Sites of infection in neutropenic patients
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"986",leadTitle:null,fullTitle:"Psoriasis",title:"Psoriasis",subtitle:null,reviewType:"peer-reviewed",abstract:"We hope you enjoy and find the information provided in this book useful in your research or practice. We urge that you continue to keep abreast of the new developments in psoriasis and share your knowledge so that we may advance treatment and cures of psoriasis.",isbn:null,printIsbn:"978-953-307-878-6",pdfIsbn:"978-953-51-6743-3",doi:"10.5772/1492",price:139,priceEur:155,priceUsd:179,slug:"psoriasis",numberOfPages:384,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"58eb38a9c38ca3147540eea11410ec58",bookSignature:"Jennifer Soung and Bonnie Koo",publishedDate:"February 15th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/986.jpg",numberOfDownloads:68696,numberOfWosCitations:11,numberOfCrossrefCitations:16,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:38,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:65,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 25th 2011",dateEndSecondStepPublish:"February 22nd 2011",dateEndThirdStepPublish:"June 29th 2011",dateEndFourthStepPublish:"July 29th 2011",dateEndFifthStepPublish:"November 26th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"63932",title:"Dr.",name:"Jennifer",middleName:null,surname:"Soung",slug:"jennifer-soung",fullName:"Jennifer Soung",profilePictureURL:"https://mts.intechopen.com/storage/users/63932/images/5523_n.jpg",biography:"Dr. Jennifer Soung is a board certified dermatologist and Assistant Clinical Professor of Dermatology at the University of California, Irvine. As the director of Dermatology Clinical Research at UC Irvine, Dr. Soung has a broad interest in medical and cosmetic dermatology as well as clinical research. Her clinical and research interest is the treatment of psoriasis. She is currently the Principal Investigator of two large clinical trials focused \non examining new medications for the treatment of psoriasis. Besides psoriasis, Dr. Soung plans to explore new treatment options in rosacea and discoid lupus. Dr. \nSoung treats adult and pediatric skin conditions, including acne, eczema, rosacea, and skin cancer. She is well versed in techniques for cosmetic rejuvenation of the aging face including Botox, lasers and chemical peels.\nDr. Soung received her Bachelor of Arts at Brown University and earned a medical degree from the Albert Einstein College of Medicine. She completed a medical internship at the West Los Angeles-UCLA Veterans Hospital and a dermatology residency at the University of California, Irvine. Dr. Soung also pursued advanced fellowship training in dermatopharmacology at the Mount Sinai Medical Center, NY and earned top honors for her research on pharmacogenetics.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1002",title:"Dermatoepidemiology",slug:"dermatoepidemiology"}],chapters:[{id:"28299",title:"Psoriasis and Stem Cells",doi:"10.5772/25430",slug:"psoriasis-and-stem-cells",totalDownloads:3190,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Kaiming Zhang, Guohua Yin, Xinhua Li, Xuping Niu, Ruixia Hou, Ruifeng Liu and Junqin 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The interplay between the endoplasmic reticulum membrane and the outer mitochondrial membrane, called mitochondria-associated endoplasmic reticulum membranes (MAMs), permits a wide range of cellular activity, including the division and fusion of mitochondria and the dynamic passage of lipids, glycogen, and calcium ions.
\r\n\tIt has been established that energy/nutrient depletion, calcium flux injury, or oxidative stress disrupt endoplasmic reticulum homeostasis and even induce accumulation of misfolded/unfolded proteins leading to endoplasmic reticulum stress. Under endoplasmic reticulum stress conditions, an adaptive mechanism of coordinated signaling pathways, defined unfolded protein response (UPR), is activated to return the endoplasmic reticulum to its healthy functioning state. The aging causes a decrease of the protective adaptive response of the UPR and an increase of the pro-apoptotic pathway together with endoplasmic reticulum ultrastructural injury. Controlling endoplasmic reticulum stress response, maintaining the appropriate endoplasmic reticulum ultrastructure and homeostasis, and retaining mitochondria interplay are crucial aspects for cellular health.
\r\n\tThis book presents a comprehensive overview of endoplasmic reticulum, including, but not limited to, endoplasmic reticulum ultrastructural anatomy, MAMs, endoplasmic reticulum stress, and their implication in health and diseases. Additionally, identifying perturbations in the endoplasmic reticulum stress response could lead to early detection of age-related disease and may help develop therapeutic approaches.
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She is currently engaged as a researcher for the Scientific-Disciplinary Sector BIO/16 Human Anatomy at the Anatomy and Pathophysiology Division, Department of Clinical and Experimental Sciences, University of Brescia (Italy).\r\nDr. Favero focuses on aging-related morphological dysfunctions as the prelude to various pathophysiological processes in her research programs. The central hypothesis is that natural antioxidants and, in particular, melatonin may act as molecular "switches" that modulate cells and tissues by suppressing, at various levels, oxidative stress and inflammatory signalling cascades. These research approaches represent powerful tools for developing innovative preventive strategies and identifying novel prognostic biomarkers for several diseases. 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The implementation of empiric antibiotic therapy in febrile neutropenia led to dramatic reduction in mortality and was hailed as a turning point in cancer treatment [1]. Nonetheless, the development of more effective and dose intensive salvage chemotherapy regimens, incorporation of monoclonal antibodies, use of consolidation and maintenance strategies, and increased use of indwelling venous catheters have increased susceptibility to infections and changed the spectrum of infections in patients with leukemia [1]. Specifically, multidrug resistant organisms, as well as those previously considered innocuous have emerged. Even under the optimal circumstances i.e. timely diagnosis and implementation of appropriate therapy, infections in leukemia remain a therapeutic challenge. Furthermore, delayed recognition and/or poor implementation of the appropriate treatment strategy can lead to significant morbidity and mortality while potentially increasing the economic burden associated with the infections seen in this immunocompromised population. Therefore, it is imperative that clinicians caring for this vulnerable group of patients have a thorough understanding of the infectious complications associated with leukemia and leukemia directed therapy.
This chapter includes a discussion of
Basic concepts and definitions;
Pathogenesis of infections in acute and chronic leukemia;
Spectrum of infections, with a focus on new and emerging infections;
Risk of certain infections associated with specific chemotherapy medications;
Clinical evaluation of suspected infection;
Treatment strategies, including empiric therapy and management of documented infection;
Role of prophylactic and preventive measures, in patients with acute and chronic leukemia;
Economic impact and outcomes.
The acute leukemias are characterized by the rapid proliferation of immature progenitor cells and include acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL). Chronic leukemias typically run a more indolent course. This group includes chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL). The accumulation and slow proliferation of mature appearing but functionally incompetent leukocytes is the common underlying pathology in chronic leukemias. The clinical presentations of infections are determined by a complex interplay between the pathogen and its virulence and the defense mechanisms of the host and the degree to which this is impaired.
Disease specific factors associated with host immune response
Studies in the early twentieth century led to a gradual shift in our understanding of the pathogenesis of infections. It became apparent that infections were not solely determined by the inherent virulence of the organism but also the susceptibility of the host [6].
In acute leukemia normal hematopoiesis is replaced by abnormal maturation and dysregulated proliferation of leukocytes [7]. Coupled with significant bone marrow infiltration, this leads to decreased production of normal granulocytes resulting in neutropenia and impaired granulocyte function. Additionally, the presence of a large number of immature myeloid cells can inhibit antigen specific T cell response [8] Therefore, newly diagnosed leukemia patients often present with concurrent infections [7]. Treatment with standard induction regimens results in prolonged neutropenia that can last weeks, rendering the host highly susceptible to bacterial and fungal infections [7]. Furthermore, polymorphonuclear leucocyte function may be adversely affected by several chemotherapeutic medications such as high dose glucocorticoids, vincristine, vinblastine, carmustine, cyclophosphamide and 6- mercaptopurine [9]. The risk of severe infections is not uniform among these patients and is related to the degree and duration of neutropenia [7] with the risk of developing more serious infections increasing with prolonged neutropenia [10] [11], the use of salvage chemotherapy, and previous antibiotic exposures [12]. In acute leukemia patients, the risk of infection does not fully abate after achieving remission as patients can have prolonged defects in humoral immunity [13]. This risk increases further with relapse of disease [14].
In addition, chemotherapy-induced mucosal disruption of the oropharynx and gastrointestinal tract enables normal commensals to access the bloodstream and cause invasive disease [15]. In the 1980s, the use of central lines became widespread and contributed to the increased incidence of blood stream and systemic infections with skin flora [15].
Patients with CLL have defects in both humoral and cellular immunity as a result of their underlying malignancy, as well as therapy-related immune suppression from chemotherapeutics such as alkylating agents, purine analogues and monoclonal antibodies [16]. Although these drugs have dramatically improved CLL outcomes, the predisposition to serious infections can result in significant morbidity - 80% of CLL patients will have a significant infection over the course of their disease, with up to 60% of people dying from infection [17].
B cell defects in patients with CLL can lead to hypogammaglobulinemia in the majority of patients (up to 70% within seven years of diagnosis) [18]. Deficiencies can be seen in all three classes of immunoglobulins -IgG, A and M and is worse with advanced disease stage [19, 20]. Severity and incidence of infections particularly respiratory infections correlated with low levels of serum IgG [19] as well as IgA [21,22]. Decreased levels of opsonizing antibodies typically result in infections due to encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenza, and Neisseria meningitides [17]. These patients also tend to respond poorly to vaccination [23]. Impaired function of NK cells (lack of azurophilic granules that are necessary for normal killing activity [24]), neutrophils (reduced chemotaxis and migration) and monocytes and macrophage system have also been noted. T cells show a number of defects including abnormalities in gene expression and CD30 response, decreased CD4 to CD8 ratio [25], impaired Th2 polarization, and reversible acquired CD40 ligand deficiency [26]) all of which prevent T cells from initiating or maintaining and completing an immune response[18]. Furthermore, patients can develop disease or therapy related neutropenia. These multiple immune defects predispose patients to bacterial, fungal, and viral infections.
