\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"10718",leadTitle:null,fullTitle:"Gallstones - Review and Recent Progress",title:"Gallstones",subtitle:"Review and Recent Progress",reviewType:"peer-reviewed",abstract:"Gallstones are one of the most common digestive system diseases in the world that can potentially lead to serious complications and even death. As such, this book discusses the epidemiological and pathophysiological characteristics of gallstones, the latest progress in the treatment of different types of gallstones, and the management of complications.",isbn:"978-1-83880-676-7",printIsbn:"978-1-83880-675-0",pdfIsbn:"978-1-83880-677-4",doi:"10.5772/intechopen.94688",price:119,priceEur:129,priceUsd:155,slug:"gallstones-review-and-recent-progress",numberOfPages:110,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"c5ec96a74d97248d64208d5f3c94c6a1",bookSignature:"Qiang Yan and Huaping Shen",publishedDate:"May 11th 2022",coverURL:"https://cdn.intechopen.com/books/images_new/10718.jpg",numberOfDownloads:984,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:0,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 5th 2021",dateEndSecondStepPublish:"May 7th 2021",dateEndThirdStepPublish:"July 6th 2021",dateEndFourthStepPublish:"September 24th 2021",dateEndFifthStepPublish:"November 23rd 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"247970",title:"Prof.",name:"Qiang",middleName:null,surname:"Yan",slug:"qiang-yan",fullName:"Qiang Yan",profilePictureURL:"https://mts.intechopen.com/storage/users/247970/images/system/247970.png",biography:"Qiang Yan, MD, is a master’s supervisor, adjunct professor, and Fellow of the American College of Surgeons (FACS). He is the chairman of the Department of General Surgery and the director of the Department of Hepatopancreatic and Biliary Surgery and Department of Surgery Teaching and Research, Zhejiang University Huzhou Hospital.\nDr. Yan is a member of the Committees of Biliary Surgeons, Department of Surgeons and Hepatobiliary Minimal of Non-invasive Surgery, Chinese Medical Doctor Association, and many other academic associations. He is also a special member of the editorial committees of the Chinese Journal of General Surgery, Liver Cancer, and Chinese Journal of Clinicians. He is a participant in the High-Level Talents of Zhejiang Medicine and Zhejiang Province 151 Talents. Dr. Yan completed advanced studies in hepatobiliary pancreatic surgery at Stanford University Medical Center, California, and University Hospital Regensburg, Germany. He has more than thirty high-quality papers to his credit.",institutionString:"Huzhou Central Hospital",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Zhejiang University",institutionURL:null,country:{name:"China"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"344080",title:"Dr.",name:"Huaping",middleName:null,surname:"Shen",slug:"huaping-shen",fullName:"Huaping Shen",profilePictureURL:"https://mts.intechopen.com/storage/users/344080/images/system/344080.png",biography:"Huaping Shen is an associate chief of the Department of Hepatopancreatic and Biliary (HPB) Surgery, Zhejiang University Huzhou Hospital. He has been engaged in hepatobiliary and pancreatic surgery for 10 years and is an expert in diagnosis and treatment of hepatobiliary and pancreatic diseases. Dr. Shen has ten medical papers to his credit and has participated in seven research projects.",institutionString:"Zhejiang University Huzhou Hospital",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Zhejiang University",institutionURL:null,country:{name:"China"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"181",title:"Gastroenterology",slug:"gastroenterology"}],chapters:[{id:"77803",title:"Gall Stones in Pediatric Population",doi:"10.5772/intechopen.99020",slug:"gall-stones-in-pediatric-population",totalDownloads:252,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Gall stones is a known entity in adults, but are considered uncommon in pediatric population, however in the recent years, mainly with wide spread use of ultrasonography, cholelithiasis in children is being frequently reported. Etiology of gall stones in children is not similar to adults. Pigment stones are the most frequently seen in children with hemolytic disease as the most common cause, however with the increase in obesity in children there is also rise in cholesterol stones. Many other causes like drugs, congenital hepatobiliary malformation and genetic causes are to be kept during evaluation of gall stones. Management of gall stones need a proper and timely work up for the causes of cholelithiasis is necessary in children. Surgical management with laparoscopic cholecystectomy is the treatment of choice in most of the cases however the timing of surgery should be optimized case to case basis.",signatures:"Nida Mirza Shaikh",downloadPdfUrl:"/chapter/pdf-download/77803",previewPdfUrl:"/chapter/pdf-preview/77803",authors:[{id:"353559",title:"Dr.",name:"Nida",surname:"Mirza Shaikh",slug:"nida-mirza-shaikh",fullName:"Nida Mirza Shaikh"}],corrections:null},{id:"77668",title:"Minimally Invasive Treatment for Cholelithiasis",doi:"10.5772/intechopen.98874",slug:"minimally-invasive-treatment-for-cholelithiasis",totalDownloads:113,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Gallstone disease, cholecysto- and choledocho-lithiasis, is one of the most common digestive diseases. Most patients with symptomatic cholecystolithiasis are recommended to undergo cholecystectomy to alleviate their symptoms like abdominal pain and jaundice. Approximately 10–20% of patients who undergo cholecystectomy for gallstones have choledocholithiasis. Nowadays, endoscopic and/or laparoscopic approaches are widely accepted as the treatment for patients with gallstone. Patients with cholecystolithiasis are usually treated by laparoscopic cholecystectomy, whereas patients with choledocholithiasis are done by endoscopic sphincterotomy (EST) or laparoscopic common bile duct exploration (LCBDE). Additionally, some cases are treated by biliary reconstruction such as biliary enteric anastomosis. In this chapter, currently available laparoscopic approaches as a minimally invasive surgery are introduced and discussed on the basis of pathogenesis of the gallstone.",signatures:"Hirotaka Okamoto",downloadPdfUrl:"/chapter/pdf-download/77668",previewPdfUrl:"/chapter/pdf-preview/77668",authors:[{id:"170986",title:"Dr.",name:"Hirotaka",surname:"Okamoto",slug:"hirotaka-okamoto",fullName:"Hirotaka Okamoto"}],corrections:null},{id:"79571",title:"Routine and Innovation in Surgical Therapy of Gallstones",doi:"10.5772/intechopen.100570",slug:"routine-and-innovation-in-surgical-therapy-of-gallstones",totalDownloads:126,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter discusses the anatomy of the gallbladder with the anatomical variations potentially impacting surgical therapy. It is dissertated upon the clinical indication for the surgical therapy with consecutive treatment. The discussion on the surgery focuses on the patient’s safety and strategies for safe cholecystectomy with an optimal approach. Even though the efforts to minimise potential complications are made, the complication may arise, and therefore, the last part of this chapter discusses such cases with optimal clinical management.",signatures:"Peter Dubovan, Ramadan Aziri and Miroslav Tomáš",downloadPdfUrl:"/chapter/pdf-download/79571",previewPdfUrl:"/chapter/pdf-preview/79571",authors:[{id:"236591",title:"Dr.",name:"Miroslav",surname:"Tomáš",slug:"miroslav-tomas",fullName:"Miroslav Tomáš"},{id:"416150",title:"M.D.",name:"Peter",surname:"Dubovan",slug:"peter-dubovan",fullName:"Peter Dubovan"},{id:"427787",title:"Dr.",name:"Ramadan",surname:"Aziri",slug:"ramadan-aziri",fullName:"Ramadan Aziri"}],corrections:null},{id:"79601",title:"Infections of Biliary Tract",doi:"10.5772/intechopen.100063",slug:"infections-of-biliary-tract",totalDownloads:100,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Biliary tract infections include cholangitis and cholecystitis. They are associated with high morbidity and mortality in elderly patients with comorbid disease. The most common infecting organisms are Enterobacteriaceae ascending from the gastrointestinal tract, Gram-positive pathogens like Enterococci spp.; the infections are rarely caused by fungi, viruses, and parasites. The prime reason for biliary tract infections is the ascending infection due to the reflux of duodenal contents and also the blood-borne infection or infection spreading through the portal-venous channels. The other predisposing conditions causing biliary tract infections include critical illnesses such as trauma, burns, sepsis, HIV infection, immunosuppression, diabetes, non-biliary surgery, and childbirth. The infection is reduced by β-lactam antibiotics or their derivatives, cephalosporins, carbapenems, fluoroquinolones, etc. Empiric treatment with piperacillin/tazobactam or a cephalosporin with or without metronidazole is recommended for moderate and severe acute cholecystitis irrespective of whether there is growth by culture. Patients with severe cholecystitis are unfortunately difficult to identify properly, both clinically and radiologically, because clinical symptoms are