmacology and CBT is superior to either modality alone, suggesting a synergistic effect. However, CBT requires a major investment of time and resources. Thus, in public systems, CBT has limited availability and is subject to long waiting times; primary-care physicians and psychiatrists may not offer CBT.",signatures:"David Gratzer, Faiza Khalid-Khan and Sarosh Khalid-Khan",downloadPdfUrl:"/chapter/pdf-download/49059",previewPdfUrl:"/chapter/pdf-preview/49059",authors:[{id:"174558",title:"Dr.",name:"Sarosh",surname:"Khalid-Khan",slug:"sarosh-khalid-khan",fullName:"Sarosh Khalid-Khan"},{id:"174958",title:"Dr.",name:"David",surname:"Gratzer",slug:"david-gratzer",fullName:"David Gratzer"},{id:"174996",title:"Ms.",name:"Faiza",surname:"Khalid-Khan",slug:"faiza-khalid-khan",fullName:"Faiza Khalid-Khan"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6493",title:"Psychotic Disorders",subtitle:"An Update",isOpenForSubmission:!1,hash:"10c61c9adb13a7f0780176f556353b2e",slug:"psychotic-disorders-an-update",bookSignature:"Federico Durbano",coverURL:"https://cdn.intechopen.com/books/images_new/6493.jpg",editedByType:"Edited by",editors:[{id:"157077",title:"Dr.",name:"Federico",surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3295",title:"New Insights into Anxiety Disorders",subtitle:null,isOpenForSubmission:!1,hash:"013c40f1052a8d6b3ab2d6bb6f797921",slug:"new-insights-into-anxiety-disorders",bookSignature:"Federico Durbano",coverURL:"https://cdn.intechopen.com/books/images_new/3295.jpg",editedByType:"Edited by",editors:[{id:"157077",title:"Dr.",name:"Federico",surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5384",title:"New Developments in Anxiety Disorders",subtitle:null,isOpenForSubmission:!1,hash:"c355c8b1bce4b291f916878f12e0ab8a",slug:"new-developments-in-anxiety-disorders",bookSignature:"Federico Durbano and Barbara Marchesi",coverURL:"https://cdn.intechopen.com/books/images_new/5384.jpg",editedByType:"Edited by",editors:[{id:"157077",title:"Dr.",name:"Federico",surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5795",title:"Psychopathy",subtitle:"New Updates on an Old Phenomenon",isOpenForSubmission:!1,hash:"2e33769ff3c930094c4e350ec6a2b6b5",slug:"psychopathy-new-updates-on-an-old-phenomenon",bookSignature:"Federico Durbano",coverURL:"https://cdn.intechopen.com/books/images_new/5795.jpg",editedByType:"Edited by",editors:[{id:"157077",title:"Dr.",name:"Federico",surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"510",title:"Anxiety Disorders",subtitle:null,isOpenForSubmission:!1,hash:"183445801a9be3bfbce31fe9752ad3db",slug:"anxiety-disorders",bookSignature:"Vladimir Kalinin",coverURL:"https://cdn.intechopen.com/books/images_new/510.jpg",editedByType:"Edited by",editors:[{id:"31572",title:null,name:"Vladimir V.",surname:"Kalinin",slug:"vladimir-v.-kalinin",fullName:"Vladimir V. 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Nascimento",dateSubmitted:"August 27th 2021",dateReviewed:"August 31st 2021",datePrePublished:"October 2nd 2021",datePublished:null,book:{id:"10780",title:"Current Trends in Orthodontics",subtitle:null,fullTitle:"Current Trends in Orthodontics",slug:"current-trends-in-orthodontics",publishedDate:"August 17th 2022",bookSignature:"Farid Bourzgui",coverURL:"https://cdn.intechopen.com/books/images_new/10780.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"52177",title:"Prof.",name:"Farid",middleName:null,surname:"Bourzgui",slug:"farid-bourzgui",fullName:"Farid Bourzgui"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null},book:{id:"10780",title:"Current Trends in Orthodontics",subtitle:null,fullTitle:"Current Trends in Orthodontics",slug:"current-trends-in-orthodontics",publishedDate:"August 17th 2022",bookSignature:"Farid 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The surgical activity should be completed by a deep understanding of the patient and the commitment to ensure a rapid return to normal after surgical treatment. The surgeon’s initial contact with the patient is important. That is the opportunity to gain the patient’s confidence and convey the assurance that the therapeutic procedure is available and effective. The surgeon needs to demonstrate concern and commitment for the patient as a person who requires care and not just a “case” to be treated by surgical therapy. Today we must believe that the rapid and safe recovery after surgical therapy is a fundamental feature alongside the results of resolution/control of the pathology. The first revolutionary step in this perspective has been taken, and for thirty years it has continued and evolved universally, through the introduction of minimally invasive therapeutic approaches. The pathway of control and improvement of perioperative care have had great diffusion, in the last years, in the current practice of surgical wards. The perioperative procedure scheme that applies the principle of a safe and rapid postoperative recovery is standardized in the system unanimously called Enhanced Recovery After Surgery (ERAS). The basic characteristics of the procedure are the enterprise to improve surgical quality, the choice of innovative management and therapeutic procedures, but always based on evidence, and finally the multidisciplinarity that involves medical skills from various medical specialties in the management of treatments. Therefore all surgical specialties are involved in what we can define as a cultural movement in medical practice. The particular aspects of improving recovery following surgical procedures are summarized in the following actions: to support patient mobilization, decrease complication rates after surgery, shorten the length of hospital stay and reduce costs. The components of enhanced recovery after surgery are varied and numerous and can be divided in detail into the pre, intra, and postoperative phases. Among other elements are included: smoking and alcohol use stopped some weeks and nutritional assessment before surgery, intraoperative use of antibiotics, postoperative multimodal analgesia and nausea control, active and early mobilization, early feeding, reduce as much as possible the use of the nasogastric tube and abdominal drains, early removal of a urinary catheter. Finally, two propositions are in evidence. a multidisciplinary medical team should be implicated in achieving the accomplishment of an ERAS pathway; moreover, the main purposes of ERAS are to reduce the surgical stress and to preserve, how is it possible, the physiological conditions, consequently these therapeutic choices should, in principle. be employed routine, currently in surgery.
",isbn:"978-1-80356-762-4",printIsbn:"978-1-80356-761-7",pdfIsbn:"978-1-80356-763-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"134f0a1f56e2a14a8328a8b1221523ec",bookSignature:"Prof. Vincenzo Neri",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11869.jpg",keywords:"Bowel Preparation, Anemia Control Before Surgery, ERAS, Preoperative Counseling, Intraoperative Antibiotics, Minimally Invasive Approach, Enhanced Recovery Pathways, Postoperative Analgesia, Mininvasive Approach, Health Care Team, Nutritional Status, Carbohydrate Loading",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 25th 2022",dateEndSecondStepPublish:"April 22nd 2022",dateEndThirdStepPublish:"June 21st 2022",dateEndFourthStepPublish:"September 9th 2022",dateEndFifthStepPublish:"November 8th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"4 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Neri is the author of more than 330 scientific papers edited in national and international journals and chapters of books. He obtained the certificate of “Maitrise Universitaire en Pedagogie des Sciences de la Santè” on the Universitè Paris – Nord Bobigny. Dr. Neri is a member of scientific societies: SIC, IHPBA, AISP, EASL, NESA, SLS.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"170938",title:"Prof.",name:"Vincenzo",middleName:null,surname:"Neri",slug:"vincenzo-neri",fullName:"Vincenzo Neri",profilePictureURL:"https://mts.intechopen.com/storage/users/170938/images/system/170938.jpeg",biography:"Vincenzo Neri is a former Professor of General Surgery (retired), Department of Medical and Surgical Sciences, University of Foggia, Italy. He also held positions such as Director of Division of General Surgery, Director of Residency School of General Surgery, Director of Department of Surgical Sciences, and President of Course of Degree of Medicine and Surgery at the same university. He also served as an assistant professor (1974–1982) and associate professor (1982–2001) at the School of Medicine and Surgery, University of Bari, Italy, where he obtained a degree in Medicine and Surgery and completed postgraduate training in General Surgery and Emergency Surgery. He obtained a diploma of 'Maitrise Universitaire en Pedagogie des Sciences de la Santè” from the University Paris-Nord Bobigny in 1995. Dr. Neri’s research interests include hepatobiliary pancreatic surgery, acute pancreatitis, and treatment of pancreatic and liver tumors. He has published research papers, reviews, congress proceedings, and book chapters. In the period 1991–2016, he attended the Hepatobiliarypancreatic Surgery Service of Beaujon Hospital, Universitè de Paris, Clichy. As part of the 2010–2011 ERASMUS Program, Dr. Neri developed a seminar on 'Cystic Tumours of the Pancreas” at Ghent University, Belgium. He is a member of several scientific associations including Società Italiana di Chirurgia (SIC), International Hepato-Pancreato Biliary Association (IHPBA), European Association for the Study of the Liver (EASL), New European Surgical Academy (NESA), and Society of Laparoscopic and Robotic Surgeons (SLS).",institutionString:"University of Foggia",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"9",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"University of Foggia",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"455410",firstName:"Dajana",lastName:"Jusic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/455410/images/20500_n.jpeg",email:"dajana.j@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"48993",title:"Preoperative Evaluation and Management of Patients with Liver Disease",doi:"10.5772/60999",slug:"preoperative-evaluation-and-management-of-patients-with-liver-disease",body:'Patients with liver disease who undergo surgery have an increased risk of morbidity and mortality [1-3].
The optimal management of such patients requires the following:
Diagnosis of the underlying liver disease
Assessment and stratification of the risk of surgery
Estimation of functional hepatic reserve
Correction of underlying conditions if feasible
Hepatic hemodynamic evaluation and identification of the site of upper gastrointestinal hemorrhage, if present
Impairment of the liver functions increases the risks of surgery and anesthesia in several ways, including the following [4-6]:
Bleeding risk may increase because of coagulopathy
Susceptibility to infection is increased due to altered functions of the hepatic reticuloendothelial cells and changes in the immune system and portal hypertension
Reduced hepatic blood flow
Altered drug metabolism
Hyperdynamic circulation with increased cardiac output and decreased systemic vascular resistance
Systemic and splanchnic vasodilation, with subsequent activation of the sympathetic nervous system and neurohormonal axis in an attempt to maintain arterial perfusion pressure
Alterations in the systemic circulation due to arteriovenous shunting and reduced splanchnic inflow
Anesthetic agents may reduce hepatic blood flow
The compensatory inotropic and chronotropic response to pharmacologic and physiologic stress, including surgery, is blunted
The duration of action of many drugs can be increased as a result of [10]
altered metabolism by cytochrome P450 enzymes,
decreased concentration of plasma-binding proteins,
decreased biliary excretion.
Hepatic dysfunction can significantly impair the metabolism of certain medications. Examples are as follows [10, 11]:
The volume of distribution of nondepolarizing muscle relaxants is increased, and larger doses may be required to achieve adequate neuromuscular block.
Sedatives, narcotics, and intravenous induction agents must be used with caution, as they may result in prolonged depression of consciousness and may lead to hepatic encephalopathy. The perioperative use of opioids as morphine should be avoided, as their bioavailability is increased.
Benzodiazepines should be avoided, and, if necessary, remifentanil and oxazepam are the preferred narcotic and sedative because their metabolism is not affected by liver disease.
Isoflurane is the recommended volatile anesthetic because it does not impair hepatic blood flow and undergoes the least amount of hepatic metabolism.
