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Sherief and Marwa Zakaria",authors:[{id:"106463",title:"Prof.",name:"Tamer",middleName:"Hasan",surname:"Hassan",fullName:"Tamer Hassan",slug:"tamer-hassan"},{id:"110940",title:"Prof.",name:"Laila",middleName:null,surname:"Sherief",fullName:"Laila Sherief",slug:"laila-sherief"},{id:"174733",title:"Dr.",name:"Usama",middleName:null,surname:"El Safy",fullName:"Usama El Safy",slug:"usama-el-safy"},{id:"187306",title:"Prof.",name:"Mohamed",middleName:null,surname:"Badr",fullName:"Mohamed Badr",slug:"mohamed-badr"},{id:"187544",title:"Prof.",name:"Mervat",middleName:null,surname:"Hesham",fullName:"Mervat Hesham",slug:"mervat-hesham"},{id:"187545",title:"Dr.",name:"Marwa",middleName:null,surname:"Zakaria",fullName:"Marwa Zakaria",slug:"marwa-zakaria"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"67722",title:"Clinical Features and Management of Chronic Chikungunya Arthritis",doi:"10.5772/intechopen.86486",slug:"clinical-features-and-management-of-chronic-chikungunya-arthritis",body:'\nChikungunya virus (CHIKV) is a small, single-stranded RNA alphavirus transmitted to humans by Aedes species mosquitoes, including Aedes aegypti and Aedes albopictus. CHIKV was initially isolated in Tanzania in 1952–1953 [1]. The word “chikungunya” means “that which bends up” or “to become contorted” in the Makonde language, referring to the prostrated appearance of affected patients [2].
\nPrior to its isolation, chikungunya (CHIK) was often misdiagnosed as dengue [3]. During the twentieth century, chikungunya fever (CHIKF) epidemics occurred sporadically and were limited to Africa and Asia, but in the twenty-first century CHIK has become a global disease. There was a major outbreak in coastal Kenya in 2004, which subsequently spread to Réunion in 2005 and throughout the Indian Ocean region [4]. Cases among travelers returning from endemic regions were reported in Italy in 2007 [5].
\nCHIKV reached the Western Hemisphere in 2013 with an outbreak on the island of Saint Martin. Since then, the virus has spread throughout the region with more than 2 million cases documented in the Americas by the end of 2016, though the actual number is likely much higher [3]. In the United States, cases involving travelers to endemic regions have been documented in 49 states, and locally-acquired cases have occurred in Florida and Texas [6].
\nFactors contributing to the spread of CHIK include increasing urbanization, overstrained health care infrastructures in developing countries, ease of international travel, and climate change with expansion of mosquito vectors [7].
\nThere are three known genotypes of CHIKV: Asia, East/Central/South Africa, and West Africa. The 2004–2005 pandemic that originated in Kenya and subsequently spread throughout the Indian Ocean region involved the East/Central/South Africa genotype. The pandemic that emerged in the Americas in 2013 originally involved the Asia genotype, although more recently the East/Central/South Africa lineage has been reported in the Western Hemisphere [8, 9].
\nCHIKV infection results from transmission by the mosquito vector. Following an incubation period of 5–7 days, patients develop an acute febrile illness, chikungunya fever (CHIKF), characterized by high fevers, maculopapular rash, headaches, polyarthritis/arthralgias, myalgias, nausea, vomiting, and diarrhea [1]. Joint pain is often severe, and most often involves the metacarpal-phalangeal and interphalangeal joints of the hands, the wrists, the ankles, and the metatarsal-phalangeal joints of the feet. Less commonly involved but described joints include the shoulders, elbows, hips, knees, and inter-vertebral joints [10]. Acute CHIKF causes significant physical disability. For example, during the 2005 Comoros epidemic, an estimated 80% of affected patients were hospitalized or bed-bound due to severity of their symptoms [11].
\nMore severely affected patients can develop neurological disease including meningoencephalitis, myelitis, radiculitis, and/or peripheral neuropathy, including reports of Guillain-Barré syndrome [12]. Rare ophthalmological manifestations reported include keratitis, episcleritis, optic neuritis, uveitis, and retinal detachment [13]. Uncommon but serious cardiac manifestations include arrhythmias, vasculopathy, myocarditis, and/or dilated cardiomyopathy [14, 15]. Patients with acute infection can have laboratory abnormalities including thrombocytopenia and leukopenia (lymphopenia is more common than neutropenia) [4].
