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Pre-clinical studies in mice [1, 2, 3], clinical studies in affected people [4], and a clinical trial [5] with patients in the early stages of CCC were performed. Here we revisit and build the narrative of this process, from the very first ideas, through all the difficulties that we faced until the present days and the perspectives to introduce a new treatment for a neglected disease.
Chagas disease (CD) is caused by infection with the protozoa
To enhance the visibility to the real dimension of CD, WHO instituted a
Five different therapeutic strategies that may be applied for Chagas disease treatment in the complexity of its multifactorial causality. Anti-parasite (AP) drugs such as benznidazole and nifurtimox, as well as others that are currently been studied, may reduce the parasite load in the early acute phase and in chronic infection when the parasite still evading the immune system. Infection in the hosts/patients triggers both local and systemic inflammation and a strong specific immune response. An adequate balance of these two mechanisms regulates the control of parasite growth and the regulation of physiopathology. Different strategies are under study in basic research for intervention in these four arms—Modulators of inflammation (MI), as cytokines, chemokines and their antagonists, immune stimulators (IS) as adjuvants, vaccines, and antioxidants, such as Se, regulators of pathology (RP) as neuro-humoral blockers, anti-fibrotic and anti-arrhythmic agents, prevention of thromboembolic events, cell therapy and others. The combination of different therapeutic strategies (CT) should help to face this complexity. However, the translation from basic to clinical studies and to patient access is still far.
The idea of using Se as a complementary treatment rises from its role in 25 human selenoproteins, some of them acting as antioxidants and others in endocrine and immune pathways [13, 14]. Therefore, the effect of Se therapy in CD development needed proof of concept related to experimental infection and in patients. Our group and other researchers are adding evidence in this direction.
However, combined therapies are scarcely being tested in basic science [15, 16], and its translation to humans must also be investigated, mainly related to more clinical trials, as we performed for Se [5], opening more new doors than solving questions. As shown in Figure 1, the strategies of using combined trypanocidal chemotherapy and other agents to mitigate inflammatory disbalance, in which cytokine networks assume pathological roles, as well as increased fibrinogenic and neurodegenerative mechanisms, became co-protagonists in CD physiopathology [9, 10, 17].
In 1996, we were introduced to Se effects in cardiopathies through contact with Belgian colleagues that worked with
We then asked Prof. Alejandro Luquetti, from the Federal University of Goiás, to give us some serum samples from CD patients at different stages of cardiac disease and measured Se levels. In the five pilot samples tested, two from non-infected and three from CD-infected people, we found that those with the lowest level of Se were the ones with the more advanced cardiac disease. It would be worth persisting in testing the hypothesis, thus starting the timeline of this long project. Figure 2 shows this 30-year timeline, writing in black the yearly landmarks, in blue the application and approval of financial support projects, and in red the main publications.
Main landmarks of the STCC clinical trial. Starting from the first ideas in 1996, three decades will lead to evidence to support public policies. Financial supports are shown in blue and main publications are shown in red; yellow dots at left indicate the critical points that threatened or delayed the project. The orange gradient background indicates the three main phases of the translational roadmap—(a) ideas, conceptualization, and basic preclinical studies, from 1996 to 2015, including the three PhD thesis, (b) pretrial activities conditioning the start of recruitment phase, from 2004 to 2014, and (c) the first clinical trial (STCC) from 2013 to 2020, with results published in 2021. This first trial used a short follow-up and showed a significant effect only in patients of the B2 stage of chronic Chagas cardiopathy, leaving some questions that implicated the design of new clinical trials to elucidate points that remained open, thus opening a fourth phase (white background) that deserves planning, financial funding, and implementation.
The next step, in 1999, was to enhance the number of patients studied to confirm whether Se levels would be lower in patients with more severe cardiac disease. The first partnership was made with Dr. Alejandro M. Hasslocher-Moreno, who was the physician responsible for the clinic management and follow-up of CD patients at the Evandro Chagas National Institute of Infectious Diseases (INI), Fiocruz, Rio de Janeiro city. Se levels were measured and a very large variation was observed. We then decided that patients with different nutritional habits from another state in Brazil should also be analyzed. It implicated a new partnership with colleagues from Belo Horizonte city and CD patients from Dr. Manoel Otávio Rocha, enrolling a total of 273 patients in the study [4]. We observed that Se levels in patients with moderate and severe cardiopathy were lower than in patients with mild cardiopathy and indeterminate form, as well as in uninfected individuals [4].