unexpected, and imaging investigations are frequently ambiguous. However, there are significant differences in morbidity and death rates between individuals with mild cholecystitis and those with severe cholecystitis. Preventing related consequences requires early identification and effective therapy of individuals at risk of severe cholecystitis.",signatures:"Hema Prakash Kumari Pilli and Vijayalakshmi Payala",downloadPdfUrl:"/chapter/pdf-download/79601",previewPdfUrl:"/chapter/pdf-preview/79601",authors:[{id:"418972",title:"Prof.",name:"Hema Prakash Kumari",surname:"Pilli",slug:"hema-prakash-kumari-pilli",fullName:"Hema Prakash Kumari Pilli"},{id:"425006",title:"Dr.",name:"Vijayalakshmi",surname:"Payala",slug:"vijayalakshmi-payala",fullName:"Vijayalakshmi Payala"}],corrections:null},{id:"78708",title:"The Role of Endoscopic Ultrasound in Acute Cholecystitis",doi:"10.5772/intechopen.99856",slug:"the-role-of-endoscopic-ultrasound-in-acute-cholecystitis",totalDownloads:126,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Acute cholecystitis (AC) is one of challenging clinical conditions in biliary disorders as it can carry high morbidity and mortality. Gallstone disease is still the main cause of AC in clinical practice. Transabdominal ultrasound, abdominal CT scan and abdominal MRI are the standard diagnostic tools in AC, however, some obstacles can be found which are associated to the patient’s factor, anatomy or anomaly of biliary system, the disease severity, and the operator. Cholecystectomy is still the primary choice management in AC condition, however, several issues need to be encountered, such as critically ill condition, sepsis, and patient’s comorbidity. Percutaneous approach has become an alternative as it is considered as a simple procedure to be performed in clinical practice. Catheter dislodgement, the risk of bile leakage, and uncooperative patients have raised major concerns for this procedure. Another method, such as endoscopic approach has been studied as well and it seemed to have more advantage when compared to the percutaneous approach. Recently, endoscopic ultrasound (EUS) has been used as a combined diagnostic as well as therapeutic tools in managing biliary disorders. Recent evidences about the role of EUS approach for gallbladder drainage (EUS GBD) in patients who unsuitable for surgery have emerged in the past one decade. However, comprehensive evaluation before which approach is the best option is needed as expertise, cost, and patient’s outcome prediction are the most important factors to be considered in the real clinical practice.",signatures:"Cosmas Rinaldi A. Lesmana and Laurentius A. Lesmana",downloadPdfUrl:"/chapter/pdf-download/78708",previewPdfUrl:"/chapter/pdf-preview/78708",authors:[{id:"35361",title:"Dr.",name:"Cosmas",surname:"Rinaldi A. Lesmana",slug:"cosmas-rinaldi-a.-lesmana",fullName:"Cosmas Rinaldi A. Lesmana"},{id:"281814",title:"Prof.",name:"Laurentius",surname:"A. Lesmana",slug:"laurentius-a.-lesmana",fullName:"Laurentius A. Lesmana"}],corrections:null},{id:"78740",title:"Acute Alitasic Cholecystitis",doi:"10.5772/intechopen.99188",slug:"acute-alitasic-cholecystitis",totalDownloads:117,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Acute acalculous cholecystitis (AAC) is the inflammatory disease of the gallbladder in the absence of gallstones. Typically affects critically ill patients. Diagnosis is not straightforward as Murphy’s sign is difficult to detect in critically ill and many imaging findings are numb or nonspecific. Acalculous cholecystitis is a life-threatening disorder that has a high risk of perforation and necrosis compared to the more typical calculous disease. Management involves a percutaneous cholecystostomy, a surgical cholecystectomy, or, more recently, a metal stent placed endoscopically through the gastrointestinal tract into the gallbladder. Acalculous cholecystitis is a serious illness that has high morbidity and mortality. The reported mortality of the condition varies from 30 to 50% depending on the age of the patient. Even those who survive have a long recovery that can take months.",signatures:"Giovanni Petracca, Francesco Zappia, Maccarone Giuseppe, Mazzeo Mariano, Mio Francesco, Fabrizio Silvaggio, Mileto Ivana, Plutino Francesco, Posterino Antonietta and Danilo Cafaro",downloadPdfUrl:"/chapter/pdf-download/78740",previewPdfUrl:"/chapter/pdf-preview/78740",authors:[{id:"310797",title:"Dr.",name:"Giovanni",surname:"Petracca",slug:"giovanni-petracca",fullName:"Giovanni Petracca"},{id:"329332",title:"Dr.",name:"Francesco",surname:"Zappia",slug:"francesco-zappia",fullName:"Francesco Zappia"},{id:"353778",title:"Dr.",name:"Fabrizio",surname:"Silvaggio",slug:"fabrizio-silvaggio",fullName:"Fabrizio Silvaggio"},{id:"429097",title:"M.D.",name:"Giuseppe",surname:"Maccarone",slug:"giuseppe-maccarone",fullName:"Giuseppe Maccarone"},{id:"429098",title:"M.D.",name:"Mariano",surname:"Mazzeo",slug:"mariano-mazzeo",fullName:"Mariano Mazzeo"},{id:"429099",title:"M.D.",name:"Francesco",surname:"Mio",slug:"francesco-mio",fullName:"Francesco Mio"}],corrections:null},{id:"79566",title:"Pathophysiology of Gallstones",doi:"10.5772/intechopen.100553",slug:"pathophysiology-of-gallstones",totalDownloads:150,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Gallstones are the stones developing in the gallbladder. Evolution of pathophysiology changes the trends of treatment of a disease. Laparoscopic revolution was only because of gallstones diseases. The shifting of food habits increased the incidence of diseases in developing countries. There are mainly three types of stones Cholesterol, pigment and brown stones. The pathophysiology of which is different for each type. Cholesterol stones being most common owing to the risk factors being prevalent in the developing and developed societies. Pigment stones being most common in blood disorder patients while brown stones are most common in common bile duct and are infected ones.",signatures:"Mela Ram Attri, Irshad Ahmad Kumar, Ferkhand Mohi Ud Din, Ashiq Hussain Raina and Aakarshit Attri",downloadPdfUrl:"/chapter/pdf-download/79566",previewPdfUrl:"/chapter/pdf-preview/79566",authors:[{id:"353314",title:"Dr.",name:"Irshad Ahmad",surname:"Kumar",slug:"irshad-ahmad-kumar",fullName:"Irshad Ahmad Kumar"},{id:"429226",title:"Dr.",name:"Ferkhand Mohi",surname:"Ud Din",slug:"ferkhand-mohi-ud-din",fullName:"Ferkhand Mohi Ud Din"},{id:"429227",title:"Dr.",name:"Ashiq Hussain",surname:"Raina",slug:"ashiq-hussain-raina",fullName:"Ashiq Hussain Raina"},{id:"429366",title:"Prof.",name:"Mela Ram",surname:"Attri",slug:"mela-ram-attri",fullName:"Mela Ram Attri"},{id:"443910",title:"Dr.",name:"Aakarshit",surname:"Attri",slug:"aakarshit-attri",fullName:"Aakarshit Attri"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"10318",title:"Recent Advances in Pancreatitis",subtitle:null,isOpenForSubmission:!1,hash:"4660cc6cfdbc562d1f25e6e05b6b77f1",slug:"recent-advances-in-pancreatitis",bookSignature:"Qiang Yan",coverURL:"https://cdn.intechopen.com/books/images_new/10318.jpg",editedByType:"Edited by",editors:[{id:"247970",title:"Prof.",name:"Qiang",surname:"Yan",slug:"qiang-yan",fullName:"Qiang Yan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7869",title:"Advanced Endoscopy",subtitle:null,isOpenForSubmission:!1,hash:"92f6ce51b737e9086a6059ab7470eee9",slug:"advanced-endoscopy",bookSignature:"Qiang Yan and Xu Sun",coverURL:"https://cdn.intechopen.com/books/images_new/7869.jpg",editedByType:"Edited by",editors:[{id:"247970",title:"Prof.",name:"Qiang",surname:"Yan",slug:"qiang-yan",fullName:"Qiang Yan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. 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This phenomenon is partly due to the popularity of the sport, as well as the growing influence of technology on the training process and match performance. Also, the number of publications about football has been increasing substantially, with literature focusing on several interesting topics. This book aims to compile the most recent research developments in Football Science. Firstly, one of the emerging themes in Football research is the performance analysis, however it has become urgent to develop new methods for a more integrative approach to the large datasets collected by wearable and tracking devices. This integrative approach should aggregate the actual sub-topics already extensively discussed in the literature such as training load monitoring, match analysis, technical-tactical analysis and psychophysiological approaches. The optical performance also depends on the football player’s health, well-being and readiness. Subsequently, this book will aim to examine the current perspectives on assessment, rehabilitation and prevention in football medicine. On the spectrum of Women's football, talent identification and development will also be analysed through theoretical and practical considerations. Finally, this book intends to present the latest research carried out on other football codes such as futsal, beach soccer, street football, rugby football and e-sports (football). Future directions in Football Science will be raised based on emerging research topics such as big data, neurosciences and virtual reality.
