Global prevalence of PIDs reported by Jeffrey Modell Centers Network [5].
\\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
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\r\n\r\n\tThe following chapters will offer an overview of the most predominant presentations of Personality disorders in clinical practice, namely the Borderline, Narcissistic, Schizoid and Antisocial types. Case studies arising from clinical practice will be presented and the chapters will offer a comprehensive discussion of the processes and treatment outcomes of various psychotherapeutic models employed in treatment.
\r\n\r\n\tThe final chapter is dedicated to broader manifestations of Personality Disorders and their associated clinical presentations which may have not received sufficient clinical attention, arising challenges and treatment approaches.
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Academically she is based at London Metropolitan University where she holds a Senior Lecturer post in Counselling Psychology. Clinically, she is a Lead Psychologist in the NHS where she practices in the area of substance misuse and clinical neuropsychology. She has over 15 years of clinical experience in various clinical settings in the UK and she specializes in Psychodynamic, CBT and integrative models of practice. 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The diseases are often accompanied by a predisposition to autoimmune disorders, autoinflammation, atopy, and malignancy [1, 2, 3, 4]. Unlike secondary immunodeficiency acquired from other diseases or conditions such as malnutrition, immunosuppression, or HIV infections, PIDs are triggered by genetic defects. Based on the abnormality of one or more components of human immunity, PIDs can be divided into antibody deficiencies, combined T- and B-cell deficiencies, deficiencies in the phagocytic or complement system, and immune dysregulation [1]. Diagnosis of these disorders requires good clinical awareness and specialized laboratory testing. Flow cytometry and genetic testing are essential to identify the phenotypic and genetic defects of the diseases and to confirm the diagnosis. Accurate diagnosis and efficient management are important for reducing morbidity and mortality in patients with PID [2]. The chapter provides an overview of the classification and manifestation as well as the diagnosis and management of these disorders.
Individual type of PIDs is considered to be rare in the population; however, recent studies have shown that PIDs may be more common than previously estimated 1% of the population when all varieties are combined [5]. The prevalence of PIDs varies depending on the type of immunodeficiencies and is difficult to be precisely calculated as the number of diagnosed cases is rapidly increasing. A 2018 global survey from the Jeffrey Modell Centers Network (JMCN) reported the case of PID patients followed in the JMCN increased by 35.4% to 102,097, while the case of patients identified with a specific gene defect increased 21.8% to 67,308 during the same period [5]. Up to 2018, 354 distinct disorders with 344 different gene defects were recognized [6]. Of note, most of the cases reported are from developed countries. It is estimated that 70–90% of individuals living with a PID are undiagnosed [7], particularly in the area with poor medical condition and lacking laboratory resources. With the extensive application of exome or whole genome sequencing, it was predicted that the associated PID genetic defects would reach 1000 under current trend in next decade [5]. Table 1 listed the reported number of 18 most common PID defects among 354 inborn errors of immunity [5]. As shown, antibody deficiencies have much higher occurrence rate against other types of the disorders. Studies also showed that the selective IgA deficiency has the highest prevalence worldwide with a range from 1 in 223 to 1 in 1000 depending on ethnic background [8], while severe combined immunodeficiency (SCID), although fatal, is much rarer (1 in 100,000) [9, 10].
Global prevalence of PIDs reported by Jeffrey Modell Centers Network [5].
The classification of PIDs is generally based on the defects of the major components of human immunity, such as innate/adaptive immunodeficiencies, phagocytic deficiencies, complement deficiencies, and immune dysregulation. The classification has evolved over time with more phenotypic and genetic defects identified [4, 11].
The International Union of Immunological Societies (IUIS) expert committee, currently named as Inborn Errors of Immunity Committee, has been responsible for issuing the classification of PIDs every other year from 1970. The complete catalog of classification has now been widely used as a reference by clinicians and researchers. From 2013, IUIS published more user-friendly phenotypic classification in two formats: one is a pdf file, namely clinically oriented phenotype categorization in the Journal of Clinical Immunology, and the other is a csv file containing a comprehensive list of various disorders that can be downloaded from http://www.iuisonline.org [6, 11]. The phenotypic categorization published in the journal has been well designed for clinical use, while the online list contains the most updated information demonstrated in a digital friendly excel format that can be sorted by phenotypic and genetic features, which are very useful for designing sequencing panels, disease code lists, and diagnostic algorithms.
The major category and subcategory of PIDs from the revised 2017 IUIS phenotypic classification are summarized in Table 2.
Patients with PID present highly heterogeneous clinical symptoms with increased susceptibility to infections and other immune complications [12, 13]. Recurrent infection is the hallmark of the PIDs although a variety of other clinical manifestations may appear before the infection [13, 14]. In fact, noninfectious manifestations, such as gastrointestinal disorders, hematological diseases, autoimmune/autoinflammatory conditions, atopy or malignancy, can be the predominant clinical presentations in some patients with underlying immunodeficiency [3, 15]. Furthermore, patients with PID also demonstrate overlapping symptoms and share similarities with many “routine” diseases.
Majority of patients with PID suffer mild to severe or life-threatening infections. The unique clinical characteristics of infections in PIDs are recurring, chronic, and can appear in multiple anatomic sites. Recurrent infections in both the sinuses and the respiratory tract, such as sinusitis, bronchitis, otitis, and pneumonia, are the most frequent symptoms observed in patients with PID [16], while recurrent systemic infections (e.g., meningitis and bacteremia) are also not rare [17, 18]. Patients with SCID may suffer from unusual or opportunistic infections leading to unexpected complications or death [19].
Autoimmune and autoinflammatory disorders are more frequently seen in some categories of the PIDs than in other diseases [20]. The associated conditions in PID individuals may present in a single tissue or organ, such as autoimmune hemolytic anemia, thrombocytopenia, and autoimmune thyroiditis, or affect multiple organs, exemplified by an related vasculitis, or resemble rheumatic symptoms such as (e.g., dermatomyositis, rheumatoid arthritis, and systemic lupus erythematosus) [3, 20, 21]. To note, family members that carry the same gene mutation may present different types of autoimmune/autoinflammatory symptoms, or without such disorders [22]. In comparison with other types of defects, the autoimmune presentations are relatively common in PIDs with antibody deficiencies (e.g., CVID, selective IgA deficiency), and absence of initial components (C1–C4) of the classical complement system [23, 24].
Patients with PID, particularly infants and young children, may manifest chronic diarrhea, malnutrition, and malabsorption. Some individuals may undergo infections in gastrointestinal tract, such as chronic giardiasis and rotavirus [25], while others may experience a variety of autoimmune or autoinflammatory disorders including inflammatory bowel disease, atrophic gastritis with pernicious anemia, or gluten-sensitive enteropathy [20].
Hematological disorders, such as autoimmune hemolytic anemia, and/or neutropenia and/or thrombocytopenia, are also frequently seen in patients with CVID or selective IgA deficiency [26]. Patients with the Wiskott-Aldrich syndrome, a disease characterized by variable defects in B- and T-lymphocyte function, can present with reduced platelet volume and significant thrombocytopenia [27].