In parallel, we performed some proof-of-concept studies, showing in experimentally
In 2004, we started to move on to the clinical trials stage. We designed a placebo-controlled, double-blind trial, recruiting patients with mild heart disease (stages B1 and B2 defined by the Brazilian Consensus on CD) followed at the Chagas clinic at INI-Fiocruz, for treatment of 100 mcg/day Se for 1 year. Two outcomes were defined—50% reduction in progression of heart disease and a significant reduction in left ventricular ejection fraction (LVEF) value in 5 years of follow-up. However, we did not previously contact a Se supplier. Our first impediment was to think that it should be easy to find a Se source in the Brazilian pharmaceutical market. The saga was in the early beginning. Figure 2 represent the historical saga of the Se clinical trial, including the first step (1996–2004 period) of developing ideas, hypothesis, and pre-clinical studies.
In 2005, the Brazilian National Health Surveillance Agency (ANVISA), the drug regulatory agency, changed the criteria for daily supplementation dose of Se for 34.5 mcg. Therefore, the predicted dose of 100 mcg/day would be considered as treatment and not supplementation, implying the need to change the clinical trial regulatory licenses. Then, in June 2006, a second version of the trial was approved by the Ethics Committee.
In 2005, we found no Se supplier in Brazil under good manufacturing practices (GMP) conditions for clinical trials, either organic or inorganic. In sequence and based on the opportunity that Fiocruz has an industry sector for drugs and medicines production (FarManguinhos/Fiocruz), we tried a partnership for Se production, but it was not possible due to technical restrictions.
In 2006, the production was staggered at other Fiocruz industry sectors (BioManguinhos/Fiocruz) and we initially succeeded. One year later we signed a contract and the first batch of liquid sodium selenite in ampoules was manufactured by BioManguinhos.
In June 2009, we submitted the essay proposal to ANVISA, which approved it in 5 months, after a single meeting for clarification and adjustments.
In early 2010, we received the bad news that BioManguinhos would have to interrupt the GMP production of Se due to a priority of the factory’s response to the shortage of yellow fever vaccine.
We then started a journey to find a private industry partner. In 2011, based on the experience of the recently organized Fiocruz Clinical Research Platform (http://www.ppt.fiocruz.br/fiochagas/2021/09/27/quem-somos/), we found the
In 2013, the team that worked in the pre-clinical studies and that was initially trained for the clinical trial, was partially disarticulated with the departure of the project manager and other technicians.
In 2013, we reorganized the STCC team, with the completion of the database preparation and training of the new group in Good Clinical Research Practices (GCP). The database was structured with 389 fields to be filled in the Research Electronic Data Capture (REDCap), a web-based application to capture data for clinical research and create databases, divided into (i) Tracking and inclusion, (ii) Baseline visit for cardiac and clinical data (history and physical examination); (iii) Clinical follow-up, electrocardiogram (ECG) and echocardiogram (ECO); (iv) polymerase chain reaction for
In 2015, the manufacturer
On April 6th, 2016, a meeting of the external data safety monitoring board [24] was called to analyze some adverse effects recorded and to discuss the possible need for interrupting the clinical trial. Without the need of breaking the STCC blinding, this analysis concluded that a possibly intercurrent dengue virus endemic infection could have caused the noted effects (leukopenia/neutropenia) and the continuity of the trial was recommended. After ending the first year of STCC follow-up, the results published clearly confirmed the absence of adverse effects related to Se treatment [5].
During this long time, it occurred many advances in the knowledge about the effect of Se treatment in cancer and heart disease. It became clear that perhaps the dose provided in our clinical trial (100 mcg/day) could not be sufficient. From 2013 to 2018, four articles showed that 200 mcg was ideal for cardiovascular protection [25, 26, 27, 28], and Swedish studies in elderly people proposed the benefits of the association of Se with the co-factor coenzyme Q10 for the expected outcomes. There was then a risk that STCC could end with no significant results, due to the lower concentration of Se chosen in 2004, based on cardiovascular literature related to Se treatment available at that time.