",isbn:"978-1-83768-412-0",printIsbn:"978-1-83768-411-3",pdfIsbn:"978-1-83768-413-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"bed0ea442dab20d921bb27c471b4d5a7",bookSignature:"Prof. José Eduardo Teixeira, Dr. Luís Branquinho, Dr. Ricardo Ferraz and Dr. Pedro Forte",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11838.jpg",keywords:"Wearable and Tracking Technology, Training Load Monitoring, Well-Being and Readiness, Recovery Strategies, Match Analysis, Training Representativeness, Scouting, Key-Performance Indicators, Futsal, Beach Soccer, Big Data and Analytics, EEG Patterns",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 15th 2022",dateEndSecondStepPublish:"July 13th 2022",dateEndThirdStepPublish:"September 11th 2022",dateEndFourthStepPublish:"November 30th 2022",dateEndFifthStepPublish:"January 29th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"6 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Teixeira has published several studies in the area of exercise physiology, monitoring training load, and performance analysis in team sports. 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He is the author of more than 50 documents, between books, book chapters, papers in peer-reviewed journals, and conference proceedings.",coeditorThreeBiosketch:"Dr. Forte is a basketball and football coach. He is a Coordinator Professor at the Instituto Superior de Ciências Educativas do Douro and Guest Professor at the Instituto Politécnico de Bragança. His research is based on sports science with an emphasis on biomechanics. His areas of research in terms of the contextualization of scientific, technological, and artistic-cultural production are Prevalence, Posture, Youth, Asymmetries, Risk-factors, and Football among others.",coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"423226",title:"Prof.",name:"José Eduardo",middleName:null,surname:"Teixeira",slug:"jose-eduardo-teixeira",fullName:"José Eduardo Teixeira",profilePictureURL:"https://mts.intechopen.com/storage/users/423226/images/system/423226.jpg",biography:"José Eduardo de Araújo Teixeira graduated in Cardiopneumology at the Polytechnic Institute of Castelo Branco (2009-2013), Portugal, and in Sports Sciences at the Polytechnic Institute of Bragança (2014-2017), Portugal. He holds a Ph.D. in Sports Sciences from the University of Trás-os-Montes (2017-2022), Portugal, and a Master\\'s degree in Exercise and Health (2020-2022) from the Polytechnic Institute of Bragança, Portugal. Dr. Teixeira has published several studies in the area of exercise physiology, monitoring training load, and performance analysis in team sports. Additionally, Dr. Teixeira\\'s knowledge extends to medical and health sciences focusing on cardiovascular, respiratory, and metabolic systems. Dr. Teixeira has already integrated three research projects: \\'Importance of the Electrocardiogram in the Sports Medical Evaluation\\' (2011-2013), \\'Sport Management Unit Research\\' (smUr, 2014-2017), and \\'Surveillance and Monitoring System for Physical and Sports Activity\\' (2018). 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Most of that work was dedicated to minimize the great mental effort needed to control the prosthetic limb, especially during the first stages of training. When working with myoelectric prosthesis, that effort increases dramatically. These devices use EMG signals (the electrical manifestation of the neuromuscular activation associated with a contracting muscle) collected from remnant muscles to generate control inputs for the artificial limb. As these devices use a biological signal to control their movements, it is expected that they should be much easier to control. However, the prosthesis control is very unnatural and requires a great mental effort, especially during the first months after fitting [2, 7, 8]. As a result, a number of patients give up the use of those devices very soon. To overcome those problems, different techniques have been tried as an attempt to devise better strategies for myoelectric control.
This chapter describes the advent of Virtual Reality (VR) systems to create training environments dedicated to users of prosthetic devices. Those VR systems generally simulate a prosthesis that can react to commands issued by the users. A sophisticated system proposed by the authors is also described. Known as “
The human body has been considered a perfect machine, in which all parts work in harmony one with each other. Most of us can control this “machine“ without much effort, until some disturbance caused by disease or injury results in loss of some of its functionality.
The absence of limbs caused by trauma or congenital disorders, can affect our lives profoundly. Simple tasks such as walking or dressing can become extremely difficult or even impossible to execute. There is no doubt that the best solution for the loss of a limb might be the development of some kind of genetic manipulation that stimulates the regeneration of tissue. However, while this is not possible, the best we can do is to restore some of the lost functionality by means of artificial limbs.
For centuries, mankind seek ways to replace lost limbs by mechanical devices. Several ancient designs can be found in museums and libraries. However, the first artifact to be formally named artificial limb was a Roman prosthesis, made of wood and bronze, which appeared around 300 BC [9]. During the Middle Ages, while the poor wore “wooden legs", which were simple, inexpensive and stable, the rich nobles used devices made of iron, which were more decorative than functional. In 1818 Peter Ballif designed the first prosthesis actuated by movements of healthy parts of the body. Before this, the upper limb prostheses were heavy and depended on an able hand for operation [10]. Thereafter, a number of experiments have been carried out seeking the “perfect prosthesis“, a device that could be similar to what Wolfe had visualized in 1952 in his book “
As we know, to date, this prediction has yet to be completely materialized, but much has been done since then. Due to the great number of casualties of World War II, the government of the United States created in 1945 a program of research and development from which scientists and engineers were deeply involved in projects aimed at the development of artificial limbs for amputees [10].
Another fact that lead to the acceleration of the researches in the area, was the large number of congenital defects caused by the use of a drug called Thalidomide. As describe by Soares [10], it was synthesized by the German laboratory Chemie Grünenthal in 1957 and marketed worldwide between 1958 and 1962. This drug was prescribed to minimize sickness during pregnancy. The Thalidomide consumers were not warned that the drug could exceed the placenta affecting the fetus. This oversight had a catastrophic effect: drug abuse, especially during the first trimester of pregnancy, has killed thousands of babies. Those who survived experienced birth defects such as deafness, blindness, disfigurement, and especially the shortening or absence of members. Responding to this tragedy, several research centers intensified the efforts towards the design of artificial limbs as an attempt to improve the lives of those children.
Also, during that period, russian scientists had introduced a prosthetic hand controlled by a signal generated by the activity of remaining muscles from amputated limbs [8]. That type of control has been described as “myoelectric control” and the prosthesis, by extension, has been described as “myoelectric prosthesis“.
The control of prostheses can be considered one of the most interesting challenges related to prosthetics. Ideally, a prosthetic limb should be controlled without any effort from the user, similar to the subconscious control of a natural limb.
Currently, there are two main strategies for controlling artificial limbs: biomechanical and bioelectrical. In the first, the motion of parts of the body results in the activation of the limb, whereas, in the latter, biosignals, generated from the electrical activity of muscles, are detected and interpreted in order to generate commands for controlling the prosthesis. Nevertheless, there is ongoing research seeking other forms of control based on more natural strategies, such as those that employ brain or neuronal activity together with sensory feedback [5-7, 12-14].
As described earlier, the first prostheses were generally passive devices that relied on intact parts of the body for their positioning and controlling. This extremely successful design allowed the user to control the device so that the movement of a part of the body was reflected in movements of parts of the prosthesis. Despite some modifications, this design remains basically the same nowadays, being the most popular control mechanism among users [10]. The reasons for such success are not well established, but according to Doeringer and Hogan [15] some of the key factors are: it results in a relatively inexpensive prosthesis; the final prosthesis is not too heavy; after training, the user begins to use the prosthesis as a natural extension of his body, having, for example, the notion of weight and size of the prosthetic limb. Kruit and Cool [16] described the main drawbacks: the mechanism of harnesses used to propagate the movements of the body is usually uncomfortable; the movement of the prosthesis requires significantly large forces; the number of control inputs is limited and thus the number of degrees of freedom of the prosthesis is also limited.
