The intestinal microbiota: Most common commensal anaerobic bacteria species in the human intestines (95% of them are obligate and 5% are facultative anaerobes) [16].
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"7844",leadTitle:null,fullTitle:"Voice and Swallowing Disorders",title:"Voice and Swallowing Disorders",subtitle:null,reviewType:"peer-reviewed",abstract:"The purpose of writing this book is to discuss the updated information on voice and swallowing disorders. The book has been written by international authors and experts in this field. You will find not only clinical aspects but also basic science aspects of voice and swallowing disorders. The chapters include the quantitative analysis of activity patterns of muscles of mastication and deglutition, and salivary secretion after facial massage and vibrotactile stimulation. You will also find the updated management of oropharyngeal dysphagia, dysphagia due to cervical facial tumors, radiation-induced dysphagia, and dysphagia in patients with a stroke. This book can be an important guide to the practicing physicians and surgeons managing voice and swallowing disorders.",isbn:"978-1-83880-366-7",printIsbn:"978-1-83880-365-0",pdfIsbn:"978-1-83880-105-2",doi:"10.5772/intechopen.77662",price:119,priceEur:129,priceUsd:155,slug:"voice-and-swallowing-disorders",numberOfPages:146,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"9a81e27eb29c12553e9524f20a93b57d",bookSignature:"Monjur Ahmed",publishedDate:"March 11th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/7844.jpg",numberOfDownloads:6096,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:4,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:4,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 15th 2019",dateEndSecondStepPublish:"September 16th 2019",dateEndThirdStepPublish:"November 15th 2019",dateEndFourthStepPublish:"February 3rd 2020",dateEndFifthStepPublish:"April 3rd 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"206355",title:"Associate Prof.",name:"Monjur",middleName:null,surname:"Ahmed",slug:"monjur-ahmed",fullName:"Monjur Ahmed",profilePictureURL:"https://mts.intechopen.com/storage/users/206355/images/system/206355.jpeg",biography:"Monjur Ahmed, MD, FRCP, is an Associate Professor of Medicine at Thomas Jefferson University, Philadelphia, Pennsylvania, USA. He has been a practicing gastroenterologist for twenty-two years. He has a special interest in inflammatory bowel disease, eosinophilic esophagitis, gastrointestinal motility, and dysphagia. Dr. Ahmed also serves as an editor in chief for the World Journal of Gastrointestinal Oncology.",institutionString:"Thomas Jefferson University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Thomas Jefferson University",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1098",title:"Otolaryngology",slug:"otorhinolaryngology-otolaryngology"}],chapters:[{id:"68087",title:"Quantitative Analysis of Activity Patterns in the Muscles of Mastication and Deglutition",doi:"10.5772/intechopen.88108",slug:"quantitative-analysis-of-activity-patterns-in-the-muscles-of-mastication-and-deglutition",totalDownloads:657,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Surface electromyograms (EMGs) were recorded from the masseter (Mass), one of the major muscles for chewing, and from the suprahyoid (SH) muscles, involved in swallowing. Activity patterns of these EMGs were analyzed with a TP method that was developed specifically to quantify muscle activity patterns. To compare individual EMG bursts in a participant with different amplitudes and active durations, the bursts were cumulatively integrated to standardize the amplitudes and active durations. Each TP value calculated by this method indicated a relative location of an EMG burst on a standardized time scale free from changes in the amplitudes and active durations. Both InP and DP values were derived from the TP values and also applied to the burst. A T50 value indicated the standardized time for half of the final cumulatively integrated EMG burst. Five groups of application samples were introduced to demonstrate the usefulness of the TP method in comparing activity patterns of the Mass and SH EMGs during chewing and swallowing, while participants were in different body positions and experiencing different tastes and textures of sample foods. Finally, limitations and perspectives of the TP method are discussed.",signatures:"Yozo Miyaoka",downloadPdfUrl:"/chapter/pdf-download/68087",previewPdfUrl:"/chapter/pdf-preview/68087",authors:[null],corrections:null},{id:"68687",title:"Pathology of Nonneoplastic Lesions of the Vocal Folds",doi:"10.5772/intechopen.88735",slug:"pathology-of-nonneoplastic-lesions-of-the-vocal-folds",totalDownloads:1088,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Nonneoplastic vocal fold lesions are common that can cause hoarseness and voice change. Reactive lesions of Reinke’s space can be observed in all ages and genders and comprise the majority of the benign nonneoplastic vocal fold lesions. Although clinically different terms are used to define reactive lesions of Reinke’s space, they share the same histopathologic features. In order to differentiate vocal fold polyp and nodule and Reinke’s edema, clinical findings should be considered. Epithelial changes such as pseudoepitheliomatous and verrucous hyperplasia may cause diagnostic challenge due to resemblance of squamous cell carcinoma. Evaluation of the invasion border and cellular atypia may aid in correct diagnosis.",signatures:"Nil Çomunoğlu, Şebnem Batur and Ayşe Mine Önenerk",downloadPdfUrl:"/chapter/pdf-download/68687",previewPdfUrl:"/chapter/pdf-preview/68687",authors:[null],corrections:null},{id:"68352",title:"Swallowing Disorders in Patients with Stroke",doi:"10.5772/intechopen.88341",slug:"swallowing-disorders-in-patients-with-stroke",totalDownloads:1074,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Swallowing disturbance often causes by stroke and may predispose patients to malnutrition and dehydration, as well as increases the risk of such complications as suffocation and aspiration pneumonia. As an initial evaluation, the water swallowing test can be easily carried out, but not all of the aspiration can be excluded. Therefore, videofluorography (VF) and videoendoscopic examination (VE) of swallowing should be performed to find a safety method of oral intake for providing visualization of the pharynx and larynx dysfunction. Clinical severity scale is important because once the severity is determined, the treatment strategy is also known. Swallowing training can be divided into indirect training without food (basic training) and direct training with food (eating training). In general, it is important to select conditions and training diets that are easy to swallow and have a low risk of aspiration while using indirect training and direct training that aim at gradually improving the level of oral intake.",signatures:"Aiko Osawa and Shinichiro Maeshima",downloadPdfUrl:"/chapter/pdf-download/68352",previewPdfUrl:"/chapter/pdf-preview/68352",authors:[null],corrections:null},{id:"70060",title:"Maxillofacial and Oral Aspects of Dysphagia",doi:"10.5772/intechopen.89751",slug:"maxillofacial-and-oral-aspects-of-dysphagia",totalDownloads:1005,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Oral cavity/mouth is first recipient of food. Food is broken down and prepared for initial phases of digestion. The oral preparatory phase is voluntary. In this phase, food is manipulated by the tongue and teeth. A bolus which is ready to swallow is prepared. Any disruption of oral cavity functions commonly due to oral infections, space infections, facial trauma, congenital-cleft lip and palate, temporo-mandibular joint disorders, salivary gland pathology, oral cancers, radiation therapy, etc., can cause dysphagia. In this chapter, we would explain the maxillofacial and oral aspects of dysphagia along with diagnosis and treatment aspects.",signatures:"Mohammed Basha",downloadPdfUrl:"/chapter/pdf-download/70060",previewPdfUrl:"/chapter/pdf-preview/70060",authors:[null],corrections:null},{id:"69127",title:"Radiation-Related Dysphagia: From Pathophysiology to Clinical Aspects",doi:"10.5772/intechopen.88779",slug:"radiation-related-dysphagia-from-pathophysiology-to-clinical-aspects",totalDownloads:789,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"In Western countries, head and neck cancers (HNCs) account for about 5% of all tumors. Due to tumor locations at the aero-digestive crossroad, patients frequently suffer from swallowing dysfunction caused both by primary cancer (baseline dysphagia) and cancer therapies (treatment-related dysphagia). In this regard, radiation-induced dysphagia represents a real “Achille’s heel” which historically occurs in more than 50% of patients and can lead to a malnutritional status and an increased risk of aspiration pneumonia. In fact radiotherapy, by restricting the driving pressure of the bolus through the pharynx and/or limiting the opening of the cricopharyngeal muscle, leads to a post-swallowing pharyngeal residue that may spill into the airway causing ab ingestis pneumonia. On the contrary, an organ preservation strategy should provide both the highest tumor control probability (TCP) and the minimum function impairment with the subsequent maximum therapeutic index gain. In this regard, intensity-modulated RT (IMRT) might reduce the probability of postradiation dysphagia by producing concave dose distributions with better avoidance of several critical structures, such as swallowing organs at risk (SWOARs), which might result in better functional outcomes. Similarly, a prompt swallowing rehabilitation provided before, during, and soon after radiotherapy plays an important role in improving oncologic swallowing outcomes.",signatures:"Stefano Ursino, Paola Cocuzza, Stefania Santopadre, Fabiola Paiar and Bruno Fattori",downloadPdfUrl:"/chapter/pdf-download/69127",previewPdfUrl:"/chapter/pdf-preview/69127",authors:[null],corrections:null},{id:"68661",title:"Effect of Salivation by Facial Somatosensory Stimuli of Facial Massage and Vibrotactile Apparatus",doi:"10.5772/intechopen.88495",slug:"effect-of-salivation-by-facial-somatosensory-stimuli-of-facial-massage-and-vibrotactile-apparatus",totalDownloads:745,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"We studied the effects of salivary promotion of fluid secretion after hand massage, and the apparatus of vibrotactile stimulation (89 Hz frequency, 15 min) in normal humans. Personal massage cannot be performed on handicap and stroke patients, and then giving hand massage to them for 5 min massage gives a tired feeling. So, we focused 3 min stranger massage. Salivary glands can discharge the accumulated saliva by extrusion from the acinus glands’ massages as described in the recent Japanese textbook. We think that this method may not produce realistic recovery. Our aim ideas are to relieve stress and increase temperature with lightly touch massage of the skin and for a 1 cycle of 1 s. We recorded RR interval of ECG, total salivation, facial skin temperature, OxyHb of fNIRS on the frontal cortex, and amylase activity for the autonomic changes. In increased 2°C of the facial skin temperature, the hand massage had a need for 3 min and the vibrotactile stimulation for 15 min. Increase from 700 to 1000 ms of RR intervals had a need for 3 min in the hand massage and had 15 min in the vibrotactile stimulation. Although vibrotactile stimulation needs long time of 4–7 years as effective recovery, hand massage may have more effect with a repetition of day after day.",signatures:"Tsunoda Yumi, Akatuka Sumiko, Fukui Sayaka, Nakayama Enri, Abe Kimiko, Sato Mituyasu, Kimura Masanori, Kato Syunnichiryou, Sakai Maho, Yamaoka Masaru, Watanabe Mao, Ueda Koichirou and Hiraba Hisao",downloadPdfUrl:"/chapter/pdf-download/68661",previewPdfUrl:"/chapter/pdf-preview/68661",authors:[null],corrections:null},{id:"70540",title:"Swallowing Disorders in Cervical Facial Tumors",doi:"10.5772/intechopen.90624",slug:"swallowing-disorders-in-cervical-facial-tumors",totalDownloads:738,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"We review current state of the art protocols on swallowing disorders associated to cervical facial tumors. The clinician needs to translate physiology notions to bedside diagnosis. Facing such a case the ENT surgeon must follow several key steps: thorough history taking, barium transit, endoscopy evaluation of swallowing, high resolution diagnosis imaging. Afterwards surgical treatment plan should take into consideration the need to careful dissection of vascular and nervous structures. Dysphagia may present from initial diagnosis or after surgical resection of the tumor or during radiation and chemotherapy. We discuss the use of various staging scales or questionnaires for assessing quality of life. We illustrate the importance of swallowing disorders management with various cases of tumors at the level of skull base, pharynx, salivary glands, larynx, esophagus, etc. There are various solutions for dysphagia ranging from nasogastric feeding tube placement to percutaneous endoscopic gastrostomy to specially designed exercises. Sometimes the surgeon neglects these disorders and focuses on airway