At the end of 2014, after 1 year of patients recruitment, we noted that the rate of recruitment was very slow (Figure 3), compromising the ability to reach the 163 volunteers needed for STCC protocol. It was 2015 when the third idea was planted—how to think about strategies to bring people with Chagas disease closer together and interest them in participating in the study to test/develop new medication and vaccines? Would it be possible to make them partners in the study or in actions to engage more patients in the knowledge of their own disease?
At this point, we decided to develop what we call the social arm of the clinical project.
April 14, 2015, we organized a meeting to make a public launch of the project, and to propose workshops of playful activities to “Talk about Chagas with Science and Art,” inspired by the work of the Argentine group “Hablamos de Chagas” [29]. These initiatives quickly produced results—(i) we organized five successive editions of the course “We talk about Chagas with Science and Art” from 2015 to 2019, for people with CD, their family members, and health professionals; (ii) we created a “Rio Chagas Collective” on social media, which gave rise to the (iii) “Rio Chagas Association,” founded on April 8, 2016, in which we participate in the Scientific Council; and (iv) the Rio Chagas Association participants inspired us to conceive the “Chagas Express XXI” social technology [30].
In 2018, we created a
Chagas Express XXI was created as an “imaginary train” with around 40 ArtScience workshops, games, laboratory activities, and conversation circles. It was structured with an entry and exit point, followed by six more modules of activities that combined a focus on associations of affected people, on opportunities for the public to rediscover Carlos Chagas’ discoveries, on microscopic observations and play, on health education in approach. A One Health approach was adopted, with a focus on home care, environment and reservoirs, and wellness activities. Chagas Express XXI was conceived as a social technology since all processes were co-created by scientists and patients with Chagas disease and worked with local cross-sector partnerships. We observed that 81% of the more than 2000 participants were unaware of the possibility of treating Chagas disease and 52% requested a blood test to diagnose CD. From the 1100 adults tested, 20% were diagnosed as positive for
The fourth idea would then be: if the clinical trial of Se becomes unfeasible, we will have a social legacy to be able to continue later.
However, the problem was not only in the communication and mobilization of patients to participate in STCC, since in INI/Fiocruz cohort the number of patients in the B1 and B2 stages of CCC was small as compared to patients in other clinical stages (indeterminate, A and C/D). Besides, a new risk for the project was arising: a long time had passed and the patients in the INI/Fiocruz cohort aged, acquiring comorbidities that were predicted as exclusion criteria and entering other studies that were ongoing, almost making the trial unfeasible due to a very slow rate of inclusion, as shown in Figure 3, during the years 2016 and 2017. To overcome this problem, the clinicians proposed to increase the age of recruitment from 65 to 75 years and to consider diabetes mellitus as a non-exclusion criterion.
Besides, the statisticians carried out other scenario studies for the feasibility of the STCC. They concluded that by extending the age range to up to 75 years, reducing the time of follow-up to one year, and focusing as a primary outcome only on the reduction of LVEF values (and not on the rate of CCC progression), we would conclude the inclusion of participants and generate some valid results. Then, in 2018, we published an update of the protocol [31] and started working to include 62 patients, divided into the two groups (placebo and Se treatment) for a follow-up of one year. We were then able to include all the expected patients and on August 8th, 2018, we were able to complete the last 12 months’ visit of the last participant included.