An alternative to the Body-Powered control is to employ the myoelectric control, which uses the electrical activity of muscle contraction (electromyographic signal) as a primary source of control. The prostheses that use this type of control typically do not require cables and, in some situations, there is no need for suspension straps. The operation of a myoelectric device can be summarized as follows: the brain sends commands, i.e., neuronal impulses that travel through nerves and reach the endplate of a given muscle, which, in turn, causes muscle contraction; The electrical muscle activity is then captured by electrodes (normally in a socket attached to the stump), interpreted by customized programs in a microcontroller, and used to activate the actuator of the prosthesis.
Many myoelectric prostheses employed a type of control called “two-site two-states”, from which a pair of electrodes is placed on two distinct muscles. The contraction of one of these muscles produces the opening of the hand. The antagonist muscle is used in the same way to control the closing of the hand. As pointed out by Scott and Parker [8], this approach works in a manner analogous to the human body, i.e., two antagonistic muscles (or group of muscles) control the movement of a joint. However, as patients must learn to generate independent contractions of the muscles, which requires a high degree of concentration, the training can be lengthy and demand a lot of mental effort. There are also some situations in which it is not possible to find two available groups of muscles, or there might be more than one joint to be controlled. For these situations other controlling approaches have been developed [17]. For instance, the “one-site three-states", from which a little contraction of a muscle produces the closing of the hand, a strong contraction open it, and the lack muscle activity stops the hand. Figure 1 shows an example of a hand prosthesis controlled by electromyographic signals captured by four pairs of dome electrodes, distributed around the residual limb ([18]).
An experimental setup for a myoelectric prosthesis, developed at the University of New Bruswick, Canada (extracted from [
Currently there are a number of methods using proportional control based on the electrical activity of muscles to control the speed, torque and position of prosthetic joints. However, due to the nature of the myoelectric signal, errors and inaccuracies may occur [19]. Myoelectric signals can be detected using basically two types of electrodes: surface electrodes positioned on the skin surface, and needle electrodes inserted in relevant positions of the muscle. In both cases the electrodes produce a difference of potential relative to a reference (typically another electrode located elsewhere on the body). This voltage is the result of an asynchronous activation of hundreds of muscle fibers. The signal is similar to a random noise whose amplitude is modulated by a voluntary input. Its shape depends on variables such as strength and speed of activation, positioning and types of electrodes used in its detection, electronic circuits used for acquisition, amplification and processing [20]. These factors make the translation of myoelectric activity into commands for a prosthetic limb a challenge. Moreover, the generation of myoelectric patterns must be learned by the user, and this is a task which requires concentration, regular training and a great amount of physical effort.
A common way of training an individual to generate myoelectric patterns is by using feedback software, which provides the user with visual feedback about the relation between the forces associated to the contraction with the amplitude of the generated myoelectric signal. The main drawback of this strategy is that it does not give the user feedback information or sense of proprioception. Recent studies have suggested that virtual and augmented reality [21] may be a relevant tool to address the limitations of conventional training techniques. The main advantage of this technique is that it can simulate the physical presence of the artificial limb in the real world, as well as in imaginary worlds. Moreover, some simulations may include additional sensory information, such as sound through speakers or headphones. It is also possible to include tactile information, generally known as force feedback, for the individual.
Virtual Reality (VR) can be defined as an advanced computer interface where the user can, in real time, navigate within a tridimensional environment interacting with its virtual objects. Such interaction is achieved in a very intuitive and natural way. To do so, multisensory devices are supplied [22].
In order to illustrate this concept, consider Figure 2, in which a user is shown standing inside a research laboratory. However, since she is equipped with multisensory devices (Head Mounted Display – HMD and hand (glove) sensors), a computer-based system provides her the feeling of being steeped into a different environment.
The system, known as BioSimMER© (from Sandia National Laboratories) [23], is used to train rescue personnel to respond to terrorist attacks. The screen on the top shows the working environment displayed only for the eyes of the health professional and the virtual patient exhibits realistic symptoms. Such facilities are not supported by traditional computer interfaces.
Therefore, to achieve the high level of natural interface required by VR systems, it is important to provide the user with the feeling of immersion and the ability for interaction. To reach such requirements, VR developers must guarantee: 1) Real life 3D object images from the user´s perspective; 2) The aptitude to track the user\'s motions, particularly his head and eye movements, and correspondingly adjust the images on the output device to reflect the change in perspective.
Experiment with virtual reality techniques and devices (extracted from [
Augmented Reality (AR) is a technique that allows the integration of virtual objects within a real physical environment. Interaction is again supported by multisensory equipment. Essentially, a real scene, captured by a digital camera, is “augmented” with the insertion of virtual objects [24]. Figure 3 illustrates this concept.
An example of Augmented Reality extracted from [
In Figure 3(a), an engineer uses a fiduciary square marker to identify the heating distribution throughout a mechanical part, as shown in Figure 3(b). However, this “virtual” information can only be seen by him, through the equipment and glasses he carries.
A very well-known framework to support AR is the ARToolKit ([26]). It provides Computer Vision techniques to calculate position and orientation of a digital camera in relation to fiduciary markers. The augmentation is produced after a series of transformations, as shown in Figure 4. First, the real video image is transformed into a binary one. Then, this image is processed in order to determine square black regions (fiduciary markers – regions whose outline contour can be fitted by four line segments) containing an image pattern that is compared to patterns stored in a database. Next, the algorithm uses size-known squares and the pattern orientation as the base for the coordinates frame and to calculate the real position of the digital camera in relation to the physical marker. After that, the 3D objects are placed over the fiduciary markers, and the final image is sent to the display.
ARToolKit workflow.
Nowadays, VR and AR systems have been intensively used for training and simulation. According to [27] and [28], the main reasons for that are:
It provides “Learning by doing” - according to pedagogical studies, the learning curve and the amount of knowledge acquired are intensified when the apprentice plays an active role during the process;
It supports virtual and interactive experiments/simulations - replacing physical counterparts that could pose health hazard or even be too expensive in real life;
It allows training to be executed outside classes and clinics; and
It inspires creativity.
The strategies adopted by systems like the ARToolKit are promising and relatively simple to be incorporated into final applications. However, the need for physical markers can limit their application in many areas. Hence, an interface that is able to represent the real environment, capture movements and sounds and transforming them into actions to interact with virtual objects, have been the focus of many recent researches seeking a human-computer dialogue closer to natural. That’s why the expression “natural user interface” has emerged as new computer interaction technology. It focuses on human abilities such as touch, vision, voice and higher cognitive functions, such as expression, perception and recall [29]. The main objective here is to give a physical meaning for the digital information. In so doing, data manipulation with the use of bare hands, gestures, voice commands and pattern recognition are supported.
Recently, Santos et al. [30] presented an application that uses gestures to interact with virtual objects in an Augmented Reality, based on Kinect© (a motion sensing input device developed by Microsoft Inc.). The application is not limited by environment, lighting or skin color and doesn´t require fiduciary markers. The system allows the user to perform operations on menus and interact with virtual objects solely by hand gestures (Figure 5).
Natural User Interface with Augmented Reality: (a) User selecting menu options; and (b) User manipulating a virtual object (extracted from [
In recent past years, it has been observed a steady growth in the use of Virtual and Augmented Reality in health care [31, 32]. There a number of examples in the literature. However, to ilustrate the technique, let´s take two examples into account.
Payandeh and Shi [33] presented a mechanics-based interactive multi-modal environment designed to teach basic suturing and knotting techniques for simple skin or soft tissue wound closure. Two haptic devices are used for force-feedback, simulating the experience of suturing a real tissue (Figure 6).
That realist feeling was provided by a number computer-based techniques, such as mass-spring system, to simulate the deformable tissue (skin), mechanics-based techniques to simulate the deformations of a linear object (the suturing material) and collision detection for the interactions between the soft tissue and the needle. Figure 7 shows a pre-wound scene (a) and the result after the virtual suture (b).
Virtual and Augmented Reality have also been studied as a tool for phobia treatment [34]. As an example, consider the system describe in [35]. The project, which is accompanied by a psychologist, aims to design a system to gradually confrontate the patient with his object phobia. Clinical studies have shown that some patients cannot handle, or even do not evolve in the treatment, if exposed to a real arachnid in the initial sessions. Thus, AR is used to present the patient with virtual objects that reminds a spider (like a cartoon) and this object, gradually, becomes a very ‘realistic’ virtual one (with photorealism modeling techniques). Figure 8(a) shows a potential user wearing the system apparatus and Figure 8(b) shows the image seen by the user.