Although the advent of improved diagnostics and more effective therapies have largely obviated the need for splenectomy across a number of hematologic malignancies, it may be performed for diagnostic reasons or in the setting of symptomatic splenomegaly, refractory autoimmune hemolytic anemia or thrombocytopenia [27,28]. The spleen is a large mass of lymphoid tissue pivotal in filtering blood borne pathogens. It is also an antibody producing organ [29] and plays a role in the activation of alternative complement pathway which may be abnormal in those with anatomic or functional asplenia [30]. Splenectomy therefore further predisposes this already at risk population serious infections including rapidly fatal infections with encapsulated organisms (see above), babesiosis, and capnocytophaga canimorsus [31-34].
HCL is an uncommon adult B-cell lymphoid leukemia that typically runs an indolent course and like CLL, many patients do not require immediate treatment [35]. Clinical features include pancytopenia, splenomegaly (which may be complicated by rupture or infarction), and absolute monocytopenia [35]. Infections remain a significant problem, presumably due to neutropenia and monocytopenia [36], and have been found to be prognostic. For example, survival at 4 years from diagnosis is markedly lower in individuals who have had infections as opposed to those who have not (49% versus 92%, p=0.0012)[36].
Age and malnutrition
Other factors that have been evaluated in the pathogenesis of infections in patients with leukemia include age and nutritional deficiencies. Fanci and colleagues compared the effect of age on the incidence of nosocomial infections in patients with acute leukemia older than 60 yrs compared to younger patients [37]. The authors concluded that the risk of infection was no different in the study groups despite the added decline in immune function with age. However these results needed to be evaluated with caution as they were likely confounded by the fact that elderly patients with relapsed/ refractory disease were generally treated with less aggressive treatment regimens [37] which inherently may be associated with less infectious risk.
Nutritional deficiencies may also adversely affect the ability of normal tissue to withstand toxicity from chemotherapy resulting in need for discontinuation or dose reduction of chemotherapy [38]; however, its impact on infections in leukemia is not well defined.
Key points
In acute leukemia there are quantitative and qualitative defects in leukocyte function.
The risk of infections in neutropenic fever is determined by the severity and duration of neutropenia.
Disruption of mucosal lining due to toxic effects of chemotherapeutic drugs and the use of central venous catheters contribute to the risk of infection due to commensal organisms.
In CLL both humoral and cellular immunity are impaired leading to a predilection to infection with encapsulated and intracellular organisms respectively.
Patients with HCL are also at increased risk for infections which may be associated with worse outcomes.
Febrile neutropenia
The most common bacterial pathogen in the 1960s in neutropenic patients was Staphylococcus aureus [10,39]. However, presumably due to the widespread use of methicillin, fatal staphylococcal infection rates dropped from 23.5% in 1954 to 3.1% in 1963 according to a ten year review of National Cancer Institute data [40]. This success was dampened in the late 1960s and early 1970s by the emergence of aerobic gram-negative bacilli such as Klebsiella pneumonia, enterobacter, E. coli, Pseudomonas and other enteric organisms such as enterococci and anerobes[39]. Cephalothin, a first-generation cephalosporin, led to improved outcomes with these infections. This period marked the emergence of Pseudomonas aeruginosa as a major pathogen associated with high mortality rates in this population [39]. Although polymyxin and gentamicin were available as monotherapies to treat Pseudomonas bacteremia, the use of the first anti-pseudomonal carboxy penicillin carbenicillin, in combination with gentamicin, significantly reduced mortality from 60% in the 1960s to 10-30% in the 1980s [39].
In the 1990s, given their oral route of administration, broad spectrum of activity including against gram negatives, good bioavailability, and general low toxicity, prophylactic fluoroquinolone use became widespread. In addition, emerging resistance patterns resulted in an increased reliance on third generation cephalosporins for prophylaxis, empiric therapy for neutropenic fever, or treatment of gram negative infections. These developments, along with the increased use of implantable venous catheters, shifted the spectrum of infections back towards gram positive organisms such as staphylococcus and streptococcus species [41]. Use of H2 antagonists and other antacids in conjunction with fluoroquinolones have also been implicated as a potential contributing factor to this shift [41,42].
Bloodstream infections (BSI) are commonly associated with mucositis, cellulitis, pneumonia, neutropenic enterocolitis, invasive fungal disease and central venous catheters [43,44]. The clinical presentations of BSI may vary from bacteremia to fulminant shock. In a survey of 49 hospitals between 1995 and 2001, the frequency of gram positive bloodstream infections increased from 62% in 1995 to 76% in 2001[45]. The source of BSI was not identified in 52% of cases in this study. One hospital based study reported the re-emergence of gram negative organisms in primary nosocomial BSI [46]. Interestingly, a seasonal increase in the incidence of gram negative BSI, particularly Acinetobacter, and to a lesser degree E.coli has recently been noted, stressing a need for greater vigilance during summer months [47]. The epidemiology of BSI is included in Table 1. Coagulase negative staphylococci, Staphylococcus aureus, Viridans streptococci, and gram negatives are the most likely pathogens. Although candida is well known as a cause of catheter related blood stream infection, atypical catheter related infections from mycobacteria, nocardia, and Tsukamurella have been reported [48-52].
It should be emphasized that gram-negative organisms continue to dominate the scene as the most frequent pathogens causing infections in febrile neutropenic patients. Apart from BSI, other sites of infection include the respiratory tract (pneumonia, sinus), skin and soft tissue (mucositis and cellulitis), gastrointestinal (diarrhea, typhlitis, perirectal abscess, and enterocolitis) and genitourinary tract (UTI,) in order of frequency [53-55]. Neutropenic enterocolitis, notorious for its morbidity and mortality may be further complicated by polymicrobial BSI due to aerobic gram negative bacilli and anerobes such as Clostridium septicum [56]. The gastrointestinal tract (including the oral cavity) is often the site of origin of polymicrobial BSI. Elting and colleagues delineated factors associated with the poor response to treatment in a large study of polymicrobial infections in cancer patients. These included persistent neutropenia (25%), pneumonia (19%), and bloodstream infection caused by multiple gram-negative organisms (49%) [57].
Upper gastrointestinal -Gingivostomatitis and periodontal lesions | Streptococci, gram negatives, herpes simplex, candida and uncommon bacteria like stomatococcus and aerococcus |
Gastrointestinal infections- Typhlitis, neutropenic enterocolitis, perirectal abscess | Gram negatives and anerobes, C-diff. |
Lower respiratory tract infections-Pneumonia [64][65] | Gram negative bacilli, pneumococci, moulds, virus e.g CMV |
Blood stream infections [45,66]. | Coagulase negative staphylococcus (the most common isolate), S. aureus, E.coli and P.aeruginosa |
Polymicrobial infections [67] | Gram-positive, anaerobic, or fungal , often seen with concurrent presence of a gram-negative bacillus. |
Skin and soft tissue -cellulitis and folliculitis | Streptococci, staphylococci, anaerobes and gram negatives |
Sites of infection in neutropenic patients
Clostridium difficile associated diarrhea is common is patients with acute leukemia especially AML [58,59]. It accounts for approximately one third of episodes of diarrhea and is more common with older age, number and duration of antibiotics and prolonged neutropenia prior to onset of diarrhea [59]. Fluoroquinolone use has been implicated in the increased incidence of resistant Clostridium difficile (C-diff) infections [60]. Toxin negative Clostridium infections which have been described in up to 10% of patients, are particularly problematic, and require endoscopic studies for diagnosis [61]. C-Diff therapy consists of metronidazole or, in severe cases, oral vancomycin [62], which has become the initial agent of choice at some institutions [63] due to increasing emergence of metronidazole resistance. Fidaxomicin is a new macrocyclic antibiotic has been shown to have clinical cure rates similar to vancomycin but superior in terms of lower recurrence rates [62]. Table 1 summarizes the clinical syndromes, sites of infection and associated pathogens in neutropenic patients.
Resistant bacterial pathogens
Patients with leukemia are predisposed to infections and thus exposed to multiple antibiotics during the course of their therapy. The emergence of resistant organisms in this cohort of patients can be catastrophic.
Methicillin resistant Staphylococcus aureus (MRSA): accounts for 20-30% of nosocomial BSI and can lead to metastatic complications such as deep tissue and focal abscesses (e.g epidural, splenic), endocarditis and septic arthritis. MRSA is resistant to penicillin, cephalosporins and quinolones.
Vancomycin resistant staphylococci (VRSA): has become a growing concern no doubt due to the widespread use of vancomycin. Although linezolid and daptomycin can be used, these isolates may be less sensitive to these agents as well [68].
Vancomycin sensitive and vancomycin resistant enterococci (VRE): Risk factors include neutropenia, fluoroquinolone use, and previous treatment with vancomycin. E. faecium, which is often vancomycin resistant, has now surpassed E. faecealis as the predominant organism and is associated with a two-fold risk of higher mortality-in excess of 70% in the setting of neutropenia. In an attempt to decrease this risk, some centers have begun to isolate immunosuppressed VRE-colonized patients and employ barrier precautions (i.e. gowns, gloves); however, it is not yet clear if this approach impacts the outcomes of VRE infections. Linezolid and daptomycin are reasonable therapeutic options for the treatment of VRE infection. [41,69,70].
Multidrug resistant gram negative organisms have become especially problematic presumably due to the widespread use of antibiotics in this population. Extended spectrum beta-lactamase producing bacteria, such as Klebsiella and E coli, are resistant to fluoroquinolones, cephalosporins and penicillins [71]. The carbapenams are usually effective in treatment. However in cases of carbapenamase producing Klebsiella, colistin can be used. Multidrug resistant pseudomonas requires colistin or polymixin B therapy [72].