The next step was to include all the laboratory and the nutritional data in the database, to run quality control for it, and to start the statistical analysis, both for descriptions of the clinical findings of participants and for comparisons between the placebo and Se-treated groups, as well as sub-group analyses, whenever possible. The study results were finally published in September 2021 [5]. When comparing the mean values of LVEF recorded in Se treated with the placebo group at baseline and after 1 year of follow-up, we did not find significant differences in the B1/B2 stages patients (overall), nor in the B1 stage patients, but found a significant effect (
After one year (Figure 4, gray bars), all the groups showed a lower mean of LVEF when compared to baseline values (Figure 4, black bars). However only those already on the B2 subgroup, with LVEF <45%, showed a high decrease in LVEF in 1-year, which was reversed by Se treatment. The differences in LVEF longitudinal changes between groups were evaluated using linear mixed effect models in intention-to-treat analyses. This type of analysis assesses the rate of change of the outcomes by the time X intervention group interaction term, considering the correlations between repeated measures over time and missing data. In the B2 subgroup, the worsening of cardiac dysfunction was significantly reduced by Se treatment, and while the placebo group had a drop in LVEF, the Se group remained stable. In addition, only in the Se group, we observed cases of LVEF increase of more than 10 absolute points in 5 patients (n = 3) and recovery from stage B2 to B1 (n = 2), as reported [5]. In this short-term follow-up (1 year), the secondary outcomes observed were all related to LVEF as the underlying cause and could not be weighted in the analysis. We also observed that treatment with Se was safe for patients with CCC and that the low percentage of adverse effects detected were similar in the two groups. However, there was no complete shift of patients treated with Se to a safe range of serum Se (>100mcg/L), indicating that the dose of 100 mcg per day may have been insufficient. Further studies are needed to explore higher doses and/or associations of Se at different stages of CCC (B2 and C) at a short follow-up (one year) and at early diseases stages (A and B1), with longer follow-up.
The paper with STCC results [5] discussed some possibilities and pointed that “new clinical trials with a longer follow-up are needed to investigate the effects of Se in the mild (stages A and B) or severe (stages C and D) CCC, and in the asymptomatic indeterminate clinical form”. The limitations of STCC were reported and the future outspread of the project is depicted in Figure 2 from 2022 to, at least, 2026. The design of new projects (STCC#2 and STCC#3) is underway, and when the adequate industry partnership(s) will be signed, the proposal is that the new clinical trials will have a following of 3 to 10 years to generate the necessary evidence to support public policies recommendations.
Time sequence of inclusion of participants on the STCC clinical trial. Black solid line shows the putative participants tracked, dashed line shows the participants included after signing the project voluntary consent form, and solid line with white dots shows the number of patients that completed the one-year treatment. Note that after 2015 the slope angle of the inclusion curve rise, denoting a success in the recruiting phase.
Mean values for left ventricular ejection fraction recorded for all the patients participating in the STCC clinical trial, at baseline (baseline, black bars) and after 12 months (gray bars). In the X-axis it is shown the comparison of the groups treated with placebo or selenium, considering all the participants in each group and in the subgroups B1 and B2 stages. For details, see reference #5.
From basic research to a putative public health recommendation in clinical protocols and therapeutic guidelines, the roadmap of the Se project was a real saga, with many obstacles that tested team resilience and Brazilian conditions of science development.
This resilience derived from the strength of the encounter between a basic research group (in Oswaldo Cruz Institute (IOC), founded by TCAJ) and a clinic research group (INI, founded by AMHM). Both groups were very active in producing new knowledge in CD and were excited with the idea of conceiving and performing the first Brazilian clinical trial [23] with a strategy based on one of the pathological mechanisms implicated in CCC [8, 9]. Overpassing all the difficulties that were listed in Figure 2 (item 3), one after another, and attaining the conclusion of the trial gave even more strength to this partnership, our self-confidence, and our mutual respect increased.
The progress attained in the social arm of the project was also a source of resilience. More IOC/Fiocruz laboratories are associated with the project, as we could see from the Chagas Express publication [30] in August 2021. A project recently approved is preparing a virtual version of Chagas Express (https://expressochagas.com/), integrating contents related to COVID-19 as well as new expeditions to other endemic regions, planned for 2022.
In addition, this social arm of the project was developed at a very important moment in the struggle for the rights of patients with Chagas’ disease. In 2018, the Ministry of Health, through its National Commission of Technology Incorporation, offered Therapeutic Guideline for CD Diagnosis and Treatment (PCDT Chagas) to public consultation, fostering discussions that lead to reformulations and publication in 2019. It was one of the main documents disseminated in the expedition to Minas Gerais by Expresso Chagas XXI [30]. We also participated in the advocacy movement that led to compulsory notification of chronic cases. Together with the traditional surveillance of cases in the acute phase, ordinance No. 1.061, May 18, 2020, introduced notification of chronic cases in Brazilian territory, strengthening the construction of public policies based on scientific evidence.