VR multi-modal experimental setup for simulating surgical sutures (extracted from [
a) Virtual pre-wound tissue for suturing; (b) Virtual wound closed (extracted from [
a) User wearing HMD for arachnophobia treatment; (b) The AR image, as seen by the user.
Based on the discussions above, we can infer that VR and AR incorporate a number of features with great potential to overcome some of the difficulties associated with the training of prosthetic users.
As described earlier, great effort has been devoted to devise new strategies for the control of artificial limbs fitted to patients with congenital defects or who have lost their limbs in accidents or surgery. In general, the devices do not properly resemble the real counterpart, do not react in the same manner, do not provide proper feedback and cannot be controlled using the “natural” interfaces, i.e., signals emanated from the central nervous system. Therefore, a number of difficulties arise when a new user tries to control an artificial limb, since he/she will have to devise a completely new strategy to generate input signals for the prostheses, so that it will act according to his/her wishes. This leads to a lengthy, tiring, and sometimes frustrating, training period. That is true for the great majority of the strategies for prosthesis control that have been designed to date.
Recently, a number of research groups turned their attention to VR and AR, in an attempt to overcome some of those problems. Although many works can be found in the literature, we have chosen just a few to illustrate the concept.
Pons
One of the MANUS users performing a combined cylindrical grasp and wrist rotation (extracted from [
As expected, multifunctional prostheses pose an additional problem for users: the more dexterous the device, the higher the number of command channels required to control it. As a result, a large number of different EMG commands, generally obtained by extra EMG channels, are required for successful management of the prosthesis. To minimize the number of channels, the authors proposed a three-bit ternary EMG command strategy. The users were asked to produce EMG bursts (by sudden contraction of a single muscle) and, if proper EMG thresholds could be defined, each burst was classified in three different levels. Each of those three levels were then given the digital values “0”, “1” or “2” (no signal, low, high), corresponding to one ternary bit. In so doing, if the user generates three bits, he/she could generate up to 27 different combinations (commands) from a single muscle. However, since the commands starting with “0” (i.e., “0XY”) were not valid, the three-bit ternary strategy allowed the generation of 18 effective commands. This means that, from a single muscle, the user could control up to 18 different functions/actions of the prosthesis. However, that is no easy task to learn. Hence, a special training device, based on VR simulation of the multifunctional prosthesis, was created to enable the learning of that “EMG command language”. Only after the training process was finished, the prosthesis was fitted and real manipulative operation started. The authors report that all of the volunteers were able to successfully perform basic commands after about 45 minutes.
In similar fashion, Resnik
a) DEKA Arm displayed on manikin; (b) VR avatar (extracted from [
The authors report that the VR environment allows a gradual acclimatization to the arm, as the experience with the arm-control scheme prior to use of the physical arm allows a staged introduction of the new elements of the system. However, the system did not allow for interaction with virtual objects, i.e., it was not possible, for instance, the manipulation of an object with the virtual hand. Nevertheless, the system proved to be an important asset for upper-limb users who must master a large number of controls and for those who need a structured learning environment, due to cognitive deficits.
Although VR has been extensively used as an aiding tool for users of prosthetic devices, the interaction with the virtual world still needs to be improved, in order to provide a real immersive training environment. To do so, the research group headed by the authors, have developed new techniques for VR interaction and for detection and processing of EMG signals, in order to extract the correct commands issued by the user which, in turn, could be used to control the movements of a device in a VR environment [21, 28, 30, 38]. However, although a purely non-immersive VR environment showed some good results, it was thought that an Augmented Reality (AR) environment would provide a more realistic experience. Hence, an AR environment was designed so that images of the virtual device (the prosthesis) are combined with images of the real world, providing a realistic environment for training upper limb prosthetic users [39]. A simplified block diagram of the system is shown in Figure 11.
The authors’ approach for a Virtual Myoelectric Prosthesis (extracted from [
In the system, the user is fitted with a head mounted device that includes a camera, for capturing the real images of the user´s view point, and a display to show the mixed images (augmented: real and virtual). The EMG signals are collected and processed to generate inputs to the VR unit [21]. A processing center decides when to update both the virtual arm (Figure 12) and the augmented reality image, to further send them to the graphics user interface (the head mounted display).
A Virtual Prosthesis designed by the authors.
During operation, the camera captures the image and locates a marker at the user´s shoulder. The algorithm then searches for a virtual object that corresponds to such marker (Figure 13) and inserts it into the real world, captured by a camera.
Image of a virtual object combined with the real world scene – an outsider point of view (extracted from [
As described in [39], the control inputs for the AR environment are generated by EMG signals, collected from remnant muscles. The raw EMG signal, detected by surface electrodes is conditioned and processed to find out which movement the user wants to perform. To do so, the areas of activity in the EMG data were detected (windowing) and the resulting signal was then processed to generate a set of features used by an artificial neural network classifier. Basically, each EMG contraction was represented by a set of Auto-Regressive (AR) coefficients calculated according to a modified algorithm described in [38]. According to the authors, the choice of a neural network as a classifier was due to its ability to learn and later recognize signals as being part of the same class of movement in real time. Also, depending on the level of amputation, different users may generate different levels of contractions of the remaining part of the limb, for the same class movement. Besides, even if a single user performs only isometric or isotonic contractions, there will not be two identical contractions for the same movement. The neural network was trained with four classes of movements (elbow flexion, elbow extension, wrist pronation and wrist supination). The results showed a near perfect performance of the classifier (95% to 100% rate of success). The output of the neural network is then used as control input (position and motion) to the virtual device, which can be rendered and mixed with the real world scene, as shown in Figure 14.
User´s point of view within the AR environment (extracted from [
Note that this system allows the user to interact within the virtual environment - the virtual myoelectric prosthesis can touch and grab other virtual objects embedded in the real scene (such as the cube and the kettle in Figure 14). Also, a strong cognitive feedback is provided by this real time mixture of virtual objects with the real environment, given the feeling that it is almost possible to touch the virtual arm with the real one, and vice-versa.
This chapter presented an overview on the search of human beings for artificial devices capable of restoring, if not all, at least part of the functionality lost when we are affected by diseases, congenital disorders or trauma that results in the loss of a limb. Focusing on upper limb prosthesis, a series of sophisticated technical solutions have been proposed during the past decade to design devices whose behavior and control approach that of their healthy natural counterparts. However, as described along this chapter, operating a highly complex artificial limb is not a simple task. This is especially true for myoelectric multifunctional prostheses with many degrees of freedom. Since the necessary control commands, in most instances, can be very different from the “natural” commands, learning how to produce them is extremely difficult and time consuming. With the advent of Virtual and Augmented Reality, those technologies have been proposed as relevant tools to address some of the limitations of conventional training techniques. It is possible to design a virtual device very similar, in shape and behavior, to a real one. Also, it is even possible to collect commands from the real world (EMG signals generated by remnant muscles) and use them as inputs to control the actions of a virtual prosthesis in an Augment Reality Environment, according to the training stage of the user, or any other setup defined by the therapist. In so doing, those techniques allow for a considerable reduction of physical and metal efforts usually necessary to master the control of a prosthetic device.
Despite the progress achieved so far, the authors believe that, as technology advances, the use of virtual and augmented reality for controlling myoelectric prostheses should also undergo continuous improvements. These future developments should be focused on issues such as: (i) improving the modeling of the virtual devices, in order to increase the sense of realism when compared to actual prostheses; (ii) new adaptive protocols for controlling the virtual prosthesis, so that it could emulated different strategies and different joint actuators; and (iii) the design of new devices to provide physiological feedback, allowing the user to "feel" what the virtual prosthesis is actually doing, thus, increasing the feeling of a complete mix between the real and virtual worlds.
The authors would like to express their gratitude to “Coordenação de Aperfeiçoamento de Pessoal de Nível Superior” (CAPES - Brazil), “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq – Brazil) and “Fundação de Amparo à Pesquisa do Estado de Minas Gerais” (FAPEMIG – MG – Brazil) for the financial support.
The rotation of the Earth on its axis is the root of the 24-h light-dark cycle and all of the astronomical phenomena that are measured concerning the plane of the horizon—the sunrise and sunset, twilight periods, photoperiod, solar eclipses, movement of the tides, and the lunar perigee and apogee. These phenomena all have the common denominator that they cause variations in the periods of light versus darkness. This light-dark cycle and its variations directly influence the myriad of activities of living organisms, including sleep and wakefulness, rest and activity, feeding, and body temperature changes [1].