If liver dysfunction is suspected, elective surgery should be deferred until extensive evaluation is made. Evaluation will include the following items [12].
Thorough history and physical examination usually provide important informatation.
History of previous blood transfusions, drug abuse, or excessive alcohol intake.
Family history of jaundice, anemia, hereditary liver disease, and prior adverse reactions to anesthesia.
Medication history includes the use of analgesics and alternative medications.
Physical examination may identify signs of underlying liver disease, as temporal wasting, jaundice, palmar erythema, spider nevi, ascites, or hepatosplenomegaly.
The term “liver function tests” is a misnomer and can be misleading. Because of the complexity of liver functions, the ideal liver function test has not been invented yet. A successful liver function test, to assist with preoperative assessment of liver function, should be safe, reproducible, and easily performed.
The aims of the tests are as follows:
To determine the presence or absence of hepatic injury
To decide whether the injury is cell necrosis or cholestasis
To specify the particular disease
To determine its severity
Markers of hepatocellular injury include aminotransferases and lactate dehydrogenase
Markers of cholestasis include alkaline phosphatase, gamma glutamyl transpeptidase, 5′-nucleotidase, and bilirubin
Markers of synthetic functions of the liver are prothrombin time and albumin
Alanine aminotransferase (ALT) (normal range: 10-55 U/L)
Aspartate aminotransferase (AST) (normal range: 10-40 U/L)
Serum level rises as a result of leakage from damaged tissue
Mild to moderate elevations occur in many types of liver disease
Marked elevations occur in hepatitis (viral, toxic, autoimmune, and ischemic)
AST/ALT >2 suggests alcoholic liver disease or cirrhosis of any etiology
ALT is more specific than AST for hepatic injury
AST is nonspecific and can originate from skeletal muscle, red blood cell, kidney, pancreas, brain, and myocardium
Normal range 45-115 U/L
Serum level rises as a result of increased production and leaks into the serum
Moderate rises occur in many liver diseases
Marked rises occur in extra- and intrahepatic cholestasis, diffuse infiltrating disease (e.g., liver neoplasms), and rarely alcoholic cirrhosis
Considerable rises occur in bone diseases (e.g., tumor, fracture, Paget’s disease)
It also originates from the intestine, placenta, and some neoplasms
Normal range: 0-30 U/L
Serum level rises as a result of overproduction and leakage into serum, as for AP; induced by ethanol and drugs
GGTP/AP >2.5 suggests alcoholic liver disease
Kidney, spleen, pancreas, heart, lung, and brain are other sources
Normal range:: 0-11 U/L
Serum level rises as a result of overproduction and leakage into serum, as for AP
Found in many tissues, but serum elevation is relatively specific for liver disease
Normal range::0.0-1.0 mg/dL
Unconjugated hyperbilirubinemia
The mechanisms that result in elevation of serum unconjugated bilirubin levels include increased production (increased breakdown of hemoglobin (resulting from hemolysis, disordered erythropoiesis, and resorption of hematoma) or myoglobin (resulting from muscle injury)) and defects in hepatic uptake or conjugation.
Conjugated hyperbilirubinemia
The mechanisms that result in the elevation of serum-conjugated bilirubin levels are hepatobiliary diseases, including extrahepatic and intrahepatic bile duct obstruction, viral, alcoholic or drug-induced hepatitis, and inherited hyperbilirubinemia.
All clotting factors except factor VIII are synthesized by hepatocytes; factor VIII is produced by vascular endothelium and reticuloendothelial cells.
Serum values rise as a result of the following:
Decreased synthetic capacity as in acute or chronic liver failure (prolonged PT unresponsive to vitamin K)
Biliary obstruction (prolonged PT usually responsive to vitamin K administration)
Vitamin K deficiency (secondary to malabsorption, malnutrition, and antibiotics) and consumptive coagulopathy
Normal range: 3.5-5.0 g/dL
Serum level decreases as a result of decreased synthesis; or increased loss as in
chronic liver failure
nephrotic syndrome, protein-losing enteropathy, and vascular leak
Acute infection is confirmed by detection of IgM anti-hepatitis A antibody (IgM HAV), which appears early in the course of infection and has high sensitivity and specificity. IgG anti-HAV predominates in convalescence and persists throughout life.
Acute infection is associated with the presence of hepatitis B surface antigen (HBsAg).
Detection of HBsAg precedes serum aminotransferase elevations.
HBsAg becomes undetectable 1-3 months after jaundice.
Some time after HBsAg disappears; HBsAg antibody (anti-HBs) appears and persists for life.
In the interval between disappearance of HBsAg and appearance of anti-HBs, hepatitis core antigen antibody (anti-HBc) is present and helps as a marker for current or recent HBV infection.
Anti-HBc may remain for years after infection longer than anti-HBs.
IgM anti-HBc distinguishes recent from remote infection
Hepatitis C antibodies are detected relatively late in the course of the HCV infection.
False-positive test is a problem.
Reverse transcriptase polymerase chain reaction and branched amplification assays are the most sensitive and specific.
These tests offer attractive means to assess the liver functions. However, they have limitations, including expense, availability, invasiveness, and lack of validity.
This dye is taken up almost exclusively by hepatocytes and excreted unchanged into the bile. It is measured photometrically in blood samples taken at regular intervals after a bolus intravenous injection (0.5 mg/kg). Clearance of the dye decreases with loss of hepatocyte mass.
Radioactivity (14CO2) is measured in breath at 15-min intervals for 2 h after oral or intravenous administration of 14C-labeled methyl aminopyrine. It may predict death and histology in chronic hepatitis.
This lidocaine metabolite is measured in blood samples 15 min after intravenous administration of lidocaine (1 mg/kg). It may predict death and complications before and after liver transplantation
Ultrasound is useful for assessing liver size, spleen size, intra- and extrahepatic biliary tree, and the presence of liver masses. It can also detect ascites in its earliest stages (≥100 mL). Doppler ultrasonography is helpful in assessment of portal venous patency, direction of portal flow.
The risk of surgery in patients with impairment of liver functions depends on the severity of liver disease, nature of the surgery, and comorbid conditions. Patients with compensated cirrhosis and normal synthetic function have a low risk. The risk increases for patients with decompensated liver cirrhosis. Patients with advanced liver disease may benefit from nonsurgical therapy when appropriate.
Elective surgery should be postponed in patients with abnormal liver tests. All patients should have thorough preoperative evaluation, and their conditions are to be optimized before elective surgery. Elective surgery can be rescheduled or cancelled once the severity of underlying liver disease is assessed.
When surgery is mandatory, meticulous perioperative management is required, including hemodynamic stability, broad-spectrum antibiotics, correction of coagulopathy, improvement of nutritional status, avoidance of nephrotoxins and sedatives that could precipitate hepatic encephalopathy, and intensive care unit admission if needed.
Operative risks are markedly influenced by the severity and nature of the underlying liver disease.
The amount of perioperative risks is related to the degree of liver decompensation. An accurate assessment of the degree of liver decompensation is important for determination of the perioperative risk.
This is based on the patient’s serum bilirubin and albumin levels, prothrombin time, and severity of encephalopathy and ascites.
\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
Ascites | \n\t\t\tNone | \n\t\t\tSmall or diuretic controlled | \n\t\t\tTense | \n\t\t
Encephalopathy | \n\t\t\tAbsent | \n\t\t\tStates I–II | \n\t\t\tStates III–IV | \n\t\t
Albumin (g/L) | \n\t\t\t>3.5 | \n\t\t\t2.8–3.5 | \n\t\t\t<2.8 | \n\t\t
Bilirubin (mg/dL) | \n\t\t\t<2 | \n\t\t\t2–3 | \n\t\t\t>3 | \n\t\t
PT(sec above control), or INR | \n\t\t\t<4 <1.7 | \n\t\t\t4–6 1.7–2.3 | \n\t\t\t>6 >2.3 | \n\t\t
In general, elective surgery is well tolerated in patients with Child class A, permitted with careful preoperative preparation in patients with Child class B, and contraindicated in patients with Child class C.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
5–6 | \n\t\t\tA | \n\t\t
7–9 | \n\t\t\tB | \n\t\t
10–15 | \n\t\t\tC | \n\t\t
Other factors can also increase the perioperative risk beyond the Child classification. The perioperative risk is increased if there is portal hypertension. Emergency surgery is associated with a higher mortality rates.
Child score for estimating the perioperative risks has been shown to be quite variable. This may be explained by the following:
Patients with class A may have ascites, hyperbilirubinemia, and portal hypertension.
The variables (ascites and hepatic encephalopathy are graded subjectively) are operator dependent.
It is unable to stratify patients with severely decompensated liver disease.
For this reason, alternative systems have been sought
The MELD score is a linear regression model based on a patient’s serum bilirubin and creatinine levels and international normalized ratio (INR).
MELD score for TIPS = 0.957 × loge (creatinine [mg/dL]) + 0.378 × loge (bilirubin [mg/dL]) + 1.120 × loge (INR) + 0.643 (cause of liver disease)
MELD score for liver transplantation = 0.957 × loge(creatinine [mg/dL]) + 0.378 × loge(bilirubin [mg/dL]) + 1.120 × loge(INR) + 0.643
It was created to predict mortality after TIPS, then to stratify the risks in patients awaiting liver transplant, and recently used to predict perioperative mortality. It has several distinct advantages over the Child classification, being objective, and does not rely on cutoff values.
The general guidelines are as follows:
Patient with an MELD score below 10 can undergo elective surgery.
Patient with an MELD score of 10-15 should be managed with caution.
In patients with an MELD score above 15, elective surgery should be avoided and the patient should be considered for liver transplantation.
These guidelines should be modified for specific circumstances.
The operative risk is higher with certain types of surgery, such as hepatic resection, biliary surgery, gastric surgery, colectomy, and cardiac surgery.
Prophylactic measures to prevent complications
Early recognition and treatment of complications
Refractory ascites
Spontaneous bacterial peritonitis (SBP)
Fluid and electrolyte disturbances
Hepatorenal syndrome (HRS)
Portal hypertensive bleedings
Hepatic encephalopathy (HE)
Hepatocellular carcinoma (HCC)
Malnutrition
Progress of other medical diseases
Liver imaging and AFP, CA19-9 to exclude neoplasms
Doppler ultrasound: to exclude portal vein thrombosis
Upper GI endoscopy: to assess portal hypertension
Bone densitometry: in selected patients
Neuropsychologic testing: selected patients
ABG: to exclude hypoxemia-hepatopulmonary syndrome
Particular attention needs to be paid to the management of common complications of advanced liver disease, as coagulopathy, thrombocytopenia, ascites, renal insufficiency, encephalopathy, and malnutrition, as well as to disease-specific factors.
The cause of coagulopathy is multifactorial. It may result from poor absorption of vitamin K due to cholestasis or impaired synthesis of coagulation factors.
Parenteral vitamin K and transfusions of fresh frozen plasma can be used before surgery.
Intravenous cryoprecipitate may be infused with a minimal volume load. It contains large amounts of fibrinogen and von Willebrand factor together with clotting factors.
Intravenous recombinant factor VIIa is a safe and effective in correcting coagulopathy and normalizing the INR.
For patients with thrombocytopenia, platelet transfusion of may be recommended.
Prolonged bleeding time can be corrected bydesmopressin acetate.
Grades of ascites:
Grade 1: ascites only detected by ultrasound
Grade 2: moderate with symmetrical distention of the abdomen
Grade 3: large or tense with marked abdominal distension
Fluid restriction is not necessary in most patients.