In a recent review [32], Morel discussed that CD is an example of successful translational research integrating basic and applied science, attaining the control of its transmission by insect vectors in large regions of the Southern Cone countries in the 90s. However, if the successful control of CD transmission by insect vectors is, in fact, a paradigmatic achievement in science translation, in addition to organizing a strong scientific community in Brazil and in Latin America, the translational research to focus on vaccines and treatments suffers extremely negative pressures as the ones we reported above. One important lesson to take home after this saga is that translational science on a neglected disease in
What are the lessons learned and the next steps?
Four lessons were learned during the STCC saga—#1: the harmonious interaction between the clinical and basic research teams is essential to allow translational research to proceed; # 2: even in the pre-clinical phase, it is essential to identify potential suppliers in the market for the formulations that are intended to be used as treatment and/or industry partners interested in leading the product to the market; #3: the inclusion of master’s and doctoral students should only be done in pre-clinical studies. In clinical trials, the stable inclusion of trained and mature professionals, economically stable, is necessary to avoid the shortage of human resources during the study; #4: a national and international network of experts is critical to overcoming the numerous doubts that arise in such a long study. In this case, we learned a lot about the clinical use of Se during the 15 years of the clinical trial, and we continue to learn about the physiopathology and clinical management of patients with Chagas disease.
Concerning the next steps, we are at the stage of preparing the reports for the sponsors and for our patients participating in the study. We will have several consequences in the clinical scope:
to carry out the cardiological follow-up of the study participants for another 4 to 10 years;
to conduct a clinical trial with Brazil nuts as a natural source of Se;
to identify PCR-
to accomplish the study of immunological biomarkers and gene polymorphism for cytokines and selenoproteins in samples from participants in the published study;
to contact suppliers and industry partners to enable further studies with Se in different settings, conditions, and associations and in multicenter and international arrangements.
As a second initiative, we will prepare a dossier for the National Commission of Technology Incorporation in the Health System (Comissão Nacional de Incorporação de Tecnologias no SUS” – CONITEC) to evaluate the recommendation of dietary supplementation for patients with Chagas disease with Se, either by supplementation with one Brazil nut per day (about R $20 per month) or by supplementation with Se and Coenzyme Q10 (about R$80 per month), due to type B levels of evidence for therapeutic studies in the literature and the safety when administering Se to elderly persons [25, 26, 27].
Last, but not least, we intend to incorporate Chagas Express XXI as cutting-edge educational technology, since we have already demonstrated its potential as an instrument of field epidemiology. In the next expeditions planned for 2022 in the states of Pernambuco, Goiás, and Minas Gerais, we will include a rapid test for a local screening of positive people and inclusion in the National Health System for diagnostic confirmation and clinical follow-up. We will also include a local digital electrocardiogram to screen for possible abnormalities related to Chagas disease in individuals with mild cardiac form/stage A. The Chagas Express XXI is a potentially useful social technology for health and science education and active search for chronic cases of disease of asymptomatic CD patients, contributing to the notification of chronic cases and their inclusion in the lines of care of PCDT-Chagas. Furthermore, this technology can be adapted to understand and cooperate in other potentially epidemic situations, especially related to other neglected diseases, such as leishmaniasis, tuberculosis, and arboviruses.