PID patients may also present with a syndrome complex. For example, recurrent bacterial/fungal infections and chronic inflammation of the gastrointestinal and respiratory tract often present in patients with chronic granulomatous disease, while an individual suffering from Wiskott-Aldrich syndrome may have manifestations of eczema, recurrent bacterial infections, autoimmune disorders, and thrombocytopenia [27]. In addition, congenital heart disease and hypocalcemic tetany frequently appear in a newborn baby with the DiGeorge syndrome [28, 29]. In fact, the investigation of patients with a syndrome derived from immunodeficiency may trigger an early diagnosis of PID before the typical immunodeficiency symptoms appear [4].
Compared to individuals with a healthy immune system, patients with PID are expected to have higher prevalence and/or broader spectrum of malignancies [30]. A study showed that lymphoma, the most common malignancy seen in PID patients, has increased 10-folds in male and 8.34-folds in female compared to age-matched controls [31]. Other types of cancer with higher frequency in PIDs are leukemia, digestive tract cancers, and virus-induced cancers [30]. Interestingly, the four most common cancers routinely occurred in men and women (lung, colon, breast, and prostate cancers) do not have significant elevation in subjects diagnosed with PID [31]. Evidence also demonstrated that patients with specific forms of immunodeficiency caused by highly penetrant gene defects have higher risk of developing cancer [32].
Early diagnosis of PID is critical for reducing morbidity or mortality and improving treatment outcomes. Review of clinical and family history and physical examination are the first steps in evaluating the need for further laboratory investigation.
The differentiation of PIDs from other medical conditions can be complicated as the symptoms of infection (e.g., sinusitis, bronchitis, pneumonia, gastroenteritis, meningitis, or sepsis) and other manifestations often present in patients with non-PID. Hence, it is important to delineate the infectious organisms, the pattern of infections, and clinical pictures for guiding the clinical judgment, prior to focusing on laboratory testing.
Due to the highly variable clinical presentations and low frequency of the PIDs, the diagnosis of patients is often delayed for years. To raise clinical awareness, JMCN has promoted 10 warning signs for children and adults (Table 3). Patients presenting with two or more of the clinical warning signs should be prompted for further investigation for the possible underlying immunodeficiencies and referred to immunologists for proper disease management.
Clinical warning signs of PIDs.
The laboratory testing is essential to diagnose and delineate the immunologic defects of PIDs. Patients with clinical suspicion should be further investigated for the response of innate immunity and adaptive immunity [33, 34]. Table 4 listed the most common tests used for initial screening of PIDs.
Measurement of serum immunoglobulins is the first-line test for evaluating B-lymphocyte functions. Quantitative measurements of IgG, IgA, IgM, and IgE will identify either hypogammaglobulinemia or deficiency of an individual class of immunoglobulins. Evaluation of IgG subclasses may be required when a patient has strong implication of humoral immunodeficiency but the total IgG is normal. To be mindful, the results of immunoglobulin quantitation must be interpreted with appropriate age-specific ranges. Assessment of antibody responses to immunization with protein antigens (e.g., tetanus or diphtheria toxoids) and polysaccharide antigens (e.g., pneumococcal capsular) is another way to evaluate humoral immunity, although note is to be taken that live viral vaccines must be restricted to a patient with underlying immunodeficiency [35].
Delayed-type hypersensitivity (DTH) skin test is commonly used to screen whether the patient has intact cell-mediated immune response. A positive DTH skin test generally rules out the possible defect of cellular immunity [36]. Nevertheless, the test requires that individuals must have sufficient prior exposure and sensitization to the testing antigen; therefore, it may not be suitable for infants and young children. Quantitation of T-lymphocytes (CD3, CD4, CD8) in peripheral blood is able to indirectly reflect the aberrant cellular immunity and can be easily performed by flow cytometry. More specialized T-cell function tests would provide in-depth information in immune system, which include the assessment of lymphocyte proliferation in response to stimulus such as mitogens (e.g., phytohemagglutinin, ConA, and PMA), or specific antigens (e.g., candida). Furthermore, in vitro measurements of intra- and/or extracellular cytokine responses (e.g., interleukin 2, interferon-gamma, BAFF, and TNF) are informative for the investigation of T- and B-lymphocyte regulation [37].
Leukocyte count and differential can assess the phagocytic disorders such as congenital agranulocytosis or cyclic neutropenia. Phagocytic function can be indirectly assessed by traditional nitroblue tetrazolium (NBT) assay, which measures phagocytic cells’ killing capability in response to an oxidative burst. More recently, a simpler dihydrorhodamine 123 (DHR) assay based on flow cytometry has replaced NBT test for assisting the diagnosis of chronic granulomatous disease (CGD), Rac2 deficiency, and complete myeloperoxidase deficiency [38, 39]. Other complicated in-vitro functional methods such as the measurement of directed cell movement (chemotaxis), ingestion (phagocytosis), and intracellular killing (bactericidal activity) are available in some specialized laboratories [40].
The importance of evaluating NK cells in human immunity has been previously underscored, and this is supported by two evidences: significantly increased number of patients with reduced NK cells and/or functions, and over 40 genetically defined congenital immunodeficiencies present with impaired NK cell functions [41]. There are several methods utilized for the examination of NK cell functions including 51chromium release assay, flow cytometry-based perforin/granzyme expression and CD107a degranulation. These assays are particularly valuable for the patients suspected of primary hemophagocytic lymphohistiocytosis [42, 43].
The complement system can be evaluated by measuring the level or function of complement proteins that are involved in the classical and alternative activation pathways. C3 and C4 are the complements routinely tested. Quantitative and functional assay of C1 esterase inhibitor is essential for the diagnosis of hereditary angioedema. Assays of CH50 and AH50 are, respectively, used to measure the overall complement activity in the classical or alternative pathway. Combining the results of CH50 and AH50 is indicative for further investigation of individual complement proteins that initiate the classical or alternative pathway or common terminal pathway [44].
As our understanding of the defect or dysfunction of immune system increases, immunophenotypic and functional assays based on flow cytometry have been extensively used in identifying the abnormality of various cell types and their functions associated with certain diseases, including PIDs. Furthermore, flow cytometry is also a favorable technique for the measurement of intra- and extracellular cytokine production (e.g., IL12, IFN, TNF, and TH17), cell surface protein expression (e.g., Foxp3, CTLA-4, and BTK), and cellular signaling pathways (e.g., phosphor-STAT) [45]. The information gained from flow cytometry analysis can assist not only in the diagnosis, monitoring, and treatment of the diseases but also in understanding the influence of immune system associated with genetic defects that are newly identified. Table 5 lists the flow cytometry assays used for common PID disorders. Most of the tests listed are required to be undertaken in a specialized laboratory, with the exception of TBNK cell populations, memory B cells, and some function assays that can be performed in a routine diagnostic laboratory.
Initial laboratory tests for PIDs.
Proper instrument setting, standardized operating procedures, and good quality controls must be exercised when performing flow cytometric analysis, as flow cytometry is susceptible to assay variation,. The reported data must include both percentage and absolute number of specific cell population. Moreover, appropriate age-matched reference ranges should also be provided in the final report [47, 48]. Ideally, each laboratory should establish their own normal ranges, but this is often not feasible; alternatively, published reference ranges may be used if a proper validation has been undertaken.