Due to hyperkalemia, spironolactone as a single agent is recommended only in minimal fluid overload.
The usual regimen is a single morning dose of 100 mg spironolactone and 40 mg furosemide. The dose can be increased every 3-5 days, if weight loss is not satisfactory. Maximum doses are 600 mg/day spironolactone and 200 mg/day furosemide.
Side effects include volume depletion, which may precipitate encephalopathy, or renal failure.
Weekly monitoring of electrolytes and weight must be undertaken when initiating or changing therapy.
Encephalopathy, serum Na <125 mmol/L, creatinine >1.7mg/dL, should lead to cessation of diuretic use.
Treatment options include the following:
Paracentesis with albumin replacement remains the first treatment option for patients on the waiting list and are likely to undergo LT within a few months.
For large volume paracentesis, an albumin infusion of 8-10 g/L of fluid removed should be considered.
Paracentesis increases the risk of peritonitis.
TIPS is considered for the following:
Cases where the frequency of paracentesis is >3 times/month
Patients not tolerating large-volume paracentesis
Large-volume paracentesis is ineffective due to multiple adhesions or loculated ascites
Refractory hepatic hydrothorax
The major disadvantages are shunt stenosis and HE.
Peritoneovenous shunt: for historical interest only
Surgical shunts are rarely indicated
Its prevalence justifies diagnostic paracentesis in cirrhotics with ascites admitted to the hospital. Norfloxacin (400 mg/day) significantly reduces the probability of SBP.
Secondary long-term prophylaxis is recommended for all patients with a history of SBP. Antibiotic prophylaxis is recommended in patients with an upper GI bleed irrespective of the presence or absence of ascites.
Patients with ESLD are at increased risk to develop renal failure (RF), either spontaneously (hepatorenal syndrome [HRS]) or iatrogenically (diuretics, nephrotoxic drugs). Preoperative renal function significantly affects postoperative survival.
HRS can only be diagnosed after other causes of renal failure are excluded: obstruction, volume depletion, ATN, and drug-induced nephrotoxicity. All diuretics should be stopped. Fluid challenge with 1.5 L of isotonic saline should be administered to exclude volume depletion.
Combination of
vasoconstrictor drugs, such as vasopressin analogues, noradrenalin, and the combination of midodrine and octreotide together,
plasma volume expansion with albumin (1 g/kg intravenously on day 1, 20-40 daily thereafter).
It represents a late event and indicates poor prognosis. Occurs months after the onset of Na retention.
It has been proposed to incorporate serum Na concentration in the MELD score; however, this remains controversial.
As long as the serum Na remains >125 mmol/L, no specific measures are required.
If the serum Na level is <125 mmol/L, the following should be considered:
Diuretics should be stopped.
Infusion of albumin (100 g/24 h) or red blood cells is instituted attempting at expanding the effective circulating blood volume.
Na level will increase as a result of turning off ADH secretion by the increased blood volume. Once the serum sodium starts to rise, the albumin infusion is tapered.
Free water restriction.
Attempts to rapid correction with hypertonic saline can lead to more complications.
HE is a diagnosis of exclusion. Other etiologies as space-occupying lesions, vascular events, metabolic disorders, and infectious diseases should be excluded.
Slowing of consciousness
Drowsiness
Confusion, reactive only to vocal stimuli
Coma
Renal and electrolyte abnormalities
Gastrointestinal bleeding
Infection
Constipation
Benzodiazepines, narcotics, or other sedatives
Excessive dietary protein intake
Worsening liver function, e.g., portal vein thrombosis
Noncompliance with medications, especially lactulose
The mainstay is correcting the precipitating event.
Intubation has to be considered to prevent aspiration, depending on the level of consciousness.
Nasogastric tube should be placed.
Nonabsorbable disaccharides such as lactulose: The usual starting dose is 20 mL, 3-4 times daily with the aim of achieving 2-4 soft bowel movements per day.
Neomycin 3-6 g/day in divided doses might be added. Alternatively, metronidazole can be used.
Low-protein diet (minimum 30 g/day).
Gluconeogenesis is a significant source of production of endogenous ammonia and may result in worsening of the encephalopathy. Patients should be provided with at least of 400 calories daily in the form of IV glucose to reduce gluconeogenesis.
Once the patient recovers, a moderate amount of protein (40 g/day) is given and increased to the maximum tolerated dose within few days.
It is important to avoid protein restriction for a long time to prevent worsening of the nutritional state.
The role of ornithine-aspartate, sodium benzoate, and branched-chain amino acids is questioned.
Ammonia level is a poor predictor of the degree of encephalopathy. Changes in ammonia levels should not be considered an indicator of therapeutic benefit; improvement in mental status is the therapeutic end point.
The detection of PPHTN is crucial as it increases the perioperative and long-term risks.
The most common presenting symptom is progressive dyspnea on excretion; however, patients with even severe PPHTN can be completely asymptomatic. Echocardiography is the screening method of choice. A systolic right ventricular pressure (RVsys) of >50 mm Hg as a cutoff is used. Only these patients need to undergo right heart catheterization to characterize pulmonary hemodynamics.
This is defined as a triad of the following:
Chronic liver disease
Hypoxemia (PaO2 <70 mm Hg or alveolar to arterial oxygen gradient >20 mm Hg)
Intrapulmonary arteriovenous dilatation or shunts as detected by contrast echocardiography, lung perfusion scanning, or pulmonary angiography
Hypoxemia at rest is the prerequisite for the diagnosis. Medical management is disappointing, and liver transplant is advocated as the treatment of choice.
Malnutrition is common with liver impairment and is a risk factor for mortality following LT. Nutritional supplementation has not been proven to affect outcome. The total amount of calories provided should be at least 30-35 kcal/kg/day. Adults can receive daily 1-2 g protein/kg of dry body weight. Patients should take daily multivitamin and other supplements as needed. Specific fat-soluble vitamin supplements are provided if a deficiency is present.
The preoperative period can be extremely stressful. Declining health, uncertainty about the results, and inability to continue working and participating in daily activities may increase the risk of depression and/or anxiety. Patients with chronic HCV have a greater incidence of depression and anxiety. Patients who experience significant psychological distress have increased complications.
The preoperative evaluation concludes with a review of all pertinent studies and information obtained from investigative tests.
Informed consent after discussion with the patient and family members regarding the indication for the anticipated surgical procedure, as well as its risks and proposed benefits
Review the need for β-blockade, DVT prophylaxis
Antibiotic prophylaxis: The appropriate antibiotic is chosen before surgery and administered before the skin incision is made
Preoperative mechanical bowel cleansing, whenever indicated
Revision of medications
Careful review of the patient’s medications is important.
The aim is to judiciously give medications that control the patient’s illnesses and at the same time minimizing the risk associated with anesthetic and other drugs interactions.
In general, patients taking cardiac drugs, pulmonary drugs or anticonvulsants, antihypertensives, or psychiatric drugs are advised to take their medications with sips of water on the morning of operation.
Parenteral medications are used if the patient remains NPO for any significant period postoperatively.
It is important to restitute patients to their usual medications as soon as possible.
Drugs affecting platelet function are withheld for variable time: aspirin and clopidogrel (Plavix) are withheld for 7-10 days, while NSAIDs are withheld depending on the drug’s half-life between 1 day (ibuprofen and indomethacin) and 3 days (naproxen and sulindac).
Preoperative fasting
The patients are monitored for signs of hepatic decompensation, such as ascites, worsening jaundice encephalopathy, coagulopathy, and renal impairment.
If any of these occur, supportive therapy is started immediately.
Prothrombin time is the single best indicator of the synthetic function of the liver.
Elevated serum bilirubin level may result from worsening of the liver function and also may be elevated because of other conditions, as blood transfusions, blood extravasation, or infection.
Renal function must be monitored closely. If renal impairment occurs, the cause should be suspected and treatment started.
In cases of severe impairment of the liver functions, hypoglycemia may occur as a result of depletion of liver glycogen stores and impaired gluconeogenesis. Serum levels of glucose should be monitored closely if postoperative liver failure is suspected.
Careful attention should be paid to the IV fluid infusions.
Intravascular volume maintenance minimizes the risk of hepatic and renal underperfusion.
At the same time, crystalloid overinfusion results in liver congestion, venous oozing and pulmonary congestion and edema, ascites, peripheral edema, and wound disruption.
Accurate preoperative identification of patients with liver disease allows their treatment plans to be adjusted.
In patients with acute liver disease, elective surgery should be postponed until symptoms resolve.
Elective surgery should be avoided in patients with acute liver diseases such as acute viral hepatitis or alcoholic hepatitis, if there is evidence of ongoing hepatic injury.
In cases of chronic liver diseases, it is mandatory to assess the severity of underlying disease before deciding whether to proceed with surgery.
MELD and CTP scores can be used to stratify the risks of surgery for patients with chronic liver disease.
Optimal preoperative management can reduce the risk of postoperative morbidity and mortality.
Preoperative management of complications related to patients’ underlying liver disease is essential to optimize their outcomes.
Glutamatergic signaling plays a critical role in the CNS function under physiological and pathophysiological states via two major types of receptor: ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs) [1]. mGluRs consist of three subgroups (Group I-III), while iGluRs comprise four subgroups (AMPARs, KARs, Gluδs, and NMDARs). Among all GluRs, NMDARs play a crucial role in brain development, mediating the physiological functions, such as synaptic plasticity, learning, and memory. NMDARs are voltage-dependent glutamate- or aspartate-gated cation channels with two prerequisites for channel opening: 1) depolarization-induced unblockage of magnesium ions; 2). concomitant binding of glutamate (or aspartate) and glycine (or D-serine). When the NMDARs are either aberrantly enhanced or encumbered opening, various CNS symptoms/disorders may develop, such as depression, psychosis, and cognitive impairment.
CNS disorders still loom over many people’s health with limited effective treatment. The role of NMDARs playing in CNS disorders has been gaining attention owing to the finding of ketamine as an antidepressant [2]. This new therapeutic mechanism promotes NMDARs as an emerging therapeutic target. Ketamine, a NMDAR antagonist, exerts rapid and robust antidepressant effects in depressed patients [3]. On the contrary, a NMDAR agonist, D-serine, could alleviate schizophrenic and depressive symptoms in the clinical trial [4]. These contrary modulations on NMDAR further support the importance of NMDAR homeostasis leveraged by NMDAR modulators [5].
NMDAR modulators, with positive or negative modulation, have been designed to alleviate various symptoms of CNS through distinct mechanisms. Positive NMDAR modulators elevate NMDARs via direct and indirect approaches. Direct NMDAR enhancers fit into the glutamate site or glycine site of NMDARs, or they bind the allosteric pockets of the glutamate/glycine sites. In contrast to direct enhancement, several NMDAR enhancers improve NMDAR functions by modulating indirect pathways, for example, by inhibiting glycine transporter or D-amino acid oxidase (DAAO). Negative NMDAR modulators, on the contrary, work as competitive antagonists to directly occupy the glycine site, or bind an allosteric site (known as non-competitive antagonists), or block NMDAR channel pore (known as uncompetitive antagonists) [6]. All above modulators have shown potential for clinical use in CNS disorders but without one-size-fits-all approach.
The excitatory neurotransmission of mammalian CNS is largely dictated through glutamate and its receptors, particularly NMDAR. Because its critical roles in mediating synaptic plasticity related to learning and memory formation, the dysfunction of the NMDAR-based signaling is implicated in the neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), as described below.