management. However, the rule should be to encourage swallowing as soon as possible after surgery. A good nutritional status is necessary for a positive prognosis in swallowing disorders. Team effort in tertiary oncology units is the key in supporting such complex cases.",signatures:"Daniela Vrinceanu and Mihai Dumitru",downloadPdfUrl:"/chapter/pdf-download/70540",previewPdfUrl:"/chapter/pdf-preview/70540",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"10315",title:"Crohn’s Disease",subtitle:"Recent Advances",isOpenForSubmission:!1,hash:"1ddf7dda3ec43e99aefd9d1ac1ecc35e",slug:"crohn-s-disease-recent-advances",bookSignature:"Monjur Ahmed",coverURL:"https://cdn.intechopen.com/books/images_new/10315.jpg",editedByType:"Edited by",editors:[{id:"206355",title:"Associate Prof.",name:"Monjur",surname:"Ahmed",slug:"monjur-ahmed",fullName:"Monjur Ahmed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1758",title:"Otolaryngology",subtitle:null,isOpenForSubmission:!1,hash:"8b845def701f65d6ae3487686581983f",slug:"otolaryngology",bookSignature:"Balwant Singh Gendeh",coverURL:"https://cdn.intechopen.com/books/images_new/1758.jpg",editedByType:"Edited by",editors:[{id:"67669",title:null,name:"Balwant Singh",surname:"Gendeh",slug:"balwant-singh-gendeh",fullName:"Balwant Singh Gendeh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8732",title:"Sino-Nasal and Olfactory System Disorders",subtitle:null,isOpenForSubmission:!1,hash:"2170e4de59f7b95f9fad8d3dc343aae0",slug:"sino-nasal-and-olfactory-system-disorders",bookSignature:"Thomas Heinbockel and Balwant Singh Gendeh",coverURL:"https://cdn.intechopen.com/books/images_new/8732.jpg",editedByType:"Edited by",editors:[{id:"70569",title:"Dr.",name:"Thomas",surname:"Heinbockel",slug:"thomas-heinbockel",fullName:"Thomas Heinbockel"}],equalEditorOne:{id:"67669",title:null,name:"Balwant Singh",middleName:null,surname:"Gendeh",slug:"balwant-singh-gendeh",fullName:"Balwant Singh Gendeh",profilePictureURL:"https://mts.intechopen.com/storage/users/67669/images/system/67669.png",biography:"Dr Balwant Singh Gendeh is a senior consultant ENT surgeon with sub-specialty interest in rhinology (allergy, Sino nasal diseases, endoscopic sinus, anterior and ventral skull base surgery and functional and cosmetic nasal surgery). He was an ENT registrar at the Royal Infirmary, Middlesbrough, United Kingdom in 1993 and subsequently a JW Fulbright scholar at the University of Pittsburgh, USA in 1997. During his Fulbright experience, he also worked at the Hospital of University of Pennsylvania (HUP), Philadelphia and St Joseph’s Hospital, Chicago, USA with sub-specialty interest in rhinology and aesthetic nasal surgery. Dr BS Gendeh retired after 38 years government service as a consultant ENT surgeon at the National University of Malaysia Medical Centre (UKMMC) in 2014, and presently is a Visiting Professor at the Department of Otorhinolaryngology-Head and Neck Surgery at UKMMC and is a resident ENT consultant at Pantai Hospital Kuala Lumpur since 2014. Is an executive member of numerous National and International bodies including Board Chairman of Malaysian American Commission on Educational Exchange (MACEE) from 2013-2015. Due to his vast contribution to the academia in research and clinical publication, he was elected as a Diploma of Fellowship Academy of Medicine Malaysia (FAMM) in October 2000, International Fellow of the Academy of Otolaryngology Head and Neck Surgery in April 2004, Fellow of the Academy of Sciences Malaysia (FASc) in April 2016 and as Fellow of Malaysian Scientific Association (FMSA) in September 2017. He has written 96 scientific papers with more than 550 citations and editor/co-editor of 8 books and 37 book chapters an H index of 15.",institutionString:"Pantai Hospital Kuala Lumpur",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"4",institution:null},equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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\r\n\tDementia has become the leading neurological problem for human beings associated not only with the old population but newer generations as well. Various environmental and genetic factors are reported to be involved in the disease. This book hopes to comprise a detailed discussion on the relationship between different brain areas and cognition. Pathophysiology of dementia containing molecular mechanisms will be explained as well as the memory function that depends on the neuronal circuits among the different brain areas. Other neuronal circuits involved in memory, learning, and dementia will also be discussed. Mechanism of neuronal circuits involved in memory consolidation, the main neurological disorders associated with dementia, dementia screening, and its validation, along with neurophysiological tests, will be covered. Another aspect that this book hopes to cover is the modern therapeutic trends for the management of dementia. Biologics will be changing the therapeutic world of dementia in the near future. We aim to have a project that consists of various cutting-edge technologies that have been adopted for the treatment of dementia.
",isbn:"978-1-80356-783-9",printIsbn:"978-1-80356-782-2",pdfIsbn:"978-1-80356-784-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"d40f707b9ef020bb202be89404f77a1e",bookSignature:"Dr. Devendra Kumar, Prof. Sushil Kumar Singh and Dr. Ankit Ganeshpurkar",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11637.jpg",keywords:"Cognition, Neuronal Circuits, Learning and Memories, Memory Consolidation in Dementia, Neuropsychological Tests, Treatments, New Therapeutic Tools, Biologics, Brain Areas and Cognition, Neuropsychology, Neurological Disorders, Modern Therapeutic Trends",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 1st 2022",dateEndSecondStepPublish:"June 16th 2022",dateEndThirdStepPublish:"August 15th 2022",dateEndFourthStepPublish:"November 3rd 2022",dateEndFifthStepPublish:"January 2nd 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"11 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Devendra Kumar's research interest includes the Design, Devolvement, and Biological screening of Small molecules, Metal complexes, Peptides for the management of Alzheimer's disease, Fragile X Syndrome, and Tuberculosis. Dr. Kumar worked on Alzheimer's disease and developed CNS active small molecules such as Acetylcholine, Butyl choline, Beta-secretase 1, Matrix Metalloprotein-2 and 9 inhibitors, and NMDA receptor antagonist.",coeditorOneBiosketch:"Dr. Singh is an eminent scientist and teacher in the field of neurodegenerative disorders. He was the Principal Investigator in the Development of bioactive molecules as therapeutic agents for Alzheimer’s disease and screening of their toxicity; IIT (BHU), Varanasi, as well as the Principal Investigator in Design and synthesis, is of Matrix Metallo Proteinase (MMP -2 & 9) inhibitors as therapeutic agents for Alzheimer’s disease; DBT, New Delhi.",coeditorTwoBiosketch:"Dr. Ganeshpurkar's objective is to create a niche in the field of medicinal chemistry and drug design research with an emphasis on the use of computational tools and artificial intelligence in lead identification and optimization. His research interest is in silico drug designing, lead identification, and optimization as well as design, synthesis and biological evaluation of Novel leads for various pathophysiological conditions such as Alzheimer’s and other neurodegenerative diseases.",coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"454030",title:"Dr.",name:"Devendra",middleName:null,surname:"Kumar",slug:"devendra-kumar",fullName:"Devendra Kumar",profilePictureURL:"https://mts.intechopen.com/storage/users/454030/images/system/454030.jpg",biography:"Dr. Devendra Kumar is an Assistant Professor in the Department of Pharmacy. Dr. Kumar did his Ph.D. in Pharmaceutical Sciences from the Indian Institute of Technology (Banaras Hindu University) and completed his postdoctoral research at the University of Texas, USA (2019-2021). His research interest includes Design, Devolvement, and Biological screening of Small molecules, Metal complexes, Peptides for the management of Alzheimer\\'s disease, Fragile X Syndrome, and Tuberculosis. Dr. Kumar worked on Alzheimer\\'s disease and developed CNS active small molecules such as Acetylcholine, Butyl choline, Beta-secretase 1, Matrix Metalloprotein-2 and 9 inhibitors, and NMDA receptor antagonist.\nAlong with the Drug Discovery, he is also working on the Pathophysiology of Fragile X Syndrome. His work on the Fragile X Syndrome includes identification of spine abnormality and the role of Microglia. The study of Microglia-Neuron communication in genetically modified animals is his thrust area. He is also working on the gene-editing tools using CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology and the development of Blood-Brain Barrier penetrating Polymers as a delivery vehicle for CRISPR molecules.",institutionString:"Dehradun Institute of Technology University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Dehradun Institute of Technology University",institutionURL:null,country:{name:"India"}}}],coeditorOne:{id:"182874",title:"Prof.",name:"Sushil Kumar",middleName:null,surname:"Singh",slug:"sushil-kumar-singh",fullName:"Sushil Kumar Singh",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSAm4QAG/Profile_Picture_2022-04-07T11:17:21.JPG",biography:"Principal Investigator, Development of bioactive molecules as therapeutic agent for Alzheimer’s disease and screening their toxicity; IIT (BHU), Varanasi.\r\nPrincipal Investigator, Design and synthesis is of Matrix Metallo Proteinase (MMP -2 & 9) inhibitors as therapeutic agents for Alzheimer’s disease; DBT, New Delhi.\r\nCo- Principal Investigator, Cestocidal activity of glands and hairs of fruits of Mallotus phillippinensis (Kampillaka Plant); ICMR, New Delhi.\r\nPrincipal Investigator, Ethno-medicinal plants as a source of new therapeutic agents against psoriasis; National medicinal Plant Board, AYUSH, New Delhi.\r\nPrincipal Investigator, Isolation of marker compounds from Withania somnifera; Natreon Inc., Kolkata.\r\nPrincipal Investigator, Isolation of marker Compounds from natural Sources; Drug Research and Development Center, Kolkata.\r\nOne of the Investigators of the Centre, Establishment of facilities for identification, chemical characterization, standardization and quality control of medicinal plants found in tribal area in central India; DST, New Delhi.",institutionString:"Banaras Hindu University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Banaras Hindu University",institutionURL:null,country:{name:"India"}}},coeditorTwo:{id:"465935",title:"Dr.",name:"Ankit",middleName:null,surname:"Ganeshpurkar",slug:"ankit-ganeshpurkar",fullName:"Ankit Ganeshpurkar",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003RKF6EQAX/Profile_Picture_2022-04-07T11:30:06.jpg",biography:null,institutionString:"Bharati Vidyapeeth Deemed University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Bharati Vidyapeeth Deemed University",institutionURL:null,country:{name:"India"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"18",title:"Neuroscience",slug:"life-sciences-neuroscience"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453623",firstName:"Silvia",lastName:"Sabo",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/453623/images/20396_n.jpg",email:"silvia@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"6628",title:"Circadian Rhythm",subtitle:"Cellular and Molecular Mechanisms",isOpenForSubmission:!1,hash:"628bbcbfaf54a56710498540efe51b87",slug:"circadian-rhythm-cellular-and-molecular-mechanisms",bookSignature:"Mohamed Ahmed El-Esawi",coverURL:"https://cdn.intechopen.com/books/images_new/6628.jpg",editedByType:"Edited by",editors:[{id:"191770",title:"Dr.",name:"Mohamed A.",surname:"El-Esawi",slug:"mohamed-a.-el-esawi",fullName:"Mohamed A. 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They might be considered as ‘automated textbooks’ which by the use of a digitalized infrastructure not only deliver immediately all the necessary health care knowledge to the clinician but also has the capability of intelligently monitoring the actual health status of any given patient – ‘smart monitoring’. It is obvious that in the context of anesthesia, critical – emergency – care and intensive care medicine, such systems are a vital backbone of medical care of the 21st century with a growing number of parameters, growing number of diseases, diagnostic possibilities and treatment options. Decision support systems have the potential to bridge the gap between the theoretical performance of a well trained physicians –who has spent a decade acquiring knowledge and a multitude of manual skills – and his or her actual performance in daily practice. This latter performance can be influenced by any given contextual condition, be it emotional, intellectual or behavioral pattern. What we define as ‘clinical error’ is influenced by several mistakes, one of the most prominent the impossibility to recall all diagnostic and therapeutic options any time for any patient – ‘prospective recall failure’. Computerized information tools have been investigated for more than 2 decades and have been proven to be highly effective in a research environment.