\nMaternal-to-child transmission has also been reported, with up to 50% of neonates acquiring infection during childbirth if born within 5 days of maternal infection. Musculoskeletal manifestations are less prominent in newborns, with CHIKF being more notable for fevers, rash, cytopenias, hepatitis, and/or encephalitis [16].
\nAcute CHIKF typically resolves in 10–14 days, and has an overall reported case fatality rate of <1% based on epidemics in the Indian Ocean region and the Americas. However, the case fatality rate is higher among newborns, the elderly, and patients with underlying cardiovascular and pulmonary conditions [7, 17, 18]. Economopoulou and colleagues studied the case fatality rate among atypical cases of CHIKF in Réunion (defined as patients presenting with symptoms other than fevers and arthralgias); 65/610 patients from this group died for a case fatality rate of 10.6% [19].
\nDuring the widespread Indian Ocean region pandemic, a point mutation (A226V) in the E1 surface glycoprotein of CHIKV may have allowed better adaptation in Aedes albopictus, which had previously been a minor vector [20]. Along with low background immunity among populations residing in regions not historically affected, this may account for the rapid spread and high rates of infectivity seen for CHIKV in the twenty-first century.
\nArthritis/arthralgia is a principal feature of CHIKF. Many patients recover within several weeks, but up to 50% develop chronic joint pain and swelling. When rheumatic disease persists for more than 12 weeks, we refer to these symptoms as chronic chikungunya arthritis (CCA). Arthritic manifestations can last for weeks, months, or even years [21]. Rodriguez-Morales and colleagues retrospectively studied 283 patients from the 2015 epidemic in Risaralda Department, Colombia. At 26 weeks post-infection, 53.7% of the patients reported chronic musculoskeletal symptoms, including 49.5% with morning stiffness, 40.6% with joint swelling, and 16.6% with joint erythema [22]. Another large observational study from Kerala, India found that 57% of patients had chronic polyarthralgias, 22% chronic polyarthritis, and 19.5% chronic tenosynovitis 15 months after CHIKF [23].
\nThe classical pattern of arthritis involves the small-to-medium sized joints in a peripheral and symmetric distribution [24]. This pattern can resemble rheumatoid arthritis (RA). Joint pain with/without synovitis can persist following acute CHIKF, or joint symptoms may remit and then recur at a later time [21].
\nPatient with chronic chikungunya arthritis (CCA). A 50-year-old woman with CCA and synovitis of the right third PIP and left second PIP joints. She had acute CHIKF 3 years prior and subsequently developed CCA of the hand joints. Image courtesy of José Kennedy Amaral, M.D., Pernambuco, Brazil.
A prospective Mexican cohort study showed that greater severity of acute infection predicted development of chronic arthritis, as measured by the disease activity index 28 (DAS28), World Health Organization Disablement Assessment Schedule II (WHODAS-II), and serum IL-6 level [25]. Other risk factors for chronic disease include patient age >45 years and high viral load (>109 per ml) during acute infection [26].
\nDuring acute CHIK infection, serum cytokines IL-1Ra, IL-1β, IL-6, IL-7, IL-8, IL-12, IL-15, and IFN-α increase, while RANTES (CCL5) decreases [27, 28]. With the transition to CCA, elevated levels of IL-6, GM-CSF, and IL-17 become predominant [28]. The IL-17 signature in particular may drive chronic joint inflammation, stimulating the upregulation of other pro-inflammatory cytokines, including IL-1, IL-6, and TNF-α, matrix metalloproteinases, and RANK-RANKL leading to osteoclastogenesis and bone erosions [29]. Alphavirus infection of osteoblasts has been shown to perturb the RANKL-osteoprotegerin ratio, contributing to bone loss. This imbalance may also provide a mechanism for joint erosions in chronic disease [30].
\nCHIKV primarily infects human epithelial and endothelial cells, fibroblasts, and macrophages. Replication has not been observed in lymphocytes, monocytes, or monocyte-derived dendritic cells [31]. Viral tropism to the highly-vascularized synovial tissues of the joints may be responsible for the prominence of arthritis following acute infection. Whether CHIKV persists in synovial tissue during the chronic phase remains unclear, however, and there is ongoing debate about whether CCA arises secondary to immunological dysregulation or is due to persistent alphavirus infection of the synovial tissue.