AD is the most common cause of dementia to induce not only cognitive impairments in memory and thought, but also behavioral and psychiatric symptoms [7]. Current understanding to AD relies on two main histopathological abnormalities: (1) amyloid plaques composed of amyloid ß (Aß) peptides cleaved from amyloid precursor proteins in the brain tissue, and (2) the formation of intraneuronal neurofibrillary tangles due to phosphorylated and aggregated tau proteins. Although Aß and tau serve as the most discussed mechanisms through which cause AD, no effective treatment was developed successfully. Coincidently, the neurotransmitter systems, including cholinergic, adrenergic and glutamatergic pathways are considered critical in AD progression and development [8]. In this chapter, we focus on the discussion of how NMDAR involves in AD.
NMDAR is the major regulator associated with long-term synaptic plasticity. Studies have reported that AD brains contain neurotoxins consisted of soluble Aß oligomers. The binding of Aß 42 oligomers to forebrain synaptosomes is associated with post-synaptic density complexes containing NMDAR subunits NR1 and NR2B [9]. Consistently, Aß oligomers were found to ablate long-term potentiation in hippocampal brain slices and the cortices of AD brains via overactivating extrasynaptic NMDAR containing NR2B [10]. The over-activation of extrasynaptic NMDAR linked to neurodegeneration in AD has also been supported by the pharmacotherapeutic use of NMDAR inhibitor memantine [11].
Indirect modulation of NMDAR via glutamate release or glycine transporter-1 (GlyT1) are considered feasible for AD. An escalated stimulation via glutamatergic signaling causes glutamate excitotoxicity that results in damaged nerve cells, and such neuronal toxicity is coined “excitotoxicity”. In AD, glutamate uptake and recycling systems are severely impaired [12], which therefore increases glutamate availability, resulting in excessive NMDAR stimulation. Additionally, Aß peptides may increase glutamate availability by weakening glutamate uptake and recycling systems [13] that may contribute to AD pathology. On the other hand, at glutamatergic synapses, glycine is transported by GlyT1, a Na+/Cl−-dependent carrier protein playing a major role in maintaining glycine concentration below saturation at postsynaptic NMDAR, sculpturing GlyT1 as an intriguing target for NMDAR modulation.
Overall, direct and indirect NMDAR inhibition strategies through the discussed mechanisms to attenuate the overactivation of NMDA function have shown rationale for developing medicine for late-stage AD to attenuate the neuronal death.
PD, the second most common neurodegenerative disease, is a progressive disorder with symptoms of onset gradually, motor disturbances and cognitive impairment. Due to the rapidly aging population worldwide, PD also receives increasing attention from communities [14]. The pathophysiology of PD is due to the degeneration of pigmented dopaminergic neurons, resulting in functional changes to the circuitry of basal ganglia nuclei. Accordingly, levo-dopa, a precursor of dopamine, and dopamine receptor agonists have been serving as the standard treatments for PD. However, long-term use of these standard therapies contribute to the loss of efficacy and development of disfiguring motor complications [15]. Novel PD treatments based on different mechanism is long awaited.
Regulating glutamatergic receptors, particularly NMDAR, has been found to be altered in the basal ganglia of PD where NMDAR is widely expressed. Specifically, NR2B-containing NMDARs may significantly influence the PD pathology while NR2B was found to be substantially distributed in the striatum and other basal ganglia areas. An increasing body of literature has reported that not only experimental PD models but also PD patients present substantially elevated NMDA-sensitive glutamate binding in the striatum [16]. In levo-dopa-treated rodent and primate, GluN2A and the ratio of GluN2A/GluN2B are increased. The findings are also reported in PD patients [17], suggesting that attenuated NMDAR activity may help halt the progression of PD.
Alternately, reshaping synaptic connections for PD patients via brief activation of NMDAR can increase axonal growth rate and axonal branching. The brief NMDAR activation can be achieved through inhibiting GlyT1 to increase levels of extracellular glycine [18]. In addition, activating NMDAR via weak NMDAR glycine binding agonists can also achieve similar effects. This hypothesis remains to be investigated.
HD is a progressive CNS disorder due to a single defective gene on chromosome 4 that encodes the protein huntingtin. The defect is hereditary and will eventually develop symptoms in lifetime. At the beginning of symptom onset, patients often have subtle abnormalities in mood, usually followed by a lack of coordination and unsteady gaits [19].
Since the altered function of huntingtin induces neuronal cell death, research focuses on mechanisms towards regulation of such cell death. It has been revealed that the formation of the nuclear protein aggregates, oxidative stress, and mitochondrial dysfunction are associated with neuronal cell death in HD [20]. NMDARs have also been found to regulate neuronal cell death of HD, and by modulating NMDAR activity, psychotic symptoms of HD due to low NMDA function can be alleviated simultaneously. In this chapter, we focus on the discussion of NMDAR in HD.
Animal studies have shown that neuroexcitatory agonists kainic or quinolinic acids can induce lesions similar to those in HD, indicating that excitotoxicity from NMDAR over-activation could contribute to the progression of the disease [21]. Post-synaptic density protein 95 (PSD-95), a scaffolding protein, can bind huntingtin and the NR2 subunit of NMDAR. At the molecular level in HD, the presence of abnormal huntingtin protein causes the interruption of PSD-95 binding onto NMDAR. The unbinding of PSD-95 results in excitotoxicity and neuronal cell death consistent with HD [20]. Therefore, among the known mechanisms inducing HD progression, NMDAR remains a primary target to develop therapeutic intervention.
Existing high concentration of post-synaptic NMDAR in limbic structures [22] highlights the homeostasis of NMDAR activity as be of uttermost significance in behavioral regulation of the brain. The dysfunction of NMDAR can cause a variety of psychiatric disorders such as depression, schizophrenia, bipolar disorder (BD), and anxiety disorder [23].
Depression is a chronic mental disorder characterized by persistent low mood, loss of interest/pleasure, lack of appetite, sleep disturbance, low energy, and poor concentration. Depression can affect people irrespective of age, ethnicity, and gender. Major depressive disorder (MDD) is the most studied type of depression characterized by one or more major depressive events, that is, the presence of low mood and/or loss of interest for at least 14 days in company with depression symptoms. MDD leads to suicide that takes 2160 self-harm deaths per day in US [24]. Decades of research on depression have yielded several mechanisms that may explain its pathophysiology, including biogenic amine (e.g., monoamine) hypothesis, abnormal endocrine factors, genetic and environmental factors, neurogenesis, and the dysregulation of second messenger systems, which have been extensively reviewed elsewhere [25]. Among them, monoamine-based mechanisms were the most studied with successful development of antidepressants.
Although monoamine treatments are available for MDD, they have not been optimal. Currently, standard monoamine antidepressants require one month or more to exert antidepressant effects [26]. Such time lag has put MDD patients at risk of suicide and other self-harm acts. In recent decades, the NMDAR has emerged as a central player in MDD research, resulting in a paradigm shift from the monoamine-based to the NMDAR-based hypothesis. The NMDAR-based hypothesis of depression originated from early findings in the 1990’s that NMDAR antagonists exerted quick antidepressant-like action [27]. Subsequently, many studies have reported abnormal glutamate levels in frontal and occipital cortices in MDD; however, these findings infer the complex role of NMDAR in the brain of MDD patients. The regionally decreased glutamate level in the brain demonstrates an association with the pathophysiology of MDD [28]; on the contrary, the elevated glutamate levels occurs in medication-free MDD patients during an active depressive episode, in remission, and in young people [29]. Since glutamate is a major excitatory neurotransmitter dictating the neural plasticity and process of learning and memory, the alteration to NMDAR causes region-specific maladaptive neurocircuitry in depression and decreases in cognitive controls over negative emotion.
At the molecular level, postmortem brain analyses from MDD patients show alterations in the NMDAR subunit profile, such as reduced GluN2A and GluN2B subunits in locus coeruleus, and decreased GluN1 and GluN2A expression levels but no changes to those of GluN2B, GluN2C and GluN2D subunits in dorsolateral prefrontal cortex of MDD subjects [30]. Further studies have found that biologically, the activation of NMDAR requires both the binding of glycine and glutamate onto their binding sites, and therefore, modulating the release of the two amino acids into synapses are considered feasible. At glutamatergic synapses, glycine is transported by GlyT1, maintaining glycine concentration below saturation at postsynaptic NMDAR. Accordingly, GlyT1 has become an intriguing target for NMDAR activity modulation [31]. Alternatively, inhibiting glutamate levels at synapses renders reduced glutamate binding to NMDAR [32]. In summary, the above findings provide a solid basis for developing chemotherapeutics for treating MDD via modulating NMDA.
Schizophrenia is a psychotic illness presenting symptoms with processing thoughts and contents, and develops positive, negative and/or cognitive symptoms. Concurrently, depression and suicidal thoughts and attempts happen often in people suffering from schizophrenia. Because schizophrenia patients require lifelong treatment, early intervention may improve the long-term outlook. Conventional therapies for schizophrenia are developed based on a dopamine hypothesis which has been prevailing to explain symptoms associated with the positive symptoms. However, these treatments have not been optimal and often induce substantial adverse side effects [33].
Glutamate hypofunction hypothesis of schizophrenia has been supported by several lines of studies. Low level of glutamate in cerebrospinal fluid was reported in patients with schizophrenia [34]. The worsening of schizophrenic symptoms was observed in patients treated with NMDAR inhibitors such as ketamine. Healthy people administered with similar inhibitors were reported to develop symptoms of schizophrenia [35]. Building on these data, upregulating NMDA function serves as a promising target for treating schizophrenia [36].
Although NMDAR is a focus for antipsychotic drug development for schizophrenia, direct activation of the NMDAR via targeting the glutamate site is reported to cause excitotoxicity. The finding suggests the demand for targeting the glycine site as an alternative, but direct approach. To reduce glycine site vacancy, a number of studies have synthesized amino-acid derivatives to occupy it [37]. Alternatively, enhancing the glycine levels through GlyT1 inhibition has also shown promise, which is used as an adjunct to conventional therapies [38].
BD, as its name suggested, causes extremes of mood fluctuations that a person will be either in emotional highs (mania or hypomania) or lows (depression). BD is a lifelong disease that episodes of mood swings may occur infrequently or several times in a year. Typically, BD patients spend more time in depressive mood than mania or hypomania. Currently, treatments for BD are limited to symptom reduction and prevention of the occurrence of mood episodes [39].
Neuroimaging [40] and genetic findings [41] have revealed that glutamatergic abnormality is associated with the pathophysiology of BD, indicating NMDAR may play a role in the disease. The use of NMDAR inhibitor further evidences the role of NMDAR in the regulation of BD. Ketamine has shown to improve depressive symptom. One of possible mechanisms of ketamine in regulating BD symptoms is to increase presynaptic levels of glutamate which in turn binds to AMPAR instead of NMDAR. The increased ratio of AMPAR-to-NMDAR neurotransmission is implicated to induce the antidepressant effects of ketamine [42].
At the molecular level, postmortem findings suggest that BD is associated with a reduced expression of NR1 subunit in the prefrontal cortex [30]. The genetic polymorphisms in the 3’UTR region of GRIN2B gene that encodes for the NR2B subunit has been found to play a role in BD etiology, although its expression level is not significantly different from the control [43]. Together, these studies suggest NMDAR is associated with BD.
Having occasional anxiety is a normal part of life. However, intense, excessive, and persistent worries and fear about specific situation would be in the category of anxiety disorder that needs intervention. Types of anxiety disorders include panic attack, generalized anxiety disorder, and separation anxiety disorder. An anxiety patient may experience one or more of them and can experience anxiety at very young age [44].