Fungal infections
Invasive fungal infections (IFI) have been implicated as a complication in leukemia since the 1940s [10] and continue to be a major cause of morbidity and mortality in leukemia patients. Autopsy studies identified IFI as a cause of persistent fever and subsequent demise in neutropenic patients unresponsive to broad spectrum antibiotic therapy [10]. The use of empiric antifungal therapy led to improved survival; however, it was often difficult to confirm a diagnosis of IFI. This in turn often led to overtreatment with antifungal medications and thereby significant treatment related costs and morbidity [73]. Table 2 outlines the spectrum of fungal infections in neutropenic seen in leukemia patients. Although candidiasis and aspergillosis continue to be the predominant pathogens, additional fungi have emerged (Table 2). IFI should be suspected in the setting of persistent fever despite broad spectrum antibiotics.
Candida spp. [74] | Most common IFI infection. Severe immune suppression, broad spectrum antibiotics and central venous catheters are risk factors. Clinical presentation can range from BSI, gastrointestinal candidiasis and acute disseminated candidiasis. |
Trichosporon spp. [75][76] | Unusual fungal infection more often diagnosed per case reports in AML patients. It presents similar to candidemia and may also be associated with skin, kidney and lung findings if disseminated. |
Rare in leukemia, likely due to widespread prophylaxis with fluconazole, but if seen, occurs most often in AML, CLL and CML. Underlying severe T cell depletion, diabetes mellitus and use of steroids are added risk factors. Lung and nervous system often affected. | |
Lungs, sinus and CNS infections often seen. Risk factors include prolonged neutropenia especially AML and steroid use (non neutropenic patients). Lung infections can present as fever, cough, pleuritic chest pain and massive pulmonary hemorrhage. Nodular pneumonia and CT finding of a nodule with a halo sign are characteristic. Serum galactomannan (GM) assay used with variable success in screening and diagnosis. Bronchoalveolar lavage (BAL) galactomannan optical density "/> 3.0 had 100% positive predictive value and less than 0.5 had high negative predictive value. False positive GM may be seen with concomitant administration of piperacillin/tazobactam, severe gastrointestinal mucosal disruption, and pneumocystis ( | |
Zygomycetes [80-82] | Presents similar to aspergillus infections. Pathogenesis involves vascular invasion and tissue infarction manifesting as pulmonary, rhinocerebral and cutaneous infections. May progress rapidly; mortality in excess of 80% in disseminated disease. |
Scedosporium [76)][83] | Can cause skin or pulmonary involvement. Associated with high mortality. Surgical drainage of fluid collections in skin, joint or soft tissue and systemic treatment are the cornerstones of therapy. |
Endemic mycoses [84-88] | Reactivation of endemic fungal infections such as histoplasmosis, blastomycosis and coccidiomycosis can occur in the setting of immune suppression and can occur several years after leaving the region of original infection. Histoplasmosis may present in a disseminated fashion. |
Fungal infections in leukemia
Key points
In neutropenic patients gram negative organisms remain the most frequent pathogens at sites other than blood stream infections.
Gram positive organisms particularly oral commensals emerged as the leading cause of bloodstream infections in the 1980s.
A number of factors such as the increased use of antibiotic prophylaxis and indwelling venous catheters have altered the spectrum of infections in leukemia patients.
Clostridium Difficile infection has emerged as a major cause of morbidity in leukemia patients.
Persistent fever after 4-7 days of broad spectrum antibiotics may indicate occult IFI.
Non- neutropenic patients
Among non-neutropenic patients with leukemia, a number of bacterial, viral, fungal and other opportunistic infections have been described. With the introduction of newer immunosuppressive or more aggressive therapies such as purine analogues, multiagent combination chemotherapy, monoclonal antibodies and steroids, the increased frequency of more atypical infections. With the introduction of newer immunsosuppressive or more aggressive therapies more atypical infections, such as CMV, Pneumocystis jirovecci pneumonia (PJP), liseria meningitis, and IFI have been seen highlighting the need for deliberation when selecting the the appropriate treatment regimen. Individuals at greatest risk of infection include those who have active disease, have undergone multiple previous treatment regimens, and longer disease duration [18].
Among the infections in patients with both acute and chronic leukemia, listeriosis is notable for its predilection for the central nervous system [90, 91]. Listeria is a gram positive bacillus that gains entry into the blood stream via the gastrointestinal tract [90]. Listeriosis can present with bacteremia or with CNS involvement (meningitis [92], meningoencephalitis or cerebritis). Steroid therapy and nucleoside analogs such as fludarabine, which deplete T cells, are treatment associated risk factors [90]. Ampicillin is the drug of choice, although vancomycin, carbapenams, fluoroquinolones and linezolid have good in vitro activity. Among viral infections, herpes virus reactivation is relatively common, with localized Herpes zoster reported more often than [93] disseminated infections [94-96]. In addition, Epstein-Barr virus (EBV) reactivation is important and has been implicated in Richter’s transformation [97].
Tuberculosis is seen in CLL more frequently than in other hematological malignancies [98]. This is especially true for patients treated with fludarabine and the anti-CD52 monoclonal antibody alemtuzumab (as described in section C) [98]. Atypical mycobacterial [99] infection in chronic leukemia is linked to a high mortality especially if disseminated [99-101]. Clinical sites include skin [102,103], lung and multifocal osteomyelitis [104], but occasionally there may be no signs and symptoms other than fever. Bone marrow culture has a high diagnostic yield.
Key points
Non-neutropenic patients with leukemia are susceptible to a host of bacterial, viral, IFI and other opportunistic infections.
Patients with CLL and HCL who have been treated with newer immunosuppressive therapies remain profoundly lymphopenic several months after cessation of therapy and at risk for various opportunistic infections.
Factors associated with increased risk of infection include duration of disease, T cell depletion, active disease and individuals who have undergone multiple prior therapies.
Other emerging pathogens
Unless the treating physician is aware of the pathogenic potential of bacteria widely believed to be harmless in the immunocompetent host, positive culture results may be dismissed as insignificant or as a contaminant.
Alkylating agents and Anthracyclines
Purine and Pyrimidine analogues
Of the
Corticosteroids
Corticosteroids are synthetic analogs of hormones produced in the adrenal cortex and are frequently used in the management of leukemia patients, particularly those with lymphoid malignancies. Despite their widespread benefits, the risk of infections is well known. Steroids impair T cell and neutrophil function, may camouflage classic signs and symptoms of inflammation, and are an independent risk factor for serious opportunistic infections in patients receiving other immunosuppressive therapy such as induction chemotherapy, alkylating agents and nucleoside analogues [17] [89].
A wide spectrum of bacterial, viral (CMV, HSV, VZV), fungal, tubercular and opportunistic infections have been reported in patients treated with chronic steroids [134,135].
Infections associated with corticosteroids are dependent on the route of administration (parenteral worse risk than oral route), dose, and duration of therapy -daily dose greater than 10 mg per day or a cumulative dose of more than 700 mg- as evidenced by data from 71 clinical trials [135]. Unfortunately this analysis excluded trials in which patients were already on antiviral, antibacterial or antifungal prophylaxis, preventative practices common in this group of patients.
Monoclonal antibodies
Tyrosine Kinase inhibitors
Tyrosine kinase inhibitors (TKI) disrupt T-cell receptor mediated T-cell proliferation, activation and selective inhibition of memory CTL responses without interfering with primary T or B cell responses.
Nilotinib
Nilotinib is an orally bioavailable TKI with increased selectivity for bcr-abl relative to other targets such as Src family or c-kit kinases. This probably accounts for the high efficacy of nilotinib without severe myelosuppression [155]. Although all tyrosine kinase inhibitors cause myelosuppression, nilotinib is associated with more garden variety types of infections. In a phase II trial involving 280 patients with CML in chronic phase, grade 3/4 neutropenia (ANC < 1000) was noted in 29% of patients with a median duration of 15 days and need for dose interruptions or modifications in 10% of patients [155].
Key points
Atypical infections are common in patients with CLL and HCL treated with monoclonal antibodies and purine nucleosides.
Alemtuzumab is particularly immunosuppressive and its use requires close monitoring for CMV reactivation as well as prophylaxis for
Concurrent use of steroids significantly increases the risk of infections.
Risk of severe infections may persist for months after cessation of therapy.
The risk of infections in patients with CML receiving TKIs is relatively low.
Neutropenic fever is a medical emergency and thus requires prompt evaluation and initiation of empiric therapy. While a variety of noninfectious causes including transfusion of blood products, medications, and the underlying malignancy itself, may cause fever, the presence of fever should always be presumed to be due to an underlying infection until proven otherwise. Initial evaluation of the neutropenic patient should include a complete history, with special attention given to identifying prior chemotherapies, previous infectious complications, and recent or current prophylactic antimicrobial therapies. A thorough physical examination, blood and bodily fluid cultures -based on clinical suspicion-, and appropriate radiographic imaging are integral to the evaluation of these patients. Clinicians should be aware that in the neutropenic host, signs and symptoms of infection may be blunted by a decreased inflammatory response and therefore, a high index of clinical suspicion is essential for expeditious diagnosis and treatment. For example, only 8% of neutropenic patients with pneumonia produce sputum compared to 84% in non neutropenic patients [64].
In order to better stratify which patients require more intensive management, scoring systems and treatment algorithms have been devised. For example, the Multinational Association for Supportive Care in Cancer (MASCC) scoring system is a well validated tool for risk stratification of febrile neutropenic patients based on the burden of illness (mild, moderate or severe), absence of hypotension, absence of chronic obstructive lung disease, absence of dehydration, age less than 60 years, outpatient status at the time of onset of fever and solid tumor or lymphoma with no previous fungal infection [156,157]. A cumulative score of 20 or more is predictive of a less than 5% chance of developing serious medical complications. This is a valuable tool to identify low risk patients who may be treated as an outpatient [158]. However, it is more common practice to observe the patient in the hospital for at least 24 hours on empiric IV antibiotics to confirm low risk status [159].
Key. points
Patients with neutropenic fever should undergo a rapid and comprehensive evaluation.
MASCC scoring can be used as a general guide to help risk stratify patients and identify those who would benefit from outpatient treatment noting that most leukemia patients are high risk and warrant a period of hospitalization.