To date, flow cytometry has also been widely used for evaluating cell functions. Traditionally, lymphocyte functions were tested by radioactive methods, such as cytotoxicity of T and NK cells (chromium release) or proliferation of T cells (tritiated thymidine uptake). These approaches are still recognized as gold standard by some clinicians. However, radioactive methods have the following intrinsic limitations: involvement of radioactivity, labor intensive, high expertise required, and poor result reproducibility. Additionally, seeking for a consistent healthy fresh blood as assay normal control and obtaining a proper reference range can be challenging in routine laboratory practice. Therefore, they have been gradually replaced by other methodologies, such as bioluminescence-based assay or flow cytometry–based assay, which use specific dye for the detection of cell proliferation (e.g., CFSE, PKH-2, or PKH-26) or cell death (e.g., 7AAD and Annexing V) [49]. Many assays based on flow cytometry have been increasingly popular as they are easier to perform, have quicker turnaround time, are nonradioactive, are capable of using whole blood, and are more robust compared to the traditional radioactive assays.
Genetic testing plays a critical role in patients with PID in confirming diagnosis, predicting the prognosis, assessing the influences of genotype-phenotype associations, and family planning [50, 51]. Besides, early and accurate molecular diagnosis is vital for guiding the selection of appropriate treatment including genetic therapy. Several molecular tests are available in identifying the genetic defects of PIDs, such as chromosomal analysis, fluorescence in situ hybridization, chromosomal microarray, single gene by Sanger sequencing, gene panels by massively parallel, whole exome, and genome by next-generation sequencing [52]. The selection of these assays should consider their inherent advantages and limitations [50, 53]. The summary of these tests is shown in Table 6. Recent emerged simple molecular assays for measuring circular DNA segments namely T-cell receptor excision circles and kappa-deleting recombination excision circles, based on quantitative PCR amplification of DNA extracted from dried blood spots, enable for a quick screening of newborn SCID [54].
The choice of specific gene(s) for examination is suggested by the patient’s clinical history and phenotypical and functional results. Clinicians are required to have a basic understanding of the utility, accessibility of different genetic approaches. The selection criteria of molecular methodology should be based on the greatest odds of achieving the diagnosis within an acceptable time frame with the most cost-effective test. There is no specific algorithm for genetic testing in patients with PID as individual’s genetic mutation is often unique, the technology, cost, and the assay turnaround time are constantly changing, and each molecular method has inherent advantages and limitations. Practically, two or more approaches are often used together to achieve an optimal diagnosis [50]. For example, single gene Sanger sequencing is considered to be not only a simple and reliable assay for testing patients with known monogenic mutations of PID or their family members, but it can also serve as a tool for confirming the genetic variants detected by whole exome sequencing. When assessing large numbers of mutations, gene panels or whole genome/exome approach may be more cost-effective and faster than single gene analysis. Since genetic testing in primary immunodeficiency is highly personalized, and a specific genetic mutation does not always translate into a disease, test results must be interpreted with caution by genetic consultants and immunologists.
The recent advances of sequencing technologies have facilitated the genomic assays to become the standard of care in some hospitals although these techniques may face the challenges of cost, accessibility, and interpretation issues. The exponential growth of genetic analysis by next-generation sequencing and other novel molecular technologies has enabled quick identification of known and novel mutations, which contributed to a dramatic expansion of the number and types of PIDs [16, 53, 55].
Treatments for PIDs involve preventing and controlling recurrent infections, treating symptoms, strengthening the immunity, and treating the underlying cause of the immune defects. Illness associated with PIDs such as autoimmune disorders or malignancies should also be managed [1, 13].
More aggressive and/or longer course of antibiotics than “normal infections” is usually prescribed in patients with PID, in order to control the infections caused by bacteria or fungi. Some patients may require prolonged antibiotic therapy to prevent infections and permanent damage to organs [13]. Routine immunizations can also provide protective immunity to those at risk of infections, but the attenuated vaccines such as oral polio and measles-mumps-rubella might not be suitable for children with PIDs. For viral infection, interferon-gamma therapy may be of choice besides other antiviral drugs routinely used (e.g., amantadine and acyclovir) [13]. In patients with chronic granulomatous disease, using granulocyte colony–stimulating factor, a glycoprotein that is able to stimulate the proliferation/differentiation and improve the functions of neutrophil, can help increase the levels of immune-strengthening leukocytes to control the infections [56].
Immunoglobulin replacement has been the pillar of therapy for recurrent infections of PIDs, since around 60% of PID cases have impaired antibody production [57]. In fact, most of these patients will require life-time immunoglobulin replacement therapy. Immunoglobulin can be delivered either intravenously (abbreviated IVIG) or subcutaneously (abbreviated SCIG). The choice of which route depends on the circumstance although both of them have been demonstrated to be effective. Because higher IgG levels can be obtained through intravenous administration, IVIG has been routinely used for preventing serious/recurrent infections [58]; however, SCIG has recently emerged as a popular route for delivery due to its fewer side effects and greater flexibility [57, 59]. Future research direction is focusing on more precise IgG replacement in PIDs, such as the development of IgG subclass-specific enriched preparation and microbe-specific IgG [58].
Apart from controlling infections, the considerable morbidity and mortality caused by noninfectious complications of PIDs can also be troublesome to clinicians. To standardize clinical practices and improve treatment outcome, British Society of Immunology has recently published the first set of recommendations for monitoring and managing the noninfectious complications of CVID [60].
Bone marrow transplantation (BMT) and hematopoietic stem cell transplantation (HSCT) are feasible options for a permanent cure for several types of life-threatening immunodeficiency, with SCID in particular [61, 62]. Immune system can reconstitute when stem cells harvested from bone marrow or cord blood are transferred to the patients with PID. However, the successful rate of biological match, possibility of life-threatening graft-versus-host-disease, and the risk of uncontrolled infections following the destruction of the patient’s own immune system prior to the transplant should be well evaluated.
The technical advances of genetic engineering provide another hope to cure PIDs. Substantial progress has been made in the past decade in treating several types of PIDs (e.g., adenosine deaminase-SCID, SCID-X1, chronic granulomatous disorder, and Wiskott-Aldrich syndrome) with gene therapy [63, 64, 65]. Current treatment scenario is mostly based on ex-vivo deliver of therapeutic transgene through viral vectors to autologous stem cells, followed by transplantation back to the same patient. Although the overall outcome from all the clinical trials targeting different PIDs has been extremely promising, however, serious adverse events (e.g., vector-mediated oncogenesis) and high cost may be a hindrance to clinical trials and promotion of gene therapy [63, 65]. A summary of current strategies for treatment and management of PIDs is shown in Table 7.
The prognosis of patients with PID is extremely variable depending on the type of immune defects. Infants with SCID will die in the first 2 years of life without HSCT/BMT or gene therapy. Individuals who obtained stem cell transplantation in early childhood (before 3.5 months) have better prognosis [67]. Many PID patients who received proper medical care and treatments are able to live healthy and independent life for a long term. With the enhancement in managing infections and other complications and growing application of definitive therapies, the outcomes and long-term survival of PIDs have improved dramatically since the 1970s [13].
The investigation of PIDs has provided valuable insights to understand the specific gene defect that impairs the immune system. Flow cytometry and genetic testing enable to identify existing and novel phenotypes and genotypes as well as their impact on PIDs. The applications of flow cytometry and genetic technologies have expanded dramatically with more types of PID is defined, and the use of mass sequencing technologies has accelerated the identification of novel disorders. To efficiently use these complex assays, clinicians should have a good understanding of these methods and know how to interpret the results for diagnosis and disease management [33].