\n\t\t\tHowever, especially in the specialties which are the object of this chapter, they have not been widely introduced into practice.
\n\t\t\tOne of the problems is the clustering of information in modern healthcare facilities between hospital administrators, several laboratory or investigative units and health care providers. The complexity of modern diagnostic and therapeutic options is such that only the most complete coverage of all available patient information can deliver a most complete decision support for the clinician. A lack of standardization, immediate delivery of patient data due to inherent lag times of different working systems, make some of these systems inefficient in reality. Another problem is the ‘user-friendliness’ of these systems – the significant additional time necessary to ‘feed’ the data into the system, as well as the gradual integration of these decision support systems into the daily work pattern: accessibility of the information in a most efficient way for a variety of health care providers with different technological and intellectual background is another problem. The widespread introduction of simple anesthesia information management systems (AIMS) into the daily practice, especially in North America – has also been impaired by shrinking health care budgets and administrative ignorance.
\n\t\t\tThis chapter will focus on painting an outline of possible DSSs in anesthesia, critical care and intensive care medicine with a special attention on presenting a vision of what is needed for the future.
\n\t\t\tIt is beyond the scope of this chapter to present all the research which has been done in designing and testing DSSs in these three specialties. It is tried to present exemplary case studies of DSSs which are not merely theoretical constructs but close to clinical usability. The examples used shall spur the reader’s curiosity and show what is feasible in the context of modern health care systems, presenting both present challenges and future directions. At the end of this chapter, some recent review articles on the topic are added to instigate further reading.
\n\t\tDecision support systems have been used in research and clinical studies in the fields of anesthesia, emergency medicine and intensive care medicine. It is beyond the scope of this chapter to present all studies and clinical applications; instead, the author tried to outline the characteristics of DSSs in all three specialties with specific examples highlighting the advantages of these systems as well as specific challenges.
\n\t\t\tAnesthesia is characterized by being a specialty where more than 100 parameters have to be monitored constantly and rapid and appropriate action often defines the difference between good or adverse outcome. Anesthesiologists are often compared with pilots, and described as ‘pilots of the human biosphere’ (Hemmerling, 2009). Similar to pilots, they need to coordinate their monitoring with direct supervision of surgical progress and interact with health care providers from different background, nurses, anesthesia technicians and surgical team. Organizational accidents can easily develop in this environment (Reason, 2005); an example of a schematic development of an organizational accident is described in figure 1.
\n\t\t\t\tStages in the development of an organizational accident. (
Organizational deficits can be based on a specific culture, e.g. strictly hierarchical command structure, certain management decisions, e.g. organizational deficits in providing important drugs or devices or other forms of mistakes. The workplace can be faulted by lack of teamwork, communication issues, non-standardized or badly maintained equipment-or simply its absence – problems with proper drug labeling, delivery, OR scheduling or other planning deficits. All these deficits can lead to errors or violations of existing ‘best evidence practice’ with subsequent bad outcome.
\n\t\t\t\tAs much as the various development stages of organizational accidents in anesthesia are common knowledge, as difficult is their analysis and efficient accident investigation. A possible model of efficient – in terms of avoiding subsequent bad outcome – accident investigation has long been presented (Eagle et al., 1992, Fig.2).
\n\t\t\t\tA model of accident investigation. (
Any adverse incident should therefore trigger a team-directed inquiry – any individualized search for mistakes will be doomed to fail. The correct establishment of both facts and timeline is the key for a successful analysis of the event. This will lead to the determination of both active failures, such as a lack of skill (e.g. intubation skill) and – more difficult to overcome – latent failures, such lack of equipment, wrongful procedures or policies. This can lead to better organizational DSS which allows to avoid bad outcome.
\n\t\t\t\tThe influx of electronic data management systems – anesthesia information management systems (AIMS) – has helped to make this cascade of accident analysis readily available, reliable and easy to use. The fact that less than 10% of North American hospitals have AIMS available is still a major setback for proper management of accidents and adverse events. However, recently, DSSs have been developed to extract events from the AIMSs for an improvement of quality of care, compliance to established best evidence practices and documentation of outcome, be it good or bad. However, the performance of the DSS is influenced by the timeliness of the data entry, the incidence of missing data and any possible query interval. These latencies of data entry can be caused by the simple absence of data entry, retroactive data entry – with the risk of data omission, data management delay within the AIMS or between the AIMS and any other database or clock differences. Any such latencies can influence the implementation of clinical or management workflows for improved outcome. (Epstein et al., 2009, Fig. 3)\n\t\t\t\t
\n\t\t\t\tPotential Sources of Latency in Decision Support Systems. (
Anesthesiologists constantly demand smart alarms. One of the few monitoring systems which have a good track record as ‘smart alarms’ are pulse oximeters. Any anesthesiologist of some experience will be able to follow the different tonality of the pulse oximetric signal to detect various degrees of oxygen desaturations. However, for the majority of monitoring alarms, smart decision support or monitoring systems need to be developed. One example of a simple but effective DSS for tow of the most common adverse events during anesthesia – unstable blood pressure and light anesthesia – was presented in 2000 (Krol & Reich, 2000). When computerized algorithms were compared with subjective assessment by anesthesiologists, it was found that a 12% change of mean arterial pressure in comparison to the median of the mean arterial pressure of the previous 10-min interval can be used as indicating light anesthesia. Best agreement between computer readings and human assessment was achieved when the absolute value of the fractional change of the mean arterial pressure in between 2-min periods was used. (Fig.4)\n\t\t\t\t
\n\t\t\t\tIt is not the objective of this chapter to reason whether changes in mean arterial pressure are indicative of ‘light anesthesia’; this study simply shows that very simple computerization can be helpful to readily indicate anesthesiologists – in this case anesthesiologists following the paradigm that hemodynamic ability indicates an insufficient degree of anesthesia – a decision support in daily routine.
\n\t\t\t\tHow can knowledge- and rule-based DSS be designed so that a maximum number of clinicians adhere to them and use them to improve outcome?
\n\t\t\t\tDesign considerations have recently been presented (Dunsmuir et al., 2008): rule structures should be easy to understand, the process of knowledge authoring tooling should be intuitive, all decisions visible to everybody, and the user interface easy to use for everybody. Such a user interface is presented in figure 5 by Dunsmuir et al. (Dunsmuir et al., 2008) as a smart monitoring tool for hemodynamic adverse events in children undergoing anesthesia.
\n\t\t\t\tCategorization of MAP by anesthesiologists. (
The graphical user interface of the knowledge authoring tool. (
The importance of ‘user feedback’ is clearly demonstrated in this study. Some samples of results from a user questionnaire are presented and focus on ‘user friendliness’ of the interface more than a disagreement with the rules. (Fig. 6)\n\t\t\t\t
\n\t\t\t\tSample from PSSUQ results. (
The authors conclude that anesthesiologists can rapidly develop useful rules for use in a predefined clinical scenario (Dunsmuir et al., 2008). Using a fuzzy-logic evidence based expert diagnostic alarm system, similar success can be achieved for the diagnosis of intraoperative hypovolemia (Mirza et al., 2010). Its basic structure is depicted in Fig. 7.
\n\t\t\t\tBlock diagram of the FLMS. ANFIS=Adaptive-Network-based Fuzzy Inference Systems ; FIS=fuzzy interference systems ; MF’s=membership function. (
An ideal scenario of anesthetic clinical practice almost implying the use of DSSs is the different PONV prevention strategies. The symbiosis of a clearly identified anesthetic problem – PONV -, clearly established guidelines – PONV guidelines – and the existence of several drug combinations make this an ideal work field for intelligent DSSs.
\n\t\t\t\tA recent study investigated the effect of such a DSS on guidelines adherence using an on-off design (Kooij et al., 2008). Fig. 8 presents the number of patients enrolled in this study.
\n\t\t\t\tScheduling Postoperative Nausea and Vomiting Prophylaxis. (
However, this study shows as well that the use of DSS has no impact on ‘changing the culture’ of wrong-doing as an educational tool once it is withdrawn: although the DSS very significantly improved adherence to the PONV guidelines, guideline adherence decreased to the level before the DSS was used after its withdrawal. (Fig. 9)\n\t\t\t\t
\n\t\t\t\tWeek by week analysis of all high risk patients. The bars show the percentage of high risk patients receiving postoperative nausea and vomiting prophylaxis prescribed. (
Two studies have investigated the implementation of simple DSSs using an AIMS to improve adherence to proper antibiotic prophylaxis before surgery.
\n\t\t\t\tIn one study (O’Reilly et al., 2006), a simple feedback system integrated in the AIMS was used to improve properly timed antibiotic prophylaxis provided by the anesthesiologist. (Fig.10)\n\t\t\t\t
\n\t\t\t\tAnother group used the AIMS in combination with e-mail feedback of missed documentation, monthly summary reports and real-time electronic alerts to achieve a near 100% timely antibiotic prophylaxis; without filling out the antibiotic note, the AIMS anesthesia chart cannot be closed. (Nair et al., 2010)
\n\t\t\t\tCompliance with the timely administration of antibiotics gradually increased to about 92%. (
Antibiotic compliance comment note options in AIMS (Anesthesia Information Management System). (
This was combined with ‘smart messages”. (Fig. 12) The user received messages which were displayed as a pop-up menu. These reminder messages are sent so that the users can see them before surgery starts and administer the antibiotic prophylaxis optimally timed for effect. Messages also appear when administration of antibiotics are not documented or incomplete.
\n\t\t\t\tSmart Anesthesia Messenger (SAM) alert screen overlaid on anesthesia information management system screen. (
In the course of the study period – june 2008 – jan 2010 – the weekly antibiotic compliance improved steadily, reaching a near 100% compliance at the end of step 4. (Fig. 13)\n\t\t\t\t
\n\t\t\t\tImprovement in weekly antibiotic compliance success rate with each intervention. AIMS _ Anesthesia Information Management Systems; SAM _ Smart Anesthesia Messenger. (
Another example of an anesthetic DSS is the creation of an electronic algorithm for detecting insufficient depth of anesthesia based on computing different MAC values of volatile anesthetics with different intravenous sedative or hypnotic agents administered concomitantly. (Mashour et al, 2009).