The four basic approaches to infections in leukemia patients include
During the 1950s it was not common practice to initiate antibacterial therapy before a specific pathogen was identified [10]. Not surprisingly, this fundamental principle was associated with high mortality rate among neutropenic leukemia patients. Early randomized trials failed to demonstrate improved outcomes with the use of empiric antibiotics in the management of febrile neutropenia [161]. However, shortly thereafter, subsequent studies in leukemia patients showed a significant benefit for patients treated with empiric antibiotic therapy prior to bacteriological data becoming available [162,163]. This established the paradigm of empiric antibiotic use which is still used to guide the initial approach to managing neutropenic leukemia patients. In the setting of neutropenic fever, treatment of the most likely focus should be initiated and include coverage for the most virulent and prevalent pathogens. In the absence of an obvious focus, broad spectrum empiric therapy covering gram positives and gram negatives should be initiated and be guided by institutional protocols based on local resistance patterns pending results of initial tests. Initial combination therapy should take into consideration any recent antibiotic prophylaxis, prior infections including with resistant organisms, presenting signs and symptoms, exam findings, severity of infection, organ function, and co-morbidities.
The three basic antibiotic regimens include: 1) monotherapy with an antipseudomonal beta-lactam such as cefepime, 2) a beta lactam plus an aminoglycoside or a fluoroquinolone, and 3) a glycopeptide in addition to beta lactam monotherapy. Due to the concern for emergence of resistance, vancomycin is not routinely used in the empiric treatment of neutropenic fever unless any of the following criteria are met: positive blood cultures with smears showing gram positive cocci, critically ill patients, presence of skin or soft tissue infection, suspicion of catheter related infection, or known colonization or prior infection with MRSA [2].
There are several options for the treatment of MRSA infection. Vancomycin has been used traditionally for this indication. Vancomycin dosing should be adjusted based on trough levels, with a goal trough of 15-20 mcg/mL.[164] Toxicities associated with high trough levels include renal injury, ototoxicity, and myelosuppresison. Vancomycin should not be used to treat MRSA infection if the MIC of the MRSA is ≥ 2 µg/ml due to a high rate of treatment failure [164]. Daptomycin has become the second-line agent of choice for MRSA infections. Daptomycin can induce eosinophilic pneumonia [165] and has been associated with rhabdomyolysis (package insert). Linezolid has the advantage of good bioavailability after oral administration, but is bacteriostatic against MRSA and therefore, should be used with caution in life-threatening MRSA infections. Myelosuppression, serotonin syndrome when administered concurrently with serotonin uptake inhibitors (SSRI)), and rhabdomyolysis are notable linezolid related toxicities [166,167]. Ceftaroline is a new cephalosporin that has activity against MRSA and is approved for use in skin and soft tissue infections [168]. Doxycycline, TMP/SMX, and clindamycin all possess activity against most MRSA isolates but are traditionally reserved for the treatment of non-life threatening infections such as uncomplicated skin and soft tissue infections.
Even with the initiation of the appropriate empiric antibiotic, it may take days for fevers to abate in neutropenic patients; however, if fevers persist without an obvious focus or culture result after 4-7days of antibacterial therapy, persistent fever atypical organisms and IFI must be considered. In this case, empiric antifungal therapy may be initiated while further diagnostic tests are done. Prompt removal of catheters is essential if suspected to be the source of infection. Due to the widespread use of fluconazole and posaconazole as antifungal prophylaxis, the possibility of azole resistance should be borne in mind. In the treatment of candidemia, IDSA guidelines recommend fluconazole for the less critically ill who have not been exposed to this drug or echinocandins, such as micafungin or caspofungin [169]. Voriconazole or liposomal amphotericin may be used as first line in more critically ill individuals. Voriconazole has emerged as a safe and more efficacious alternative to liposomal amphotericin for the empiric treatment of fungal infections in febrile neutropenia [170] and as the primary therapy of invasive aspergillosis [171] based on two landmark randomized trials. The 2008 IDSA guidelines recommend voriconazole as first line therapy for invasive aspergillosis [2,74]. This drug has high bioavailability in both oral and intravenous forms. For patients who fail voriconazole or therapy is limited by toxicity such as hallucinations, hepatotoxicity, or skin rash, conventional amphotericin B or liposomal preparation can be used [74]. Both forms of amphotericin have similar success rates but the latter has less toxicity allowing for the use of higher doses. Infusional toxicity (fever, chills, and hypotension), potassium and magnesium wasting and frequent renal toxicity are complications of amphotericin.
The three echinocandins in clinical use are caspofungin, micafungin and anidulafungin. This class of medications inhibits the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall [172]. All three drugs are fungistatic against Aspergillus spp although the minimal effective concentration for micafungin and anidulafungin are 2- 10 fold lower than caspofungin [172]. Caspofungin has been approved for use in refractory aspergillosis or invasive disease where other treatment options cannot be tolerated. It has also been used as a single agent in pulmonary aspergillosis in patients with hematological malignancies [173]. Micafungin has a clinical efficacy that is comparable to caspofungin [174]. Unlike, the other echinocandins anidulafungin is unique in that it undergoes elimination by breakdown in the bile rather than via hepatic metabolism [172] and like micafungin has the added advantage of not requiring dose reduction in moderate liver disease [172].
Surgical debridement followed by antifungal treatment for zygomycosis (mucormycosis) with lipid formulations of amphotericin B is the standard of care [74]. Posaconazole is recommended as salvage therapy but not as first line [175]. Voriconazole is the drug of choice in the treatment of scedosporium [176]. The optimal duration of therapy in these infections has not been determined by clinical trials and is largely determined by the treating physician.
Observational studies have indicated increased mortality with delay in starting antifungal therapy [177,178]. The dilemma in initiating prompt antifungal therapy is complicated by the fact that fewer than 5% patients who receive empiric therapy go on to develop or demonstrate evidence of IFI in the first 48 hours [179]. Therefore, with the increasing availability of newer diagnostic techniques in IFI, there is an interest in active surveillance with non-culture based methods and initiation of treatment before the onset of signs and symptoms. This pre-emptive therapy, although being practiced by clinicians, is still considered experimental [180] and the NCCN (National Comprehensive Cancer Network) does not currently recommend pre- emptive therapy due to lack of sufficient evidence to support routine use [181]. However, a number of leukemia centers have adopted prophylactic and empiric treatment strategies which incorporate anti-fungal therapy. Although combination therapy for invasive aspergillosis has shown therapeutic promise in a number of small studies [182,183], this approach has not been validated in large prospective randomized studies and is not currently recommended.
In
Key points:
Empiric treatment with broad spectrum coverage in the absence of an obvious focus should follow institutional guidelines according to local resistance patterns.
Delay in instituting empiric antibiotic and antifungal therapy is associated with worse outcomes.
One should consider IFI if fever persists > 4-7 days in the setting of appropriate broad spectrum antibiotic therapy and negative cultures.
If a source of infection is identified, the therapy should be appropriately tailored/ adjusted.
Preemptive therapy involves active surveillance to detect viral and fungal infections based on rising titers and institution of treatment with onset of symptoms
A number of antifungal therapies are available for the treatment of fungal infections in leukemia patients and should be selected based on the suspected pathogen, severity of illness, and co-morbidities.
Due to the high mortality and costs associated with infections, there is a great interest in preventing them. Various approaches have been adopted and this is an area of active research.
Vaccine based strategies to prevent IFI are hampered by the fact that the population that will most benefit from this approach is able to mount the least immune response.. Torosantucci et al have developed a fungal vaccine consisting of laminarin that was protective against candidiasis and aspergillosis [196]. Currently, developing vaccines for this immunosuppressed patient population remains an active area of research [197].
Key. points
Prophylactic antibiotics, antivirals and antifungals should be given to patients at highest risk for these infections.
The role of IVIG in CLL is controversial and not routinely recommended due to lack of cost effectiveness although moderate reduction in infections have been noted and its use should be considered in patients with hypogammaglobulinemia and recurrent sinopulmonary infections.
Patients with CLL should be vaccinated earlier in their disease to reap maximum benefit due to decline in antibody response with disease duration.
Live virus vaccines should be avoided in immunosuppressed patients.
Growth factors shorten the duration of neutropenia but do not impact mortality.
Infections increase the costs of treatment in patients with leukemia and can drastically influence the economic burden of the disease [198]. There are no recent direct studies that have addressed the economic burden related to infections in patients with leukemia. However, in 2000, aggregate US hospital costs were 2.1 billion dollars with AML being the most costly leukemia followed by ALL, CML and CLL [198]. In patients with CLL, infections have been shown to contribute to higher total cost of care [198]. Patients with leukemia who are critically ill have worse outcomes than non- cancer patients. Relapsed/ refractory status of disease and high Sequential Organ Failure Assessment (SOFA) score (a simple and objective score that allows for calculation of both the number and the severity of organ dysfunction in six organ systems -respiratory, coagulation, liver, cardiovascular, renal, and neurologic) [199] have been found to be predictive of high mortality [200]. Among ICU survivors 1 year mortality for acute leukemia patients is lower than patients with other malignancies [201]. In a study by Thakkar et al evaluating predictors of outcome for patients with acute leukemia admitted to the ICU, respiratory distress was the most frequently observed reason for ICU admission or transfer with the majority requiring ventilator support [202]. The two, six, and twelvemonth overall survival was 24 (27%), 16 (18%), and 14 (16%), respectively. Higher APACHE II score (a severity of disease classification system that helps prognostically risk stratify acutely ill patients) [203], use of vasopressors, undergoing bone marrow transplantation preparative regimen, and adverse cytogenetics were predictors of worse outcomes whereas a new diagnosis of leukemia, type of leukemia and age were not significant. [202].
