Summary of main clinical trials on anti VEGF treatment for AMD
\r\n\t1. Role and utility of animal models to understand the pathophysiology of PD and screening therapeutic molecules of dopaminergic neuroprotection
\r\n\t2. Importance of epidemiological studies and available therapeutic strategies for PD
\r\n\t3. Mechanistic insights into dopaminergic neuroprotection/neurodegeneration relating to PD
\r\n\tThe present project concerns “reducing the burden of disease” which is the prime aim of biomedical research.
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He follows Drosophila approaches to understand dopaminergic neurodegeneration and identification of therapeutic targets for neuroprotection; knowledge of which may help to reduce the burden of Parkinson’s disease (PD) in humans.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"181774",title:"Prof.",name:"Sarat Chandra",middleName:null,surname:"Yenisetti",slug:"sarat-chandra-yenisetti",fullName:"Sarat Chandra Yenisetti",profilePictureURL:"https://mts.intechopen.com/storage/users/181774/images/system/181774.jpeg",biography:"Dr. Sarat Chandra Yenisetti is an Associate Professor and Head of Drosophila Neurobiology Laboratory in Department of Zoology, Nagaland University (Central), Nagaland, India. He completed M.Sc. from Bangaluru University, India and was awarded a Ph.D. from Kuvempu University, India. Dr. Sarat obtained post-doctoral training in 'modelling Parkinson’s disease using Drosophila” from Neurogenetics, National Institute of Neurological Disorders and Stroke (NINDS) of National Institutes of Health (NIH), Bethesda, USA and University of Regensburg, Germany. His laboratory, funded through multiple research grants from Department of Biotechnology (DBT), India, University of Grants Commission (UGC), India and Department of Science and Technology (DST), India, focuses on Drosophila approach to understand Parkinson's Disease associated neurodegeneration as well as identification of novel therapeutic targets which may help to reduce the burden of PD in human.",institutionString:"Nagaland University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Nagaland University",institutionURL:null,country:{name:"India"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453624",firstName:"Martina",lastName:"Scerbe",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/453624/images/20399_n.jpg",email:"martina.s@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"7256",title:"Dopamine",subtitle:"Health and Disease",isOpenForSubmission:!1,hash:"e46d08f526c35d787be15bcb17126fb8",slug:"dopamine-health-and-disease",bookSignature:"Sarat Chandra Yenisetti",coverURL:"https://cdn.intechopen.com/books/images_new/7256.jpg",editedByType:"Edited by",editors:[{id:"181774",title:"Prof.",name:"Sarat Chandra",surname:"Yenisetti",slug:"sarat-chandra-yenisetti",fullName:"Sarat Chandra Yenisetti"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6406",title:"Parkinson's Disease",subtitle:"Understanding Pathophysiology and Developing Therapeutic Strategies",isOpenForSubmission:!1,hash:"0038453d1272466535c41e37d94ee52f",slug:"parkinson-s-disease-understanding-pathophysiology-and-developing-therapeutic-strategies",bookSignature:"Sarat Chandra Yenisetti",coverURL:"https://cdn.intechopen.com/books/images_new/6406.jpg",editedByType:"Edited by",editors:[{id:"181774",title:"Prof.",name:"Sarat Chandra",surname:"Yenisetti",slug:"sarat-chandra-yenisetti",fullName:"Sarat Chandra Yenisetti"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. 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Therefore, the choroid, the most vascular layer of the eye also nourishing the retina, has one of the highest blood-flow rates in the body, 800 – 1000 mL/100 g tissue/min [1]. In healthy adults this delicate ocular vascular system is maintained and controlled by the balance between the angiogenic factors and angiogenic inhibitors [2].
Age-related macular degeneration (AMD) is the result of complex interactions between lipofuscinogenesis, drusenogenesis, and inflammation which can lead to choroidal neovascularization(CNV)[3]. An imbalance between the proangiogenic vascular endothelial growth factor (VEGF) and the antiangiogenic pigment epithelium-derived factor (PEDF)[3-4], plays a major role in the pathogenesis of the disease.