The timing and pattern of mammalian behavioral activities are regulated by an evolutionarily optimized interplay between the genetically based biological (circadian) clock and superimposed environmental factors and thus mask the effects mediated by the clock. The main regulator in endogenous circadian rhythms is the suprachiasmatic nucleus, which sits above the optic chiasm and, in humans, is composed of approximately 20,000 neurons. The most important external synchronizing factors, or “Zeitgebers,” is the light-induced phase-setting of the circadian rhythmicity to the 24-h solar day. This influence results in a roughly 24-h activity-rest cycle in diurnal organisms and the converse rest-activity cycle in nocturnal organisms.
Although the 24-h light-dark cycle is the most important Zeitgeber, there are many other modulators that further synchronize or mask circadian rhythms, including social stimuli, sounds, smells, or physical contact, which generate behavioral states that impact endogenous clocks [2]. Regarding the light-dark cycle as a Zeitgeber, the production of melatonin (5-methoxitriptamine), an indolamine secreted by the pineal gland, is dependent on the photoperiod. This hormone is released at night by the pineal gland and collected by the internal recess, the third ventricle. From this location, melatonin is distributed by the cerebrospinal fluid to the brain tissue acting as a synchronizing signal of the internal media with the environmental light [3]. The circadian production of melatonin by the pineal gland is controlled by the circadian clock through a multi-synaptic pathway and released melatonin carries the timing information to the peripheral oscillating structures to couple the oscillating functions (Figure 1).
Regulation pattern of melatonin synthesis. In the scheme is showed the principal structures involved in the circadian rhythm of melatonin synthesis, the suprachiasmatic nucleus and the pineal gland as well as the neuronal and the endocrine pathways to transmit the circadian information, the autonomous nervous system and the variation of circulating melatonin.
The role of melatonin as circadian messenger, as well as the organization of the circadian system, has been described mainly using confined animals; however, studying biological rhythms under natural conditions allows us to understand how geophysical variables impact endogenous clocks. In this regard, initially, chronobiologists conducted their studies under experimental laboratory conditions, while behavioral ecologists have focused their research on observing the behavior of free-living organisms. In the year 2000, in their book “Activity patterns in small mammals” Halle and Stenth of the University of Jena in Germany proposed the integration of behavioral ecology and chronobiology under natural and semi-natural conditions, founding the new discipline of “behavioral chrono ecology,” that is, the study of rhythms under natural conditions and the synchronization of rhythms with nature [4].
In behavioral field studies of primates’ activity rhythms and their modulation by environmental variables, the possible dual, synchronizing and/or masking effects of variables other than light-dark cycles are often ignored. However, there are some studies that addressed these issues. One of these was studied in the Mexican spider monkeys (
Circadian rhythm of motor activity in the Mexican spider monkeys
In other study, additional environmental variables such as the effect of housing conditions and season were incorporated to the daily timing and pattern of activity in this species. Thus, the activity patterns between monkeys living under natural lighting and climatic conditions in either a large wire netting cage or a 0.25-ha forest enclosure in the primatological field station of Veracruz State University near Catemaco, Mexico, were studied. Also, a pregnant female was followed in the forest enclosure, which gave us insight into the effect of late pregnancy and parturition on the monkey’s activity rhythm. Spider moneys are strictly diurnal, with 90% of their total activity occurring during daylight. Monkeys that lived in the forest enclosure had a higher second activity peak in the late afternoon compared to those living in the caged area, resulting in a more pronounced bimodal activity pattern. The spider monkeys kept there had an earlier activity onset and morning activity peak than their conspecifics in the cage; however, no differences were found in the phase-setting parameters of the circadian system to the environmental 24-h periodicity, either by comparison or correlation with the sunrise and sunset. The late pregnancy, parturition, and lactation induced a reduction on the activity level during the week of parturition and the following week. The long days of the summer season and the short days of the winter season were decisive in the expression of the activity time of the morning and evening peaks. Together, data suggest that in Mexican spider monkeys, a weak circadian component and strong direct masking effects of multiple environmental factors are involved in the regulation of the daily activity rhythm [6].
The study of the monkeys under their natural environment may allow us to obtain evidence to highlight the importance of melatonin to modulate diverse oscillating functions and behavioral activities controlled by the circadian clock that can repercuss on mental health. Hence, the main goal of this chapter is to review and discuss the evidence that supports the influence of melatonin on circadian physiology focusing on its modulatory effects on neurodevelopment and brain plasticity as well as on the importance of this indole for the treatment of neuropsychiatric diseases.
Melatonin (
Synthesis pathway of melatonin. The metabolic pathway for melatonin biosynthesis begins necessarily with tryptophan This synthesis consists of several enzymatic reactions; among them the hydroxylation by tryptophan hydroxylase (TPH) produces 5-hydroxytryptophan; in addition, serotonin is formed by the aromatic amino acid decarboxylase (AADC); at the end,
As mentioned previously, circulating melatonin concentration oscillates following a circadian rhythm with a nocturnal peak in almost all studied species (Figure 4). This oscillation is regulated by light implying that the rhythm could be synchronized by the photoperiod, in the same manner as other functions [11]. The most ancient function of melatonin apparently is the protection against oxidative stress. Still, in animals, this indole regulates even complex behaviors such as daily activity and seasonal reproduction, some sleep properties, as well as retinal, hormonal, metabolic, and immune functions [12]. In contrast to non-mammalian vertebrates, pinealectomy in rat or mouse does not disrupt the circadian rhythmicity; instead, these animals retain most of their circadian rhythms, including the oscillating locomotor activity; however, a subtle uncoupling of several physiological functions occurs [13]. In mammals, the melatonergic system has only a secondary rank in the circadian system [14]. Apparently, the temporal signal produced by SCN is distributed to peripheral clocks by both neural pathways through the hypothalamic nucleus and the autonomous nervous system [15, 16], and endocrine pathways mediated mainly through melatonin from the pineal gland. An example of the latter is the requirement of melatonin signal in the maintenance of circadian activity in the
Circadian rhythm of melatonin release. The hormone melatonin is released from the pineal gland in mammals at night. This molecule has been considered the signal of darkness to adjust the circadian system.
To address the role of melatonin as a synchronizer molecule, several experimental strategies have been developed. For example, the organisms are maintained under constant environmental conditions in which the circadian rhythms present a free-running period that could be shorter or longer than 24 h. In this condition, one stimulation with exogenous melatonin applied at different circadian times can induce a phase shift in the oscillation; this change can be a delay or an advance of the rhythm phase. Also, under the same constant environmental condition, a daily melatonin stimulus is applied at a specific external time, so the rhythm becomes adjusted with respect to the periodic stimulation. Both the period and the phase of the rhythms change and are synchronized by melatonin. In both cases, the conclusion is that melatonin is a synchronizer acting on the circadian pacemaker.
In all vertebrates, melatonin membrane receptors seem to be involved in both the phase shifts induced in the circadian oscillations and in the synchronization of the rhythms by injected or infused melatonin [18, 19, 20]. It has been proposed that the pathway activated by melatonin is dependent on the subtype of membrane receptors distributed in the SCN or in the pineal gland itself. In many non-mammalian vertebrates, melatonin receptors distributed in different tissues, including the SCN, seem to be involved in the transduction of the timing of circadian rhythms, but also in phase shifts and synchronization [20].
Melatonin shifts the phase of the locomotor activity rhythm and the firing rate of the mammalian SCN neurons. These actions can be mediated by MT2 receptors. The mammalian circadian pacemaker is sensitive to exogenous melatonin at the hours around day-night and night-day transitions [21, 22]. When melatonin is applied to male C3H/HeN mice at CT10, that is, two circadian hours before the onset of activity, the hormone induces dose-dependent phase advances [23]. This effect is significantly reduced by application of the selective MT2 antagonist 4P-PDOT. This antagonist also diminishes the melatonin-induced phase advances of the SCN neuronal firing rhythm in male Long-Evans rats [24]. In MT1 receptor-deficient mice, the application of melatonin at CT10 still produced phase advances [25]. A common example of circadian rhythms phase shift is the so-called jet lag induced by traveling across several time zones. Melatonergic agonists such as ramelteon and tasimelteon (nonselective MT1/MT2 agonists) have been used as therapeutic options for alleviating the sleep disturbances associated with this transient perturbation in the temporal organization of the circadian system [26].