\nHoarau and colleagues demonstrated the presence of CHIKV RNA and viral proteins within perivascular synovial macrophages from one patient with CCA 18 months following acute infection [32]. This finding has not been replicated in other patients with chronic joint disease, however. Viral RNA has been isolated from knee synovial tissue of patients infected with a related alphavirus, Ross River virus [33]. In non-human primates, CHIKV can be recovered from muscle, synovial, lymphoid, and hepatic tissues following resolution of acute infection. Macrophages have also been identified as viral reservoirs [34].
\nIn a cohort from the Réunion epidemic, 16 CCA patients were evaluated for persistence of viral infection. Synovial fluid (10 patients) and biopsied tissue (6 patients) was evaluated with reverse transcriptase polymerase chain reaction (RT-PCR) for CHIKV. All samples were negative, suggesting active viral replication is not the cause of chronic articular disease [35].
\nThese findings were replicated in a Colombian cohort with CCA, evaluated during the 2014–2015 epidemic. In all patients, synovial fluid was aspirated from inflamed joints. CHIKV DNA was not recovered by RT-PCR, viral proteins were not detected by mass spectrometry, and viral cultures were also negative for all patients. The authors concluded that CCA is probably a post-infectious autoimmune process [36]. Evidence for molecular mimicry between host tissues and CHIKV E1 glycoprotein has been postulated [37]. However, the specific mechanisms by which CHIK infection might lead to immunological dysregulation and autoimmunity are unknown.
\nThe diagnosis of CHIK depends on epidemiologic information, characteristic clinical features, the time course of the infection, and laboratory confirmation. Many patients live in or have had recent travel to an area with endemic transmission of Aedes mosquitos. Laboratory testing depends on the time course of infection. During acute disease, CHIK viremia lasts for 5–7 days. At this time, RT-PCR of serum can be diagnostic. Anti-CHIKV IgM antibodies appear at 3–8 days and remain positive for 1–3 months. Anti-CHIKV IgG antibodies are detectable at 4–10 days and remain positive for months to years [1].
\nCCA patients present with chronic debilitating joint symptoms ranging from morning stiffness and arthralgias to frank inflammatory synovitis. A classical pattern of small-and-medium joint peripheral involvement has been described, but mono- and oligoarthritis can also occur (Figure 1). In some patients, CCA presents clinically as an RA “mimic,” but most patients have negative tests for rheumatoid factor and anti-cyclic citrullinated peptide antibodies [38]. Patients with CCA often meet diagnostic and/or clinical criteria for RA or spondyloarthritis [39]. The distinguishing clinical feature is a previous history of acute CHIKF, with laboratory confirmation of serum positivity for IgM and/or IgG anti-CHIK antibodies.
\nRadiographic imaging of involved joints may be normal, especially early in the disease, with progression to bone erosions in some patients over time. Magnetic resonance imaging has greater sensitivity for the detection of inflammatory changes, and can show synovial thickening, bone marrow edema, effusions, and/or tenosynovitis [38].
\nGuidelines for the management of CCA emphasize symptomatic pain control with acetaminophen/paracetamol, codeine, and/or neuropathic medications such as gabapentin. Adjunctive treatment includes physical therapy, thermotherapy, and/or cryotherapy [16]. These approaches can relieve pain and improve function, but are not disease-modifying.
\nIn an uncontrolled case series during the 2005–2006 Indian Ocean pandemic, short-term corticosteroid treatment improved arthritis and tenosynovitis, and reduced disability in patients with CCA [40]. Corticosteroid treatment led to greater pain relief and patient satisfaction compared to paracetamol, NSAIDs, medicinal herbs, and physical exercise [41].
\nPadmakumar and colleagues performed a randomized-controlled trial evaluating the efficacy of single and combination NSAID and corticosteroid treatment regimens for CCA. Functional and pain assessments improved with corticosteroids (prednisolone 10 mg daily) in addition to the NSAID aceclofenac 200 mg daily, compared to those who received aceclofenac alone. The addition of hydroxychloroquine (HCQ) did not provide added benefit [42].
\nDespite positive results, long-term use of corticosteroids is not advised due to well-known risks of infection, cataracts, glaucoma, hyperglycemia and diabetes mellitus, and osteopenia/osteoporosis associated with chronic corticosteroid use.