Benzodiazepine and selective serotonin reuptake inhibitors (SSRIs) or selective serotonin-norepinephrine reuptake inhibitors (SNRIs) are recommended as first line drug treatment, because of their more favorable profile than tricyclic antidepressants and monoamine oxidase inhibitors. Nevertheless, some SNRIs are also antagonists of metabolic enzyme cytochrome P450, therefore causing drug–drug interactions [45]. In addition, discontinuation of SSRIs or SNRIs may experience withdrawal reactions [46]. These unwanted outcomes suggest an essential for developing next generation anxiolytic treatments based on novel mechanisms.
Fear often occurs together and share similar stress responses with anxiety, and therefore, both are often put into the same context when discussing the underlying mechanisms. Currently, studies have found that the neuronal modulatory systems in brain areas contributing to fear and anxiety share a high degree of overlap [47]. In particular, regulating extinction learning of fear through NMDAR within amygdala, medial prefrontal cortex, and hippocampus is considered critical among the neuronal modulatory systems [48]. Hippocampus and amygdala of the medial temporal lobe situate at the interface between cognition and emotion, which is believed to be potential sites where NMDAR inhibitors exert anxiolytic effects [49]. NMDAR regulates emotionality and cognition, and its antagonists have shown promising effects on them. In contrast to NMDAR antagonism, partial activation of NMDAR facilitates fear extinction in rodents. In clinical setting, partial agonists used as an adjuvant increase psychotherapeutic effects in patients suffering fear-related disorders [50]. These finding suggest that a balanced modulation of NMDAR activity can bring benefits for the patients with anxiety disorder.
In this section, positive NMDAR modulators for CNS disorders will be discussed (Figures 1 and 2, Table 1). To enhance NMDAR function, two approaches could achieve: direct or indirect modulation. For direct modulation, three types of enhancers are categorized according to their binding sites: glutamate site, glycine site, and allosteric site of NMDAR.
Scheme of direct agonism/antagonism via various binding sites of NMDAR. NAM, negative allosteric modulators; PAM, positive allosteric modulators.
Indirect NMDAR agonism/antagonism through activation or inhibition on diverse channels or transporters or enzymes. ASCT-1, alanine/serine/cysteine transporter-1; DAAO, D-amino acid oxidase; EAAT2, excitatory amino acid transporter-2; GlyT1, glycine transporter-1; NMDAR, N-methyl-D-aspartate receptor; SNAT2, sodium-coupled neutral amino-acid transporter-2; VGSC, voltage-gated sodium channel.
Drug | Mechanism | Disease | Study |
---|---|---|---|
glutamate site agonist | MDD | NCT03414931 NCT04637620 | |
glycine site agonist | Schizophrenia | [53] | |
glycine site agonist | Schizophrenia | [54] | |
glycine site agonist | MDD Schizophrenia | NCT04721249 NCT00322023 | |
glycine site partial agonist | AD MDD Schizophrenia BD Anxiety | [55] NCT00408031 [56] NCT01833897 NCT00515879 | |
PAM | MDD | NCT01684163 | |
PAM | MDD | NCT02067793 | |
Indirect enhancer (SNAT2 inhibitor) | PD MDD Schizophrenia BD | NCT00004826 [57] [58] [59] | |
Indirect enhancer (GlyT1 inhibitor) | AD Schizophrenia | NCT02788513 NCT02832037 | |
Indirect enhancer (GlyT1 inhibitor) | Schizophrenia | NCT01235585 | |
Indirect enhancer (GlyT1 inhibitor) | PD MDD Schizophrenia | NCT01785628 NCT00977353 [60] | |
Indirect enhancer (D-serine retention) | AD MDD Schizophrenia | [61] [62] NCT01908192 | |
glycine site antagonist | PD MDD | NCT04147949 NCT02484456 | |
NAM | AD HD | NCT00377715 NCT00497159 | |
NAM | MDD | NCT04688164 | |
NAM | MDD | NCT01941043 | |
Uncompetitive antagonist | PD HD | NCT00632762 [63] | |
Uncompetitive antagonist | AD PD MDD SchizophreniaBD Anxiety | [64] [65] [66] [67] [68] [69] | |
Uncompetitive antagonist | MDD BD | NCT04226352 [70] | |
Uncompetitive antagonist | MDD BD | NCT01882829 [71] | |
Uncompetitive antagonist | AD MDD Schizophrenia | NCT03393520 NCT02153502 NCT03896945 | |
(Axsome, | Uncompetitive antagonist | AD MDD | NCT04797715 NCT02741791 |
Uncompetitive antagonist | MDD BD Anxiety | [72] [73] [74] | |
Uncompetitive antagonist | MDD BD | [75] NCT03965871 | |
Uncompetitive antagonist | MDD | NCT04108234 | |
Uncompetitive antagonist | AD | [76] | |
Uncompetitive antagonist | MDD Anxiety | [77] NCT02243826 | |
Indirect blocker (glutamate release inhibitor) | MDD Schizophrenia BD | [78] [67] [78] | |
Indirect blocker (glutamate release inhibitor) | AD MDD BD Anxiety | [79] [52] [52] [80] | |
Indirect blocker (glutamate uptake activator) | AD Anxiety | NCT03605667 NCT03829241 |
AD, Alzheimer’s disease; BD, bipolar disorder; GlyT1, Glycine transporter-1; HD, Huntington’s disease; MDD, major depressive disorder; NAM, negative allosteric modulators; PAM, positive allosteric modulators; PD, Parkinson’s disease; SNAT2, sodium-coupled neutral amino-acid transporter-2.
Cognitive deficits occur often in elderly MDD patients, hardly to be relieved with the existing treatment. NMDA enhancement via the glutamate site has been proved to enhance cognitive functions in previous studies [81]. NMDA enhancer (NMDAE), binding the NMDAR glutamate site as an agonist, has been offered for the elderly (>55 years) and adults (18–55 years) with MDD. To testify the efficacy, safety, and the cognitive improvement of NMDAE in those patients, the NMDAE treatment results were compared with sertraline (SSRI) and placebo. The results of those clinical studies are not disclosed as of August 2021 (NCT03414931 and NCT04637620). The potential risk of this approach is the excitotoxicity caused by overactivation through the glutamate-binding site.
Another ligand binding site on NMDAR is the glycine site, which can also be targeted to modulate the NMDAR activation for the treatments of psychiatric disorders [82]. Glycine, acting as an agonist via binding the glycine site, can ameliorate negative symptoms in schizophrenia patients [53]. This preliminary finding encourages the development of other endogenous co-agonists, such as D-alanine. D-alanine, working as an add-on antipsychotic medication, improved schizophrenic symptoms without significant side effects, which further supports that the pathophysiology of schizophrenia is due to the hypofunction of NMDA neurotransmission [54]. D-serine, an NMDAR co-agonist without psychotomimetic effects, emerges as a novel glutamatergic antidepressant as an adjuvant therapy in MDD patients (NCT04721249). On the other hand, the therapeutic effects of D-serine at low dose (30 mg/kg/d) in schizophrenic patients are inconsistent. Some clinical studies showed significant improvement in positive, negative, and cognitive symptoms [83], whereas others presented no significant improvement [84]. Interestingly, high doses of D-serine (≥60 mg/kg/d) could possess consistent significant improvement in negative symptoms, strongly suggesting a therapeutic dose–response of D-serine for the treatment of schizophrenia (NCT00322023).
D-cycloserine (DCS), a partial agonist of NMDAR with agonism at low doses but antagonism at high doses depending on the intrinsic tone of NMDA function [85], exhibits controversial therapeutic effects on CNS disorders. In some AD studies, a dose as high as 100 mg/d could improve the cognitive symptoms, while a low dose of 15 mg/d could improve memory deficits [55, 86]. However, other studies presented no cognitive improvement from low (10 mg/d) to high dose (500 mg/d) in AD patients [87].
When the high dose of DCS (≥ 500 mg/d) was employed in MDD patients, depressive symptoms could be improved (NCT00408031) [88]. These observations implied that NMDAR antagonism might be a potential target for the development of novel antidepressant. The clinical studies of DCS at a dose of 50 mg/d is argumentative, some claimed to possess significant clinical improvement [89], while the others found no clinical improvement [90]. In the dose finding phase, the dose of 100 mg/d of DCS seemed to be more effective than 50 or 250 mg/d in improving schizophrenic symptoms [56]. In combination with ketamine, DCS could ameliorate depression symptoms in BD (NCT01833897). Cognitive behavioral therapy with DCS also reduced social anxiety (NCT00515879) and PTSD [91]. Overall, the dose selection of DCS determines its agonistic vs. antagonistic effects on NMDAR, hence modulating its therapeutic efficacy for a variety of CNS disorders.
Rapastinel (GLYX-13/BV-102), an amidated tetrapeptide acting as a NMDA allosteric glycine site partial agonist, is administered intravenously to treat MDD in clinical trial (NCT01684163). Rapastinel infusion achieved antidepressant effects without psychotomimetic properties and serious adverse events, therefore acquiring FDA Fast-Track and Breakthrough Therapy designations for adjunctive treatment of MDD. However, rapastinel failed to meet primary and key secondary endpoints in three acute studies (RAP-MD-01, −02, −03 by Allergan).
Apimostinel (NRX-1074), a chemical structure like rapastinel with an additional benzyl group, is administered intravenously and orally under the studies of efficacy and safety evaluation for MDD patients and healthy individuals (NCT02067793 and NCT02366364). Benefiting from its molecular weight and orally stability, apimostinel is 100-fold more potent than rapastinel and is also well tolerated without psychotomimetic symptoms [92]. The findings of the studies are not available yet.
To enhance NMDAR function, “consolidating” amino acids (e.g., glycine or D-serine, glutamate, and aspartate) in the synaptic cleft could achieve that goal. With the use of inhibitors of amino acid transporters or degrading enzymes, the concentration of those specific amino acids could sustain in the synaptic cleft to boost NMDAR function [58]. Clozapine, a modest inhibitor of sodium-coupled neutral amino acid transporter-2 (SNAT2), indirectly activates NMDAR via augmenting synaptic glycine levels. Clozapine could also improve symptoms of psychosis, tremor, and dyskinesias in PD patients (NCT00004826) [58]. In addition to reducing the risk of hospital re-admission for MDD patients, clozapine administration also demonstrated higher efficacy than quetiapine by ameliorating depressive symptoms [57]. As approved by Food and Drug Administration (FDA) of the USA, clozapine is utilized to treat treatment-resistant schizophrenia and symptoms of self-harm in patients with schizophrenia. Clozapine is also more effective than other antipsychotics in improving treatment-resistant bipolar disorder [59]. However, clozapine can cause potentially lethal agranulocytosis.
Other than SNAT2 inhibitor, GlyT1 inhibitor could also increase synaptic glycine level by blocking the GlyT1 to enhance NMDAR function. BI 425809, a selective GlyT1 inhibitor, emerges as a potential treatment of cognitive impairment of AD and schizophrenia. Although BI 425809 failed to improve cognition in AD study (NCT02788513), it improved cognition in patients with schizophrenia (NCT02832037). Bitopertin (RO-4917838), a selective and potent GlyT1 inhibitor, modulates both glutamatergic and dopaminergic neurotransmission in animal models of schizophrenia [93]. In six active treatment arms across three clinical studies, only one of them proved improvement in symptoms of schizophrenia (NCT01235585) [94]. However, the magnitude of improvement was small. Because of its strong antagonism, bitopertin induces NMDAR internalization, counter-productive to improve the NMDA function.