\n\t\t\t\tThe need for DSSs even for very simple anesthetic gestures, such as turning on the ventilator alarms after separation from cardiopulmonary bypass (which cardiac anesthesiologist has not forgotten this?), is demonstrated in a recent study (Eden et al., 2009). A simple electronic reminder as part of the AIMS (Fig. 14) improves significantly the incidence of alarm reactivation from 22% to 83%. (Fig. 15) At the end of the study period, there were significantly less electronic reminders and alarms were spontaneously reset after cardiopulmonary bypass.
\n\t\t\t\tThe appearance of the electronic reminder on the anesthesia information management system main window. (
System Performance by Implementation Stage. (
However, these DSSs do not cover the actual administration of anesthetic agents, nor do they present different treatment options for adverse incidents. They mostly focus on the concept of smart monitoring, alarms for administering concomitant drugs, such as drugs for PONV prophylaxis or antibiotic prophylaxis, or alarms for insufficient depth of anesthesia or hemodynamic. They do not give several treatment options to the user – anesthesiologist.
\n\t\t\t\tRecently, a hybrid system for conscious sedation with DSS was presented. (Hemmerling, STA abstract 2011). This system integrates closed loop sedation with a DSS, offering pop-up menus as smart alarms with several treatment advices for hemodynamic or respiratory adverse events, which need to be confirmed by the anesthetic team by clicking respective touch buttons on a touch screen. (Fig.16)\n\t\t\t\t
\n\t\t\t\tPop-up menu for respiratory rate critical event. (
The DSS significantly improved the incidence of critical event detection as well as time between event occurrence and event recognition. (Fig. 17.)
\n\t\t\t\tPerformance of anesthesiologists in detecting critical events. (
The above presented examples show that DSSs can be created for perioperative use in anesthesia; whereas most research has focused on designing DSS as smart monitoring and alert systems, future research has to focus on combining purely ‘Monitoring-DSS’ to alerting several treatment options for providing anesthesia or treating critical events thus integrating best evidence based treatment options in modern DSSs.
\n\t\t\tDecision support systems have long played a significant role in the management of emergency patients. Emergency medicine is driven by a combination of out-of-hospital and in-hospital complex scenarios which pose logistical difficulties because of the following demands:
\n\t\t\t\trapid access to patients outside the hospital
immediate care (both in diagnostics and treatment) by paramedical staff
immediate link with logistical coordinators for transport organization
acuteness of illness or trauma
very often limited experience of health care providers as primary care
resource management of both manpower and diagnostic tools
single or mass casualties of primarily un-known trauma
The sheer combination of very often life-threatening illness or trauma with the need to rapidly diagnose and treat these pathologies is an ideal playing field for the implementation of computer-based decision support systems.
\n\t\t\t\tHowever, the studies are somewhat inconclusive: whereas DSSs have very successfully been implemented in the pre-hospital care system, making triage and organization far easier than without them, their implementation in the hospital based emergency care system is somewhat disappointing.
\n\t\t\t\tFor the pre-hospital care system, the iRevive EMT application is a very good example of successful implementation of a DSS in a complex environment (Gaynor et al, 2005).
\n\t\t\t\tIt is designed as a network of wireless, handheld computers, with wireless patient location and vital sign sensors, connected to an ambulance base station, and a central command center. (Fig. 18)\n\t\t\t\t
\n\t\t\t\tiRevive System Architecture. (
It provides decision support at the site of the incident (pre-hospital), at local command centers, and at a central point of coordination. It is unique through its integration of vital sign parameters which are transmitted wirelessly. It is a key feature of emergency management in a pre-hospital setup to react not only to an initial patient conditions but adjust management and triage towards possible dynamic changes in the patient’s status: both elements are provided successfully by the iRevive structure as illustrated in Figure 19 (left side: stable condition, right side: vital sign changes)
\n\t\t\t\tDynamic triage function in iRevive. (
A similar approach is presented by another Australian group for the in-hospital based emergency care management (Ceglowski et al, 2005). The task faced for the establishment of a DSS for the in-hospital based emergency department is illustrated in Fig. 20:
\n\t\t\t\tEDIS support for emergency department patient flow (
The combination of hardware interfaces, readily available through modern technologies, such as smart phones, and sophisticated software allow the modeling of a DSS, ready to help triage and improve the workflow of patients entering the emergency department.
\n\t\t\t\tHowever: how do these DSSs perform in a real-life setting?
\n\t\t\t\tGraber’s study (Graber & VanScoy, 2003) has investigated the performance of a DSS in an emergency department. Whilst they could show that DSSs performed as well in this complex setup as in other medical fields, they also found a surprising under-performance of the DSS in comparison to the final human based emergency diagnosis: the final diagnosis was only found in 50 to 70% of the differential diagnosis, depending on which DSS was used, and only in approximately 30% of the time was the final diagnosis amongst the top 5 of the different diagnosis of the DSS. This means that its accuracy is not sufficient to allow to use it reliably at present. In addition, their use obviously takes considerable time, a key criticism when used in the emergency setting.
\n\t\t\t\tSimilar results have been found when DSSs are used in the exemplary case of diagnosing a pulmonary embolism, which is always a difficult diagnosis to make: the characteristic element of this diagnostic setup – probability assessment based on several clinical and diagnostic tools rather than one single test confirming the diagnosis – should actually play in the hands of DSSs.
\n\t\t\t\tThe study of Roy and another study of Drescher have looked at the performance of DSSs to diagnose pulmonary embolism. The first study (Roy et al, 2009) showed an improvement in the application of appropriate diagnostic strategies which was significantly better when a computer-based guidelines structure was used versus paper-based guidelines structure in a multi-centre study involving 20 centers and more than 1000 patients. (Fig. 21)\n\t\t\t\t
\n\t\t\t\tIn the computer-based guidelines group, the same guidelines were used but on a handheld device into which the patients’ parameters were entered: all clinical variables to derive a Geneva score, a probability score for pulmonary embolism are entered into the DSS. Then the DSS offers all necessary and available diagnostic tests to confirm or exclude the diagnosis of pulmonary embolism with probability thresholds. (Fig. 22)\n\t\t\t\t
\n\t\t\t\tThis study clearly showed the superior performance of DSSs, which was confirmed for the same diagnostic setup by the second study (Drescher et al, 2010). However, the second study also showed one of the key problems of implementing DSSs in the context of in-hospital emergency departments: poor user (physician) acceptance. (Fig. 23)\n\t\t\t\t
\n\t\t\t\tThe range of non-adherence to the DSS varied from 5% to 100% depending on the individual physician: only part of this non-adherence can be attributed to increased computer time in order to use the DSS. The authors state: ‘emergency physicians attributed disbelief in its clinical utility and impatience with the time it required as the reasons for not following its recommendations or for opting out.’
\n\t\t\t\tImplementation of DSSs in the emergency medicine setting have been very successful for the preoperative environment; they can help make triage more efficient. Systems can help to provide better pre-hospital patient care.
\n\t\t\t\tIn the in-hospital emergency medicine setting, the acceptance of DSSs is still limited: the significant amount of time necessary to enter all the data is one of the key aspects limiting their widespread use. However, the influence of human, emotional resentment towards the introduction of computer based decision-making cannot be excluded.
\n\t\t\t\tImprovements in Application of Appropriate Diagnostic Strategy for Pulmonary Embolism (
Recommendations for Exclusion or Confirmation of PE on the Basis of Test Results, by Clinical Probability (
Adherence of individual emergency physicians to the clinical decision support system algorithm (
One of the most complex environments for physicians: there is an overload of parameters to watch, access to the patients can be limited, there is often a combination of very complex pathologies and the amount of technologies whose management needs mastering is significant. The main focus of initial DSSs in this setup is the idea of making all relevant patient data readily available.
\n\t\t\t\tTwo of these systems shall initially be discussed here: the ACUDES system and the Rhea.
\n\t\t\t\tThe ACUDES system (Palma et al, 2002) makes all patient data, be it clinical, based on monitoring or laboratory/investigative results available within the temporal context of relation to other data, trying to explain disease evolution, relationship between different abnormalities. ACUDES uses three modules, a temporal behavior model (TBM), the causal and temporal knowledge acquisition tool (CTKAT) and the diagnosis agent (DA). (Fig.24)\n\t\t\t\t
\n\t\t\t\tThis combination allows the physician to have access to a knowledge data base (TBM) in a causal network, relating each abnormality with both a temporal evolution and a causality. The physician can mange, build, construct the data within the TBM – as long as any changes fit within the basic ontological structure of the system, thus avoiding any inconclusive data entry. The DA gives an explanatory framework from which diagnostic reasoning can be deducted.
\n\t\t\t\tThe Rhea system (Metais et al, 2006) integrates a similar set of data as the ACUDES with the focus on iatrogenic adverse effects and nosocomial infections. At the time of writing the publication, 30 French hospitals participated in this project with more than 3000 patients’ data set entered. The assembly of data serves to perform knowledge discovery for research purposes. Some of the proprieties which Rhea can deliver are the establishing of disease course models, alert rules depending on the individual patient’s data and establishing procedural guidelines in order to decrease nosocomial infections. (Fig. 25)\n\t\t\t\t
\n\t\t\t\tACUDES General Architecture (
General principle of Rhea project (
Each individual user can enter relevant data into the system at any time which renders the DSS ‘dynamic’ whilst making it available instantly to all users. (Fig. 26)\n\t\t\t\t
\n\t\t\t\tSo far, Rhea has been solely used for biostatistical research; the increasing pressure on health care providers to audit safety and quality of their activities has led to the introduction of these DSSs. However, these systems only provide actual ‘decision support’ with a significant lag time since they rely on studying data, auditing procedures and identifying possible shortcomings but do not provide an instantaneous help to the clinicians.
\n\t\t\t\tEvolving data, tab "mechanical ventilation" (
The main area of DSSs in the field of intensive care medicine is a DSS for mechanical ventilation. Numerous systems have been developed and used for clinical trials. The fundamentals are outlines in a recent review of DSSs for mechanical ventilation (Tehrani & Roum, 2008, Fig. 27).
\n\t\t\t\tThe efficacy of a DSS for mechanical ventilation is demonstrated in exemplary fashion by East’s study (East et al, 1999) which was performed in 10 centers across the US. The use of DSS significantly reduced the overall morbidity in comparison to standard mechanical ventilation (Fig. 29) and a significant reduction in the incidence and degree of barotraumas. (Fig. 30)\n\t\t\t\t
\n\t\t\t\tIn comparison to the poor efficacy of DSSs in in-hospital emergency medicine, the overall acceptance of these DSSs in this study was very good: 94% of the instructions were followed (out of 38546 instructions in total).
\n\t\t\t\tMight the high rate of DSS acceptance by the physician be a key to its success?