Inhibitors of VEGF represent a relatively new treatment for CNV. These agents include the Macugen (aptamer) which was almost completely abandoned with the introduction of the efficient FDA approved Ranibizumab (Lucentis; Genentech, Inc, South San Francisco, CA), in addition to others such as the Bevacizumab (Avastin; Genentech, Inc), and the new FDA approved drug Eylea(VEGF Trap Eye Regeneron, Tarrytown, NY, USA).
Vascular endothelial growth factor (VEGF) plays a key role in ocular angiogenesis and vascular permeability. Several VEGF family members have been discovered (VEGF-A, B, C, D and PIGF). These isoforms of VEGF have different effects in ocular pathologies and may differ in their neuroprotective abilities [5, 6]. RPE and Müller cells are the major sources of VEGF and they exert their effects through multiple receptors that are mostly expressed on endothelial cells and are also found on monocytes and macrophages [7].
VEGF-A, has been most strongly associated with angiogenesis and thus consists the target of most anti-VEGF treatments [8, 9]. VEGF-A signals through two receptor tyrosine kinases, VEGFR1 and VEGFR2, and is induced by hypoxia, unlike other VEGF isoforms [7, 10].
Alternative exon splicing of the human VEGF-A gene results in at least four major biologically active isoforms, containing 121, 165, 189, and 208 aminoacids (five more are VEGFA-145, VEGFA-162, VEGFA-165b, VEGFA-183, and VEGFA-206) [11].
Different VEGF-A isoforms may have different functions in ocular diseases.
VEGF 121 appears to be essential for normal retinal vascular function [12-13], and VEGFA-165 is the predominant isoform in the human eye. It isa heparin-binding, homodimeric, 45-kDa glycoprotein that is predominantly secreted, although a substantial fraction is bound to the cell surface and to the extracellular matrix[13-14].It appears to be the isoform responsible for pathological ocular neovascularization.
Both isoforms are found in CNV tissue excised from patients with AMD.
In autopsy studies, VEGF levels were found to be elevated in the retinal pigment epithelium (RPE) and choroidal blood vessels within the macular area of eyes with AMD [15].
In summary VEGF-A acts through various pathways which result in promoting pathologic neovascularization:
It stimulates angiogenesis by being a potent endothelial cell mitogen [10-11].
It sustains endothelial survival by inhibiting apoptosis [10-12].
VEGF is a chemo-attractant for endothelial cell precursors, promoting their differentiation [12-13].
It is a powerful agonist of vascular permeability which is particularly important in CNV. Increased vascular permeability in response to VEGF may be due to formation of fenestrations in microvascular endothelium [12-14].
Leukocytes may amplify the effects of VEGF via their own secretion of VEGF. Furthermore, VEGF’s pro-inflammatory activity, predominantly through the 164 isoform, contributes to pathological ocular neovascularization [14]. It is therefore a crucial target in combating neovascular and ischemic eye diseases such as: choroidal neovascularization, macular edema secondary to diabetic retinopathy (DME) or retinal vein occlusion and retinal neovascularisation that may develop in retinal vein occlusion (RVO) or diabetic retinopathy (DR).
Several anti-VEGF drugs have been studied and have been shown to be effective. However, effective, long-term drug-delivery remains a challenge. Two multi-center, randomized controlled trials comparing the two most commonly drugs available were published recently. A summary of the available drugs (table 1), their mechanism of action and results from large multicenter trials evaluating their efficacy and safety is presented below.
This intravitreal RNA aptamer drug was the first anti-VEGF drug approved by the FDA in 2004 for use in neovascular AMD (nvAMD). It targets VEGFA-165[11]Its efficacy and safety were evaluated in the large VISION trial [16, 17].
Patients with different types of sub foveal CNV secondary to AMD were randomized into four groups. Three groups received an intravitreal injection of pegaptanib sodium at a dose of 0.3mg, 1.0mg, 3.0mg to one eye respectively. The injection was given every 6 weeks for a period of 48 weeks in total. The forth group was the control group and subjects in this group received a sham injection every 6 weeks. Primary outcome was mean change in visual acuity from baseline.