\nAn open-label pilot study of chloroquine (CQ) treatment for CCA in South Africa showed improvement in patient and physician disease activity assessments, though this trial was not blinded [43]. Brito and colleagues recommended HCQ at a dose of 6 mg/kg daily as first-line treatment for CCA, as part of a regimen potentially escalating to triple therapy with sulfasalazine (SSZ) and methotrexate (MTX) [44].
\nHowever, a randomized-controlled trial comparing short-term treatment with CQ to placebo for acute CHIK arthritis found no differences between-group in the duration of arthralgias or viremia, but increased rates of chronic arthralgias in the treated group [45]. Chopra and colleagues performed a comparative effectiveness trial between CQ 250 mg daily and meloxicam 7.5 mg daily in patients with CCA and found no difference in efficacy [46].
\nIn the open-label randomized trial by Ravindran and Alias, combination therapy (MTX 15 mg weekly, SSZ 1000 mg daily, and HCQ 400 mg daily) was superior to HCQ monotherapy [47]. The trial did not include a placebo group, precluding the possibility of determining the efficacy of HCQ.
\nOverall, most current evidence suggests that antimalarials such as CQ and HCQ are not effective for the treatment of CCA.
\nThe Ravindran and Alias trial included SSZ 1000 mg daily in combination with HCQ and MTX as part of triple therapy, compared to HCQ [47]. While combination therapy was more efficacious, the contribution of SSZ separate from MTX could not be established.
\nGanu and Ganu evaluated a cohort of 16 patients with persistent arthritis following acute CHIKF, comparing treatment with SSZ and MTX to SSZ alone. Improvement was noted in 71.4% of patients receiving combination therapy compared to 12.5% of patients receiving SSZ monotherapy [48]. A significant limitation of this trial was the lack of a control group; it remains questionable whether SSZ was any more effective than a placebo response. In addition, a majority of the patients had anti-cyclic citrullinated peptide antibodies, suggesting they had RA rather than CCA.
\nOverall, there is very limited data suggesting efficacy of SSZ monotherapy for the treatment of CCA, but it may be efficacious in combination with other medications such as MTX.
\nPandya treated 149 Indian patients with CCA with MTX 15–20 mg weekly in combination with HCQ. At 16 weeks, ACR20 responses were achieved in 48.9%, ACR50 in 18.8%, and ACR70 in 4.0%. Clinical response was less robust as measured by DAS28-ESR, with just 1/149 patients achieving clinical remission (DAS28-ESR <2.6) and only 4/149 with a good clinical response (DAS28-ESR <3.2) [49]. One important limitation of the study was that the diagnosis of CCA was made entirely on clinical grounds, without serological confirmation of anti-CHIKV antibodies. As such, the patient population may have been heterogeneous, including non-CHIK inflammatory arthritis syndromes.
\nIn the trial by Ravindran and Alias, the combination therapy regimen including MTX 15 mg weekly (along with SSZ 1000 mg daily and HCQ 400 mg daily) was superior to HCQ alone (DAS28-ESR <3.2 at 24 weeks, 84% versus 14% respectively). Both groups also received prednisolone 7.5 mg daily, but this was tapered off by 6 weeks [47]. In another trial by Ganu and Ganu, patients with an inadequate treatment response to combination SSZ and HCQ were escalated to treatment with MTX 15–20 mg weekly versus placebo. The MTX group achieved a superior clinical response versus SSZ/HCQ (71.4% versus 12.5%) [48].
\nJavelle and colleagues reported on treatment of a Réunion cohort with CCA following the 2005-2006 epidemic. Among patients treated with MTX 7.5–25 mg weekly, 54/72 (75%) achieved a good clinical response [39].
\nBouquillard and Combe treated patients with acute CHIKF who were subsequently diagnosed with RA. Among 19 patients treated with MTX, 13 had a good clinical response (68.4%). Among these patients, 54.1% were positive for rheumatoid factor, and 28.6% had anti-cyclic citrullinated peptide antibodies [50]. As such, many of the patients were diagnosed with seronegative RA, which can closely mimic the signs and symptoms of CCA, and which might respond to similar treatments.