We dedicate this work to all the patients who participate in the STCC trial, some of them contributing to the creation of the Rio Chagas Association. We thank all the basic and the clinical groups´ members of the Selenium project: Maria Teresa Rivera, Jean Vanderpas, Andrea P. Souza, Bianca P. Olivieri, Solange L. de Castro, Gabriel M. Oliveira, and Andrea P. Souza. Constança Britto, Otacílio C. Moreira, Erica R. Maciel, Fernanda M. Carneiro, Sérgio S. Xavier, Priscila F. Santos, Henrique H. Veloso, Pedro E.A.A. Brasil, Andrea S. de Sousa, Paula S. da Silva and Luiz Henrique C. Sangenis. We also thank Catalent Brasil Ltda for supplying free-of-charge sodium selenite and placebo for the STCC study. T.C.A-J represents Fiocruz in the Ibero-American New Tools for the Diagnosis and Evaluation of CD (NHEPACHA) network. This work was supported by the Department of the Industrial Complex and Innovation in Health from the Brazilian Health Ministry (IOC Fiotec IOC-001-LIV-11-2-1; 25380.001603/2017-2089), the governmental agencies CNPq (306184/2010-9, 309545/2014-5;313011/2018-4), FAPERJ (E26/151.506/99; Protocol 33); and the Innovation and the Research Vice-Presidencies of Fiocruz. Students who participated in the project received fellowships from Coordenação de Aperfeiçoamento de Pessoal do Ensino Superior (CAPES) related to their respective Fiocruz post-graduation courses.
The authors declare no conflict of interest. The funders had no role in the design of the study nor in the writing of the manuscript, or in the decision to publish the results.
IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
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\\n\\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
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\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
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\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
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\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
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\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
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\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
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Caron",authors:[{id:"28397",title:"Prof.",name:"Philippe",middleName:null,surname:"CARON",slug:"philippe-caron",fullName:"Philippe CARON"},{id:"41398",title:"Dr.",name:"Delphine",middleName:null,surname:"Vezzosi",slug:"delphine-vezzosi",fullName:"Delphine Vezzosi"},{id:"41399",title:"Dr.",name:"Antoine",middleName:null,surname:"Bennet",slug:"antoine-bennet",fullName:"Antoine Bennet"},{id:"41400",title:"Dr.",name:"Jean-Christophe",middleName:null,surname:"Maiza",slug:"jean-christophe-maiza",fullName:"Jean-Christophe Maiza"},{id:"41401",title:"Dr.",name:"Alexandre",middleName:null,surname:"Buffet",slug:"alexandre-buffet",fullName:"Alexandre Buffet"},{id:"41402",title:"Dr.",name:"Solange",middleName:null,surname:"Grunenwald",slug:"solange-grunenwald",fullName:"Solange Grunenwald"},{id:"41403",title:"Dr.",name:"Josette",middleName:null,surname:"Fauvel",slug:"josette-fauvel",fullName:"Josette Fauvel"},{id:"41404",title:"Dr.",name:"Frédéric",middleName:null,surname:"Courbon",slug:"frederic-courbon",fullName:"Frédéric Courbon"},{id:"41405",title:"Prof.",name:"Philippe",middleName:null,surname:"Otal",slug:"philippe-otal",fullName:"Philippe Otal"},{id:"41406",title:"Prof.",name:"Nicolas",middleName:null,surname:"Carrere",slug:"nicolas-carrere",fullName:"Nicolas Carrere"}]},{id:"21812",doi:"10.5772/17172",title:"Estradiol Regulation of Prostanoids Production in Endothelium",slug:"estradiol-regulation-of-prostanoids-production-in-endothelium",totalDownloads:1826,totalCrossrefCites:0,totalDimensionsCites:2,abstract:null,book:{id:"505",slug:"basic-and-clinical-endocrinology-up-to-date",title:"Basic and Clinical Endocrinology Up-to-Date",fullTitle:"Basic and Clinical Endocrinology Up-to-Date"},signatures:"Susana Novella and Carlos Hermenegildo",authors:[{id:"27480",title:"Dr.",name:"Carlos",middleName:null,surname:"Hermenegildo",slug:"carlos-hermenegildo",fullName:"Carlos Hermenegildo"},{id:"27492",title:"Dr.",name:"Susana",middleName:null,surname:"Novella",slug:"susana-novella",fullName:"Susana Novella"}]},{id:"21802",doi:"10.5772/17843",title:"Cardiovascular Effects of