Results from a combined analysis showed that for all three doses of pegaptanib (P<0.001 for the comparison of 0.3 mg with sham injection; P<0.001 for the comparison of 1.0 mg with sham injection; and P=0.03 for the comparison of 3.0 mg with sham injection) there was a significant difference between the patients receiving treatment and those receiving a sham injection. In the group dosed with pegaptanib 0.3 mg, 70 percent of patients lost fewer than 15 letters of visual acuity (VA), as compared with 55 percent among the controls (P<0.001). The risk of severe loss of VA (loss of 30 letters or more) was reduced from 22 percent in the sham-injection group to 10 percent in the group receiving 0.3 mg of pegaptanib (P<0.001). More patients receiving pegaptanib (0.3 mg), as compared with sham injection, maintained their VA or gained acuity (33 % vs. 23%; P=0.003). As early as six weeks after beginning therapy with the study drug, and at all subsequent points, the mean visual acuity among patients receiving 0.3 mg of pegaptanib was better than in those receiving sham injections (P<0.002). During the second year, patients initially assigned to pegaptanib were re-randomized (1:1) to continue or discontinue therapy for 48 additional weeks (8 injections). Those initially assigned to sham were re-randomized to continue sham, discontinue sham, or receive 1 of 3 pegaptanib doses. The proportion of patients who lost more than 15 letters or more in vision between week 52 to week 96 was double (14
The VA results of the VISION study are clearly inferior to those of the MARINA and ANCHOR studies evaluating the efficacy of intravitreal ranibizumab for nvAMD (detailed later). However, VA efficacy is only one of the clinical considerations that must be taken into account. The safety profile of the drug is not less important. The Macugen was proven to be safe in the VISION study as well as in the smaller study by N. Feucht et al. [19]; in both studies no relevant systemic or ocular adverse effects were noted. Cardiovascular incidents and overall mortality in the Pegaptanib sodium group were comparable to those of the sham injection group.
Thus, we can conclude that stable vision can be achieved with repeated injections as frequent as every 6 weeks with pegaptanib. This treatment may still be taken into consideration especially in subjects suffering from cardiovascular diseases.
Ranibizumab is a small 48kDa recombinant humanized monoclonal antibody fragment. Its small molecular weight enables it to penetrate the inner limiting membrane and reach the subretinal space when injected intravitreally [5,8-9]. It binds all biologically active isotypes of VEGF with high affinity. The half-life of ranibizumab is 2 – 4 days [5, 8], resulting in a rapid systemic clearance and good systemic safety profile.
FDA has approved the use of ranibizumab for treatment of all angiographic subtypes of subfoveal CNV due to AMD. The phase III MARINA trial evaluated the efficacy and safety of ranibizumab for the treatment of minimally classic or occult with no classic CNV associated with AMD. This 2-year, prospective randomized, double-masked, sham-controlled trial enrolled 716 patients. Patients were randomized in a 1 : 1 : 1 ratio to receive intravitreal ranibizumab at a dose of either 0.3 mg or 0.5mg or sham injection monthly in one eye for 2 years [9]. The primary outcome was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months.
At 24 months, 92% of patients who received 0.3 mg of ranibizumab and 90% of patients who received 0.5 mg ranibizumab lost fewer than 15 letters, compared with 52.9% in the sham group. The proportion of patients who gained at least 15 letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart from baseline to 24 months was 33.3% in the 0.5mg group, 26.1% in the 0.3mggroup, and 3.8% in the sham group. The mean change in ETDRS VA from baseline to 24 months was a gain of 6.6 letters in the 0.5mg group, a gain of 5.4 letters in the 0.3mg group, and a loss of 14.9 letters in the sham-injection group [9].
The ANCHOR study evaluated the efficacy of Ranibizumab for treatment of Predominantly Classic sub foveal CNV due to AMD. The ANCHOR trial was a multicenter, randomized double-blind trial that enrolled 423 patients to compare the efficacy and safety of ranibizumab vs PDT with verteporfin[20]. Patients were assigned randomly to receive either 0.3 or 0.5mg of ranibizumab plus sham verteporfin, or sham intravitreal injection plus active verteporfin therapy. Ranibizumab or sham intravitreal injections were given monthly, and the verteporfin or sham was administered on day 0 and then as needed at months 3,6, 9, and 12.