A study by Schapira in 1993 evaluated the economic cost of survival in patients with hematologic malignancies. Factors noted to be significant for survival included: the nadir platelet count and albumin level prior to and during the ICU stay, the BUN, creatinine, and the need for mechanical ventilation. Seventy-eight percent of patients survived less than five months and spent less than two and a half months at home after discharge. Fifty percent of patients expired during their ICU stay. The cost per year of life gained for the entire group of patients was $189,339 per.admission [204]. However, this study did not differentiate between relapsed/refractory or de novo disease. Documented infection was noted in 54.7% of individuals who expired in the hospital. Among patients who were discharged from the hospital, documented infections were noted in 29.3% of patients who survived for less than 6 months but in only 16% of patients who survived for more than 6 months. Taken together, these studies highlight the impact of infections in leukemia patients, especially those with relapsed/refractory disease, with a direct correlation to hospital mortality and post discharge survival [204].
Careful patient selection improves outcomes without the burden of futile economic costs. It has been recommended that patients with good performance status, where life prolonging treatment options are available- especially patients with new or recent diagnosis of leukemia, should be given the benefit of intensive care support, while patients with poor prognosis who may benefit from a palliative care approach should not. This is often a difficult choice for the treating provider. A middle of the road approach might be to initiate ICU care unless declined by the patient with a goal to regularly reassess the patients wishes and/or condition [205] and proceed to comfort care if continued aggressive therapies are deemed to be of minimal benefit.
Key points
Intensive care costs for treatment of patients with leukemia are significant
Careful selection of patients improves outcomes without adding significantly to economic costs.
Patients with refractory or relapsed leukemia and poor performance status are unlikely to benefit from ICU stay
Identifying low risk patients with neutropenia using MASCC scoring can help minimize the costs of treatment of neutropenic fever.
With rapid advances in diagnostic techniques and availability of newer chemotherapeutic and antibiotic medications in the armamentarium against leukemia, the spectrum of infections continues to change. Clinicians face evolving clinical, diagnostic and ethical challenges to select the most cost effective and evidence based care. The cornerstone of therapy should however be an individualized and patient oriented approach in order to achieve the best outcomes.
The chapter is devoted to the discussion of the telecommunications development strategy. Communication specialists all around the world are facing the problem: how to shift from circuit switching to packet switching. The same problem is the main challenge for the U.S. Department of Defense.
Cyber threats are another hard obstacle in a move to IP world. In October of 2018, the Government Accounting Office (GAO) has reported [2], the United States weapons systems developed between 2012 and 2017 have severe, even “mission critical” cyber vulnerabilities. DoD weapon systems nowadays are more and more software dependent (Figure 1). We observe the weapons, from ships to aircrafts; use more software than even before. For example, the aircraft F-35 Lighting II software contains eight million lines of code [3].
Software and information technology systems in aircraft (shown for classification reasons) [
The rest of paper is as follows. Sections 2 and 3 are about DoD’s strategies “Joint Vision 2010” and “Joint Vision 2020,” respectively. In Sections 4 and 5, we consider the target DISN infrastructure and Joint regional security stacks. In Section 6, the up-to-date JEDI Cloud Strategy and Artificial Intelligence Initiative have given in short. In the concluding Section 7, we point out rather unsuccessful US Army Regulator fights for IP technology. It is exampled by Defense Red Switch Network using 40 years old ISDN technology.
The Defense Information Systems Network (DISN) is a global network. It provides the transfer of various types of information (speech, data, video, multimedia). Its purpose is to provide the effective and secure control of troops, communications, reconnaissance, and electronic warfare.
The new DoD Doctrine [4] had issued by General J. Shalikashvili in 1995. This is the keystone document for Command, Control, Communications, and Computer (C4) systems up to now. At that time, “Joint Vision 2010” doctrine met a strong criticism from the US GAO side [5]. The GAO pointed out that the military services are operating as many as 87 independent networks. DISA initiated a similar data call after GAO survey and identified much more - 153 networks throughout Defense.
General J. Shalikashvili had met the technological uncertainty and the controversial requirements. Under these conditions, DISA (Defense Information Systems Agency) has made a very important decision - to use the “open architecture” and commercial-off-the-shelf (COTS) products only for military communication networks. The decision was – to use widely tested developments of Bell Labs, namely, the telephone signaling protocol SS7 and the Advanced Intelligent Network (AIN). These products were rather ‘old’ at that time: SS7 protocols had developed at Bell Labs since 1975 and defined as ITU standards in 1981.
The details regarding the transition to SS7 and AIN we found in a paper [6] from Lockheed Martin Missiles & Space – the well-known Defense contractor.
SS7 is an architecture for performing out-of-band signaling. In supports the call establishment, routing, and information exchange functions as well as enables network performance. In own order, the Advanced Intelligent Network was originally designed as a critical tool to offer sophisticated services such as “800” calls and directory assistance. The functional structure of the SS7 makes it possible to create the AIN by putting together functional parts: Service Control Point, Service Switching Point, the Service Creation Environment, Service Management System, Intelligent Peripheral, Adjunct, and the Network Access Point. Figure 2 describes the AIN components that operate in the worldwide military telecommunication network, as well as how they are deployed in SS7 backbone, the space Wide Area Network (WAN), circuit switched voice network and the packet switched terrestrial WAN.
Advanced intelligent network military service architecture [
To illustrate the current DISN architecture (Figure 3) we refer to the certification of Avaya PBX by DISA Joint Interoperability Test Command in 2012 [7]. The SS7 network is some kind of the nervous system of DISN up to the resent time. It connects the channel mode MFS (MultiFunctional Switches) and many others network components. That is, within the DISN network, the connections have established by means of SS7 signaling. All new terminal equipment what appears is largely IP type, nevertheless SS7 network retains its central place.
The simplified DISN view: The current state [
Just a few years later as “Joint Vision 2010” had introduced, namely, in 2007 the next Pentagon strategy “Joint Vision 2020” appeared. Pentagon published a fundamental program [8]. There we find the most important point: DISN have been built on basis of IP protocol (Figure 4). IP protocol should be the only means of communication between the network’s transport layer and all available applications. The following 10 years have shown it is an extremely hard challenge.
Joint vision 2020: Each warfare object has own IP address.
To implement Joint Vision 2020, the most important step is the replacing of channel switching electronic Multifunctional switches (MFS) by packet switching routers. The transition to IP protocol has based on the use of Multifunctional SoftSwiches (MFSS) and new signaling protocol AS-SIP (Assured Services Session Initiation Protocol). MFSS operates as a media gateway (MG) between TDM circuits switching and IP packet switching components. During the transition phase, MFSS operates under the control of the media gateway controller (MGC). Communications control protocol H.248 has used between MG and MGC. As shown in Figure 5, MFSS should be pure packet switch besides DRSN ‘island’ using ISDN protocol.
Reference model for multifunction SoftSwitch [
A few words about SIP signaling. The SIP protocol widely used now for internet telephony is not able to provide secrecy during transmission (under cyber warfare conditions) and to provide priority calls. Therefore, the Department of Defense ordered to develop one new secure AS-SIP protocol [10]. The AS-SIP protocol turned out to be extremely difficult. AS-SIP uses the services of almost 200 different RFC standards while ordinary SIP uses only 11 RFC standards.
The aim of “Joint Vision 2020” concept is to implement unified services based on Unified Capabilities concept. Army Unified Capabilities (UC) have defined as the integration of voice, video, and/or data services. These services have delivered across secure and highly available network infrastructure [11].
The following are the basic Voice Features and Capabilities:
Call Forwarding (selective, on busy line, etc.)
Multi-Level Precedence and Preemption (MLPP)
Precedence Call Waiting (Busy with higher precedence call, busy with Equal precedence call, etc.)
Call Transfer (at different precedence levels)
Call Hold and Three-Way Calling and many others.
The Unified Capabilities services are covering a plenty of communication capabilities: from point-to-point to multipoint, voice-only to rich-media, multiple devices to a single device, wired to wireless, non-real time to real time, etc. A collection of services include email and calendaring, instant messaging and chat, unified messaging, video conferencing, voice conferencing, web conferencing (Figure 6).
Rich information services surrounding a soldier: not too much?
The target DISN infrastructure contains two level switching nodes: Tier0 and Tier1 (Figure 7). Top level Tier0 nodes interconnect as geographic cluster and a cluster typically contains at least three Tier0 SoftSwitches. The distance between the clustered SoftSwitches must planned so that the return transmission time does not exceed 40 ms. As propagation delay equals 6 μs/km thus the distance between Tier0 should not exceed 6600 km. The classified signaling environment uses a mix of protocols including the vendor-based H.323 and the AS-SIP signaling. The use of H.323 has allowed only during the transition period to all IP protocol based DISN CVVoIP (Classified VoIP and Video). Classified VVoIP interfaces to the TDM Defense RED Switch Network (DRSN) via a proprietary ISDN PRI as a temporary exception.
DISN classified VoIP and video signaling design [
In October 2010, the US Army Cyber Command had set up. USCYBERCOM is now a part of the Strategic Command along with strategic nuclear forces, missile defense and space forces [13]. One of Cyber Command key tasks is to build Joint Information Environment (JIE) and to implement Single Security Architecture (SSA).
It is worth noting the US Cyber Command activities significantly slow down the transition to IP world. Cyber Command shall receive UC network situational awareness from all network agents including DoD Network Operations Security Centers (NOSCs), and the DISA Network Operation Center (NOC) infrastructure (Figure 8). Thus, DISA and the other DoD Components shall be responsible for end-to-end UC network management providing the strong cybersecurity requirements. The solution of cyber defense tasks radically changes the all DISN network modernization plans.
Operational construct for unified capabilities network operations [
The essence of the Joint Information Environment concept is to create a common military infrastructure, provide corporate services and a unified security architecture. The very concept of JIE is extremely complex, and the requirements of cybersecurity make it even more difficult. According to SSA, Joint regional security stacks (JRSS) are the main components of the JIE environment providing a unified approach to the structure of cybersecurity as well as protecting computers and information networks everywhere in military organizations.