Melatonin synchronizes the locomotor circadian rhythm in Long-Evans rats, Wistar rats, and the diurnal rodent
Even though pinealectomy does not induce apparent changes in the properties of most of the circadian rhythms in mammals, it has been observed that the decrease in melatonin levels affects some important circadian functions such as the sleep-wake cycle and triggers depressive-like symptoms; these disturbances have been improved with the administration of melatonin receptor agonists [31], suggesting that the role of this pleiotropic hormone in physiology might be underestimated. One important function of melatonin that can repercuss in the brain physiology is the modulation of neurogenic processes and circuit functioning as explained below.
Similarly, to the behavioral studies of primates’ activity rhythms and their modulation by environmental variables, there are also studies about the regulation of molecular and cellular processes influenced by Zeitgebers that participate in the behavior. One example is the neurodevelopment in the hippocampus, which is the brain region where learning and memory are integrated [32]. This function plays a key role in the adaptation of the organism to the environment. Neurodevelopment implicates the formation of new neurons, cell migration, cell differentiation, and the formation of neuronal projections dendrites and axons as well as the formation of synaptic contacts that culminate in the establishment of neuronal connections that together constitute the structural network that underlies brain function.
In 1966, Altman found that new neuron formations occur in the adult brain, making a breakthrough in the concept of that times that new neuron formation occurred only at embryonic stages [33]. However, Altman, for the first time, demonstrated by immunohistology and autoradiographic technique the incorporation of 3H-thymidine into the DNA of cerebellar cells of rats at postnatal age [33]. In the last decade of the past century, further contributions to this field emerged, and it was clear that neurogenesis continues throughout the entire life at various locations in the brain such as the subventricular zone, the olfactory bulb, and the dentate gyrus of the hippocampus [34]. In an analogous manner to neurogenesis, dendrite and axonal formation as well as synaptic contact, establishment occurs during the entire life, making the brain a highly neuroplastic an adaptative organ.
Adult neurogenesis as well as neuroplasticity is conserved processes in all mammalian species studied so far including non-human primates and humans [35]. Both processes are mechanisms that allow the survival and the well adaptation of the organisms to environmental conditions. In this regard, melatonin, a phylogenetically conserved molecule, allows survival and adaptation acting as a free radical scavenger and enhancing the levels of antioxidant enzymes protecting the brain against stressful stimuli. Moreover, because the indolamine stimulates neurogenesis and new neuronal contact formation in the hippocampus, it makes the organism more competent for survival.
The evidence about circadian regulation of neurodevelopment in the adult brain was aroused by the observation that melatonin stimulates different stages of neurodevelopment and because the indolamine is synthesized according to the photoperiod and synchronized the internal activity with the environmental light. In this regard, melatonin synchronizes the sleep-wake cycle, the body temperature, the cortisol release, among other functions.
The adult brain presents neuroplastic changes that follows a circadian rhythm; for instance, the maximal amplitude of neuroplasticity occurs during the scotophase regardless of the activity pattern of the species (diurnal or nocturnal). In the hippocampal subgranular zone of murine adult, proliferation of immature neurons increases at the middle of the scotophase (
In diurnal zebrafish, and in nocturnal mice, the stages of the cell cycle in stem cells of neurogenic niches show a circadian rhythm with nocturnal peak [37]. These rhythms correlate with the expression of Clock1 and Per1 in zebrafish [37] and with Per2 and Bmal1 in mice [38]. These results suggest that cell proliferation is controlled by the clock genes in most mammalian species [39, 40, 41]; interestingly, melatonin can influence the level of clock gene expression [42] and the half-life of clock proteins by timing their degradation in the proteasome [43].
Neuroplastic changes in dendrites also follow a circadian pattern. In Siberian hamsters, the hippocampal dendritic structure of basilar dendrites of CA1pyramidal neurons revealed dendrite length increase that occurs during the dark phase [44]. Moreover, the number of branch points significantly increases during short days (8 h L: 16 h D), indicating a more complex dendritic arbor, while during long days (16 h L: 8 h D), the dendrites are longer. Administration of melatonin at the end of the light phase induces the nocturnal dendritic morphology in CA1 neurons within 4 h. In addition, in organotypic cultures of hippocampus incubated with melatonin 100 nM, dendrite formation in the hilar zone is evident after 6 h of incubation and increased formation of secondary and tertiary dendrites [45] (Figure 5). The changes in dendrite size and complexity are correlated with the increase in the expression of Per1 and Bmal1 in the hippocampus [46]. Hence, in short or long photoperiod schemes, the duration of endogenous melatonin release would change respecting the length of the dark phase, providing seasonal information to neurogenic niches [47].
Neurogenesis in hippocampus and neuronal precursor cells. The neurogenesis process has been studied in organotypic cultures and in isolated precursors obtained from the olfactory epithelium to determine the stimulatory effect of melatonin.
Synaptogenesis, the main event by which neurons are connected, is also regulated by the circadian rhythms. Two approaches have been used to study synaptic formation: (1) structural studies in which immunostaining of synaptic proteins by specific antibodies was used to label dendrite spines the site where synaptogenesis takes place and electrophysiological approaches where long-term potentiation is studied (LTP). The former showed a circadian pattern reaching a maximum number or size of dendritic spines during the dark phase in the hippocampus and somatosensory cortex in mice [48, 49]. Moreover, increased synapses formation is observed in hippocampal organotypic cultures incubated with 100 nM melatonin and by staining with an anti-synapsin antibody, which labels synapsin a protein localized in the presynapsis [45]. Despite this information, studies in Siberian hamsters indicate a decrease in dendritic spine density during the dark phase in the dentate gyrus [44, 46]. Thus, it is necessary to study more deeply the rhythmicity of synapses formation and the factors that influence it.
On the other hand, electrophysiological studies have shown that synaptic strength measured through hippocampal LTP was more significant in magnitude and stability in slices obtained during the dark phase [50]. This pattern persisted even in constant darkness or in slices obtained at daytime and recording LTP at night; these results suggest an endogenous rhythm in synaptic plasticity that could persist
Current studies indicate that olfactory neuronal precursors are a subrogate model of the central nervous system to study neurotransmitter receptors expression, enzymes involved in neurotransmitter synthesis as well as the neurodevelopment in the adulthood.
Olfactory neurons have a common ectodermal embryonic origin with the CNS neurons and are derived from embryonic placodes and the neural crest, which are structures analogous to the neural tube [53, 54].
Gene expression profiles of olfactory neuronal precursors are similar to mesenchymal stem cells and can be differentiated into mature olfactory neurons and other types of neurons such as dopaminergic neurons [55, 56]. The expression of hundreds of genes such as CNS neurons has been shown in olfactory neuroepithelial cells. Some of these are the pituitary adenylate cyclase-activating peptide and the glutamate receptor, among others [57, 58, 59]. Moreover, in postmortem samples obtained from Alzheimer’s disease patients, paired helical filaments of tau protein and amyloid-β plaques similar to those found in cortical and subcortical neurons have been described in olfactory neuroepithelial cells characterized by cytokeratin-18 expression reflecting its stromal epithelial cell nature, as well as in olfactory neurons characterized by III β-tubulin expression [60, 61]. Recently, neuronal precursors were obtained from alive patients with Alzheimer’s disease diagnosis and demonstrated the paired helical filaments, as well as increased levels of tau total and phospho-tau supporting that olfactory neuroepithelial cells are a mirror model that reflects molecular changes produced in the CNS and useful to study different stages of neurodevelopment in samples obtained from alive patients [62].
In this regard, it was demonstrated that spontaneous axogenesis occurs in olfactory neuronal precursors derived from a clone obtained by unlimited dilution from a female of 55 years with no psychiatric history. Twelve percent of these cells maintained in primary culture the ability to form axons. In the presence of melatonin, axonal formation augmented by 15% in the primary cultures of olfactory neuronal precursors [63].
In addition to these observations, spine and new neuron formation in a clone of human olfactory neuronal precursors stimulated by melatonin was demonstrated. Spines were labeled with Phalloidin-Rhodamine and an anti-spinophilin antibody and counted. The prelaminar results showed that melatonin increases spine formation in primary cultures of human olfactory neuronal precursors. Moreover, neurogenesis measured as clusters of proliferating neuronal precursors has been observed in the presence of 100 nM melatonin (manuscript in preparation). Altogether, evidence supports that melatonin stimulates three important stages of neurodevelopment, neurogenesis, spine formation, and axogenesis.