\n\t\t\t\tThe main categories of DSSs for mechanical ventilation are outlined as follows (Fig. 28):
\n\t\t\t\tBlock diagram depiction of an IDSS for mechanical ventilation. The broken lines labeled as ‘‘feedback control’’ represent the automatic supply of control signals to the ventilator in case the system is used to control the ventilator in a closed-loop manner. (
Main categories of different IDSSs for mechanical ventilation (
The maximum daily MODS score in the protocol group and control group. (
Maximum daily barotraumas score of iatrogenic lung injury in the protocol group and control group. (
There are numerous examples of DSSs in the field of anesthesia, emergency medicine and intensive care medicine. The introduction of electronic anesthesia, ER or ICU management systems has been a key issue in these developments.
\n\t\t\tThis chapter gives examples for design and smart alarm structure of DSSs in anesthesia. The introduction of DSSs in daily practice to assure following modern guidelines, as for PONV prophylaxis or proper antibiotic prophylaxis, is actually quite simple, and successful, depending on user compliance. Common areas of negligence and errors, such as turning on alarms after CPB, can be vastly improved by basic DSSs. Very few studies have looked at using DSSs in anesthesia delivery, but pop-up menus can be helpful to promote smart monitoring, alarms and help to treat critical events.
\n\t\t\tEmergency medicine is a particular arena where medical treatment needs to be coordinated between out-of-hospital and in-hospital treatment. Decision support systems provide the necessary logistical help in this complex environment. Their performance in a real life setting can be impaired by lack of compliance by physicians: however, this might be overcome with the more widespread introduction of these systems and the generational change of physicians, used to rely on technologies in their everyday life.
\n\t\t\tDecision support systems have long been introduced in intensive care medicine; complex ventilator settings are far easier to manage with DSSs than relying solely on human judgment.
\n\t\t\tDecision support systems have been studied for more than 2 decades in the fields of anesthesia, emergency medicine and intensive care medicine. They have an excellent track record for improving health care in the research setting; most of the studies have shown an improvement in outcome, reduction of workload or better performance when DSSs assist health care providers. Before the widespread introduction of DSSs in these specialties, improvements in data entering and user interfaces need to be done.
\n\t\t\tThere is no doubt that DSSs will in future healthcare systems be as common as computers in everyday life. All healthcare providers need to be ready for this.
\n\t\tThe author wishes to thank Lingshan Tang, MD, for her invaluable support in editing this chapter. I am also grateful for all suggestions and comments provided by Shantale Cyr, PhD, during the writing process.
\n\t\tSepsis has been announced to be a global health priority by the World Health Organization as in 2017, 48.9 million sepsis cases and 11 million sepsis-related deaths were reported worldwide [1, 2]. However, although significant progress has been made regarding the mechanism of sepsis, treatment modalities still have not gone beyond fluid resuscitation, vasopressors, antibiotics, and palliative care, after all [1, 3].
Sepsis is a perilous condition caused by the dysregulated and hyperactive host response to the pathogen. This response leads to an inflammation out of control and eventually multiple organ dysfunction syndrome (MODS), which is the primary cause of sepsis-related deaths. The propulsive force of the severe consequences of sepsis, such as MODS, is the intestines due to its potential to provoke systemic immune response via the injured intestinal epithelia losing its barrier function, and cannot prevent the pathogens and toxins to confined intraluminally and secreting and releasing the pro-inflammatory cytokines into the circulation [1, 3, 4, 5, 6, 7, 8, 9]. In this chapter, we aimed to cover the fate of the intestinal barrier (IB) and bacterial translocation (BT) during sepsis along with diagnostic methods and potential therapeutic options for IB dysfunction in the light of this information.
The mammalian IB is responsible for fulfilling two primary tasks: to absorb the ingested nutrients and to prevent the microorganisms, toxins, allergens, as well as luminal pro-inflammatory factors from passing through the luminal surface of the intestines into the circulatory system [6, 10, 11, 12, 13].
The gastrointestinal tract, which consists of the mouth, esophagus, stomach, small and large intestines, calls for a single layer epithelial lining with its partners in crime, such as cells of innate and adaptive immune system, forming a multifunctional system to fulfill its barrier function [11].
In the name of intestinal homeostasis, “some” (capital S should be replaced with lowercase “s”. ome of the complex functions should be performed alongside the absorption of the nutrients like to prevent the trespassing of the pathogens, toxins, or allergens limiting the pathogenic bacterial growth to maintain the balance of the luminal microbiota, detoxification of the endotoxins, and immune response on demand as it is the largest lymphoid organ of the body by a multilayer morpho-functional barrier [9, 14] (for a recent review,
Human beings are in a symbiotic relationship with millions of bacteria, fungi, and viruses colonized in our gastrointestinal tract [12, 15, 16]. This host-commensal relationship, which starts at birth, even in-utero [17, 18, 19], maintains the intestinal homeostasis as a biological barrier and responsible for the differentiation, growth, and integrity of the intestinal epithelium [12, 15, 16]. Most of the species of commensal bacteria are obligate anaerobes, and the rest are facultative anaerobes and aerobic bacteria (Table 1) [16, 20]. The majority of the anaerobic bacteria are found in the colon as the oxygen tension is relatively low, whereas the aerobic bacteria are prone to reside in the small intestines [21]. The bacterial population in the proximal small intestines and the colon are around 104 ml−1 and ∼107 ml−1, respectively [22].
Obligate anaerobes | Facultative anaerobes |
---|---|
The intestinal microbiota: Most common commensal anaerobic bacteria species in the human intestines (95% of them are obligate and 5% are facultative anaerobes) [16].
These coexisting symbiotic bacteria demonstrate immunologic and metabolic functions and protect the intestines from pathogenic bacteria growth via alimentary competition and colonization suppression. They help ferment and digest carbohydrates and synthesize vitamin B and K, along with short-chain fatty acids, which will then become the energy source for the intestinal epithelium. They are also responsible for the deconjugation of bile acids which will then reenter the enterohepatic circulation [12, 16].
The intestinal immune system is modulated via the collaboration between the gut microbiota with the adaptive and innate immune systems, which is carried out by interacting pathogen-associated molecular patterns (PAMPs) with the specific receptors in the intestinal immune cells [12, 16].
IAP, one of four of the human alkaline phosphatase family, is an intestinal epithelial cell-derived enzyme constantly staying active intraluminally and in the mucosal lining to ease the gut’s inflammatory response triggered by PAMPs. This way, it regulates the pH balance of the duodenal surface via bicarbonate secretion, helps the absorption of the long-chain fatty acids, defends the brush border membrane against the members of the intestinal microbiota. IAP also dephosphorylates bacterial endotoxin lipopolysaccharide (LPS) and pro-inflammatory nucleotides. Hence, it prevents the inhibition of the commensal microorganisms, as they are affected by the excessive luminal ATP by removing the phosphate groups from adenosine di- and triphosphate. LPS, which causes a systemic immune response and septic shock, is located on the wall of gram-negative bacteria and shows these effects by binding to toll-like receptor 4 (TLR4) thanks to its Lipid A moiety. TLR4 is expressed both in myeloid-borne immune cells (dendritic cells (DCs), macrophages, and monocytes) and in non-immune cells (i.e., endothelial cells) [23]. When dephosphorylated Lipid A moiety binds to TLR4, LPS shifts to a TLR4 antagonist, diminishes the pro-inflammatory cytokines, and activates nuclear factor-kappa-B (NF-κB), thereby minimizing the inflammatory response. It was previously shown that even being exposed to a lethal dose of E.coli, 80% of the mice survived with the help of IAP treatment. Thus, it was concluded that microbiota dysbiosis, intestinal inflammatory response, and transmigration of bacteria are inevitable in the absence of IAP [5, 14, 24, 25].
The first layer of the mechanical barrier is the mucosal layer which comprises water (95%), soluble glycoproteins (1–10%), nucleic acids, electrolytes, and antibodies. Mucin, a highly glycated protein, is secreted by goblet cells (specialized epithelial cells located in the villi), and with the help of other secreted proteins, they organize into a coherent mucus layer [11, 14].
Bacteria are responsible for the degradation of the mucus, and the balance between the secretion and the erosion of this layer determines the functionality of the IB. It was previously shown that this highly glycated structure of mucin feeds commensal bacteria, such as
The outer intestinal mucosal layer is much looser and thicker in comparison with the inner layer. Therefore, the inner layer restrains the transmigration of the bacteria as it is tightly attached to intestinal epithelia to block the direct contact between epithelial cells and the bacteria. Contrarily, the outer layer retains the commensal microbiota elements to eliminate the opportunistic activity of pathogenic bacteria. For that reason, consistent usage of pro- and prebiotic preparations is reported to boost the number of commensal microbiota in order to promote mucosal barrier function [14].
Besides, the anionic residues like sialic acid or sulfate groups at the N-terminal of the mucin glycoprotein promote convergence of the cationic immune molecules, which serve as a chemical defense mechanism [27].
The second mechanical barrier is the polarized single layer of gut epithelial cells (enterocytes-responsible for the absorption, goblet-specialized in mucus production, enteroendocrine cells-responsible for the secretion of the intestinal hormones, Paneth cells-responsible for expressing the microbicidal proteins and peptides among other properties, and microfold cells (M cells)) besides submucosal capillary endothelial cells [21, 28, 29], which act as a selectively permeable interface allowing the transmigration of the essential nutrients, water, electrolytes, and immune factors, and preventing the transfer of luminal pathogenic microorganisms, antigens, and toxins to the circulatory system [4, 12, 13, 14, 30]. This feature of selectivity is coordinated by the paracellular pathway regulated by desmosomes, adherens junctions, and tight junctions (TJs), located at the apicolateral membrane junction, lateral membrane, and basolateral membrane, respectively, and the transepithelial pathway, which is maintained mainly by the selective transporters allowing the uptake of the nutrients [13, 14, 28, 31] (for a recent review about mechanobiology of TJs, see reference [32]).
Hence their vast Golgi and endoplasmic reticulum system Paneth cells known for their cytoplasmic eosinophilic granules, [33], which are exclusively found in the crypts of the small intestine and they the secretory cells of the intestinal mucosa specialized in the secretion of the antimicrobial peptides, which are crucial modulators of innate immunity, as well as with neuropeptides and hormones [14, 34].
α-defensin, a ubiquitous antimicrobial peptide found in the intestine, along with β-defensin, has bactericidal activity, particularly against both the gram-negative and gram-positive bacteria, and any disturbance in the existence of these peptides is shown to increase predisposition to inflammatory bowel disease [14, 34].
Apart from defensins, other antimicrobial proteins such as phospholipase A2 and lysozyme are also secreted from Paneth cells in case of an interaction with bacteria or bacterial antigen [34].
Besides these Paneth cell-driven antimicrobial activities, immunoglobulin A (IgA), which is secreted by plasma immune cells through lamina propria (transcytosis) [5, 14, 35, 36, 37], also contribute to the fifth line of defense in the IB. IgA either binds directly to the potential pathogenic microorganism and toxins to counter the unwanted colonization or epithelial injury or binds and interacts with immune complexes within the lamina propria to clear out these complexes to soothe the systemic inflammatory responses [14]. It also pumps the already translocated bacteria and antigens in the lamina propria back into the lumen [38].
The previous experimental studies on the B cell-deficient mice (as the IgA secreting plasma cells are differentiated from B cells) and the polymeric immunoglobulin receptor (pIgR) knockout mice (as the transcytosis of IgA to the intestinal lumen is conducted by pIgR) noted intestinal inflammation due to faded IgA-operated adaptive immune response is seen in both mice groups [14, 39].