JRSS performs many functions as a typical IP-router providing cybersecurity: firewall functions, intrusion detection and prevention, and a lot other network security capabilities. JRSS equipment contains a complex set of cyber-protection software. For example, the typical NIPR JRSS stack is comprised physically of as many as 20 racks containing cyber-protection software and in real time testing information streams. Currently, JRSS stacks have installed for the NIPRNet (Non-classified Internet Protocol Router Network). It has planned also to install the stacks for the SIPRNet (Secret Internet Protocol Router Network). In 2014, 11 JRSS stacks had installed in the United States, 3 stacks in the Middle East and one in Germany. The total amount of works includes the installation of 23 JRSS stacks on the NIPRNet service network and 25 JRSS stacks on the secret SIPRNet network (Figure 9). By 2019, it has planned to transfer to these stacks all cybersecurity programs. In nowadays, these programs are located in more than 400 places over the world [13].
JRSS current and planned deployments [
The DISN and DoD Component enclaves provide the two main network transport elements of the DODIN (Department of Defense Information Network) with the interconnecting JRSS role as shown in Figure 10.
The leading role of JRSS in DODIN transport [
On June 2012, Lockheed Martin won the largest tender for managing the DISN network - Global Services Management-Operations (GSM-O) project. The essence of the GSM-O contract was to modernize DISN management system taking into account the USCYBERCOM security requirements. The cost of work was 4.6 billion dollars for 7 years.
In 2013, the GSM-O team began to study the current state of the DISN management. There are four management centers: two centers in the US - at the AB Scott (Illinois) and Hickam (Hawaii) and two more - in Bahrain and Germany. They are responsible for the maintenance and uninterrupted operation of all Pentagon computer networks. The work is very laborious: there are 8100 computer systems in more than 460 locations in the world, which in turn have connected by 46,000 cables. The first deal was to consolidate the operating centers - from four to two, namely, to expand the US centers by closing the centers in Bahrain and Germany.
In 2015, the telecommunications world had shocked by the news: Lockheed Martin is not coping with GSM-O project, not able to upgrade of the DISN network management. Lockheed Martin has sold its division “LM Information and Global Solutions” to the competing firm Leidos. One can assume that the failure of the work was most likely due to the inability to recruit developers. New generation of software makers are not familiar with the ‘old’ circuit switching equipment and are not capable to combine it with the latest packet switching systems. The more, they should take into account the never cybersecurity requirements [16].
This failure is much more scandalous. During several last years, the GAO criticized Pentagon’s budget, particularly paying attention to JRSS budget. Many tests regarding JRSS effectiveness were unsuccessful, they were not able to reduce the number of cyber threats [17].
Despite the strong GAO critics, DoD continues the JRSS initiative. DOD stood up 14 of the 25 security stacks planned across the network in the U.S., Europe, and Pacific and southwest regions in Asia. The final security stack has planned for completing by the end of 2019 [18].
Could be fulfilled this Pentagon’s grandiose JRSS plan? The complexity of the task, in particular, characterizes the set of requirements for potential JRSS developers, named in the invitations to work for Leidos. The requirement list includes work experience of 12–14 years and knowledge of at least two or more products from ArcSight, TippingPoint, Sourcefire, Argus, Bro, Fidelis XPS, and other companies. In reality, it is extremely hard work to combine all these software complexes for cyber defense. The more, these high-level software developers should work in top-secret environment.
It turned out that the project has a significant critical flaw: JRSS equipment is too S-L-O-W, the time for information stream processing is too long. It sounds like a sentence on the fate of the JRSS project [19]. Despite of that, the JRSS is going on.
On October 2018, the Defense Information Systems Agency has released a final solicitation for the potential 10-year 6.52 billion dollars project Global Solutions Management-Operations (GSM-O II). The contract winner is Leidos. GSM-O II is a single award contract designed to provide a full global operations and sustainment solution to support DODIN/DISN [20].
The key GSM-O II attributes include the cybersecurity defense of the DISA enterprise infrastructure and Joint Regional Security Stacks aids in the support to enhance the mission (?).
Now we are looking for Leidos success (or failure). It is yet unclear and 10-year period, of course, is a rather long time. Could Leidos cope with GSM-O II?
The Defense Department’s never initiative concerns the cloud strategy. The foundation of cloud initiative is the general-purpose Joint Enterprise Defense Infrastructure (JEDI) [21]. The strategy emphasizes a cloud hierarchy at DOD, with JEDI on top. Many fit-for-purpose military clouds, which include MilCloud 2.0 run by DISA, will be secondary to the JEDI general-purpose cloud.
On April 10, 2019, the Department of Defense confirms that Amazon and Microsoft are the cloud contract winners. The competitors Oracle and IBM are officially out of the race for a key 10 billion dollars defense cloud contract.
Could be the JEDI Cloud Strategy successful? A key technological difficulty for the JEDI project is interoperability of clouds (Figure 11). The Pentagon’s JEDI cloud strategy leaves a series of unanswered questions that could be reasons for disasters in the future [22].
DoD pathfinder to hybrid cloud environments [
For internal interoperability, the strategy lays out the correct goal, common data and application standards. There are the 500+ clouds already used within the Pentagon. They have own data formats. Now they need to migrate and interoperate onto the unique JEDI platform.
The next unanswered question regards the JEDI cloud’s external interoperability. It concerns a future conflict situation. Would America’s allies need to use the same cloud provider (e.g., Microsoft) and the same data-formatting practices as the DoD? The strategy does not discuss these long-term issues.
The cloud strategy has started in 2015 by establishing the Defense Innovation Unit (DIU). This DoD organization has founded to help the US military make easier and faster use of innovative commercial technologies. The organization has headquartered in Silicon Valley (California) with offices in Boston, Austin, and some more. The next step – the establishing of Joint Artificial Intelligence Center as a focal point of the DoD Artificial Intelligence Strategy [23].
Taking into account the potential magnitude of Artificial Intelligence’s impact on the whole of society, and the urgency of this emerging technology international race, President Trump signed the executive order “Maintaining American Leadership in Artificial Intelligence” on February 11, 2019. That document has launched the American AI Initiative. This was immediately followed by the release of DoD’s first-ever AI strategy [24].
Artificial intelligence - this is really one great idea, if it happens be successful. Could it have more success than JRSS initiative?
US Army Regulator fights for IP technology but, honesty speaking, unsuccessfully. The Army regulator recognizes in 2017 [25] that there is ‘old’ equipment on the network: time-division multiplex equipment, integrated services digital networking, channel switching video telecommunication services. According to the document [25], all these services will use IP technology, at least, in the nearest future. As an example, name the instructive claim regarding DRSN:
4–2.d. Commands that have requirements to purchase or replace existing Multilevel Secure Voice (previously known as Defense Red Switched Network (DRSN)) switches will provide a detailed justification and impact statement to the CIO/G–6 review authority.
In conditions of cyberwar, no reason to be surprised that the Defense Red Switch Network (DRSN) will use 40 years old ISDN technology for long time yet, the more – in conditions of cyberwar. DRSN is a dedicated telephone network, which provides global secure communication services for the command and control structure of both the United States Armed Forces and the NATO Allies (Figure 12). The network has maintained by DISA and has secured for communications up to the level of Top Secret.
Secure terminal equipment; note slot in front for crypto PC card (left). The DRSN architecture (right) [
“Red Phone” (Secure Terminal Equipment, STE) uses ISDN line for connections to the network. “Red Phone” operates at a speed of 128 kbps. There is the slot at the bottom right serving for a crypto-card and four buttons at the top - to select the priority of communications. The STE is the primary device for enabling security. It may be used for secure voice, data, video, or facsimile services.
As we have mentioned above citing the AT&T view [1], the DoD today still has analog, fixed, premises-based, time-division multiplexing and seems could remain for unpredictable period according to the well-known software developers slogan: “Don’t touch what works”. In conditions of cyberwar, the very transition to internet technologies in telecommunications seems doubtful. Thus, we conclude that the long-term channel-packet coexistence seems inevitable, especially in the face of growing cyber threats.