Androgens",slug:"cardiovascular-effects-of-androgens",totalDownloads:3403,totalCrossrefCites:2,totalDimensionsCites:2,abstract:null,book:{id:"505",slug:"basic-and-clinical-endocrinology-up-to-date",title:"Basic and Clinical Endocrinology Up-to-Date",fullTitle:"Basic and Clinical Endocrinology Up-to-Date"},signatures:"Carlos Wilson, Rodrigo Maass and Manuel Estrada",authors:[{id:"29615",title:"Dr.",name:"Manuel",middleName:null,surname:"Estrada",slug:"manuel-estrada",fullName:"Manuel Estrada"},{id:"37176",title:"Mr",name:"Carlos",middleName:null,surname:"Wilson",slug:"carlos-wilson",fullName:"Carlos Wilson"},{id:"80645",title:"Dr.",name:"Rodrigo",middleName:null,surname:"Maass",slug:"rodrigo-maass",fullName:"Rodrigo Maass"}]}],mostDownloadedChaptersLast30Days:[{id:"70529",title:"Thyroid Storm: Clinical Manifestation, Pathophysiology, and Treatment",slug:"thyroid-storm-clinical-manifestation-pathophysiology-and-treatment",totalDownloads:1267,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Thyroid storm is a rare but life-threatening endocrine emergency. It is an acute exaggerated clinical manifestation of thyrotoxic state. The exact incidence is unknown. It occurs in 1–2% of patients admitted for thyrotoxicosis. It has a mortality of 10–20%. This chapter would help us to understand its clinical manifestations, pathophysiology, and effective treatment. Terminal learning objective would be to diagnose impending storm early and start prompt treatment in day-to-day practice. The chapter would cover pathophysiology including triggers, clinical features including various diagnostic criteria, diagnosis, and treatment of thyroid storm. Indications of surgical treatment in storm will be discussed.",book:{id:"9077",slug:"goiter-causes-and-treatment",title:"Goiter",fullTitle:"Goiter - Causes and Treatment"},signatures:"Rahul Pandey, Sanjeev Kumar and Narendra Kotwal",authors:[{id:"309356",title:"Dr.",name:"Rahul",middleName:null,surname:"Pandey",slug:"rahul-pandey",fullName:"Rahul Pandey"},{id:"310903",title:"Dr.",name:"Sanjeev",middleName:null,surname:"Kumar",slug:"sanjeev-kumar",fullName:"Sanjeev Kumar"},{id:"310904",title:"Dr.",name:"Narendra",middleName:null,surname:"Kotwal",slug:"narendra-kotwal",fullName:"Narendra Kotwal"}]},{id:"70705",title:"Multinodular Goiter",slug:"multinodular-goiter",totalDownloads:963,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Multinodular goiter (MNG) is the most common disorder of the thyroid gland. It is highly endemic in iodine-deficient areas; MNG can be seen in almost all individuals with severe iodine-deficient areas. It starts as a diffuse enlargement of the thyroid gland and ends in a nodular enlarged thyroid. Though MNG can be sporadic, there is a strong correlation between occurrence of MNG and iodine deficiency. The characteristic feature of MNG is its functional and structural heterogeneity. The MNG usually presents as neck swelling; rarely it may produce pressure symptoms, i.e., dyspnea, hoarseness of voice, and dysphagia. It can also present with symptoms of hyperthyroidism particularly in long-standing goiter. Imaging particularly ultrasound is very useful to define characteristic of MNG and surrounding structure. The incidence of malignancy in MNG is 4–14%, and risk factors are family history of thyroid carcinoma, history of neck radiation, prior surgery, and presence of cervical lymphadenopathies. Management of MNG can be done by drugs, surgery, and radioiodine (I-131) depending on results of diagnostic evaluation and associated complications.",book:{id:"9077",slug:"goiter-causes-and-treatment",title:"Goiter",fullTitle:"Goiter - Causes and Treatment"},signatures:"Sanjay Saran",authors:[{id:"242737",title:"Dr.",name:"Sanjay",middleName:null,surname:"Saran",slug:"sanjay-saran",fullName:"Sanjay Saran"}]},{id:"61473",title:"Nuclear Medicine in the Assessment of Thyrotoxicosis Associated with Increased Thyroid Function and Radioiodine 131 Ablative Therapies",slug:"nuclear-medicine-in-the-assessment-of-thyrotoxicosis-associated-with-increased-thyroid-function-and-",totalDownloads:1463,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Nuclear medicine is directly involved in both the diagnosis and treatment of benign thyroid disease. Thyroid scintigraphy (most commonly with technetium-99 m pertechnetate) should be used as the imaging modality of choice for assessment of thyrotoxicosis, since it demonstrates the functional state of the thyroid gland. An adequate understanding of the pathophysiological mechanisms and