The management of patients with PID is based on three aspects of diagnosis: suspicious clinical manifestations, aberrant results of immune response, and the underlying genetic defect [4]. However, the diagnosis of PIDs may confront significant challenges: there are large numbers of variable types of PIDs to be recognized and most of them have alike clinical presentations with common diseases; immunodeficiencies derived from multiple gene defects can share similar symptoms, and a defect in the same gene may have various clinical manifestations [1]. While severe forms of PIDs are relatively easier to be recognized, milder immunodeficiencies may not raise alertness until typical presentation occurs [68, 69]. Additionally, the criteria for constituting a PID diagnosis are subjective, for example, the degree of frequency and the severity of the infections for establishing the diagnosis are unclear, the association of PIDs with autoimmune disorder or malignancy is ambiguous, and some individuals may not have noticeable symptoms apart from laboratory findings. Furthermore, advanced laboratory examination such as specialized flow cytometric and genetic analysis is not always easy to access. All these factors may contribute to delayed or missed diagnosis of the diseases.
To combat the challenges, clinical warning signs of PIDs should be disseminated to all clinicians for raising earlier recognition of the diseases, and an immunologist must be consulted for proper diagnosis and management. Due to the complexity of clinical presentations and large number of disease types, the use of scoring system based on the codes of the international classification of PIDs [69] assisted by artificial intelligence may be beneficial for clinicians to differentiate these disorders from other diseases and raise initial recognition. The recent advances in understanding the human immune system, development of novel cellular and molecular assays, and collaborations from the international/national organizations have led to significant increase of clinical awareness and cases diagnosed and improvement of disease management and treatment outcomes for PIDs.
The author thanks Dr. Alexander Richardson from the Royal College of Pathologists of Australasia for assisting the references work and Mrs. Xiumei Wei from the Sutherland Centre of Immunology in NSW, Australia, for valuable opinions.
The author declares that there is no conflict of interest.
Infection, preterm birth, and perinatal complications including asphyxia are among the leading causes of neonatal deaths worldwide [1, 2]. Neonatal and antenatal mortality and morbidity is most often associated with preterm birth that can result in respiratory complications, developmental abnormalities, and high-risk of infections [3, 4]. Infection has been reported in approximately 23% of worldwide neonatal deaths with an estimated 84% of instances being preventable with proper medical treatment [1, 5]. Preterm birth results in the majority of neonatal morbidity and mortality, is the direct cause of approximately 35% of neonatal deaths worldwide, and is the major risk factor for all types of neonatal deaths [1, 3, 4, 6]. Hypoxic birth asphyxia is expected to cause approximately 30% of worldwide neonatal mortality, identified by the inability to perform voluntary breathing at birth, can be observed intrapartum with techniques including Doppler ultrasound and auscultation, and can be diagnosed by an arterial pH in the umbilical cord less than 7.2 [7].
Some of the most common birth defects include congenital heart disease (CHD), down syndrome, and neural tube defects. Congenital cardiac complications are the most common form of congenital abnormalities, with an estimated worldwide prevalence in about 0.8% of all live births, resulting in approximately 1/3 of all congenital abnormalities that cause significant medical and social consequences [8, 9]. Down syndrome is expected in about 1 in 400–1500 births, is the most common chromosomal abnormality, can be diagnosed early in pregnancy with chorionic villus sampling or amniocenteses, and predominately results from trisomy of chromosome 21 [10]. Global neural tube defect prevalence is estimated at 0.05–1% of live births, are characterized by improper closure of the neural tube during fetal development, are commonly asymptomatic, with spina bifida being the most common type, of which the most severe is myelomeningocele [11, 12, 13].
The understanding of normal
MRI sequence for fetal brain analysis include functional imaging, structural imaging, and diffusion imaging [25]. The predominant sequences used in fetal MRI are single-shot T2W (SST2W) sequences, such as rapid acquisition with relaxation enhancement (RARE) sequences on Bruker, Single-Shot half-Fourier Turbo Spin Echo (SShTSE) on Philips, Single-shot Fast Spin Echo (SSFSE) on General Electric, and half-Fourier acquisition single-shot turbo spin echo (HASTE) sequences on Siemens, with protocols provided by the MRI vendor [22, 26]. These T2W sequences are quick enough to be acquired without sedation and are common for neuroanatomical fetal imaging; [9] with other common sequences being T1W to view hemorrhaging, perfusion MRI, diffusion MRI, and spectroscopy [9, 22]. Default SST2W sequences are generally capable of good image generation with 1x1x4 mm voxel size; using half-Fourier acquisitions, with refocusing pulses with flip angles between 120°-150° [22]. Though difficult to implement, diffusion-weighted imaging (DWI) allows identification of ischemic brain lesions, while T1W images can provide improvement over T2W for detection of calcifications, fat, and hemorrhaging [26].
Fetal cardiac sequences are often balanced steady state free precession (bSSFP) and HASTE to encompass small voxel size and reduce acquisition times needed to avoid motion artifacts, with bSSFP being particularly beneficial for imaging blood vessels and cavities containing fluid [26, 27]. Fetal cardiac MRI can be used to view structure, function, vasculature; in addition to performing quantitative MRI measurements including blood flow velocity and oxygen saturation [27]. Blood oxygen level-dependent (BOLD) functional MRI sequences have shown useful for illustrating the improvement of fetal oxygenation during maternal respiratory oxygen therapy for fetuses with impaired cerebral oxygenation resulting from certain types of CHD [28]. Abnormal placenta pathology has been linked with high rates of CHD and is a possible compounding factor for higher severity brain lesions [29]. Neurological implications are not distinct from CHD. Impaired cardiac development is linked with mild brain injury, delayed maturation, shorter gestational age, and smaller brain volumes [30, 31]. Fetal cardiac MRI complications include the smaller size of the fetal heart, lack of gating technologies, and higher heart rate [27].
The primary safety concerns in fetal MRI involve radiofrequency exposure in terms of specific absorption rate (SAR), high acoustic noise, and possibility of peripheral nerve stimulation [22]. MRI is generally considered safe during pregnancy with no evidence of harming the fetus, but is typically not recommended when the fetus is less than about 13 weeks gestational age, and gives best information after completion of organogenesis [22]. The United States Food and Drug Administration (FDA) fetal MRI SAR limit is set at 4 W.kg−1 [22, 32]. Fetal MRI scans are usually recommended to be performed at 1.5 T, and as a “golden rule”, remain below 25 seconds [20, 22]. 3 T fetal MRI is often used only within research settings because the SAR is four times higher than at 1.5 T; with the upper limit generally at 4 T for research applications [9]. Although, some institutions perform routine 3 T fetal imaging during the late second trimester and throughout the third trimester [33]. Contrast enhancement is not recommended in fetal MRI, thought to enter into the fetal vasculature, passing through the renal system, before emptying into the amniotic fluid [9, 34].
Prenatal MRI is most routine for neural abnormalities because of the improved capability for fetal brain scans. In addition to treatment planning of delivery complications, a variety of conditions have high diagnostic rates with fetal MRI, including diagnosis for mild to moderate ventriculomegaly, a variety of neural tube defects, posterior fossa malformations, and twin-to-twin transfusion syndrome [9, 35]. A USA retrospective study for fetal neurology consultations (n = 94) with diagnostic MRI over 14 months reported the most common conditions were posterior fossa malformations, agenesis or dysgenesis of the corpus callosum, congenital acqueductal stenosis, ventriculomegaly, isolated malformations of cortical development, and holoprosencephaly at 19%, 15%, 14%, 11%, 8.5%, and 6%, respectively [36].