As the largest immunological organ [40], the gut’s innate and adaptive immune system is in continuous interaction with the biological barrier to prevent the conversion of intestinal microbiota into pathobiota. The immune barrier consists of different types of cells, which are members of the gut-associated lymphoid tissue (GALT) like intraepithelial lymphocytes (IELs), natural killer cells (NK cells), innate lymphoid cells (ILCs), mast cells, and M cells (Table 2) [9, 12, 41, 42]. These cells reside in the intestinal mucosal lymphoid structures of GALT, including the intestinal epithelium, isolated lymphoid follicles (responsible for the local IgA response), and mesenteric lymph nodes the lamina propria and Peyer’s patches (5–10% of the follicle-associated epithelial cells) [21, 43, 44, 47] (for a recent review,
Cell type | Location | Structure and functions |
---|---|---|
IELs | Within the intestinal epithelium (between intestinal lumen and lamina propria) | T cells specialized in destroying the transformed, damaged, necrotic, or infected intestinal epithelial cells with their cytotoxic activities regulate the growth and proliferation of the enterocytes. They directly contact the antigens, microbiota, and potential pathogens, and during this interaction, interleukin-15 (IL-15) activates IELs and causes them to express cytokines like IL-2, IL-4, IL-1 and interferon-gamma (IFNγ) excessively. Although IELs are mostly T cells, they possess unconventional properties compared to other T cells due to their unique location and tasks. These functions are usually in favor of the intestine as they react immediately to the pathogenic microorganism or antigen, block the initial attempt of trespassing and invasion, and inhibit unnecessary inflammatory reactions against innocuous antigens. Nevertheless, they may mistaken self-antigens from the pathogenic antigens in a chaotic inflammatory milieu and trigger a pathological autoimmune response. There are two types of IELs: “type a” (induced IELs) and “type b” (natural IELs). Type a (induced) IELs are either CD8αβ heterodimer (Major-Histocompatibility-Complex (MHC) class I-restricted) or CD4+ (MHC class II-restricted) T cells, which express an αβ T cell receptor (αβTCR). They arise from the naive T cells and are activated postthymically (in secondary lymph nodes). After contact with the peripheral antigen as a tissue-resident memory, T cells accumulate in the gut. Type b (natural) IELs are CD8αα homodimer-T cells (do not express CD8β), expressing either a γδTCR or an αβTCR, which are thymically derived and activated by the self-antigens (they can be detected in-utero) and migrate to intestinal epithelium for further differentiation. The adult human jejunum predominantly contains type a IELs expressing CD8αβ along with αβTCR, while the ileal and colonic IELs mainly express αβTCR without CD4 and CD8 expression. Also, IELs are recruited in the small intestines via interacting with E-cadherin through their hallmark marker CD103 (αE integrin). |
M cells | Peyer’s patches | M cells contact the luminal antigens via their irregular short microvilli located on the apical surface and translocate the pathogens to the lymphocytes, or the antigen-presenting cells (APCs) are carried out by the intraepithelial pockets under the basolateral surface, which provides acquired immunity via interaction between the CD4+ T cells and the presented peptide epitopes of the pathogens. |
ILCs | Scattered both in the epithelium and the stroma | ILCs are the coordinators of mucosal immunity as they regulate other functions of the other cells that are part of innate and adaptive immunity, and they also secrete certain effector cytokines. These functions together serve to orchestrate the innate immune response during infection, tissue damage, and inflammation in order, so the gut homeostasis is maintained. Based on their cytokine production, they are classified into three groups: Type 1 ILCs (ILC1s): NK cells. They exclusively express IFNγ and no other Th-17 cell-associated cytokines. NK cells are widely in contact with the microorganisms or the microbial components due to their location, and they also interact with immune cells such as DCs, T cells, macrophages, and fibroblasts, and epithelial cells. Intestinal NK cells recruit peripheral NK cells via IFNγ production. Type 2 ILCs (ILC2s): Cells located in the lower respiratory system along with the gut and mesentery. They produce TH2-associated cytokines. Type 3 ILCs (ILC3s): Cells that produce Th-17 cytokines (IL-17 and IL-22; cytokines associated with gut inflammation and immunity to extracellular bacteria). Besides, DCs, modulated by the resident commensal bacteria, stimulate secretion of the antibacterial peptides from induced intestinal epithelial cells by activating ILC3s. |
ILCs, innate lymphoid cells; ILEs, intraepithelial lymphocytes; M cells, microfold cells; NK, natural killer; Th-17 cell, T helper-17 cell.
All of the aforementioned layers of the IB are the sole protectors of the body, acting as a barrier between 40 trillion luminal microorganisms [49] and the body. Thus they carry a heavy burden in terms of maintaining intestinal homeostasis. Therefore, luminal content should be deliberately compartmentalized, and filtered selectively via preserving intestinal integrity, otherwise increased gut permeability provokes the activation of mucosal immunity via promoting BT along with translocating endotoxins and other pro-inflammatory antigens from lumen to the circulation [3, 5, 9, 14]. This catastrophic cascade can be seen during any infection or any incident triggering local and systemic inflammatory response generating impairment of IB integrity such as sepsis, shock, trauma, abdominothoracic vascular surgery, transplantation, severe burn, and intestinal/mesenteric ischemia and reperfusion [50, 51, 52].
The concept of BT was first described in 1966 [53] and further expanded in 1979 [54] as the transportation of indigenous bacteria through the intestinal wall into the mesenteric lymph nodes and other sterile organs. Translocation of PAMPs, which are small molecular motifs (i.e., LPS, peptidoglycan, and bacterial DNA) located in the microorganism, are added to this definition later on [12]. The mechanism behind the BT are diverse.
Intestinal microbiota can be affected by diverse factors, including gastrointestinal secretions, antibiotics, secreted IgA (sIgA), bile salts, and peristalsis of the intestines. Overgrowth of the microbiota upsets the protective features of the beneficial intestinal bacteria and disrupts the first line of defense of the IB resulting in BT.
Under physiological conditions, IgA secreted by the plasma cells has a feature of encapsulation of bacteria to prevent their trespassing and encapsulation of viruses invading the cells. It also has features enhancing the effects of lysozyme and complements. However, pathological processes inhibit the functionality of IgA, including encapsulation ability, as well as their concentration via a declined number of plasma cells secreting the IgA. This will eventually cause BT.
Pathological processes such as conditions causing immunocompromisation or immunosuppression, MODS, severe burn injury generate BT via overgrowth of intestinal microbiota, immune dysfunction of the body together with the physical intestinal injury, particularly in the mucosal barrier. Oxygen depletion (caused by shock, mesenteric ischemia, cardiovascular surgery, transplant surgery) [50], acidosis, nitric oxide (NO), as exaggerated NO production by inducible NO synthase (iNOS) disturbs mitochondrial functions and cellular respiration, resulting in decreased ATP synthesis and accelerated apoptosis which causes mucosal injury, inflammatory mediators (IFN-γ, IL-4, tumor necrosis factor-α (TNF-α), platelet-activating factor (PAF), reactive oxygen species (ROS)) and endotoxins (causes edema in the submucosa, decreases the intestinal blood flow, villi necrosis) are primary factors in charge of the injured intestinal mucosal barrier and increase the intestinal permeability and BT consequently [38].
Sepsis is a hazardous organ dysfunction with high mortality and morbidity rate. The main characteristic of sepsis is “dysregulated host response to infection” [55], which will eventually bring about microvascular injury, problematic perfusion, cellular hypoxia, and finally, shock [2, 3, 4, 5, 15].
Intestines are usually referred to as the “star of the show” during sepsis as they are accused of causing MODS [4, 7, 9, 12], yet sepsis (and septic shock) also disrupts the intestines by impairing the perfusion of the intestinal mucosa, epithelial edema, initiation of excessive apoptosis and necrosis of the gut epithelia [56], coagulation-associated local dysregulation, and cause hyperpermeability, microbiota transformation into pathobiota, BT and loss of absorptive functions [3].
As an exaggerated inflammatory response is implicated in the pathophysiology of sepsis, involvement of inflammatory cells along with pro-inflammatory cytokines in this process is inevitable [2, 3, 4, 5, 15, 55].
Upregulation of the adhesion molecules in the endothelial layer of the gut, induced by damage-associated molecular patterns (DAMPs) and PAMPs, leads to migration of the neutrophils, monocytes, and macrophages to the intestinal tissue. Pro-inflammatory cytokines released from these recruited cells initiate local and systemic inflammation [5, 14]. In addition, escalated activated macrophage infiltration into the artery walls inaugurates atherogenesis [14].
Besides, pattern recognition receptors (PRR) of PAMPs (including TLRs and NLRs) recognize the cell wall components of the bacteria via TLRs. TLR4 recognizes gram-negative bacteria, whereas TLR2 recognizes gram-positive bacteria. At this point, LPS-induced TLR4 activates signaling pathways either by activation of mitogen-activated protein kinase (MAPK) and NF-κB via MyD88-dependent signaling pathways or the TIR-domain-containing adapter-inducing IFN-β (TRIF)-dependent (MyD88-independent) by TLR4 endocytosis [23]. In the MyD88-dependent pathway, nuclear translocation of NF-κB encourages the transcription of pro-inflammatory genes such as IL-1 α/β, IL-6, IL-18, and TNF-α, whereas, in the TRIF-dependent pathway, nuclear translocation of IFN regulatory factor 3 (IRF3) promotes IFN-inducible genes and the type I IFNs [14, 23, 57].
TLR4 cannot bind LPS per se, needs a cofactor, CD14, which hands the LPS to TLR4 [14], and controls the LPS-induced endocytosis of TLR4 apart from the signaling pathways mentioned above [23, 58].
Although these reactions initially manifest as local inflammation, the process ultimately transforms into a “cytokine storm” [5, 14]. On the contrary, both the MyD88-dependent and TRIF-dependent signaling pathways produce pro- and anti-inflammatory mediators (IL-10) synchronously [23]. Thus, although it has been presumed that extinguishing the hyperinflammation is beneficial in septic patients, an overbalance of anti-inflammatory activity causes an inadequate response to primary infection and makes the patient prone to secondary infections [5, 59, 60].
Additionally, TLR4 manages intestinal cell turnover. During sepsis, elevated cytokine levels shift the balance between proliferation and apoptosis of the crypt and villus in favor of apoptosis and necrosis of the intestinal mucosa, which increases the intestinal permeability as a consequence of decreased villus height, increased release of DAMPs which feed the inflammatory process and brings about ulcer development along with hemorrhage and acceleration in intestinal impairment [4, 5, 56]. The elevated levels of pro-inflammatory cytokines are also shown to reduce the thickness of the mucus layer, the adherence of the mucus layer, and the luminal coverage [4, 52].
Besides, several studies reported that M cells located in the villi provide antigens a channel to mucosal lymphoid tissue, which is a trap where they encounter antigen-presenting cells (APCs). APCs present them with the help of MHC class II to CD4+T-cells [61]. In addition to that, DCs interact with T cells and B cells and selectively generate pro- and anti-inflammatory immune responses mostly through LPS-induced TLR-associated pathways (for a recent review,
Inflammatory host response during sepsis may alter the layers of the IB and cause intestinal hyperpermeability and BT, and these alterations modulate the changes in the expression of the proteins of the TJs such as transmembrane proteins (occludin, junctional adhesion molecules, claudins) and peripheral proteins like zonula occludens-1 (ZO-1), which is in a relationship with actin-myosin complex of the cytoskeleton [11]. Furthermore, TNF-α, IL-6, and IL-1β levels can be elevated via activation of myosin light chain kinase (MLCK), an enzyme phosphorylating the myosin regulatory light chain and leading to hyperpermeability and create a positive feedback mechanism of MLCK activation through ZO-1 and occludin alterations. Aggravated systemic inflammation because of the increased permeability leads to a futile cycle [4].