In addition to natural
In human subjects, the pattern of motor activity in unmedicated schizophrenia patients and healthy subjects had been study to disclose whether the pattern was affected by treatment with typical and atypical antipsychotics (haloperidol and risperidone). Twenty unmedicated schizophrenic patients wore a wrist actigraph that recorded activity at 1-min intervals for five days. The activity pattern of patients and healthy subjects was compared; then, the patients were randomly assigned to treatment with low-dose haloperidol or risperidone, and the effect of treatment on the activity was tested. Untreated patients were less active during morning, evening, and late-night periods compared with controls. Both haloperidol and risperidone induce significant effects on activity level (this effect was more prominent with haloperidol). The results suggest that unmedicated schizophrenic patients exhibit abnormally low levels of motor activity, which persists with antipsychotic treatment, even though symptoms improve. Future studies should clarify whether motor disturbances are a primary effect of the illness or related to the lifestyle effects [64].
In addition, some antidepressants flatten the amplitude of melatonin secretion, contributing to the alterations of biological rhythms inherent to major depression. Thus, it can be suggested the use of melatonin as a therapeutical adjuvant to regulate biological rhythms such as the sleep/wake cycle.
Recently, we explored if neuroplasticity is altered in schizophrenia. By using the translational experimental model of olfactory neuronal precursors, we found that these cells derived from a patient with schizophrenia were unable to form axons spontaneously. However, in the presence of melatonin, these cells formed axons with the same rate as cells derived from a healthy subject with no psychiatric history [63]. Thus, data suggest that besides the inherent disruption of biological rhythms in schizophrenia patients and drug administration, they also have impaired axonal rhythm formation during adulthood that can be restored by melatonin.
As mentioned before, human beings have a rhythmic expression in their physiology and behavior. In homeostasis states, this endogenous rhythmicity is synchronized by cyclic environmental factors. This coupling provides several advantages: anticipating cyclical changes in the background and facilitating the organism’s adaptation to its environment. This rhythmicity has systems that allow measuring the passage of time, and it is regulated by environmental signals (exogenous) that act as external synchronizers. These rhythms oscillate approximately every 24 h, and among these, the most important is the light-dark cycle or cycle circadian. This concerted, internal, and external rhythmic expression is essential to maintain a healthy state. There is strong evidence that supports the idea that the disruption or chrono-disruption of this adaptive mechanism is detrimental to health and has, among other consequences, sleep disorders, which can lead to cognitive deterioration. It has also been associated with an increased risk of cardiovascular disease, hypertension, metabolic conditions such as diabetes, cancer, obesity, and affective disorders such as anxiety and depression, increasing the prevalence of neuropsychiatric disorders such as schizophrenia and major depression.
The synchronization of circadian rhythms with pharmacotherapy is crucial for neuropsychiatric and affective disorders treatment since it is about combining the maximum benefit with the minimum time complexity of the treatments.
Adequate coordination between drug administration schedules to obtain an optimal therapeutic response has been little explored and currently represents a challenge for chrono-pharmacology.
Desynchronization between the times of administration and the potential pharmacological effects could be one of the reasons why a high percentage of patients with major and bipolar depression (MD) are resistant to treatment, as well as the chronic recurrence of depressive and seasonal disorders. Chronotherapeutic strategies that reset the internal clock may have a specific advantage for treating depression and other mental disorders.
For instance, seasonal affective disorder (SAD) is a sub-type of depression in which individuals experience depressive symptoms and show hypersomnia only in the winter months, in which the period of darkness is more extended than at other times of the year. In a pioneering study, Rosenthal and coworkers [65] found that treatment with bright environmental light suppresses the endogen melatonin secretion and reverses the winter depressive symptoms of patients with SAD. In contrast, light too dim to suppress endogen melatonin is therapeutically ineffective.
This same paper described the antidepressant effects of phototherapy in eight SAD patients by oral melatonin administration. However, in another study with 19 SAD patients, the authors did not find any therapeutic difference between the atenolol, a beta-adrenergic blocker, which inhibits melatonin secretion, and placebo. In contrast, research with seven SAD patients showed that the antidepressant effects of phototherapy were not photoperiodic and appeared to be independent of melatonin suppression. Authors conclude that melatonin can mediate the effects of shortening days on the winter symptoms of SAD and that the modification of melatonin secretion by bright light mediates its antidepressant effects and gives evidence that melatonin secretion may be abnormal in SAD [65].
Multiple factors can disrupt this chronicity because of imbalances in the sleep-wake cycle. Disruption of circadian cycles has also been associated with affective disorders.
Depression disorders are characterized by a broad range of symptoms, including altered mood, loss of cognitive functions, and recurrent thoughts of death or suicide. The relationship between chrono-disruption and the etiology of depression is not yet clear. However, evidence suggests that existing pharmacotherapies such as lithium and antidepressants such as melatonin and agomelatine act on the circadian system.
Although it is known that melatonin is a mediator of photoperiodic changes on seasonal rhythms in animals, a gradual increase in circulating levels of melatonin occurs after lights off, reaching its maximum around the middle of the dark phase. There is contradictory evidence about the antidepressant effect of melatonin itself. We found that the melatonin administration in mice at two
Agomelatine is an antidepressant that acts as an agonist on the melatonin receptors and as a 5HT2C receptor antagonist. Several studies suggest that the antidepressant effect caused by agomelatine results from the resynchronization of circadian rhythms that are disturbed in depressed patients ameliorating symptoms of depression. In contrast to other antidepressants, this has shown low relapse rates upon discontinuation and high tolerability. Furthermore, agomelatine treatment improves the amplitude of the circadian (rest/activity) sleep/wake cycle and diminishes the depression and anxiety symptoms in comparison with sertraline treatment [67].
There is strong evidence about the association between sleep disturbances and depression; in depressive disorder (MDD), the desynchronization of circadian rhythms occurs, producing disturbed sleep and insomnia, and these symptoms improve markedly with melatonergic (MT1 and MT2) and 5HT2C agonist treatment such as melatonin and agomelatine, which act as modulating the circadian rhythmicity.
The foregoing gives evidence of the disruptions of the sleep-wake cycle (sleep architecture and timing) and residual symptoms may prevent the attainment of high-quality remission and delay recovery from MDD.
Benedetti and coworkers studied the effect of morning light therapy or placebo combined with the serotonin reuptake inhibitor citalopram in treating patients affected by a major depressive episode without psychotic features. They found that the combination of this antidepressant and light treatment was more effective than citalopram alone or placebo in the treatment of major depression, administered with an optimized timing of administration, and low-intensity light treatment that significantly hastened and potentiated the effect of citalopram. This evidence provides the clinical psychiatrists with an augmenting strategy, effective and devoid of side effects [68].
Alterations in circadian rhythmicity have been little studied in patients with schizophrenia, in which sleep disorders are common, with an 80% prevalence that often responds to circadian disruption.
This study showed that the variability of sleep-wake time is notably more significant and more remarkable in the schizophrenia group than in the people without the disorder [69].
In addition, polysomnography studies have shown that these patients present a higher sleep latency, diminished total sleep time, lower efficiency, more interruptions, a shorter duration, and latency of REM dreams, as well as a lower proportion of slow-wave sleep than people without this condition. Also, deficit sleep spindles in schizophrenia people could be an endophenotype of this disorder.
In a study of rest activity, a cohort of patients with schizophrenia matched with healthy subjects, Wulff and coworkers [69] showed that there is clear evidence of sleep and circadian rhythm disruption in schizophrenia patients, over half the cohort, tested showed severe circadian misalignment, including the melatonin cycle.
Compared rest-activity patterns in a cohort of patients with schizophrenia with matched healthy unemployed controls showed significant sleep/circadian disruption in all 20 patients studied. Of these, half showed severe circadian misalignment in sleep-wake and melatonin cycles, demonstrating that abnormal entrainment of the circadian system is prevalent in schizophrenia.
Although the results are not conclusive yet and more research is needed in this regard, chronotherapy is a relatively recent proposal to optimize pharmacological treatments based on the biological clock to maximize the pharmacological response or produce adjustments when there is a desynchronization in the biological functions that are affected in illnesses, including mental disorders. Therefore, it is necessary to adequately coordinate medication administration schedules to obtain the maximum pharmacological results and increase treatment adherence.
Evidence presented in this chapter indicates that neuroplasticity is modulated by an external
Funded by Consejo Nacional de Ciencia y Tecnología (CONACyT) Grant No. 290526 to GBK. CONACyT had no further role in review design, in the collection, analysis and interpretation of data, neither in the writing of the report, nor in the decision to submit the paper for publication.
The authors declare no conflict of interest.
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