Malformations of cortical development are a collection of developmental malformations resulting from disruption during one of the stages of cerebral cortex formation, often causing cognitive impairment, cerebral palsy, and epilepsy. The cortical development occurs in three major stages, including neuronal stem cell proliferation, neuronal migration along radial glial fibers or axons to the developing cerebral cortex, and neuronal organization [37]. Malformations due to abnormal neuronal stem cell proliferation include microcephaly, megalencephaly, and cortical dysplasia. Malformations during neuronal migration and failure for proper cessation of neuronal migration, include: periventricular heterotopia, subcortical band heterotopia, classic lissencephaly, and cobblestone lissencephaly. While, neuronal organization abnormalities include polymicrogyria and schizencephaly [37, 38]. Historically, autopsy or surgical tissue samples were used for diagnosis of these conditions, being difficult to diagnose with ultrasound. MRI has greatly improved the ability to diagnose these conditions during development, rather than in childhood [39]. Retrospective assessment of cortical development malformations has shown high diagnostic accuracy of fetal MRI when compared to postnatal MRI [40].
Ventrigulomegaly is characterized by dilation of the cerebral lateral ventricles during fetal development. Congenital hydrocephalus is a type of ventrigulomegaly that results specifically from increased cerebrospinal fluid pressure, which causes birth defects resulting in abnormally large head size and many other anomalies, and most frequently results from aqueductal stenosis from outlet obstruction in the third ventricle [41, 42]. An illustration of hydrocephalus is shown in Figure 1. Characteristic findings seen postnatally are not often observed prenatally, such as aqueduct funneling or obstruction. Fetal MRI diagnostic indicators, for disease severity from aqueductal stenosis, include the extent of enlargement in the lateral and third ventricle, increased size of the third ventricle of inferior recesses, and observance of diverticulum outpouching in the lateral ventricles [43]. A cohort at the national maternity hospital in the Republic of Ireland reported suspected ventriculomegaly as the most common indication for fetal MRI at the facility, with severe ventriculomegaly (exluding termination) showing a 72% survival rate (n = 74) and a 65% rate for cesarean delivery (n = 72) [44].
Illustration of hydrocephalus with MRI. Rumruay/
Failure of neural tube closure during development results in a variety of neural tube defects, causing spinal anomalies in cases of spinal dysraphism like spina bifida; or cranial anomalies like with anencephaly, characterized by absence of a major portion of the cranium. Though, anencephaly is less indicated for MRI [45]. Distinguishing characteristics of common types of spina bifida are shown in Figure 2. Worldwide incidence varies geographically, but estimated on average about 0.1–1% of live births, with anticonvulsants correlating with increased risk, and folic acid associated with reduced risk of neural tube defects [45]. Spinal dysraphism occurs from improper closure of the spinal cord and surrounding membranes during fetal development, and can be classified by open or closed. Closed spina bifida accounts for about 15% of instances, with spina bifida occulta as the most common form, and is usually asymptomatic [33]. Open spina bifida accounts for about 85% of open spinal dysraphisms with myelomenengocele (MMC) and myelocele being predominant, and nearly always presents with Chiari type II malformation [33]. The randomized MOMS trial compared spina bifida outcomes from fetal surgery compared to surgery after delivery, with fetal MRI playing a pivotal role in treatment planning. Outcomes showed fetal surgery for MMC allowed less need for cerebrospinal fluid shunt placement, improved cognitive function in early childhood, though higher risk of preterm birth was observed in the fetal surgery group [33, 46, 47].
Comparison of spina bifida subtypes. Rumruay/
Posterior fossa anomalies are characterized by neurodevelopmental malformations in the posterior fossa of the skull cranial cavity. Posterior fossa anomalies are some of the most frequent indications for fetal MRI, occurring in approximately 1 in 5000 live births, encompass a broad spectrum of conditions, and can be categorized as developmental disruptions and malformations [48, 49]. Posterior fossa anomalies include: mega cisterna magna, Blake’s pouch cyst, Dandy-Walker malformation, arachnoid cyst, Joubert syndrome, rhombencephalosynapsis, and Chiari malformation [50]. The malformations can present with either an enlarged cyst appearing with abnormally high retrocerebellar fluid, such as in Dandy-Walker malformation, mega cisterna magna, and Blake’s pouch cyst. Or the malformations cause an unusually small posterior fossa such as in Dandy-Walker variant [51, 52]. The most common reported malformation is generally Dandy-Walker malformation, presenting with macrocephaly in 90–100% of children within months of delivery [49]. Comparison of fetal MRI and fetal ultrasound images in the diagnosis of Dandy-Walker malformation is shown in Figure 3. Prognosis of these conditions is highly influenced by concomitant anomalies, with co-occurring conditions like agenesis and cerebral hypoplasia often resulting in cognitive impairment. Other conditions like mega cisterna magna without hydrocephalus typically result in normal development [50]. In a USA retrospective cohort for ultrasonography referrals for fetal MRI involving posterior fossa anomalies (n = 180), the most common indications for fetal MRI were Dandy-Walker continuum (Dandy-Walker malformation in addition to Dandy-Walker variant) at 42%, mega cisterna magna at 22%, with a change in diagnosis in 70% of cases, and 60% agreement between fetal MRI and postnatal MRI [54].
Dandy-Walker malformation in a 26 week fetus, first suspected as Dandy-Walker variant with ultrasonography, and confirmed as Dandy-Walker malformation with T2W HASTE MRI. A) Ultrasonography illustrating mild ventriculomegaly B) ultrasonography image illustrating cisterna magna that is abnormally large. C) MRI image illustrating direct connection between the cisterna magna and 4th ventricle. D) Sagittal MRI of abnormally large posterior fossa. Reprint Sohn et al., 2008 under CC BY-NC 3.0 [
The corpus callosum is a white matter commissural nerve tract, connecting cortical regions of left and right hemispheres, and composed of myelinated axons that allow action potential propagation [55]. The corpus callosum forms between gestational weeks 11–22, is composed of five distinct regions, and hyperplasia or hypoplasia of these regions is termed callosal dysgenesis, while total absence is deemed callosal agenesis [56]. Agenesis of the corpus callosum rarely occurs in complete isolation, and generally occurs in combination with other disorders. MRI can provide more detail for the extent of the condition than ultrasonography alone [55]. This allows confirmation that the corpus callosum is intact and visualization of co-occurring and associated malformations [9]. Diffusion tensor imaging and fiber tractography in developing research applications has greatly improved the understanding of the neuronal tracts of the corpus callosum, and complications associated with different degrees of agenesis [55]. Tractography has allowed characterization of normal developmental patterns for the nerve bundles of the corpus callosum with increasing gestational age, showing an increase in volume and fractional anisotropy, with a decrease in apparent diffusion coefficient [57].