Pancreatic enzymes are shown to cause multiple organ failure via autophagy [62]. Sepsis-induced ischemia of the gut exacerbates self-digestion and causes mucosal barrier damage leading to the release of DAMPs and pro-inflammatory cytokines from intestinal epithelial cells [5, 63].
Proteases, including pancreatic enzymes in the intestines, also activate the pro-metalloproteinases (MMPs) under ischemic conditions. Enzymatic activity of MMPs destructs intercellular junctions via proteolytic cleavage of junctional proteins’ ectodomain, therefore increasing the intestinal permeability. Additionally, MMPs can digest the endothelial basal membrane [64].
Besides, LPS can induce expression of MMP7, and Paneth cells’ degranulation, which promotes gut hyperpermeability, while MMP7 itself enhances local intestinal inflammation and intestinal damage via activation of α-defensin, subsequently stimulating the release of IL-6 from ileal epithelia and macrophages. Furthermore, it was previously confirmed that MMP7 and MMP13 are correlated with loss of intestinal integrity, inflated BT, and the development of multiple organ dysfunction [5].
After all, it has been reported in several studies that the inhibition of pancreatic enzymes protects the sepsis-induced intestinal autophagy and improves the overall progress [64, 65].
25% of the total cardiac output (up to 35% during digestion) is normally diverted to splanchnic vasculature [5]. Intestinal hypoperfusion can be caused by various reasons like mesenteric ischemia, abdominothoracic vascular surgery, shock, severe burns, transplantation surgery, necrotizing enterocolitis, sepsis, and septic shock [50], because of the redistribution of blood to protect the vital organs [38]. Intestines are highly sensitive to hypoperfusion as the enterocytes have the highest turnover rate among other fixed-cell populations in the body, with a lifespan of 2–6 days [3, 66]. Thus, hypoperfusion causes damage to the intestinal mucosal barrier [5]; moreover, the inflammation as a response to hypoperfusion caused by the ischemia/reperfusion further injures the intestines [3], resulting in loss of IB integrity, BT accompanied by systemic inflammatory response via release of pro-inflammatory cytokines [5, 50, 67].
In addition to that, vasodilation emerges as the pro-inflammatory cytokines (IFN-γ, TNF-α, IL-4, platelet-activating factor) affect vascular smooth musculature and endothelium, as well as capillary leakage, venous stasis, and ultimately diminished cardiac output, and hypoperfusion is seen [38, 68, 69]. Furthermore, compensatory mechanisms, such as the renin-angiotensin-aldosterone system, provokes the release of vasoconstriction and contribute to hypoperfusion. Also, regulatory features of the microvasculature (arterioles, venules, and capillaries) related to perfusion and oxygen distribution are lost due to sepsis-induced hyperinflammation and its inevitable outcome, ROS [38, 69, 70, 71].
Disseminated intravascular coagulation (DIC) is still an up-to-date challenge as of the significant lethal problems of sepsis. It is suggested that both intravascular and extravascular fibrin formation are seen in sepsis-associated DIC due to coagulation activation combined with fibrinolysis inhibition [72].
In sepsis, activation of coagulation is driven mainly by the tissue factor (TF) pathway, in which TF is derived from endothelial cells, monocytes, neutrophils, and liver, whereas suppression of fibrinolysis is coordinated by plasminogen activator inhibitor-1 (PAI-1) [5]. “Activation of coagulation”: Neutrophil activation, caused either by direct contact with the pathogen or damaged cell- or bacteria-originated small molecules cause neutrophils initially to release a significant amount of TF [73, 74]. Later on, elastase is released from the neutrophils as well. Elastase has the ability to inhibit plasminogen together with the TF pathway, which is a crucial coagulation suppressor system [75, 76]. Neutrophil extracellular traps (NETs), which are released from neutrophils in order to trap and eliminate the microbes, also contribute to alterations in the coagulation via activation of Factor XII due to their negatively charged surfaces, fibrin formation, and competitively blocking the binding sites of tissue plasminogen activator (tPA) for clot degradation by fibrin cleavage [77, 78, 79, 80] This explains the persevere on-going of the post-sepsis micro- and macro-thrombosis events [81]. “Inhibition of fibrinolysis”: Sepsis-associated DIC differs from malignancy-associated one, since it is characterized by intensive suppression of fibrinolysis via overproduction of PAI-1, instead of the consumption of coagulation factors, od and differs from fibrinolytic phenotype DIC, as the consequential effects of this suppression in sepsis-associated DIC lead to tissue hypoperfusion resulted in organ dysfunction. Hence, the fibrin-related markers are not safe to use to assess the severity of sepsis as hypofibrinogenemia is uncommon [81, 82].
Besides, antibody-mediated action in the presence of pathogens can activate the complement system during sepsis. Coagulation system is also affected by the activated complement factors via generating an epithelial surface to facilitate clot formation. Activated C3 also activates platelets through the alternative pathway for stimulating aggregation, while activated C5 stimulates endothelial and inflammatory cells, inducing TF expression [83, 84]. In reverse, activated coagulation system can also impact the complement system. TCC production via activation of C5 is achieved by thrombin. Additionally, plasmin can also activate C3 and C5, forby other proteases of the coagulation cascade activate several complement factors like IXa, Xa, XIa, and XIIA [85]. These factors collectively disturb intestinal microcirculation and intestinal physiology and recruit the immune cells throughout the incidence of sepsis-associated DIC [5].
It is pretty challenging to diagnose or assess the IB function directly due to the invasiveness of intestinal tissue sampling. However, there are some methods or biomarkers that indirectly assess IB function. The measurement of biomarkers in urine, blood, or feces generally needs simple, non-invasive test methods.
The tissue culture methods are based on the direct detection of intestinal bacteria in extraintestinal tissues. The mesenteric lymph nodes (MLN), extraintestinal tissues, swabs of the intestinal wall serosa or abdominal cavity, blood, and lymph are subjected to bacterial culture. Living bacteria are isolated, counted, and detected using microscopy. Direct detection has tremendous importance; however, many factors may interfere with the measurement [38]. For the culture of MLN, lymph nodes are suggested to be excised and be homogenized in saline. The homogenate can be inoculated onto Columbia blood agar and cysteine lactose electrolyte deficient media.
BT can also be measured by identifying intestinal bacteria from MLN, which is normally sterile [86]. For the culture of MLN, a lymph node from the mesentery of the terminal ileum is suggested to be excised at laparotomy and be homogenized in saline. Then, the homogenate can be inoculated onto Columbia blood agar and cysteine lactose electrolyte-free media.
Radioactive tracers or plasmids are used to label bacteria for their in vivo detection. This method can detect the bacteria which is attached to intestinal mucosa-associated lymphoid tissue. However, this method can be used primarily in scientific research labs due to its cost and technical requirements.
Fluorescence and isotopes labeling methods are recently in use. PUC19 plasmid was constructed in the 1980s and was used extensively in molecular cloning and discrimination of gene recombination [87]. In this method, the plasmid vector carries the ampicillin resistance gene; the plasmid contains polyclonal restriction endonuclease sites, which discriminates against the positive bacteria. Thus, the PUC19 plasmid is introduced as an ideal tracer for demonstrating BT.
Intestinal BT can be demonstrated by isolating bacterial DNA in patients’ blood or body fluids and then amplifying and sequencing them. The PCR detection method is more sensitive, has a higher positive rate, and can specifically detect certain bacteria when compared to blood culture methods. PCR technic is also a valuable tool for detecting BT in patients with undetected infectious focus. The disadvantage of this method is that only the presence of bacterial debris can be detected, the viability and quantity of the bacteria cannot be determined, and drug sensitivity tests cannot be performed. The quantification of total bacterial 16S rDNA in plasma is used to assess human and animal systemic microbial translocation
Lipopolysaccharide (LPS), the integral component of the outer membrane of all gram-negative bacteria are shown to lead to BT. Since sepsis leads to intestinal submucosal edema and impairs the integrity of the mucosal barrier resulting in an imbalance of gut microflora and increased bacterial endotoxin-induced mucosal injury, endotoxin detection in the blood is a good marker of BT [38, 89].
Endotoxins can be detected in biological fluids by the Limulus amoebocyte lysate assay. Methods using fluorescence phage recombinant technology are also introduced [90].
Several methods are used for the measurement and the evaluation of intestinal permeability and barrier function, such as the measurements of transepithelial resistance and assessment of macromolecular flux across isolated segments of GI tissue or colonic biopsies in Ussing chambers, measurement of permeability using fluorescein isothiocyanate (FITC)-dextran permeability in cell lines, morphological measurements of the TJ components, measurement of dilution potentials, and polyethylene glycol (PEG) profiling to assess the pore pathways [91, 92].
Methods used to measure intestinal permeability are based on detecting the passage of the molecules across the intestinal epithelium. Several markers can be used alone or in combination to assess intestinal fluxes. Large molecules, lipophilic compounds, and nutrients generally prefer the transcellular route by passing through the intestinal epithelial cells by endocytosis, passive diffusion, or membrane transporters. On the other hand, ions and small hydrophilic molecules prefer the paracellular transport pathway. Thus, molecular size and structure are significant determinants of intestinal permeability [93].
Cell culture-based models using Caco-2 or HT-29 cell lines assess electrical resistance and intestinal flux in vivo. In contrast, differential urinary excretion tests with the use of chromium-labeled EDTA (51Cr-EDTA), polyethylene glycols (PEG), or non-metabolizable sugars such as lactulose and mannitol are frequently used to measure in vivo intestinal permeability [94]. Lactulose can cross the membrane via the paracellular pathway, while mannitol can easily cross the intestinal epithelium through transcellular and paracellular routes. Multi-sugar tests are offered to assess intestinal permeability simultaneously [28, 95]. Ovalbumin, horseradish peroxidase, dextrans, and fluorescently labeled microorganisms are used to measure the intestinal permeability in the blood [96]. Claudin protein levels can be measured in urine samples for intestinal TJ loss since claudins play a critical role in regulating the paracellular barrier pathway [97].
Markers of microbial translocation, inflammation (IL-6), and intestinal damage as well as fatty acid-binding proteins (FABP) and glutathione S-transferases (GSTs), which can be determined using ELISA technics, are suggested as significant biomarkers demonstrating intestinal epithelial cell damage. Fatty acid-binding proteins (FABPs) are small intracellularly or membrane-localized proteins released in the extracellular space in their soluble extracellularly from early after a cell or tissue damage. There are three main types of FABP. Liver-type FABP, intestinal-type FABP, and ileal FABP. During intestinal cell damage, intestinal-type FABP (I-FABP) is released from the enterocytes in the systemic circulation and excreted through the kidney [98]. Therefore, it has been suggested that I-FABP is an early biomarker to detect impairment of IB and injury in sepsis [99, 100, 101].