characteristics of the patient is essential, as well as the different treatments of thyroid disorders that present with hyperthyroidism (Graves’ disease, toxic multinodular goiter, and toxic adenoma-Plummer’s disease). Therapeutic modalities include antithyroid drugs, radioiodine and surgery. Antithyroid drugs are the first line of therapy and regarding the use of radioiodine, current recommendations consider it a safe and effective therapeutic alternative in hyperthyroidism. Finally, we highlight the existence of some special situations (children, pregnancy, thyroid eye disease, chronic renal failure and dialysis patients) and the importance of radiation protection measures to the patient, the public and professionals.",book:{id:"6791",slug:"thyroid-disorders",title:"Thyroid Disorders",fullTitle:"Thyroid Disorders"},signatures:"Elena Espinosa Muñoz",authors:[{id:"241332",title:"M.Sc.",name:"Elena",middleName:null,surname:"Espinosa Muñoz",slug:"elena-espinosa-munoz",fullName:"Elena Espinosa Muñoz"}]},{id:"71040",title:"Hyperthyroidism",slug:"hyperthyroidism",totalDownloads:918,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Excess level of thyroid hormones in blood is thyrotoxicosis, which is responsible for clinical syndrome of hypermetabolism, sympathetic hyperactivity. Hyperthyroidism is the term used to denote the overproduction of thyroid hormones from the thyroid gland. Hyperthyroidism is possible with hyperactive thyroid gland due to multi/solitary nodular thyroid disease or Grave’s disease. Thyrotoxicosis associated with thyroiditis is not hyperthyroidism. Treatment of hyperthyroidism is with anti-thyroid drugs (ATT), radio-active iodine ablation (RAI), or thyroid surgery; whereas, treatment of thyroiditis is symptomatic.",book:{id:"9077",slug:"goiter-causes-and-treatment",title:"Goiter",fullTitle:"Goiter - Causes and Treatment"},signatures:"Rushikesh Maheshwari",authors:[{id:"300029",title:"Dr.",name:"Rushikesh",middleName:null,surname:"Maheshwari",slug:"rushikesh-maheshwari",fullName:"Rushikesh Maheshwari"}]},{id:"61460",title:"Thyroid Cancer: Diagnosis, Treatment and Follow-Up",slug:"thyroid-cancer-diagnosis-treatment-and-follow-up",totalDownloads:1552,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Thyroid cancer is the most common malignancy of the endocrine system and it is usually presented as nodular goiter, the last being extremely a common clinical and ultrasound finding. The widespread use of ultrasonography during the last decades has resulted in a dramatic increase in the prevalence of clinically inapparent thyroid nodules, which only in 5.0–10.0% harbor thyroid carcinoma. The goal of the initial sonographic assessment of thyroid nodules is to distinguish benign nodules that could be managed conservatively from those with suspicious or malignant features requiring further management, including fine needle aspiration biopsy (FNAB), some axillary molecular techniques and thyroid surgery. Since over 90% of malignant thyroid nodules are differentiated thyroid carcinomas (DTCs) with good prognosis, it is necessary to establish strict criteria for diagnosis, treatment and follow-up in order to minimize the potential harm of over-treatment of low-risk patients and to provide adequate therapy to patients at high risk. This often requires an interdisciplinary approach involving endocrinologists, surgeons, pathologists, radiologists and oncologists.",book:{id:"6791",slug:"thyroid-disorders",title:"Thyroid Disorders",fullTitle:"Thyroid Disorders"},signatures:"Mira Siderova",authors:[{id:"242582",title:"Associate Prof.",name:"Mira",middleName:null,surname:"Siderova",slug:"mira-siderova",fullName:"Mira Siderova"}]}],onlineFirstChaptersFilter:{topicId:"1011",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:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,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:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,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:"June 11th, 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,annualVolume:11418,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,annualVolume:11419,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,annualVolume:11420,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,annualVolume:11421,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. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. 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