At 12 months, 94.3% of patients in the 0.3mg group and96.4% in the 0.5mg group lost fewer than 15 letters from baseline compared with 64.3% in the verteporfin group. The proportion of patients who gained at least 15 letters from baseline to 12 months was 40.3% in the 0.5mg group, 35.7%in the 0.3mg group, and 5.6% in the verteporfin group. The mean change in VA from baseline to 12months was a gain of 8.5 letters in the 0.3mg group, a gain of11.3 letters in the 0.5mg group, and a loss of 9.5 letters in the verteporfin group [20]. Rates of serious ocular or systemic adverse events were low in both the MARIMA and the ANCHOR trials[20].
Both studies showed no difference in the percentage of patients losing 15 letters in vision between the 0.3 and 0.5mg. However, the 0.5 mg was statistically significant superior to the 0.3 mg in achieving 15 letters or more in vision. This difference in favor of the 0.5 mg led to its approval by the FDA, and the routine use of 0.5 mg ranibizumab.
The PIER study [21] evaluated the efficacy of 3 consecutive monthly injections of ranibizumab followed by fixed re-treatments only every 3 months. Mean changes from baseline VA at 12 months were -16.3, -1.6, and -0.2 letters loss for the sham, 0.3 mg, and 0.5 mg groups, respectively (P < or =.0001, each ranibizumab dose vs sham). Ranibizumab reduced the growth and leakage from the CNV. However, the treatment effect achieved following the first 3 consecutive injections declined in the ranibizumab groups during quarterly dosing (e.g., at three months the mean changes from baseline VA was a gain of 2.9 and 4.3 letters for the 0.3 mg and 0.5 mg doses, respectively). Results of subgroups analyses of mean change from baseline VA at 12 months by baseline age, VA, and lesion characteristics were consistent with the overall results. Overall, in this study, the proportion of gainers of more than three lines was significantly lower than in MARINA or in ANCHOR trials, and this is due to the fact that following the first 3 consecutive injections patients were shifted to a significant less frequent dosing of quarterly injections instead of monthly.
The EXCITE study evaluated the efficacy and safety of monthly versus quarterly ranibizumab treatment in nvAMD [22]. Patients were randomized (1:1:1) to 0.3 mg quarterly, 0.5 mg quarterly, or 0.3 mg monthly doses of ranibizumab. Treatment comprised of a loading phase (3 consecutive monthly injections) followed by a 9-month maintenance phase (either monthly or quarterly injection).In contrast to the PIER study in which patients were examined and injected only every 3 months following the first 3 consecutive monthly injections, in the EXCITE study, patients were followed monthly, but in the 2 quarterly groups they could receive an injection only every 3 months. BCVA increased from baseline to month 12 by 4.9, 3.8, and 8.3 letters in the 0.3 mg quarterly (104 patients), 0.5 mg quarterly (88 patients), and 0.3 mg monthly (101 patients) dosing groups, respectively. The noninferiority of a quarterly regimen was not achieved with reference to 5.0 letters, meaning dosing with ranibizumab only every 3 months is inferior than dosing every month, and results in a significant less favorable final visual outcome. The safety profile was similar to that reported in prior ranibizumab studies.
Following the results of the PIER and EXCITE study it can be concluded that monthly injections is definitely superior to quarterly injections, and that the quarterly regimen should not be applied.
This drug is a full-length recombinant humanized monoclonal antibody (149kDa).It binds to all VEGF-A isoforms. whereas Ranibizumab has only one binding site to VEGF, bevacizumab has two. Bevacizumab in addition has a longer acting effect
It was first approved by the FDA for metastatic colorectal cancer and is used off-label in ocular disease. Although systemic administration of bevacizumab was shown to be associated with increased systemic cardiovascular adverse events, these appear to be rare following intravitreal administration [8, 24].