AI | artificial intelligence |
AIN | advanced intelligent network |
AS-SIP | assured services session initiation protocol |
CS | capability set |
DISA | defense information systems agency |
DISN | defense information systems network |
DoD | department of defense |
DODIN | department of defense information network |
DRSN | defense red switched network |
GAO | Government Accounting Office |
IP | internet protocol |
ISDN | integrated services digital network |
JEDI | joint enterprise defense infrastructure |
JIE | joint information environment |
JRSS | joint regional security stack |
MFS | multifunctional switch |
MFSS | multifunctional softswich |
MG | media gateway |
MGC | media gateway control |
NIPRNet | non-classified internet protocol router network |
RFC | request for comments |
SIP | session initiation protocol |
SIPRNet | secret internet protocol router network |
SS7 | signaling system protocol #7 |
SSA | single security architecture |
UC | unified capabilities |
TDM | time division multiplexing |
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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Fuchs"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6210",title:"Thalassemia and Other Hemolytic Anemias",subtitle:null,isOpenForSubmission:!1,hash:"857e8a4bff6f78189f15a00423bde1a6",slug:"thalassemia-and-other-hemolytic-anemias",bookSignature:"Isam AL-Zwaini",coverURL:"https://cdn.intechopen.com/books/images_new/6210.jpg",editedByType:"Edited by",editors:[{id:"30993",title:"Prof.",name:"Isam Jaber",middleName:null,surname:"Al-Zwaini",slug:"isam-jaber-al-zwaini",fullName:"Isam Jaber Al-Zwaini"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6439",title:"Hematology",subtitle:"Latest Research and Clinical Advances",isOpenForSubmission:!1,hash:"38a4394f1ec01ccab623df90e56e5992",slug:"hematology-latest-research-and-clinical-advances",bookSignature:"Margarita Guenova 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Abdelaal",coverURL:"https://cdn.intechopen.com/books/images_new/832.jpg",editedByType:"Edited by",editors:[{id:"106431",title:"Dr.",name:"Mohamed A.",middleName:null,surname:"Abdelaal",slug:"mohamed-a.-abdelaal",fullName:"Mohamed A. Abdelaal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1830",title:"Hematology",subtitle:"Science and Practice",isOpenForSubmission:!1,hash:"5bcd8875467e51b02e0ea4aec429ad51",slug:"hematology-science-and-practice",bookSignature:"Charles H. Lawrie",coverURL:"https://cdn.intechopen.com/books/images_new/1830.jpg",editedByType:"Edited by",editors:[{id:"103158",title:"Dr.",name:"Charles",middleName:null,surname:"Lawrie",slug:"charles-lawrie",fullName:"Charles Lawrie"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:9,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"31178",doi:"10.5772/38961",title:"Physiological Factors in the Interpretation of Equine Hematological Profile",slug:"haematological-profile-of-the-horse-phisiological-factors-influencing-equine-haematology",totalDownloads:10779,totalCrossrefCites:15,totalDimensionsCites:35,abstract:null,book:{id:"1830",slug:"hematology-science-and-practice",title:"Hematology",fullTitle:"Hematology - Science and Practice"},signatures:"K. Satué, A. Hernández and A. Muñoz",authors:[{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo"}]},{id:"37047",doi:"10.5772/32080",title:"Microparticles: Role in Haemostasis and Venous Thromboembolism",slug:"microparticles-role-in-haemostasis-and-venous-thromboembolism",totalDownloads:2455,totalCrossrefCites:0,totalDimensionsCites:4,abstract:null,book:{id:"832",slug:"pathophysiology-and-clinical-aspects-of-venous-thromboembolism-in-neonates-renal-disease-and-cancer-patients",title:"Pathophysiology and Clinical Aspects of Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients",fullTitle:"Pathophysiology and Clinical Aspects of Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients"},signatures:"Anoop K. Enjeti and Michael Seldon",authors:[{id:"90071",title:"Dr.",name:"Anoop",middleName:null,surname:"Enjeti",slug:"anoop-enjeti",fullName:"Anoop Enjeti"},{id:"151786",title:"Dr.",name:"Michael",middleName:null,surname:"Seldon",slug:"michael-seldon",fullName:"Michael Seldon"}]},{id:"59051",doi:"10.5772/intechopen.70937",title:"Acute Myeloid Leukemia in Pediatric Patients: A Review About Current Diagnostic and Treatment Approaches",slug:"acute-myeloid-leukemia-in-pediatric-patients-a-review-about-current-diagnostic-and-treatment-approac",totalDownloads:1565,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"Acute leukemia is the most common childhood malignancy, accounting for almost 35% of all childhood cancers. Acute myeloid leukemia (AML) represents 15–20% of pediatric acute leukemia. Majority of AML cases appear de novo, however a minority of cases can present as a secondary malignancy. AML is a highly heterogeneous disease and its diagnosis involves a combination of diagnostic analyses including morphology, immunophenotyping, cytochemistry, and leukemic blasts derived from peripheral blood or bone marrow demonstrating cytogenic and molecular characteristics. Through the identification of recurrent genetic mutations, it has been made possible to refine individual prognosis and guide therapeutic management. The current survival rate of children with AML is approximately 70%. The standard therapeutic regimen is a combination of cytarabine- and anthracycline-based regimens with allogenic stem cell transplantation in appropriate patients. Relapse in pediatric patients suffering from AML occurs in approximately 30% of cases, whereas death occurs in 5–10% of patients as a result of disease complications or chemotherapeutic side effects. In understanding the genetic basis of AML, targeted therapies will have the ability to reduce treatment-related morbidity and mortality. Here, we provide a comprehensive review of AML, its biology, diagnosis and therapeutic management in pediatric patients.",book:{id:"6261",slug:"myeloid-leukemia",title:"Myeloid Leukemia",fullTitle:"Myeloid Leukemia"},signatures:"Katarzyna Derwich, Dorothy Mitkowski and Jolanta Skalska-\nSadowska",authors:[{id:"205540",title:"Dr.",name:"Katarzyna",middleName:null,surname:"Derwich",slug:"katarzyna-derwich",fullName:"Katarzyna Derwich"},{id:"214057",title:"Dr.",name:"Dorothy",middleName:null,surname:"Mitkowski",slug:"dorothy-mitkowski",fullName:"Dorothy Mitkowski"},{id:"214058",title:"Dr.",name:"Jolanta",middleName:null,surname:"Skalska-Sadowska",slug:"jolanta-skalska-sadowska",fullName:"Jolanta Skalska-Sadowska"}]},{id:"61695",doi:"10.5772/intechopen.76931",title:"Angiogenesis and Antiangiogenesis in Multiple Myeloma",slug:"angiogenesis-and-antiangiogenesis-in-multiple-myeloma",totalDownloads:1183,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"Multiple myeloma progression is characterized by a dense interaction between cancer cells and bone marrow microenvironment. The interactions of myeloma cells with various stromal cells and extracellular matrix components are the main regulator of the biological processes that underlie the progression of the disease and of the classic symptomatology correlated. The bone marrow of myeloma patients has recognized autocrine and paracrine loops that regulate multiple signaling pathways and the malignant phenotype of plasma cells. One of the pivotal biological processes which are responsible for myeloma progression is the formation of new vessels from existing ones, known as angiogenesis. It represents a constant hallmark of disease progression and a characteristic feature of the active phase of the disease. Near angiogenesis, other two ancestral processes were active in the bone marrow: vasculogenesis and vasculogenic mimicry. These processes are mediated by the angiogenic cytokines, interleukins, and inflammatory cytokines directly secreted by plasma cells and stromal cells. Neovascularization is also mediated by direct interaction between plasma cells and the various components of bone marrow microenvironment. The observation of the increased bone marrow angiogenesis in multiple myeloma and its correlation with disease activity and overall survival led to consider angiogenesis as a new target in the treatment of multiple myeloma.",book:{id:"6710",slug:"update-on-multiple-myeloma",title:"Update on Multiple Myeloma",fullTitle:"Update on Multiple Myeloma"},signatures:"Roberto Ria, Antonio Solimando, Assunta Melaccio, Azzurra\nSportelli and Angelo Vacca",authors:null},{id:"31163",doi:"10.5772/35840",title:"Intravascular Leukocyte Chemotaxis: The Rules of Attraction",slug:"intravascular-leukocyte-chemotaxis-the-rules-of-attraction",totalDownloads:2342,totalCrossrefCites:1,totalDimensionsCites:4,abstract:null,book:{id:"1830",slug:"hematology-science-and-practice",title:"Hematology",fullTitle:"Hematology - Science and Practice"},signatures:"Sara Massena and Mia Phillipson",authors:[{id:"106058",title:"Dr.",name:"Mia",middleName:null,surname:"Phillipson",slug:"mia-phillipson",fullName:"Mia Phillipson"},{id:"106366",title:"Dr.",name:"Sara",middleName:null,surname:"Massena",slug:"sara-massena",fullName:"Sara Massena"}]}],mostDownloadedChaptersLast30Days:[{id:"64871",title:"Diagnosis and Classification of Myelodysplastic Syndrome",slug:"diagnosis-and-classification-of-myelodysplastic-syndrome",totalDownloads:3255,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by morphological dysplastic changes in one or more of the major hematopoietic cell lines. MDS can present with varying degrees of single or multiple cytopenias including neutropenia, anemia and thrombocytopenia. Presentation of MDS can range from asymptomatic to life threatening. MDS diagnosis and classification present important challenges, particularly in the distinction from benign conditions. French-American-British (FAB) classification proposed a classification based on easily obtainable laboratory information and was recommended in early and as modified by guidelines of new classification of World Health Organization (WHO). The strategy of diagnostic laboratory in MDS depends on morphological changes and is based on existence of dysplastic changes in the peripheral blood and bone marrow including peripheral blood smear, bone marrow aspirate smear and bone marrow trephine biopsy. The correct morphological interpretation and the use of cytogenetics, immunophenotyping, immunohistochemistry and molecular analysis will give valuable information on diagnosis and prognosis.",book:{id:"7138",slug:"recent-developments-in-myelodysplastic-syndromes",title:"Recent Developments in Myelodysplastic Syndromes",fullTitle:"Recent Developments in Myelodysplastic Syndromes"},signatures:"Gamal Abdul Hamid, Abdul Wahab Al-Nehmi and Safa Shukry",authors:[{id:"36487",title:"Prof.",name:"Gamal",middleName:null,surname:"Abdul Hamid",slug:"gamal-abdul-hamid",fullName:"Gamal Abdul Hamid"},{id:"273724",title:"Dr.",name:"Safa",middleName:null,surname:"Shukry",slug:"safa-shukry",fullName:"Safa Shukry"},{id:"277511",title:"Dr.",name:"Abdulwahab",middleName:null,surname:"Al-Nehmi",slug:"abdulwahab-al-nehmi",fullName:"Abdulwahab Al-Nehmi"}]},{id:"60442",title:"Invasive and Noninvasive Approaches in Prenatal Diagnosis of Thalassemias",slug:"invasive-and-noninvasive-approaches-in-prenatal-diagnosis-of-thalassemias",totalDownloads:1778,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Thalassemia is a significant health problem worldwide. There are two main classifications, α- and β-thalassemias, which are usually caused by the defective synthesis of the α-globin, and which are commonly caused by different mutations of