\nAmaral and colleagues treated 48 patients with CCA with open-label MTX initiated at 7.5 mg weekly, with dose escalations for refractory symptoms at 4 weeks. The final mean MTX dose was 9.2 ± 3.2 mg per week. MTX therapy was combined with prednisone at a mean daily dose of 6.1 ± 2.2 mg for nine patients (18%). Two patients received HCQ (400 mg daily) with MTX, and one also received SSZ (1000 mg daily). At the first visit, the mean value for pain by visual analog scale was 7.7 ± 2.0. The mean values for pain at 4 and 8 weeks, compared to baseline, decreased to 3.0 and 2.6 respectively [24].
\nOverall, MTX has shown promise in the treatment of CCA, though previous trials have either combined MTX with HCQ and SSZ, or have been unblinded. Further randomized trials are needed to evaluate MTX monotherapy.
\nNo human trials have yet been conducted to evaluate the efficacy of biologic therapy with monoclonal antibodies for the treatment of CCA.
\nRoss River virus (RRV) is an alphavirus phylogenetically related to CHIKV. In RRV infected mice, treatment with the TNF-α inhibitor etanercept resulted in decreased weight gain, increased viral titers, and increased inflammatory cell recruitment and tissue damage [51]. This study suggests that etanercept treatment of human patients with acute CHIKF might be detrimental, though treatment of patients with CCA could have a different outcome.
\nBouquillard and Combe treated patients with acute CHIKF followed by the diagnosis of RA (not categorized as CCA) with TNF-α inhibitors. These patients had been refractory to initial therapy with MTX. 6/6 patients had a good clinical response (four with etanercept, two with adalimumab) [50]. The majority of the patients had been diagnosed with seronegative RA, which was not distinguished from CCA.
\nTreatment of CHIKV acutely-infected mice with the anti-CTLA-4 monoclonal antibody abatacept showed decreased T cell infiltration of joint tissues without affecting viral replication [52]. There is currently no data for its use in humans, nor for its use in treating CCA.
\nPentosan polysulfate is a novel glycosaminoglycan-like molecule developed for the treatment of alphavirus infections. Treatment of CHIKV-infected mice with pentosan polysulfate reduced cartilage thinning and immunological infiltration of joints [53]. Intra-articular levels of the pro-inflammatory cytokines IL-6, IL-9, CCL2, and G-CSF were decreased, and levels of the anti-inflammatory IL-10 were increased through unclear mechanisms [30]. While developed for the treatment of acute CHIK infection, it remains unclear if pentosan polysulfate could be used for the treatment of CCA, in particular to prevent joint erosions.
\nFingolimod is a sphingosine 1-phosphate receptor agonist developed for the treatment of multiple sclerosis. In CHIKV-infected mice, fingolimod treatment decreased the migration of CD4+ T cells into joints without affecting viral replication [54]. While the utility of fingolimod for treatment of CCA remains unknown, decreasing T cell migration into joints might be beneficial.
\nCCA is an emerging chronic and disabling rheumatological syndrome which can persist for weeks, months, or years after acute CHIKF. With the global spread of CHIKV in past decades, increasing numbers of patients from developing countries in particular have acquired or are at risk for this chronic disabling rheumatic syndrome.
\nThe pathophysiology of the disease remains uncertain, though the weight of evidence suggests that the syndrome is caused by a post-viral autoimmune process, which follows viral clearance.
\nThere is limited clinical trial evidence for the use of disease modifying therapeutics for patients with CCA. Most previous trials have been open-label or of limited quality. Empiric treatment courses with corticosteroids, NSAIDs, antimalarials, and SSZ can be considered. However, given similarities between CCA and RA, it is our opinion that management with MTX should be further evaluated. Over time, new treatments including biologics and novel agents (pentosan polysulfate, fingolimod) may also emerge as treatment options.
\nNone of the authors have any conflicts of interest to report.
\nNone.
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\\n\\nSubject to the following Article, the 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 rights:
\\n\\nThe foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
\\n\\nThe Author, on his or her own behalf and on behalf of any Co-Authors, reserves the following rights in the Work 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 Work 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 Author, and any Co-Author, confirms that they 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 Work and all versions of it created during IntechOpen's editing process, including the published version is retained by the Author and any Co-Authors.
\\n\\nSubject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
\\n\\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\\n\\nThe Author, on his or her own behalf and on behalf of any Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\\n\\nAUTHOR'S DUTIES
\\n\\nWhen distributing or re-publishing the Work, the Author agrees to credit the Publication in which the Work has been published as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Publication in which the Work has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\\n\\nThe Author agrees to:
\\n\\nThe Author is responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\\n\\nThe 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 Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or photocopies of such consents.