Many ophthalmologists until recently offered intravitreal bevacizumab to nvAMD patients based on multiple forms of evidence: results from several retrospective case series,[27-30] extrapolation from the outcomes reported in the MARINA and ANCHOR studies, the structural similarity between ranibizumab and bevacizumab, and mostly the clinical experience of rapid resolution of morphological abnormalities on optical coherence tomography (OCT) and fluorescein leakage from CNV after treatment with bevacizumab.
However, treatment with bevacizumab can nowdays be based on the 2-year results of the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT) and one year results of IVAN study (Inhibit VEGF in Age-related choroidal Neovascularisation)which compared the efficacy of bevacizumab and ranibizumab for nvAMD and will be discussed in detail later in this chapter.
VEGF Trap-Eye (EYLEA; Regeneron, Tarrytown, NY, USA) (VTE) is a soluble fusion protein consisting of 2 extracellular cytokine receptor domains and a human Fc region of immunoglobulin G (IgG). This110kDa soluble receptor binds with high affinity to all VEGFA isoforms and VEGF B, and not to VEGF-C and D [5]. The binding affinity of VEGF Trap to VEGF is 10 times higher than bevacizumab. The 2mg dose of VTE at 83days has been proven to have a similar biologic activity to ranibizumab at 30 days [5, 31]. The CLEAR-IT is a phase II trial, which was recently published and evaluated anatomic outcomes and VA, injection frequency, and safety. The study consisted of 2 phases; the first was a 12-week fixed dosing period followed by an as-needed (PRN) treatment phase to week 52 with VEGF Trap-Eye for nvAMD [31]. Patients were randomly assigned to 1 of 5 intravitreal VEGF Trap-Eye treatment groups: 0.5 mg or 2 mg every 4 weeks or 0.5, 2, or 4 mg every 12 weeks during the fixed-dosing period (weeks 1-12). From weeks 16 to 52, patients were evaluated monthly and were retreated PRN with their assigned dose (0.5, 2, or 4 mg). The decrease in CR/LT (central retinal/lesion thickness) at week 12 versus baseline remained significant at weeks 12 to 52 (-130 μm from baseline at week 52) and CNV size regressed from baseline by 2.21 mm2at 48 weeks. After achieving a significant improvement in BCVA during the 12-week- fixed-dosing phase for all groups combined, PRN dosing for 40 weeks maintained the improvement in BCVA to 52 weeks (5.3-letter gain; P<0.0001). The robust improvement and consistent maintenance of VA mainly occurred in patients initially dosed with 2 mg every 4 weeks for 12 weeks, demonstrating a gain of 9 letters at 52 weeks. Overall, a mean of 2 injections was administered after the 12-week fixed-dosing phase, and the mean time to first reinjection was 129 days; 19% of patients received no injections and 45% received 1 or 2 injections. Treatment with VEGF Trap-Eye was generally safe and well tolerated, with few ocular or systemic adverse events. They concluded that PRN dosing with VEGF Trap-Eye at weeks 16-52 maintained the significant anatomic and visual improvements established during the 12-week fixed-dosing phase with a low need for re-injections. Repeated dosing with VEGF Trap-Eye was well tolerated over 52 weeks of treatment.
VIEW1 was a phase III non-inferiority trial conducted in North America that randomized 1217 patients to VTE 0.5 mg monthly dosing (0.5q4wk), VTE 2 mg monthly (2q4wk),VTE 2 mg every two months following 3 initial monthly doses (2q8wk), or ranibizumab 0.5mg monthly (Rq4wk). The primary endpoint was the proportion of patients who lost fewer than 15 ETDRS letters from baseline to week 52 [32].
Secondary endpoints included mean change in BCVA at week 52. The percentage of participants in the Rq4wk, 0.5q4wk, 2q4wk, and 2q8wk treatment arms who gained at least 15 letters in vision were: 31%,25%, 38%, and 31%, respectively.