In twin-to-twin transfusion syndrome, unequal blood supply to the fetuses leads to demise of one twin. Untreated cases have dismal survival rates [58]. The condition indicates diagnostic fetal MRI due to improved capabilities over ultrasonography for identifying ischemic lesions and neurodevelopmental abnormalities. The condition often warrants intervention including serial amniocentesis or
Ultrasonography is the primary imaging modality for monitoring and diagnosis in both congenital and acquired pediatric heart disease and antenatal complications [61]. Ultrasonography and MRI have been determined safe for fetal imaging, but suggested to be used prudently, with common concerns and power limits due to potential tissue heating and acoustic damage [62]. Fetal cardiac MRI can improve outcomes by allowing earlier preparation of treatment procedures [63]. The American Heart Association (AHA) and British Association of Perinatal Medicine (BAPM) suggest neonatal MRI for newborn patients with high-risk CHD in combination of evidence for intracranial hemorrhaging or parenchymal brain trauma, though not recommended for routine use for CHD [9].
CHD is the most common form of congenital abnormalities, occurring in about 0.6–0.8% of live births, with as much as half of the patients requiring open-heart surgery, and is associated with high rates of neurodevelopmental problems [9]. CHD is associated with high neonatal morbidity, particularly in preterm infants [64]. Some of the most common congenital heart abnormalities include atrial septal defects, ventricular septal defects, Tetralogy of Fallot, patent ductus arteriosus, and pulmonary stenosis [65, 66]. A depiction of several types of congenital heart defects is shown in Figure 4. Ventricular septal defects are the most common congenital cardiac anomaly, often requiring surgical repair, though a high percentage will also spontaneously close with age [66, 67, 68].
Illustration of common congenital heart defects. N.Style/
Prenatal cardiac MRI for CHD has generally been limited to a research setting [69]. This has been due to factors including inability to perform electrocardiogram gating, fetal motion, insufficient safety data, and the relatively small size of the features of the fetal heart [70, 71]. Prenatal cardiac MRI allows evaluation of cardiac anatomy, cardiac function, vascular anatomy, flow quantification, and oxygen content [69].
Recent advances has allowed image reconstruction techniques to obtain high-resolution 3D MRI of the fetal heart to assess for congenital heart defects. 3D MRI with motion-corrected image registration was shown in a cohort study to significantly increase visualization and diagnosis of major fetal vascular heart defects in late-gestational age fetuses, when compared to 2D MRI [72]. Additionally, Doppler ultrasonography has shown capable of performing cardiac gating of the fetal heart to generate high-quality bSSFP cine images [73].
A cohort study reported the use of a non-contrast velocity-selective arterial spin labelling (VSASL) sequence to assess placental perfusion in fetuses with CHD compared to fetuses without CHD [74]. The study found decreased global perfusion and increased variation of regional perfusion were linked to increasing gestational age in CHD fetuses. The results also suggest that early placental perfusion may increase to compensate for the heart defect.
A Chinese retrospective study reported findings in 1379 confirmed cases for fetal cardiac MRI from 2005 to 2019, referred after echocardiography could not show the four cardiac chambers in addition to ventricular outflow [75]. Imaging sequences were SSFP, real-time cine SSFP, non-gated phase contrast sequences, and SSTSE. The findings were normal in 92.5% of cases, 5.1% presented with CHD, and 2.4% were diagnosed with an alternative heart condition. In the CHD cases, 56% received correct diagnosis with MRI, which was similar to other studies, as prenatal detection rates for CHD for patients that eventually underwent congenital heart surgery, have tended to be low and less than 50% [76].
Most conditions are best treated when the fetus is delivered at term; however, certain instances warrant the use of
Again, ultrasonography is recommended as the first imaging modality, but MRI is often indicated in a variety of maternal obstetric and non-obstetric complications during pregnancy, including placental adhesive disorders, placental abruption, prognosis of uterine rupture, restricted circulation in placental bed disorders, placental insufficiency, acute appendicitis during pregnancy, prediction of preterm labor, ovarian cysts, and urolithiasis [18, 81]. Additionally, MRI is indicated in treatment planning for difficult deliveries, such as those that require the EXIT procedure due to fetal airway obstruction [9]. Moreover, the technique has proved useful in risk scoring for massive intraoperative hemorrhage in patients with previous cesarean sections and exhibiting placenta previa and accreta [82]. Fetal MRI was recently used in a randomized control trial to assess fetal neurodevelopmental improvement for supplemental pomegranate juice in pregnancies with intrauterine growth restriction [83].
Prenatal MRI is useful for diagnosis of complications associated with maternal viral infections, including the more recent complications associated with SARS-CoV-2 infection.
A variety of fetal complications arising from viral infection can be imaged with MRI, particularly for identifying neurological sequelae, but also for conditions including fetal ascites, hydrops, cardiomegaly, and pericardial effusion [84]. Fetal MRI can be indicated for diagnosis of suspected neurotropic pathogens, such as cytomegalovirus, Zika virus, and toxoplasmosis [85, 86, 87, 88]. Cytomegalovirus is a member of the Herpesviridae family, the most common vertically transmitted congenital viral infection, and the most common infection that results in deafness and intellectual disability in children [89, 90]. MRI and ultrasonography can identify fetal brain lesions resulting from cytomegalovirus infection. MRI diagnosis of infection-related complications allows the possibility of treatment planning for investigational therapies, including antiviral therapy such as Valaciclovir or hyperimmunoglobulin therapy, in the neonates and in fetuses [18, 91, 92].
SARS-CoV-2 is a positive sense, lipid-enveloped, single-stranded, RNA coronavirus that causes both upper and lower respiratory tract infection, which can result in severe pulmonary inflammation and pneumonia, in a condition denoted human coronavirus disease or more recently COVID-19 [93, 94, 95].
SARS-CoV-2 relies upon two types of entry pathways to enter cells through the interaction of the virion spike (S) protein with angiotensin-converting enzyme 2 (ACE2), with release of internal RNA within the cell occurring after cleavage of the S-protein subunits [95]. After binding to ACE2, if transmembrane protease serine 2 (TMPRSS2) is present on the cell surface, the cleavage event occurs through TMPRSS2 and furin, initiating membrane fusion and fusion pore formation on the cell membrane, and release of viral RNA into the cellular cytoplasm [95]. Alternatively, if little or no TMPRSS2 is present on the surface, the clathrin-mediated endocytosis occurs and the virus is internalized intracellularly within endolysosomes, followed by a cathepsin-cleavage event within the endosome, resulting in membrane fusion and release of the viral RNA into the cell cytoplasm [95].
The BNT162b2 (Pfizer, BioNTech) and Spikevax (Moderna, NIAID) are both mRNA-based vaccines that encompass an mRNA strand encoding the spike protein for the original Wuhan-Hu-1 strain, in a liposomal mRNA-lipid nanoparticle, which has a notable ability for large-scale production [95, 96]. The vaccine causes cells to encode the vaccine mRNA to produce spike proteins that are then expressed into the cell membrane. This causes an antibody response that identify these spike protein antigens as a foreign body, stimulating a B-cell and T-cell lymphocyte response to produce antibodies that will tag future spike proteins from SARS-CoV-2 viremia [97]. The viral mutations of these spike protein antigens result in reduced efficacy of the vaccines to induce a immunogenic response. Because mRNA vaccines require antibody neutralization of viremia, mutations in the spike proteins can allow variants to exhibit resistance to the vaccines, potentially causing more severe infections, higher transmissibility, and the possibility of re-infection in vaccinated individuals [98, 99].