Sarcosine, a potent endogenous non-selective GlyT1 inhibitor, was applied in cognitive- and mood-related clinical studies. In PD patients, sarcosine improved depression and neuropsychiatric symptoms, especially in patients with mild–moderate severity (NCT01785628). Both in animal models and in depressed patients, sarcosine improved depression-like behaviors, further strengthening GlyT1 inhibitor as a novel class of promising antidepressant (NCT00977353) [31]. In most clinical studies of sarcosine in patents with schizophrenia, improvement in schizophrenic symptoms were reported [60]. However, when being adjunctive with clozapine, sarcosine could not produce improvement in schizophrenic patients [95]. This phenomenon may be explained by the “ceiling effect”: additional NMDAR activation may not be induced due to maximal NMDAR enhancement achieved by clozapine administration alone. In contrast, the combination therapy of sarcosine and sodium benzoate (a D-amino acid oxidase (DAAO) inhibitor) enhances the cognitive function of patients with schizophrenia [96].
DAAO, a flavoenzyme for D-amino acids (e.g., D-serine and D-alanine) degradation, could be strategically inhibited to increase endogenous D-serine levels at the synaptic cleft, resulting in strengthening NMDAR functions. In post-mortem studies, patients with schizophrenia possessed higher expression and activity of DAAO in the cortex and cerebellum [97]. Thus, DAAO inhibition provides a good rationale to be a novel therapeutic target for schizophrenia treatment. Sodium benzoate, a prototype competitive DAAO inhibitor, generated antipsychotic effects in the phencyclidine-induced model of schizophrenia [98]. In some clinical studies, sodium benzoate adjunctive therapy improved symptomatology of patients with schizophrenia [99], and a larger scale clinical trial is undergoing (NCT01908192). In patients with early-phase AD, sodium benzoate predominantly enhanced cognitive and universal functions [61]. Sodium benzoate may enlarge gray matter via synaptogenesis and neurogenesis in MDD treatment [62].
NMDAR antagonism has been a therapeutic strategy for a variety of CNS disorders [100]. To achieve NMDAR antagonism, several negative NMDAR modulators have been offered to treat patients with CNS disorders through distinct underlying mechanisms: direct blocking in competitive, non-competitive, and uncompetitive ways, and indirect blocking. All negative NMDAR modulators are introduced in this section (Figures 1 and 2, Table 1).
AV-101 (L-4-chlorokynurenine), a pro-drug of 7-Chlorokynurenic acid (7-CKA), is able to cross the blood–brain barrier and transform to 7-CKA in astrocytes [101]. 7-CKA is a potent and selective NMDAR glycine site antagonist [102]. In preclinical studies, AV-101 demonstrated dose-dependent antidepressant-like effects in animal models [103]. However, AV-101 monotherapy failed to produce the anti-depressant effects in the clinical study (NCT02484456) [104]. On the other hand, AV-101 treatment for patients with PD will be conducted (NCT04147949).
Dimebon (Latrepirdine), an NAM at the polyamine-binding site of NMDARs, was originally used as an antihistamine [51]. Assessed in clinical trials, dimebon significantly improved the neuropsychiatric symptoms of patients with mild-to-moderate AD (NCT00377715) [105]. In patients with HD, short-term administration of dimebon is beneficial for cognitive improvement (NCT00497159) [106]. Dextromethadone (D-methadone/REL-1017), a non-competitive NMDAR antagonist, provided antidepressant activity via mTORC1-mediated synaptic plasticity in the mPFC in animal models [107]. As dextromethadone performs as a rapid-acting treatment for depression in clinical studies (NCT03051256), it gained FDA Fast-Track designation as an adjunctive treatment for MDD. A phase III clinical trial of dextromethadone is currently ongoing (NCT04688164). Rislenemdaz (CERC-301/MK-0657), a NMDAR NR2B-selective antagonist, induced antidepressant properties in patients with treatment-resistant MDD [108]. Nevertheless, in a phase II study, no obvious antidepressant effects were produced by rislenemdaz (NCT01941043).
Amantadine, a low-affinity uncompetitive NMDAR antagonist with rapid blocking channel kinetics, could ameliorate several clinical symptoms in PD, and the long-term efficacy of chronic treatment with amantadine might improve apathy and fatigue in PD patients (NCT00632762) [109]. For Huntington chorea, amantadine treatment delivered no beneficial effects but brought subjectively better feelings to patients [63]. Memantine, an adamantane derivative like amantadine, is an uncompetitive, moderate affinity, open-channel NMDAR blocker with strong voltage dependency and rapid blocking and unblocking kinetics [110]. Despite being approved by the US FDA for treating moderate-to-severe AD with safe and well tolerated profile, the efficacy of memantine is inconsistent at best. Some studies proved the clinical improvement of memantine in patients with moderate to severe AD [64], while other studies showed little clinical benefits of memantine towards AD treatment [111]. Several clinical results of memantine treatment in PD were also contradictive [65]. In MDD and BD clinical studies, memantine failed to show antidepressant effects in patients [66, 68]. As treatment for schizophrenic symptoms, adjunct memantine uncovered a beneficial effect in ten studies, but no effects in two studies [67]. One study of memantine revealed minimal improvement in seven patients with anxiety [69].
Dextromethorphan, an uncompetitive NMDA receptor antagonist, is used as a cough suppressant with sedative and dissociative effects. In recent research, dextromethorphan and dextromethorphan-based compounds are considered as potential rapid-acting antidepressants, and therefore its therapeutic effect in MDD is evaluated in the clinical study (NCT04226352). In a BD study, dextromethorphan had no significant antidepressant effects compared with placebo group. This might be due to DRD2/ANKK1 TaqIA polymorphism [70]. Nuedexta, an FDA approved treatment for the pseudobulbar affect, was also utilized to treat MDD and BD. The purpose of adding dextromethorphan with quinidine in this combination is to inhibit the cytochrome P450 2D6 (CYP2D6) isoform, a dominant metabolic pathway of dextromethorphan, hence augmenting the bioavailability of dextromethorphan in CNS [112]. A proof-of-concept clinical trial demonstrated that after Nuedexta treatment, the response and remission rates in the patients with treatment resistant depression were 45% and 35%, respectively (NCT01882829). In a retrospective chart review, Nuedexta induced significant improvement in Clinical Global Impression (CGI) in depressed patients with treatment resistant bipolar disorder, implying its possible effectiveness in the BD treatment [71].
AVP-786, another dextromethorphan-based compound, is in conjunction with quinidine and deuterium to decrease the metabolism of dextromethorphan in the liver and hence increase its blood exposure. Following FDA Fast-Track designation for agitation in AD [113], four AD-related clinical studies of AVP-786 are underway (NCT02442765, NCT02442778, NCT02446132, and NCT03393520). In patients with MDD and schizophrenia, the efficacy, safety, and tolerability of AVP-786 were evaluated in the clinical studies (NCT02153502 and NCT03896945). AXS-05 (Axsome) is in combination with dextromethorphan and bupropion, which acts as an inhibitor of CYP2D6 to enhance the bioavailability of dextromethorphan [114]. In the AXS-05 treatment of agitation in patients with AD, the efficacy and safety of AXS-05 will be compared to placebo (NCT04797715). Three phase III clinical studies on the safety and efficacy of AXS-05 in patients with MDD were conducted without results posted to date (NCT02741791, NCT04019704, and NCT04039022).
(R,S)-Ketamine, an anesthetic and analgesic via intravenous administration, and its derivates (S)-ketamine (esketamine) and (R)-ketamine (arketamine) open a new era for glutamatergic rapid-acting antidepressant. At high doses (1-2 mg/kg), ketamine inhibits NMDAR as an uncompetitive antagonist to produce anesthesia, while at low doses, ketamine induces analgesia against both acute and chronic pain (0.25–0.5 mg/kg). Importantly, rapid-acting antidepressant effects of ketamine at moderate doses (0.5 mg/kg) have been proved in preclinical and clinical studies [3]. In most clinical studies of MDD, (R,S)-ketamine administration decreased depression severity with robust and rapid antidepressant effects [72], in accordance with studies of BD [73] and anxiolytic effects in anxiety disorders [74]. The (S+) enantiomer of ketamine was approved by FDA for adults with MDD with acute suicidal ideation or behavior. Esketamine improved depressive symptoms and delayed relapse in many studies [75], but did not demonstrate significant improvement as an adjunctive therapy with oral antidepressants in elderly patients with treatment-resistant depression [115]. In the study of treatment-resistant bipolar depression, the efficacy, safety, and pharmacokinetics of inhaled esketamine are still being evaluated (NCT03965871). Another enantiomer of ketamine, arketamine, is a less potent NMDAR uncompetitive antagonist, but displays greater and longer antidepressant effects than esketamine without psychotomimetic side effects [116]. In an open-label pilot study, intravenous arketamine generated fast-onset and sustained antidepressant effects in depressed patients [117], and the larger study is underway (NCT04108234).
Neramexane, a moderate-affinity NMDAR open-channel blocker, possesses similar kinetics and voltage-dependency to memantine. Although it was well tolerated at all administered doses in clinical studies, phase II/III clinical trials for moderate-to-severe AD yielded contradictory results [76]. Nitrous oxide, an uncompetitive NMDAR antagonist, is an inhaled anesthetic often used in obstetrics or dentistry [118]. One recently published research demonstrated that compared with 50% nitrous oxide, 25% nitrous oxide provides comparable antidepressant effects with a markedly lower rate of adverse effects [77]. Other studies are underway to evaluate the efficacy and safety of nitrous oxide in MDD (NCT03869736 and NCT03932825). Nitrous oxide acted as a pharmacologic treatment for lumbar puncture/other procedure-related anxiety (NCT02243826).
Lamotrigine, inhibiting voltage-dependent Na+, Ca2+, and K+ channels, acts as a presynaptic glutamate release inhibitor [119]. FDA approved lamotrigine for the maintenance treatment of BD. Lamotrigine failed to achieve clinical improvement in five clinical studies of MDD, while it induced higher response rate than placebo in BD studies [52]. In a comprehensive meta-analysis, lamotrigine performed better than placebo in improving unipolar and bipolar depressive symptoms [78]. Five of nine clinical trials of lamotrigine in schizophrenia revealed clinical improvement in a range of outcome measures [67].
Riluzole (BHV-0223), a glutamate release inhibitor, was approved by the US FDA for the treatment of amyotrophic lateral sclerosis. The mechanisms that reduce extracellular glutamate by riluzole includes reduced glutamate release through presynaptic inhibition of voltage-gated sodium channels (VGSCs), increased glutamate uptake by astroglial cells, and enhanced AMPA trafficking [120]. In a current clinical study of AD, riluzole decreased the reduction in cerebral glucose metabolism, a positive correlation with cognitive measures [79]. Additionally, riluzole only ameliorated depressive symptoms in one of four placebo-controlled MDD studies, and failed to reach clinical improvement in a BD study [52]. In one trial of anxiety disorders, eighty percent subjects responded positively to riluzole [80], and the following functional neuroimaging studies proved the alterations in hippocampal N-acetylaspartate (NAA) concentrations and volumes were in correlation with riluzole-induced improvement on anxiety scales [121]. Troriluzole (BHV-4157), a tripeptide prodrug conjugate of riluzole, has been developed to improve the bioavailability, safety, and dosing of riluzole. As a glutamate modulator, troriluzole decreases the level of synaptic glutamate via strengthening glutamate uptake, mainly through excitatory amino acid transporters (i.e., EAAT2) located on glial cells. Both in clinical studies of AD and anxiety, the clinical efficacy of troriluzole is under assessment (NCT03605667 and NCT03829241).