The proportions of patients maintaining vision at 52 weeks were 94.4%, 95.9%, 95.1%, and 95.1% for Rq4wk, 0.5q4wk, 2q4wk, and 2q8wk, respectively. All VTE groups were noninferior to ranibizumab. Mean improvement from baseline to week 52 in ETDRS letter score was 8.1, 6.9, 10.9, and 7.9 letters for Rq4wk, 0.5q4wk, 2q4wk, and 2q8wk, respectively.
There was a small significant difference in visual improvement at 52 weeks, between the 2q4wk and the Rq4weeks in favor of the 2q4weeks, however this was not found in the parallel VIEW 2 trial that will be discussed later. Differences between other VTE groups and Rq4wk were nonsignificant. The difference in the mean reduction in central retinal thickness was not significant among the groups. The incidence of adverse events was similar across all treatments, with no increase in blood pressure noted.
Overall, dosing monthly or every two months with VTE was non-inferior to monthly ranibizumab and was well tolerated [32]. The VIEW2 study was a parallel study to VIEW 1 that enrolled 1240 patients from Europe, Latin America, Asia, and Australia and yielded similar results [33]. However, minor differences exist. In the VIEW 2 study there was no statistically significant difference between all treatment arms in ETDRS letter score at week 52, and unlike VIEW1 the 2q4wk group was not superior to Lucentis.
The VIEW 1 and VIEW 2 results demonstrated non-inferior efficacy of VTE 2mg dosed at a fixed regimen every 8 weeks compared to ranibizumab 0.5mg dosed every 4 weeks. The EYLEA was approved by the FDA for injection every 8 weeks for nvAMD, and therefore may lower the injection burden on the patient as well as the medical system.
Numerous studies evaluated the effect of PRN intravitreal ranibizumab for the treatment of nvAMD.
The Prospective OCT Imaging of Patients with nvAMD Treated with Intraocular Ranibizumab (PrONTO) study was the first open-label, prospective, uncontrolled study to investigate a variable-dosing of intravitreal ranibizumab over two years [34]. Thirty-seven patients received 3 consecutive monthly injections of 0.5 mg ranibizumab and were then followed monthly and re-treated if there was an increase in OCT central retinal thickness (CRT) of at least 100 microns or a loss of BCVA of 5 letters or more. During the second year, the retreatment criteria were amended to include re-treatment if any qualitative increase in the amount of fluid was detectedon OCT. At 24 months (end of 2 years study), mean VA improved by 11letters with an average of 9.9 injections In the PrONTO study therefore we can conclude that VA outcomes were nearly comparable with those reported in the MARINA and ANCHOR, but these results were achieved with less than half number of intravitreal injections given in the MARINA and ANCHOR[34].
The SUSTAIN trial was a phase III multicenter open-label single arm study that assessed the safety and efficacy of ranibizumab in patients with sub foveal CNV secondary to AMD using a dosing regimen individualized to patient characteristics. 513 patients who were either ranibizumab treatment –naïve (69 patients) or had completed treatment with ranibizumab or verteporfin PDT in the ANCHOR trial participated in this study [35].
Patients received three consecutive monthly injections of ranibizumab 0.3mg (or 0.5mg for the ANCHOR patients) (the “loading phase”), followed by monthly monitoring visits. Further treatment was administered if VA decreased by
The SAILOR (Safety Assessment of IntravitrealLucentis for age-related macular degeneration) study, a Phase IIIb study of Lucentis for patients with all subtypes of new or recurrent active sub fovealCNV due to AMD, was a twelve-month randomized (cohort 1) or open-label (cohort 2) multicenter clinical trial [36]. 4300 subjects were recruited. Cohort 1 subjects were randomized 1:1 to receive 0.3 mg (n = 1169) or 0.5 mg (n = 1209) intravitreal ranibizumab for 3 monthly loading doses, followed by monthly visits. Cohort 2 subjects received 1 single open-label 0.5 mg intravitreal ranibizumab, and than continue the monthly follow up visits. Those groups were stratified by AMD treatment history (treatment-naïve vs. previously treated). Cohort 1 subjects were retreated on the basis of OCT or BCVA criteria. Cohort 2 subjects (n = 1922) received an initial single intravitreal dose of 0.5 mg ranibizumab and were retreated at physician discretion. Safety was evaluated at all visits. It concluded that Intravitreal ranibizumab was safe and well tolerated in a large population of subjects with neovascular AMD. Ranibizumab had a beneficial effect on VA but quarterly visits were insufficient to monitor and capture disease progression [36] If a fixed regimen of monthly injections is not applied, than monthly visits are recommended and injectios performed as needed usually guided by visual acuity and OCT findings.