A prospective U.K. cohort found 0.5% incidence of SARS-CoV-2 infection during pregnancy that required hospital admission (n = 427) [100]. Of the patients that delivered or experienced pregnancy loss at the time of the article (n = 262), 10% required intensive care unit (ICU) admission and death occurred in 1.2%. From the SARS-CoV-2 positive pregnancies with live born births, 59% had cesarean deliveries and 25% of neonates were admitted to the neonatal intensive care unit (NICU). Preterm delivery occurred in 25% of cases, most of which were induced labor due to COVID-19 complications, and 5% of neonates were COVID-19 positive within 12 hours of birth.
Pregnant women are at high risk of developing severe COVID-19 compared to non-pregnant women, in terms of adjusted risk. Comparing COVID-19 positive pregnancies with non-COVID-19 pregnancies, studies have observed a factor of 3 increase in ICU admissions and invasive intubation with mechanical ventilation, a factor of 2.4 increase in odds for extracorporeal membrane oxygenation, and 70% increase in death [101]. Severe COVID-19 complications are linked with increased rates of preterm birth, hypertensive disorders, and cesarean births [101]. Studies have linked COVID-19 with significant increased mortality for mothers post-delivery and in neonates; particularly for symptomatic patients and those with underlying comorbidities [102, 103]. Neonatal outcomes have been reported as generally favorable, with about half of cases being asymptomatic; though, neonates and children less than one year of age are thought to possibly exhibit higher risk of acute respiratory failure than other children [104].
Risk of vertical transmission of SARS-CoV-2 from mother to fetus is considered low, with the primary transmission to the neonate being through horizontal transmission [101, 105]. Although, at least one case study has confirmed vertical transplacental transmission [106]. There is little evidence for transmission of SARS-CoV-2 through breast milk to the neonate, but pasteurization has been shown to inactivate the SARS-CoV-2 virus and might be considered in specific cases for positive SARS-CoV-2 mothers [101, 105, 107]. Transmission between members of the same family cluster is the primary means of infection from SARS-CoV-2 in children [108]. Infection in children and adolescents has tended to result in milder symptoms and good prognosis, in general [109].
The American College of Radiology (ACR) has suggested limiting the use of MRI to only cases that are absolutely necessary, for COVID-19 positive patients and those suspected of infection [110]. The use of fetal MRI for COVID-19 positive mothers does not have a common indication for routine use and has mostly been reported as case studies or small cohorts. Fetal MRI has been used in cohorts to assess possible neurodevelopmental damage in the fetuses of mothers with SARS-CoV-2 infection during early pregnancy, with results showing no abnormal findings [111]. However, a case study of
A significant increase in obstetrical complications in COVID-19 has been observed, compared to non-COVID-19 pregnancies. Studies have shown higher rates of fetal deaths, maternal deaths, ICU admissions, preterm births, and cesarean deliveries. These outcomes highlight the benefit of vaccination during pregnancy, to reduce the risk of maternal and fetal complications [101].
Prenatal MRI offers useful complementary diagnostic information to ultrasonography, particularly for neurodevelopmental complications. The technique can be used for diagnosis, for guiding treatment decisions, and to counsel parents for scenarios like potential termination. MRI has been determined safe for fetal health, though low field strengths and non-contrast imaging are generally used, as these scenarios are lower risk to the fetus. MRI can improve diagnostic accuracy for neurodevelopmental and cardiac anomalies when used in conjunction with ultrasonography, but factors like additional cost limits the number of indications for prenatal diagnosis. Studies have shown increased rates of pregnancy-related complications in patients infected with SARS-CoV-2 during pregnancy. Although, studies with fetal MRI for assessing fetal developmental complications due to maternal COVID-19 has been limited, but results have been reported in case studies and small cohorts.
Thanks to the Center for Biomedical Imaging and the Image-guided Interventions Laboratory for supporting the development of this manuscript. Thanks to Dr. Daniela Dumitriu LaGrange for reviewing the manuscript and suggesting improvements.
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knowledge of node’s ability and importance in spreading information in a complex network is important for developing efficient methods either to decelerate spreading in the case of diseases or to accelerate spreading in the case of information flow, which would benefit the whole population. Some systems are highly affected by a small fraction of influential nodes. Number of fast and efficient spreaders in a network is much less compared to the number of ordinary members. Information about the influential spreaders is significant in the planning for the control of propagation of critical pieces of information in a social or information network. Identifying important members who act as the fastest and efficient spreaders is the focal theme of a large number of research papers. Researchers have identified approximately 10 different methods for this purpose. Degree centrality, closeness centrality, betweenness centrality, k‐core decomposition, mixed degree decomposition, improved k‐shell decomposition, etc., are some of these methods. In this expository article, we review all previous works done in the field of identifying potential spreaders in a network.",book:{id:"5842",slug:"graph-theory-advanced-algorithms-and-applications",title:"Graph Theory",fullTitle:"Graph Theory - Advanced Algorithms and Applications"},signatures:"Reji Kumar Karunakaran, Shibu Manuel and Edamana Narayanan\nSatheesh",authors:[{id:"200190",title:"Dr.",name:"Reji Kumar",middleName:null,surname:"Karunakaran",slug:"reji-kumar-karunakaran",fullName:"Reji Kumar Karunakaran"},{id:"200193",title:"Mr.",name:"Manuel",middleName:null,surname:"Shibu",slug:"manuel-shibu",fullName:"Manuel Shibu"},{id:"200194",title:"Dr.",name:"E N",middleName:null,surname:"Satheesh",slug:"e-n-satheesh",fullName:"E N Satheesh"}]},{id:"57940",doi:"10.5772/intechopen.72145",title:"Graph-Based Decision Making in Industry",slug:"graph-based-decision-making-in-industry",totalDownloads:1724,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Decision-making in industry can be focused on different types of problems. Classification and prediction of decision problems can be solved with the use of a decision tree, which is a graph-based method of machine learning. In the presented approach, attribute-value system and quality function deployment (QFD) were used for decision problem analysis and training dataset preparation. A decision tree was applied for generating decision rules.",book:{id:"5842",slug:"graph-theory-advanced-algorithms-and-applications",title:"Graph Theory",fullTitle:"Graph Theory - Advanced Algorithms and Applications"},signatures:"Izabela Kutschenreiter-Praszkiewicz",authors:[{id:"218951",title:"Associate Prof.",name:"Izabela",middleName:null,surname:"Kutschenreiter-Praszkiewicz",slug:"izabela-kutschenreiter-praszkiewicz",fullName:"Izabela Kutschenreiter-Praszkiewicz"}]},{id:"55541",doi:"10.5772/intechopen.68703",title:"Modeling Rooted in‐Trees by Finite p‐Groups",slug:"modeling-rooted-in-trees-by-finite-p-groups",totalDownloads:1148,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Graph theoretic foundations for a kind of infinite rooted in-trees T(R)=(V,E) with root R, weighted vertices v ∈ V, and weighted directed edges e∈E⊂V×V are described. Vertex degrees deg(v) are always finite but the trees contain infinite paths (vi)i≥0. A concrete group theoretic model of the rooted in-trees T(R) is introduced by representing vertices by isomorphism classes of finite p-groups G, for a fixed prime p, and directed edges by epimorphisms π: G → πG of finite p-groups with characteristic kernels ker(π). The weight of a vertex G is realized by its nuclear rank n(G) and the weight of a directed edge π is realized by its step size s(π)=logp(#ker(π)). These invariants are essential for understanding the phenomenon of multifurcation. Pattern recognition methods are used for finding finite subgraphs which repeat indefinitely. Several periodicities admit the reduction of the complete infinite graph to finite patterns. The proof is based on infinite limit groups and successive group extensions. It is underpinned by several explicit algorithms. As a final application, it is shown that fork topologies, arising from repeated multifurcations, provide a convenient description of complex navigation paths through the trees, which are of the greatest importance for recent progress in determining p-class field towers of algebraic number fields.",book:{id:"5842",slug:"graph-theory-advanced-algorithms-and-applications",title:"Graph Theory",fullTitle:"Graph Theory - Advanced Algorithms and Applications"},signatures:"Daniel C. Mayer",authors:[{id:"198580",title:"Dr.",name:"Daniel C.",middleName:null,surname:"Mayer",slug:"daniel-c.