Not only does the discovery of ketamine to act as a novel rapid-acting antidepressant trigger a strong interest in developing novel NMDAR-modulating agents by a variety of proof-of-concept studies for CNS disorders, but also, after exploring the potential pathological mechanisms for the major CNS disorders as described above, the aberrant NMDAR activity shows to play a pivotal role in regulating clinical symptoms, hence facilitating the development of positive and negative NMDAR modulators against those pathological aberrances in NMDAR activity. Interestingly, but not surprisingly, monotherapy of single NMDAR modulators often failed in clinical studies, boosting the prosperity of combination treatment with multiple modulators, or even with the standard treatments, further implying the intricate mechanisms underlying the CNS pathology.
To date, numerous clinical studies of NMDAR modulators are still underway. With more successful clinical improvement by NMDAR modulators in clinical studies, the mysterious puzzles of CNS disorders could be dissolved gradually, further refining the utilization of NMDAR modulators as optimal treatment with less undesirable side effects for the sophisticated CNS disorders that involve vulnerability in NMDA homeostasis.
The authors thank Hung-Chun Liu and Cheng-Shen Lee for their assistance in preparation of the manuscript.
The corresponding author is the CEO of SyneuRx International Corp., which is developing CNS therapeutics.
Ove Odredbe i uvjeti ističu pravila i regulacije u svezi korištenja IntechOpenove stranice www.intechopen.com i svih poddomena u vlasništvu IntechOpena, tvrtke sa sjedištem u 5 Princes Gate Court, London, SW7 2QJ, Ujedinjeno Kraljevstvo.
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\\n\\nSljedeća terminologija odnosi se na Odredbe i uvjete, te na sve naše ugovore:
\\n\\nKlijent, stranka, vi, vaš odnosi se na vas, osobu koja pristupa ovoj stranici i prihvaća IntechOpenove Odredbe i uvjete;
\\n\\nKompanija, tvrtka, mi, naše odnosi se na tvrtku IntechOpen;
\\n\\nStranke, strane odnosi se na klijenta i na nas, ili samo na klijenta ili nas.
\\n\\nSve odredbe koje se odnose na ponudu, prihvat ili razmatranje plaćanja, a za koja mi pružamo asistenciju klijentu, bilo na ugovoreni ili fiksni način, a s ciljem da se ostvare potrebe i želje klijenta u svezi s našim uslugama, su podložne zakonskim odredbama Ujedinjenog Kraljevstva.
\\n\\nOsim ako nije suprotno navedeno, IntechOpen i/ili svi davatelji licence vlasnici su intelektualnog vlasništva nad svim materijalima na www.intechopen.com. Sva prava intelektualnog vlasništva su pridržana. Stranice sa www.intechopen.com možete gledati, preuzimati, dijeliti, dijeliti poveznice i printati za osobnu uporabu, a temeljem pravila sadržanih u ovim Odredbama i uvjetima.
\\n\\nMi koristimo kolačiće. Korištenjem IntechOpenove stranice slažete se s korištenjem kolačića u skladu s IntechOpenovom Politikom privatnosti. Većina modernih, interaktivnih stranica koristi kolačiće kako bi omogućila ponovno pronalaženje korisničkih detalja kod svakog posjeta. Na našoj stranici kolačići se uglavnom koriste kako bi omogućili funkcionalnost i olakšali posjetiteljima korištenje stranice.
\\n\\nIntechOpen ili njegovi suradnici niti u jednom slučaju neće biti odgovorni za štete (štete uključuju gubitak podataka ili profita, druge poslovne prekide, te sve ostale štete) koje nastanu zbog korištenja materijala na IntechOpenovoj stranici ili nemogućnosti da se iste koriste, čak i ako je IntechOpen ili njegov predstavnik o takvoj šteti obaviješten pismenim ili usmenim putem. Neke jurisdikcije ne dozvoljavaju ograničenja garancija ili ograničenja obveza za posljedične ili slučajne štete pa se u tom slučaju ova ograničenja možda ne odnose na vas.
\\n\\nMaterijali koji se pojavljuju na IntechOpenovoj stranici mogu sadržavati manje greške, tipfelere ili fotografske greške. IntechOpen može napraviti promjene na bilo kojem materijalu koji se nalazi na stranici u bilo koje vrijeme.
\\n\\nIntechOpen nije formalno povezan niti s jednom vanjskom stranicom čije poveznice vode na www.intechopen.com, osim ako to nije izravno navedeno. Iz tog razloga IntechOpen nije odgovoran za sadržaj koji se pojavljuje na takvim stranicama. Poveznica na IntechOpenovu stranicu ne implicira povezanost sa IntechOpenom. Korištenje takvih poveznica isključiva je odgovornost korisnika.
\\n\\nZadržavamo pravo vlasništva nad cjelokupnom stranicom www.intechopen.com i nad svim materijalom na toj stranici. Koristeći se našim uslugama, slažete se da maknete sve poveznice na našu stranicu odmah nakon što to od vas zatražimo. Također, zadržavamo pravo da ove Odredbe i uvjete, i politiku o poveznicama izmjenimo u bilo koje vrijeme. Koristeći se poveznicama na naše stranice slažete se s ovim Odredbama i uvjetima.
\\n\\nAko smatrate da je bilo koja poveznica na našoj stranici sumnjiva iz bilo kojeg razloga, molimo vas da nas kontaktirate. U tom slučaju razmotrit ćemo micanje poveznice s naše stranice, iako nismo obvezni to napraviti.
\\n\\nBez prethodne privole i izričite pisane dozvole, ne možete stvarati okvire oko naših stranica ili koristiti druge tehnike koje na bilo koji način mogu promijeniti prezentaciju ili izgled naše stranice.
\\n\\nIntechOpen može ove Odredbe izmijeniti u bilo koje vrijeme i bez prethodne obavijesti. Koristeći ovu stranicu vi se slažete s trenutnim Odredbama i uvjetima koje su na snazi.
\\n\\nOve Odredbe i uvjeti su sastavljeni u skladu s odredbama prava Ujedinjenog Kraljevstva, a za sve sporove nadležan je sud u Londonu, Ujedinjeno Kraljevstvo.
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\n\nSljedeća terminologija odnosi se na Odredbe i uvjete, te na sve naše ugovore:
\n\nKlijent, stranka, vi, vaš odnosi se na vas, osobu koja pristupa ovoj stranici i prihvaća IntechOpenove Odredbe i uvjete;
\n\nKompanija, tvrtka, mi, naše odnosi se na tvrtku IntechOpen;
\n\nStranke, strane odnosi se na klijenta i na nas, ili samo na klijenta ili nas.
\n\nSve odredbe koje se odnose na ponudu, prihvat ili razmatranje plaćanja, a za koja mi pružamo asistenciju klijentu, bilo na ugovoreni ili fiksni način, a s ciljem da se ostvare potrebe i želje klijenta u svezi s našim uslugama, su podložne zakonskim odredbama Ujedinjenog Kraljevstva.
\n\nOsim ako nije suprotno navedeno, IntechOpen i/ili svi davatelji licence vlasnici su intelektualnog vlasništva nad svim materijalima na www.intechopen.com. Sva prava intelektualnog vlasništva su pridržana. Stranice sa www.intechopen.com možete gledati, preuzimati, dijeliti, dijeliti poveznice i printati za osobnu uporabu, a temeljem pravila sadržanih u ovim Odredbama i uvjetima.
\n\nMi koristimo kolačiće. Korištenjem IntechOpenove stranice slažete se s korištenjem kolačića u skladu s IntechOpenovom Politikom privatnosti. Većina modernih, interaktivnih stranica koristi kolačiće kako bi omogućila ponovno pronalaženje korisničkih detalja kod svakog posjeta. Na našoj stranici kolačići se uglavnom koriste kako bi omogućili funkcionalnost i olakšali posjetiteljima korištenje stranice.
\n\nIntechOpen ili njegovi suradnici niti u jednom slučaju neće biti odgovorni za štete (štete uključuju gubitak podataka ili profita, druge poslovne prekide, te sve ostale štete) koje nastanu zbog korištenja materijala na IntechOpenovoj stranici ili nemogućnosti da se iste koriste, čak i ako je IntechOpen ili njegov predstavnik o takvoj šteti obaviješten pismenim ili usmenim putem. Neke jurisdikcije ne dozvoljavaju ograničenja garancija ili ograničenja obveza za posljedične ili slučajne štete pa se u tom slučaju ova ograničenja možda ne odnose na vas.
\n\nMaterijali koji se pojavljuju na IntechOpenovoj stranici mogu sadržavati manje greške, tipfelere ili fotografske greške. IntechOpen može napraviti promjene na bilo kojem materijalu koji se nalazi na stranici u bilo koje vrijeme.
\n\nIntechOpen nije formalno povezan niti s jednom vanjskom stranicom čije poveznice vode na www.intechopen.com, osim ako to nije izravno navedeno. Iz tog razloga IntechOpen nije odgovoran za sadržaj koji se pojavljuje na takvim stranicama. Poveznica na IntechOpenovu stranicu ne implicira povezanost sa IntechOpenom. Korištenje takvih poveznica isključiva je odgovornost korisnika.
\n\nZadržavamo pravo vlasništva nad cjelokupnom stranicom www.intechopen.com i nad svim materijalom na toj stranici. Koristeći se našim uslugama, slažete se da maknete sve poveznice na našu stranicu odmah nakon što to od vas zatražimo. Također, zadržavamo pravo da ove Odredbe i uvjete, i politiku o poveznicama izmjenimo u bilo koje vrijeme. Koristeći se poveznicama na naše stranice slažete se s ovim Odredbama i uvjetima.
\n\nAko smatrate da je bilo koja poveznica na našoj stranici sumnjiva iz bilo kojeg razloga, molimo vas da nas kontaktirate. U tom slučaju razmotrit ćemo micanje poveznice s naše stranice, iako nismo obvezni to napraviti.
\n\nBez prethodne privole i izričite pisane dozvole, ne možete stvarati okvire oko naših stranica ili koristiti druge tehnike koje na bilo koji način mogu promijeniti prezentaciju ili izgled naše stranice.
\n\nIntechOpen može ove Odredbe izmijeniti u bilo koje vrijeme i bez prethodne obavijesti. Koristeći ovu stranicu vi se slažete s trenutnim Odredbama i uvjetima koje su na snazi.
\n\nOve Odredbe i uvjeti su sastavljeni u skladu s odredbama prava Ujedinjenog Kraljevstva, a za sve sporove nadležan je sud u Londonu, Ujedinjeno Kraljevstvo.