The HORIZON study was an open-label multicenter extension study that included 853 patients (600 had been previously treated with ranibizumab initially, 184 had crossed over to treatment with ranibizumab, and 69 had not been treated with ranibizumab) who had completed one of the three 2-year, randomized, controlled trials of monthly intravitreal ranibizumab treatment (MARINA, ANCHOR or FOCUS trial). Of the 853 patients, two-year VA data were available for 384 [37]. These patients could receive 0.5 mg ranibizumab at 30-day or longer intervals as needed. Of the patients who received initial treatment with ranibizumab during the ANCHOR, MARINA, and FOCUS trials, there was a mean 10.2-letter increase in VA during the first 2 years of the studies Patients that did not receive anti-VEGF therapy in those trials had worse outcomes. During the first year of the HORIZON study and the third year of the original trials, there was a 5.1-letter loss The initial VA gain decreased by a mean of 8 letters with less frequent dosing in years 3 and 4. During the as needed dosing phase, the mean number of injections in the group initially treated with ranibizumab was 3.6. compared to 4.2 injections for patients that were treated with sham in the original trials.
The results of the HORIZON trial demonstrate that a delay in the initiation of treatment is associated with poorer visual outcomes and continued but less frequent dosing in years 3 and 4 was associated as well with visual decline [37].
PRN regimen of ranibizumab guided by monthly BCVA and other ophthalmic examinations, as detailed before, appears effective in sustaining the BCVA gained with 12 monthly injections with a significant lower number of injections during the extension phase [38].
Each one of these studies evaluated PRN regimens and had its own retreatment criteria, most of them retreated patients with a 100 μm increase in CRT from the thinnest measurement, and/or a Decreased VA >5 letters compared with VA score from the previous scheduled study visit, but each study had its particular criteria, and follow up regimen. All those studies mentioned previously have used the Time Domain OCT which is less accurate than the Spectral Domain OCT (SD-OCT) – therefore re-treatment criteria usually used the 100 microns increase in thickness. Nowadays by using the SD OCT, residual or recurrent fluid which is less than 100 microns in height can be detected, so patients are re-treated earlier – which may account for a better visual outcome using the PRN regimen. Strengths of PRONTO and SUSTAIN include monthly follow-up, but the PRONTO trialconsists of only a small cohort of patients. The SAILOR trial is the largest, but mandated only quarterly follow up visits. Overall, these studies support frequent follow up and individualized retreatment to achieve the best visual acuity gains with the as-needed treatment regimen as an alternative to the traditional monthly treatments used in the ANCHOR and MARINA trials. Furthermore, the CATT study (detailed later) showed that ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly.
Treat-and-extend dosing regimen was first described by Freund et al. for the treatment of retinal angiomatous proliferation with an anti-VEGF agent. It involved increasing intervals between intravitreal injections up to 10 weeks as long as no fluid is present on OCT. If fluid is present, the interval between treatments is shortened[39].The treat-and-extend regimen is quite variable in terms of treatment criteria, which can include vision loss and/or macular hemorrhage [39], and the time between treatment, which can extend up to 12 weeks [40, 41]. Unfortunately, there are no large, randomized, prospective trials that investigated the efficacy of this regimen compared to the PRN protocol.