\\n\\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example, from case reports or photographs.
\\n\\nThe Author shall respect confidentiality 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 Authors and Co-Authors are confidential and are intended only for the recipients. The contents of any communication 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\\nAUTHOR'S WARRANTY
\\n\\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\\n\\nThe Author and Co-Authors confirm and warrant that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work 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) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement, or 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 Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses granted in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author and Co-Authors confirm and warrant that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) they have the authority to enter into this binding Publication Agreement on behalf of each Co-Author. The 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 Co-Author.
\\n\\nThe Author agrees to indemnify IntechOpen for all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\\n\\nNothing 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\\nTERMINATION
\\n\\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including, without limitation: (i) if the Author and/or any Co-Author materially breaches this Publication Agreement; (ii) if the Author and/or any individual Co-Author is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any corporate Co-Author 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 the event of termination, IntechOpen will notify the Author of the decision in writing.
\\n\\nINTECHOPEN’S DUTIES AND RIGHTS
\\n\\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\\n\\nIntechOpen has the right to include/use the Author and Co-Authors´ names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion, and marketing of the Work and has the right to contact the Author and Co-Authors until, and while, the Work is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors 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 Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the alleged infringer.
\\n\\nMISCELLANEOUS
\\n\\nFurther Assurance: The Author shall 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 providing IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\nThird 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\\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces 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 (known as the "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 any fraudulent pre-contract misrepresentation or concealment.
\\n\\nWaiver: 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\\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or by their duly authorized representatives.
\\n\\nSeverance: 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 remainder of this Publication Agreement.
\\n\\nNo 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 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\\nGoverning 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\\nPolicy last updated: 2018-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Chapters below:
\n\nAUTHOR'S GRANT OF RIGHTS
\n\nSubject to the following Article, the 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 rights:
\n\nThe foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
\n\nThe Author, on his or her own behalf and on behalf of any Co-Authors, reserves the following rights in the Work 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 Work 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 Author, and any Co-Author, confirms that they 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 Work and all versions of it created during IntechOpen's editing process, including the published version is retained by the Author and any Co-Authors.
\n\nSubject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
\n\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\n\nThe Author, on his or her own behalf and on behalf of any Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\n\nAUTHOR'S DUTIES
\n\nWhen distributing or re-publishing the Work, the Author agrees to credit the Publication in which the Work has been published as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Publication in which the Work has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\n\nThe Author agrees to:
\n\nThe Author is responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\n\nThe 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 Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or photocopies of such consents.
\n\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example, from case reports or photographs.
\n\nThe Author shall respect confidentiality 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 Authors and Co-Authors are confidential and are intended only for the recipients. The contents of any communication 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\nAUTHOR'S WARRANTY
\n\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\n\nThe Author and Co-Authors confirm and warrant that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work 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) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement, or 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 Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses granted in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author and Co-Authors confirm and warrant that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) they have the authority to enter into this binding Publication Agreement on behalf of each Co-Author. The 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 Co-Author.
\n\nThe Author agrees to indemnify IntechOpen for all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\n\nNothing 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\nTERMINATION
\n\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including, without limitation: (i) if the Author and/or any Co-Author materially breaches this Publication Agreement; (ii) if the Author and/or any individual Co-Author is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any corporate Co-Author 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 the event of termination, IntechOpen will notify the Author of the decision in writing.
\n\nINTECHOPEN’S DUTIES AND RIGHTS
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\n\nIntechOpen has the right to include/use the Author and Co-Authors´ names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion, and marketing of the Work and has the right to contact the Author and Co-Authors until, and while, the Work is publicly available on any platform owned and/or operated by IntechOpen.
\n\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors 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 Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the alleged infringer.
\n\nMISCELLANEOUS
\n\nFurther Assurance: The Author shall 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 providing IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\nThird 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\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces 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 (known as the "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 any fraudulent pre-contract misrepresentation or concealment.
\n\nWaiver: 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\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or by their duly authorized representatives.
\n\nSeverance: 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 remainder of this Publication Agreement.
\n\nNo 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 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\nGoverning 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\nPolicy last updated: 2018-09-11
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:null},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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