the β-globin chain. Different hemoglobin mutations have been identified to date. Thalassemias can result in profound anemia from early life and, if not treated with regular blood transfusions, can lead to death in the first year. Prenatal diagnosis of thalassemia is the essential part of preventive medicine and is currently dependent on the use of invasive diagnostic tests within the first 2 months of pregnancy. These diagnostic techniques carry a small but significant risk of fetal loss up to 1%. Molecular diagnostic methods have been developed for genotyping thalassemias based on PCR techniques and high-throughput technologies. Noninvasive tests using cell-free DNA (cfDNA) from a maternal blood sample is also an alternative method, thus eliminating the risk of miscarriage. This chapter summarizes the current invasive approaches and the noninvasive methods using cell-free fetal DNA as new molecular diagnostic methods for genotypic diagnosis of thalassemia in clinical practice. Prevention strategies that encompass carrier screening, genetic counseling, and prenatal diagnosis are discussed.",book:{id:"6210",slug:"thalassemia-and-other-hemolytic-anemias",title:"Thalassemia and Other Hemolytic Anemias",fullTitle:"Thalassemia and Other Hemolytic Anemias"},signatures:"Abdullah Tuli and Ebru Dündar Yenilmez",authors:[{id:"183998",title:"Ph.D.",name:"Ebru",middleName:null,surname:"Dündar Yenilmez",slug:"ebru-dundar-yenilmez",fullName:"Ebru Dündar Yenilmez"},{id:"215677",title:"Prof.",name:"Abdullah",middleName:null,surname:"Tuli",slug:"abdullah-tuli",fullName:"Abdullah Tuli"}]},{id:"62044",title:"Sickle Cell Disease: A Genetic Disorder of Beta-Globin",slug:"sickle-cell-disease-a-genetic-disorder-of-beta-globin",totalDownloads:1816,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Sickle cell disease (SCD) is a structural and monogenetic genetic disorder due to a mutation that occurs in the globin β-chain, resulting in the formation of hemoglobin S (Hb S), a protein composed of two normal, and two β-type mutant chains. Estimates indicate that the prevalence among live births is 4.4% in the world. The difficulty in circulating the sickle cell, its interaction with endothelial cells, leukocytes, platelets, endothelial dysfunction, and the abnormal expression of adhesion molecules permeate the beginning of the blood vessel occlusion process as well as pathophysiological aspects of SCD. Among the secondary complications are the stroke, pulmonary hypertension, leg ulcer, renal disorders, and all complications associated with vascular dysfunction. Clinical and biochemical markers of disease severity can be used to predict risk, prevent complications, and increase the expectation and quality of life of the SCD population. The entire scenario generated by Hb S has implications for the health and social inclusion of patients, so the treatment of the person with SCD needs an approach focused on the prevention of these complications in an individualized way.",book:{id:"6210",slug:"thalassemia-and-other-hemolytic-anemias",title:"Thalassemia and Other Hemolytic Anemias",fullTitle:"Thalassemia and Other Hemolytic Anemias"},signatures:"Karen Cordovil",authors:[{id:"228575",title:"M.D.",name:"Karen",middleName:null,surname:"Cordovil",slug:"karen-cordovil",fullName:"Karen Cordovil"}]},{id:"66394",title:"Diffuse Large B-Cell Lymphoma",slug:"diffuse-large-b-cell-lymphoma",totalDownloads:2482,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Diffuse large B-cell lymphoma (DLBCL) is a heterogenous class of aggressive lymphoma and is considered as the most common subtype of non-Hodgkin lymphomas (NHL). Several genetic anomalies such as point mutations, numerical alterations, and, more rarely, translocations and gene amplifications play a role in the pathogenesis of this class of B-cell lymphoma and have been related to specific histological and immunophenotypic subtypes. On the other hand, the treatment protocol in DLBCL did not witness significant changes during the last two decades. The widespread adoption of rituximab as an important adjuvant to standard chemotherapy protocol in CD20+ cases was a notable exception, which provided significant improvement in disease-free survival and overall survival, with limited toxicity. However, no less than 20% of patients diagnosed with DLBCL exhibit relapse after the initial response to R-CHOP regimen, while more than 15% of the patients exhibit primary refractory disease. This is the reason why a review of all the morphological, clinical, and therapeutic particularities of DLBCL is required.",book:{id:"8316",slug:"normal-and-malignant-b-cell",title:"Normal and Malignant B-Cell",fullTitle:"Normal and Malignant B-Cell"},signatures:"Patrascu Ana Maria, Ionela Rotaru, Valeriu Surlin and Stefan Patrascu",authors:[{id:"158096",title:"Associate Prof.",name:"Valeriu",middleName:null,surname:"Surlin",slug:"valeriu-surlin",fullName:"Valeriu Surlin"},{id:"194539",title:"Dr.",name:"Stefan",middleName:null,surname:"Patrascu",slug:"stefan-patrascu",fullName:"Stefan Patrascu"},{id:"290810",title:"Dr.",name:"Ana Maria",middleName:null,surname:"Patrascu",slug:"ana-maria-patrascu",fullName:"Ana Maria Patrascu"},{id:"292959",title:"Dr.",name:"Ionela",middleName:null,surname:"Rotaru",slug:"ionela-rotaru",fullName:"Ionela Rotaru"}]},{id:"61929",title:"Idiosyncratic Drug-Induced Severe Neutropenia and Agranulocytosis: State of the Art",slug:"idiosyncratic-drug-induced-severe-neutropenia-and-agranulocytosis-state-of-the-art",totalDownloads:1621,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"In this chapter, we report and discuss the diagnosis and management of idiosyncratic drug-induced, or drug-associated, severe neutropenia, and agranulocytosis (neutrophil count of <0.5 × 109/L). In this setting, neutropenia remains a potentially serious adverse event due to the frequency of severe sepsis, with severe deep tissue infections (e.g., pneumonia), life-threatening infections, septicemia, and septic shock in two-thirds of all hospitalized patients. Recently, several poor prognostic factors, impacting the hematological recovery, the duration of hospitalization, and the outcome have been identified that may be helpful when identifying “frailty” patients. These factors include: old age, poor performance status, septicemia or shock, comorbidities such as renal failure, and a neutrophil count below 0.1 × 109/L. recovery. In this situation, modern management, with broad-spectrum antibiotics in case of any sepsis sign and hematopoietic growth factors (HGF) (particularly G-CSF), is likely to improve the prognosis, with a current mortality rate around 5%.",book:{id:"6439",slug:"hematology-latest-research-and-clinical-advances",title:"Hematology",fullTitle:"Hematology - Latest Research and Clinical Advances"},signatures:"Emmanuel Andrès and Rachel Mourot-Cottet",authors:[{id:"143493",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Andrès",slug:"emmanuel-andres",fullName:"Emmanuel Andrès"}]}],onlineFirstChaptersFilter:{topicId:"1026",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:140,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"July 5th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). In addition to a number of research articles, he has written two books, Computational Intelligence: An Introduction and Fundamentals of Computational Swarm Intelligence.",institutionString:null,institution:{name:"Stellenbosch University",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",isOpenForSubmission:!0,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null},{id:"27",title:"Multi-Agent Systems",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",isOpenForSubmission:!0,editor:{id:"148497",title:"Dr.",name:"Mehmet",middleName:"Emin",surname:"Aydin",slug:"mehmet-aydin",fullName:"Mehmet Aydin",profilePictureURL:"https://mts.intechopen.com/storage/users/148497/images/system/148497.jpg",biography:"Dr. Mehmet Emin Aydin is a Senior Lecturer with the Department of Computer Science and Creative Technology, the University of the West of England, Bristol, UK. His research interests include swarm intelligence, parallel and distributed metaheuristics, machine learning, intelligent agents and multi-agent systems, resource planning, scheduling and optimization, combinatorial optimization. Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. He has served as guest editor for a number of special issues of peer-reviewed international journals.",institutionString:null,institution:{name:"University of the West of England",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:20,paginationItems:[{id:"82526",title:"Deep Multiagent Reinforcement Learning Methods Addressing the Scalability Challenge",doi:"10.5772/intechopen.105627",signatures:"Theocharis Kravaris and George A. Vouros",slug:"deep-multiagent-reinforcement-learning-methods-addressing-the-scalability-challenge",totalDownloads:19,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Multi-Agent Technologies and Machine Learning",coverURL:"https://cdn.intechopen.com/books/images_new/11445.jpg",subseries:{id:"27",title:"Multi-Agent Systems"}}},{id:"82196",title:"Multi-Features Assisted Age Invariant Face Recognition and Retrieval Using CNN with Scale Invariant Heat Kernel Signature",doi:"10.5772/intechopen.104944",signatures:"Kamarajugadda Kishore Kumar and Movva Pavani",slug:"multi-features-assisted-age-invariant-face-recognition-and-retrieval-using-cnn-with-scale-invariant-",totalDownloads:14,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"82063",title:"Evaluating Similarities and Differences between Machine Learning and Traditional Statistical Modeling in Healthcare Analytics",doi:"10.5772/intechopen.105116",signatures:"Michele Bennett, Ewa J. Kleczyk, Karin Hayes and Rajesh Mehta",slug:"evaluating-similarities-and-differences-between-machine-learning-and-traditional-statistical-modelin",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Machine Learning and Data Mining - Annual Volume 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11422.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"81791",title:"Self-Supervised Contrastive Representation Learning in Computer Vision",doi:"10.5772/intechopen.104785",signatures:"Yalin Bastanlar and Semih Orhan",slug:"self-supervised-contrastive-representation-learning-in-computer-vision",totalDownloads:59,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}}]},overviewPagePublishedBooks:{paginationCount:9,paginationItems:[{type:"book",id:"7723",title:"Artificial Intelligence",subtitle:"Applications in Medicine and Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7723.jpg",slug:"artificial-intelligence-applications-in-medicine-and-biology",publishedDate:"July 31st 2019",editedByType:"Edited by",bookSignature:"Marco Antonio Aceves-Fernandez",hash:"a3852659e727f95c98c740ed98146011",volumeInSeries:1,fullTitle:"Artificial Intelligence - Applications in Medicine and Biology",editors:[{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}}]},{type:"book",id:"7726",title:"Swarm Intelligence",subtitle:"Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/7726.jpg",slug:"swarm-intelligence-recent-advances-new-perspectives-and-applications",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Javier Del Ser, Esther Villar and Eneko Osaba",hash:"e7ea7e74ce7a7a8e5359629e07c68d31",volumeInSeries:2,fullTitle:"Swarm Intelligence - Recent Advances, New Perspectives and Applications",editors:[{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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