GSTs are cytosolic enzymes released when the cell membrane is damaged and play a crucial role in the detoxification of xenobiotics. Hence, α-GSTs are introduced as intestinal biomarkers [95].
Inflammatory molecules such as calprotectin in feces are proposed as a fecal biomarker reflecting the impaired IB function [102]. Calprotectin is a small protein in the leukocytes and is released in the lumen upon neutrophilic infiltration of the gut mucosa during inflammation and can be detected using ELISA technics.
Although it has been known that BT is strongly associated with the progress of sepsis and septic morbidity, no decisive clinical therapy is proposed for the repair of the impaired IB and the treatment of sepsis [14]. However, some strategies such as modulation of the IB, inhibiting immoderate bacterial growth, regulating the effects of immune mediators, endotoxins, and NO, preventing oxidative stress, and improving intestinal ischemia and reperfusion injury were reported the severity of sepsis-associated BT [38].
Removal of pathogenic bacteria, including gram-negative bacilli and symbiotic anaerobic bacteria, by the treatment with non-absorbed oral antibiotics such as polymyxin E, polymyxin B, amphotericin B, and tobramycin were suggested to reduce mortality [103, 104]. Although the treatment with non-absorbable antibiotics was believed to reduce the incidence of infection by pathogenic gram-negative bacteria and improve mortality rates, antibiotic resistance appeared as a limiting factor [105]. Since sepsis is an acute disease with high morbidity and mortality in intensive care units leads to intestinal flora disturbance, induces IB impairment, causes BT, systemic inflammation, and MODS; broad-spectrum antibiotics are frequently used in severe sepsis treatment [106]. Antibiotics are reported to affect the inflammatory process and ameliorate intestinal microcirculation in sepsis [107]. It was recently demonstrated that broad-spectrum antibiotics prevent BT to distant organs such as the liver and lungs in septic rats [108]. There is, however, evidence that broad-spectrum antibiotics can lead to an imbalance in the intestinal micro ecological environment, promote BT in sepsis, and cause drug resistance and pathogenicity, especially when MODS develops [109]. High-dose antibiotic therapy is also suggested to promote the translocation of native symbiotic bacteria and induce an inflammatory response, leading to late-onset sepsis [110]. It was concluded that metronidazole, an antibacterial and antiprotozoal drug used to treat giardiasis, anaerobic infections, and inflammatory bowel disease, reduces colonic bacterial counts and improves intestinal inflammation by suppressing cellular immunity [111]. Erythromycin was shown to increase gastric motility by affecting the motilin receptors in smooth muscle cells of the stomach, facilitating gastric emptying and decreasing the acidity and residual gastric fluid volume [112]. Treatment with antibiotic combinations (vancomycin, neomycin, and polymyxin b) prevented the translocation of intestinal bacteria to the pancreas by inhibiting the pancreatic NLRP3 pathway and inhibiting intestinal-pancreatic inflammatory responses [113].
During the attack of pathogenic bacteria, which destroys the IB or at decreased IAP conditions and increased LPS levels, the TJs are disintegrated. Macrophages are activated to produce pro-inflammatory cytokines, which also activate macrophages in circulation and cause the transportation of bacteria and LPS into the blood circulation [14, 114]. As previously mentioned, both the quantity and the functions of the secreted IgA diminish during pathological conditions [38]. Oral sIgA supplementation was shown to increase local sIgA levels in the intestine. Epithelial growth factor is suggested to promote the regeneration of intestinal mucosal epithelial cells, maintain the normal structure of intestinal mucosa, protect the intestinal mucosal immune barrier, and prevent BT [115]. Studies indicated that glutamine and growth hormone supplementations reduce intestinal BT and regulate inflammatory pathways [38].
Exogenous IAP administration was suggested to improve the IB function, while oral or enteral administration of IAP ameliorated the disintegrated IB [116, 117]. It was recently reported that high fat, Western-type diet-induced IB dysfunction, improved glucose intolerance, and orally administered IAP improved severe ulcerative colitis patients [118]. Since it was reported that anti-TNFα antibodies and inhibition of myosin light chain kinase (MLCK) prevented the impaired barrier function, treatment with these antibodies and inhibitors was suggested to reduce the severity of inflammatory bowel diseases. As IL-13 induces the disruption of barrier function by upregulation of claudin-2 expression, inhibition of IL-13 or claudin-2 seems to be proper targets for the treatment of BT [14]. The antimicrobial peptide cathelicidin-BF (C-BF) inhibited small IB dysfunction in the LPS-induced septic model in rodents [119].
Curcumin reduces the LPS/IL-1β-induced impairment of TJs [120], while berberine decreases the effects of LPS-mediated signaling through the Wnt/beta-catenin pathway to restore intestinal permeability in a rat model of sepsis [121]. It was suggested that cortisol reduces the expression of TJ proteins by alleviating the glucocorticoid receptor (GR) binding to the occludin and increases paracellular permeability and lubiprostone prevents stress-induced IB dysfunction [122]. A new GR agonist, 16α-hydroxytrametenolic acid (from edible mushrooms), is suggested to ameliorate the barrier dysfunction through PI3K/Akt/NF-κB signaling pathway [123]. Metformin is introduced to be beneficial for the protection of IB dysfunction by the inhibition of JNK activation through the AMPKα1-dependent signaling pathway [124]. Treatment with resveratrol increased the expression of sirtuin-1 in obese septic mice and decreased the inflammatory response. Sirtuins also play a significant role during the late onset of septic “hypo-inflammation”; SIRT-2 inhibition in obese septic mice preserved a decreased microvascular inflammation and protected against thrombotic events [125]. Tezosentan, a non-selective ETA and ETB receptor antagonist, improved intestinal microcirculation in intestinal ischemia–reperfusion injury by reversing the BT and cellular disintegrate of the intestinal mucosa [50]. Allopurinol, vitamin C, coenzyme A, Quercetin,
The World Health Organization (WHO) describes
Clinical studies showed that sepsis is influenced by gut microbiota disruption [137]. Fecal microbiota transplantation (FMT) is the administration of fecal material from a healthy donor into a patient’s intestinal tract with an altered gut microbiota to restore its functions. Randomized controlled trials showed that FMT is successfully applied in treating recurrent
Furthermore, the introduction of symbiotic bacteria may decrease the antibiotic resistance genes present in the microbiome [139]. Treatment with FMT provides a complete reversal of dysbiosis, decreases the levels of inflammatory mediators, and normalizes T helper-(Th-)1/Th2 and Th1/Th17 ratios. However, since MDR is a leading cause of sepsis complications in intensive care unit patients, FMT has been evaluated in different case series. Results cannot be easily analyzed because of the high risk of bias in smaller studies, results of different studies cannot be conclusive because of different patient populations (with the most common organisms are carbapenem-resistant Enterobacteriaceae, vancomycin-resistant Enterococci, and extended-spectrum β-lactamase-producing bacteria, and Pseudomonas, methicillin-resistant
Sepsis is a severe life-threatening organ dysfunction resulting from a systemic inflammatory response to infection. BT occurs more frequently in patients with intestinal obstruction, endogenous infections, endotoxemia, and impaired immune system, which is the cause of subsequent sepsis and ultimately leads to multiple organ dysfunction. The present chapter focused on sepsis-induced dysfunction of the IB leading to BT and multiple organ dysfunction. In addition, the underlying molecular mechanisms of BT in sepsis, diagnosis, and assessment of BT and therapeutic approaches were also discussed. Elucidating the factors affecting BT may lead to implementing interventions that contribute to improved patient outcomes. Unfortunately, there are no proven beneficial therapeutic options to prevent sepsis-induced BT yet; however, attempts at selective gut decontamination, the use of pre-or probiotics, new regimes for antibiotic prophylaxis, and fecal microbiota transplantation, to patient care will provide significant improvement for the treatment of sepsis.
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\n\nCSIC affiliated authors can also take advantage of a central Open Access fund (amounting to 10,000 EUR) to cover up to 50% of the rest of the OAPF until it expires. Effective for chapters accepted from January 1, 2020.
\n\nCorresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
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\n\nBook Chapters and Monographs
\n\nBook Chapters and Monographs
\n\n\n\nBook Chapters and Monographs
\n\nThe Claremont Colleges are pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\nCorresponding authors will receive a 15% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
\n\nThe University of Massachusetts, Amherst is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\nCorresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
\n\nThe University of Surrey is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\nCorresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
\n\nMonographs Only
\n\n\n\nImportant: You must be a member or grantee of the above listed institutions in order to apply for their Open Access publication funds.
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Mostafa",authors:[{id:"68104",title:"Prof.",name:"Soha",middleName:"Sayed Mohammad",surname:"Mostafa",slug:"soha-mostafa",fullName:"Soha Mostafa"}]},{id:"68218",doi:"10.5772/intechopen.87069",title:"Neglected and Underutilized Legume Crops: Improvement and Future Prospects",slug:"neglected-and-underutilized-legume-crops-improvement-and-future-prospects",totalDownloads:1828,totalCrossrefCites:10,totalDimensionsCites:22,abstract:"Sustainable agricultural productivity is hampered by over-dependency on major staple crops, neglect and underutilization of others, climate change, as well as land deterioration. Challenges posed by these limiting factors are undoubtedly contributing to global food insecurity, increased rural poverty, and malnutrition in the less developed countries. Miscellaneous neglected and underutilized grain legumes (MNUGLs) are crops primarily characterized by inherent features and capabilities to withstand the effects of abiotic stress and climate change, significantly replenish the soil, as well as boost food and protein security. This chapter provides insight into the benefits of MNUGLs as food and nutritional security climate smart crops, capable of growing on marginal lands. Exploring and improving MNUGLs depend on a number of factors among which are concerted research efforts, cultivation and production, as well as utilization awareness across global populace geared toward reawakening the interest on the abandoned legumes. The emergence of the clustered regularly interspaced short palindromic repeat (CRISPR/cas9) technology combined with marker-assisted selection (MAS) offers great opportunities to improve MNUGLs for sustainable utilization. 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As such, crops which are the main food source must be produced at a higher pace in order to cater in tandem with the food demand. In the past, traditional plant breeders practice classical breeding techniques to propagate plants with desirable traits. However, traditional breeding technique lies in that only individuals of the same or closely related species can be crossbred. Moreover, traditional breeders will not be able to obtain traits which are not inherent within the gene pool of their target plants through classical breeding. With recent advancements in the field of genetic engineering, it is now possible to insert beneficial genes from a completely different species or even kingdom into a target plant, yielding transgenic plants with multiple ideal traits. To develop a transgenic plant, parameters such as vector constructions, transformation methods, transgene integration, and inheritance of transgene need to be carefully considered to ensure the success of the transformation event. 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Therefore, a full understanding of plant-NP interaction and phytotoxicological mechanism is required for accurate risk assessment to ensure the safe use of nanoparticle. A range of analytical techniques have been developed to detect and characterize the uptake, translocation, cellular internalization and intracellular biotransformation of nanoparticles in plants. Imaging methodologies, including various electron microscopy, spectrometry-based techniques, together with ICP-based techniques such as ICP-OES, ICP-MS and SP-ICP-MS, have been widely used to obtain information about NPs size, morphology, size distribution, cellular localization, elemental speciation, mass concentration and so on. Due to the complexity of biological samples to be analyzed, these techniques are often combined accordingly to provide complementary information regarding plant-NP interaction. 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