-mayer",fullName:"Daniel C. Mayer"}]},{id:"57771",doi:"10.5772/intechopen.71774",title:"Governance Modeling: Dimensionality and Conjugacy",slug:"governance-modeling-dimensionality-and-conjugacy",totalDownloads:1347,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"The Q-analysis governance approach and the use of simplicial complexes—type of hypergraph—allow to introduce the formal concepts of dimension and conjugacy between the network of entities involved in governance (typically organizations) and the networks of those attributes taken into account (e.g. their competences), which offer a specific angle of analysis. The different sources of existing data (e.g. textual corpora) to feed the analysis of governance—environmental in particular—are mentioned, their reliability is briefly discussed and the required pre-processing steps are identified in the perspective of evidence-based analyses. Various indices are constructed and evaluated to characterize the context of governance as a whole, at mesoscale, or locally, i.e. at the level of each of the entities and each of the attributes considered. The analysis of ideal-type stylizing boundary cases provides useful references to the analysis of concrete systems of governance and to the interpretation of their empirically observed properties. The use of this governance modeling approach is illustrated by the analysis of a health-environment governance system in Southeast Asia, in the context of a One Health approach.",book:{id:"5842",slug:"graph-theory-advanced-algorithms-and-applications",title:"Graph Theory",fullTitle:"Graph Theory - Advanced Algorithms and Applications"},signatures:"Pierre Mazzega, Claire Lajaunie and Etienne Fieux",authors:[{id:"220099",title:"Dr.",name:"Pierre",middleName:null,surname:"Mazzega",slug:"pierre-mazzega",fullName:"Pierre Mazzega"},{id:"220102",title:"Dr.",name:"Claire",middleName:null,surname:"Lajaunie",slug:"claire-lajaunie",fullName:"Claire Lajaunie"},{id:"220103",title:"Prof.",name:"Etienne",middleName:null,surname:"Fieux",slug:"etienne-fieux",fullName:"Etienne Fieux"}]},{id:"72140",doi:"10.5772/intechopen.91972",title:"Comparative Study of Algorithms Metaheuristics Based Applied to the Solution of the Capacitated Vehicle Routing Problem",slug:"comparative-study-of-algorithms-metaheuristics-based-applied-to-the-solution-of-the-capacitated-vehi",totalDownloads:685,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"This chapter presents the best-known heuristics and metaheuristics that are applied to solve the capacitated vehicle routing problem (CVRP), which is the generalization of the TSP, in which the nodes are visited by more than one route. To find out which algorithm obtains better results, there are 30 test instances used, which are grouped into 3 sets of problems according to the position of the nodes. The study begins with an economic impact analysis of the transportation sector in companies, which represents up to 20% of the final cost of the product. This case study focuses on the CVRP for its acronym capacitated vehicle routing problem, analyzing the best-known heuristics such as Clarke & Wright and sweep, and the algorithms GRASP and simulated annealing metaheuristics based.",book:{id:"8241",slug:"novel-trends-in-the-traveling-salesman-problem",title:"Novel Trends in the Traveling Salesman Problem",fullTitle:"Novel Trends in the Traveling Salesman Problem"},signatures:"Fernando Francisco Sandoya Sánchez, Carmen Andrea Letamendi Lazo and Fanny Yamel Sanabria Quiñónez",authors:[{id:"155426",title:"Ph.D.",name:"Fernando",middleName:"Francisco",surname:"Sandoya",slug:"fernando-sandoya",fullName:"Fernando Sandoya"},{id:"313162",title:"M.Sc.",name:"Carmen",middleName:null,surname:"Letamendi",slug:"carmen-letamendi",fullName:"Carmen Letamendi"},{id:"319376",title:"Dr.",name:"Fanny",middleName:null,surname:"Sanabria",slug:"fanny-sanabria",fullName:"Fanny Sanabria"}]}],mostDownloadedChaptersLast30Days:[{id:"55642",title:"Monophonic Distance in Graphs",slug:"monophonic-distance-in-graphs",totalDownloads:1551,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"For any two vertices u and v in a connected graph G, a u − v path is a monophonic path if it contains no chords, and the monophonic distance dm(u, v) is the length of a longest u − v monophonic path in G. For any vertex v in G, the monophonic eccentricity of v is em(v) = max {dm(u, v) : u ∈ V}. The subgraph induced by the vertices of G having minimum monophonic eccentricity is the monophonic center of G, and it is proved that every graph is the monophonic center of some graph. Also it is proved that the monophonic center of every connected graph G lies in some block of G. With regard to convexity, this monophonic distance is the basis of some detour monophonic parameters such as detour monophonic number, upper detour monophonic number, forcing detour monophonic number, etc. The concept of detour monophonic sets and detour monophonic numbers by fixing a vertex of a graph would be introduced and discussed. Various interesting results based on these parameters are also discussed in this chapter.",book:{id:"5842",slug:"graph-theory-advanced-algorithms-and-applications",title:"Graph Theory",fullTitle:"Graph Theory - Advanced Algorithms and Applications"},signatures:"P. Titus and A.P. Santhakumaran",authors:[{id:"198301",title:"Dr.",name:"P.",middleName:null,surname:"Titus",slug:"p.-titus",fullName:"P. Titus"},{id:"199035",title:"Prof.",name:"A. P.",middleName:null,surname:"Santhakumaran",slug:"a.-p.-santhakumaran",fullName:"A. P. Santhakumaran"}]},{id:"71501",title:"Accelerating DNA Computing via PLP-qPCR Answer Read out to Solve Traveling Salesman Problems",slug:"accelerating-dna-computing-via-plp-qpcr-answer-read-out-to-solve-traveling-salesman-problems",totalDownloads:821,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"An asymmetric, fully-connected 8-city traveling salesman problem (TSP) was solved by DNA computing using the ordered node pair abundance (ONPA) approach through the use of pair ligation probe quantitative real time polymerase chain reaction (PLP-qPCR). The validity of using ONPA to derive the optimal answer was confirmed by in silico computing using a reverse-engineering method to reconstruct the complete tours in the feasible answer set from the measured ONPA. The high specificity of the sequence-tagged hybridization, and ligation that results from the use of PLPs significantly increased the accuracy of answer determination in DNA computing. When combined with the high throughput efficiency of qPCR, the time required to identify the optimal answer to the TSP was reduced from days to 25 min.",book:{id:"8241",slug:"novel-trends-in-the-traveling-salesman-problem",title:"Novel Trends in the Traveling Salesman Problem",fullTitle:"Novel Trends in the Traveling Salesman Problem"},signatures:"Fusheng Xiong, Michael Kuby and Wayne D. 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