\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. He has contributed in stochastic estimation of control area especially, in the Multiple Target Tracking and Interactive Multiple Model (IMM) research, Ball & Beam Control Problem, Robotics, Levitation Control. He has contributed in developing Algorithms for Fingerprint Matching, Computer Vision and Face Recognition. He has been supervising Pattern Recognition, Formal Languages and Distributed Processing projects for several years. He has reviewed many books on Management, Computer Science. Currently, he is an active and permanent reviewer for many international conferences and symposia and the program committee member for many international conferences.\nIn teaching he has taught the core computer science subjects like, Digital Design, Real Time Embedded System Programming, Operating Systems, Software Engineering, Data Structures, Databases, Compiler Construction. 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Advancement in technology now ensures power storage and delivery from few seconds to days/months. But an effective management of the distributed energy resources and its storage systems is essential to ensure efficient operation and long service life. This chapter presents the issues faced in integrating renewables in DG and the growing necessity of energy storages. Types of energy storage systems (ESSs) and their applications have also been detailed. A brief literature study on energy management of ESSs in distributed microgrids has also been included. This is followed by a simple case study to illustrate the need and effect of management of ESSs in distributed systems.",book:{id:"5186",slug:"energy-management-of-distributed-generation-systems",title:"Energy Management of Distributed Generation Systems",fullTitle:"Energy Management of Distributed Generation Systems"},signatures:"Amjed Hina Fathima and Kaliannan Palanisamy",authors:[{id:"179143",title:"Dr.",name:"Hina",middleName:null,surname:"Fathima",slug:"hina-fathima",fullName:"Hina Fathima"},{id:"185245",title:"Dr.",name:"Kaliannan",middleName:null,surname:"Palanisamy",slug:"kaliannan-palanisamy",fullName:"Kaliannan Palanisamy"}]},{id:"50727",doi:"10.5772/63631",title:"Advanced Metering Infrastructure Based on Smart Meters in Smart Grid",slug:"advanced-metering-infrastructure-based-on-smart-meters-in-smart-grid",totalDownloads:4316,totalCrossrefCites:16,totalDimensionsCites:21,abstract:"Due to lack of situational awareness, automated analysis, poor visibility, and mechanical switches, today's electric power grid has been aging and ill‐suited to the demand for electricity, which has gradually increased, in the twenty‐first century. Besides, the global climate change and the greenhouse gas emissions on the Earth caused by the electricity industries, the growing population, one‐way communication, equipment failures, energy storage problems, the capacity limitations of electricity generation, decrease in fossil fuels, and resilience problems put more stress on the existing power grid. Consequently, the smart grid (SG) has emerged to address these challenges. To realize the SG, an advanced metering infrastructure (AMI) based on smart meters is the most important key.",book:{id:"5119",slug:"smart-metering-technology-and-services-inspirations-for-energy-utilities",title:"Smart Metering Technology and Services",fullTitle:"Smart Metering Technology and Services - Inspirations for Energy Utilities"},signatures:"Trong Nghia Le, Wen‐Long Chin, Dang Khoa Truong and Tran Hiep\nNguyen",authors:[{id:"178015",title:"Dr.",name:"Trong Nghia",middleName:null,surname:"Le",slug:"trong-nghia-le",fullName:"Trong Nghia Le"},{id:"178169",title:"Prof.",name:"Wen-Long",middleName:null,surname:"Chin",slug:"wen-long-chin",fullName:"Wen-Long Chin"}]},{id:"29291",doi:"10.5772/31112",title:"Electrolyte and Solid-Electrolyte Interphase Layer in Lithium-Ion Batteries",slug:"electrolyte-and-solid-electrolyte-interphase-layer-in-lithium-ion-batteries",totalDownloads:8861,totalCrossrefCites:3,totalDimensionsCites:20,abstract:null,book:{id:"848",slug:"lithium-ion-batteries-new-developments",title:"Lithium Ion Batteries",fullTitle:"Lithium Ion Batteries - New Developments"},signatures:"Alexandre Chagnes and Jolanta Swiatowska",authors:[{id:"85632",title:"Dr.",name:"Alexandre",middleName:null,surname:"Chagnes",slug:"alexandre-chagnes",fullName:"Alexandre Chagnes"},{id:"88217",title:"Dr.",name:"Jolanta",middleName:null,surname:"Swiatowska",slug:"jolanta-swiatowska",fullName:"Jolanta Swiatowska"}]},{id:"14085",doi:"10.5772/14798",title:"Magnetic Reluctance Method for Dynamical Modeling of Squirrel Cage Induction Machines",slug:"magnetic-reluctance-method-for-dynamical-modeling-of-squirrel-cage-induction-machines",totalDownloads:5371,totalCrossrefCites:14,totalDimensionsCites:16,abstract:null,book:{id:"69",slug:"electric-machines-and-drives",title:"Electric Machines and Drives",fullTitle:"Electric Machines and Drives"},signatures:"Jalal Nazarzadeh and Vahid Naeini",authors:[{id:"18796",title:"Prof.",name:"Jalal",middleName:null,surname:"Nazarzadeh",slug:"jalal-nazarzadeh",fullName:"Jalal Nazarzadeh"},{id:"20586",title:"Prof.",name:"Vahid",middleName:null,surname:"Naeini",slug:"vahid-naeini",fullName:"Vahid Naeini"}]}],mostDownloadedChaptersLast30Days:[{id:"77871",title:"Protection of Microgrids",slug:"protection-of-microgrids",totalDownloads:301,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The concept of microgrids goes back to the early years of the electricity industry although the systems then were not formally called microgrids. Today, two types of microgrids can be seen: independent and grid connected. The protection requirement of these two types differs as the protection needs of an independent microgrid are intended for protecting components and systems within the microgrid, whereas a grid connected microgrid demands both internal and external protection. The first part of this chapter is dedicated to independent microgrids. How protection devices such as residual current circuit breakers, miniature and moulded case circuit breakers, and surge protective devices should be selected for an example microgrid is discussed while referring to the relevant standards. In the next section, the protection of a grid connected microgrid is discussed. Particularly, micro-source protection, microgrid protection, loss of mains protection and fault ride-through requirements are discussed while referring to two commonly used distributed generator connection codes. An example with simulations carried out in the IPSA simulation platform was used to explain different protection requirements and calculation procedures. Finally, grounding requirements are discussed while referring to different interfacing transformer connections and voltage source inverter connections.",book:{id:"10176",slug:"microgrids-and-local-energy-systems",title:"Microgrids and Local Energy Systems",fullTitle:"Microgrids and Local Energy Systems"},signatures:"Janaka Ekanayake",authors:[{id:"328170",title:"Prof.",name:"Janake",middleName:null,surname:"Ekanayake",slug:"janake-ekanayake",fullName:"Janake Ekanayake"}]},{id:"79509",title:"Power Electronic Converters for Microgrids",slug:"power-electronic-converters-for-microgrids",totalDownloads:274,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Power electronic converters are indispensable building blocks of microgrids. They are the enabling technology for many applications of microgrids, e.g., renewable energy integration, transportation electrification, energy storage, and power supplies for computing. In this chapter, the requirements, functions, and operation of power electronic converters are introduced. Then, different topologies of the converters used in microgrids are discussed, including DC/DC converters, single-phase DC/AC converters, three-phase three-wire, and four-wire DC/AC converters. The remaining parts of this chapter focus on how to optimally design and control these converters with the emerging wide-bandgap semiconductors. Correlated tradeoffs of converter efficiency, power density, and cost are analyzed using Artificial Neural Networks to find the optimal design of the converters.",book:{id:"10176",slug:"microgrids-and-local-energy-systems",title:"Microgrids and Local Energy Systems",fullTitle:"Microgrids and Local Energy Systems"},signatures:"Wenlong Ming",authors:[{id:"328358",title:"Dr.",name:"Wenlong",middleName:null,surname:"Ming",slug:"wenlong-ming",fullName:"Wenlong Ming"}]},{id:"65903",title:"Introductory Chapter: Power System Stability",slug:"introductory-chapter-power-system-stability",totalDownloads:2494,totalCrossrefCites:0,totalDimensionsCites:2,abstract:null,book:{id:"8358",slug:"power-system-stability",title:"Power System Stability",fullTitle:"Power System Stability"},signatures:"Kenneth Eloghene Okedu",authors:[{id:"172580",title:"Dr.",name:"Kenneth Eloghene",middleName:null,surname:"Okedu",slug:"kenneth-eloghene-okedu",fullName:"Kenneth Eloghene Okedu"}]},{id:"50520",title:"Fundamentals of Inductively Coupled Wireless Power Transfer Systems",slug:"fundamentals-of-inductively-coupled-wireless-power-transfer-systems",totalDownloads:4655,totalCrossrefCites:4,totalDimensionsCites:8,abstract:"The objective of this chapter is to study the fundamentals and operating principles of inductively coupled wireless power transfer (ICWPT) systems. This new technology can be used in various wireless power transfer applications with different specifications, necessities, and restrictions such as in electric vehicles and consumer electronics. A typical ICWPT system involves a loosely coupled magnetic coupling structure and power electronics circuitries as an integrated system. In this chapter, the emphasis is placed on the magnetic coupling structure, which is the most important part of the system. Although this technology has motivated considerable research and development in the past two decades, still there are several theoretical studies such as the level of the operating frequency, operating at high secondary circuit quality factor, coupling efficiency, etc., that need further investigation to fully develop the governing mathematical relationships of this technology.",book:{id:"5187",slug:"wireless-power-transfer-fundamentals-and-technologies",title:"Wireless Power Transfer",fullTitle:"Wireless Power Transfer - Fundamentals and Technologies"},signatures:"Ali Abdolkhani",authors:[{id:"179618",title:"Dr.",name:"Ali",middleName:null,surname:"Abdolkhani",slug:"ali-abdolkhani",fullName:"Ali Abdolkhani"}]},{id:"78626",title:"Electricity Storage in Local Energy Systems",slug:"electricity-storage-in-local-energy-systems",totalDownloads:221,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Traditionally, power system operation has relied on supply side flexibility from large fossil-based generation plants to managed swings in supply and/or demand. An increase in variable renewable generation has increased curtailment of renewable electricity and variations in electricity prices. Consumers can take advantage of volatile electricity prices and reduce their bills using electricity storage. With reduced fossil-based power generation, traditional methods for balancing supply and demand must change. Electricity storage offers an alternative to fossil-based flexibility, with an increase expected to support high levels of renewable generation. Electrochemical storage is a promising technology for local energy systems. In particular, lithium-ion batteries due to their high energy density and high efficiency. However, despite their 89% decrease in capital cost over the last 10 years, lithium-ion batteries are still relatively expensive. Local energy systems with battery storage can use their battery for different purposes such as maximising their self-consumption, minimising their operating cost through energy arbitrage which is storing energy when the electricity price is low and releasing the energy when the price increases, and increasing their revenue by providing flexibility services to the utility grid. Power rating and energy capacity are vitally important in the design of an electricity storage system. A case study is given for the purpose of providing a repeatable methodology for optimally sizing of a battery storage system for a local energy system. 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. 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He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. 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His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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Ribeiro-Barros",profilePictureURL:"https://mts.intechopen.com/storage/users/171036/images/system/171036.jpg",institutionString:"University of Lisbon",institution:{name:"University of Lisbon",institutionURL:null,country:{name:"Portugal"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Sustainable Economy and Fair Society",value:91,count:1}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:1}],authors:{paginationCount:250,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"243698",title:"Dr.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"312999",title:"Dr.",name:"Bernard O.",middleName:null,surname:"Asimeng",slug:"bernard-o.-asimeng",fullName:"Bernard O. Asimeng",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}}]}},subseries:{item:{id:"92",type:"subseries",title:"Health and Wellbeing",keywords:"Ecology, Ecological, Nature, Health, Wellbeing, Health Production",scope:"\r\n\tSustainable approaches to health and wellbeing in our COVID 19 recovery needs to focus on ecological approaches that prioritize our relationships with each other, and include engagement with nature, the arts and our heritage. This will ensure that we discover ways to live in our world that allows us and other beings to flourish. We can no longer rely on medicalized approaches to health that wait for people to become ill before attempting to treat them. We need to live in harmony with nature and rediscover the beauty and balance in our everyday lives and surroundings, which contribute to our well-being and that of all other creatures on the planet. This topic will provide insights and knowledge into how to achieve this change in health care that is based on ecologically sustainable practices.
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