Oubraham et al. compared two ranibizumab retreatment strategies; as-needed (PRN) and treat-and-extend, in a retrospective review of 90 patients, 52 in the PRN group, and 38 in the treat-and-extend group. Their treatment regimen included 3 loading doses monthly for the first three months in both groups, and the decision to re-treat was based only on the existence of fluid on OCT They found that at one year, mean gain in VA was greater in the treat-and-extend group than in the PRN (+10.8 versus +2.3 letters, resp.). Eyes in the treat-and-extend group received significantly more injections (7.8 versus 5.2). Patients in the PRN group were followed every 4-5 weeks and the number of follow-up visits was similar in both groups (8.5 versus 8.8) [40].
Gupta et al. published a retrospective case series of 92 eyes treated with the treat-and-extend ranibizumab regimen. After 2 years, 32% had gained at least3 lines of vision and received 8.36 and 7.45 injections during the first and second years, respectively. In his study, this regimen was associated with fewer patient visits, injections, and direct annual medical costs compared with monthly injections [41].
The ABC trial is a prospective, double-masked, multicenter, randomized-controlled trial that included 131 patients randomized to 3 loading doses of bevacizumab at 6-week intervals followed by as-needed treatment at six week intervals or an alternate treatment atthe start of the trial (PDT, pegaptanib, or sham). Thirty-two percent of patients in the bevacizumab group gained at least15 letters with a mean VA increase of 7 letters vs a mean decrease of 9.4 letters in the alternate group. The median number of injections during the 12 months was 7 injections [42].
Other smaller, retrospective studies note a substantial improvement in VA using a protocol of three loading doses of bvacizumab followed by a PRN regimen, based mostly on OCT findings [43, 44].
Several retrospective studies demonstrated stabilization or improvement in VA following PRN treatment regimen with bevacizumab without a loading phase [45, 46]. One prospective, open-label, nonrandomized clinical study reported a mean VA gain of 8.6 letters in 51 eyes after their second year of PRN bevacizumab treatment with a mean of only 1.5injections given during year 2 [47].
Gupta et al. retrospectively reviewed 74 eyes of 73 patients with treatment-naive nvAMD. The patients were treated monthly with intravitreal bevacizumab until no intraretinal or subretinal fluid was observed on OCT. The treatment intervals then were lengthened sequentially by 2 weeks until signs of exudation recurred and then was reduced accordingly to maintain an exudation-free macula. Main outcomes measured included mean change from baseline visual acuity, proportion of eyes losing fewer than 3 and gaining 3 or more Snellen visual acuity lines at 1 year of follow-up, annual mean number of injections, OCT (Zeiss stratus) mean central retinal thickness change from baseline, mean maximum period of extension, adverse events, and mean direct annual medical cost. The mean follow-up period was 1.41 years. Mean Snellen VA improved from 20/230 at baseline to 20/109 at 12 months (P <.001) and 20/106 at 24 months (P <.001). The mean number of injections over the first year was 7.94. The mean OCT central retinal thickness decreased from 316 to 239 μm at 12 months (P <.001). The mean direct medical cost over the first year was $3493.85.
The treat and-extend regimen in their study, was associated with significant visual improvements with fewer patient visits and injections along with lower costs when compared to the MARINA, ANCHOR, and PrONTO protocols [48].
Several retrospective studies have tried to evaluate the efficacy of ranibizumab as compared to bevacizumab, however they were not powered enough to show the differences in efficacy or safety between the 2 drugs. The CATT and the IVAN trials are two prospective large scale randomized controlled trials that compared the two drugs in different regimens of treatment. The CATT trial is a multicenter, single-blind, non-inferiority trial that collectively enrolled 1208 patients with nvAMD [49]. Patients were randomized to 4 treatment groups: monthly bevacizumab, monthly ranibizumab, as-needed bevacizumab and as needed ranibizumab. In the as needed groups, retreatment was performed if at least one of the following criteria was met: fluid present on Time Domain OCT, decreased VA as compared to previous exam, new or persistent hemorrhage detected on clinical exam, or dye leakage or increased lesion size visible on fluorescein angiography. The primary outcome measure was mean change in VA at one year. The results at 12 months showed that Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. Ranibizumab as-needed was found to be equivalent to monthly ranibizumab, but the comparison between bevacizumab as-needed and monthly ranibizumab was inconclusive [49]. This could be due to the less durable treatment effect of bevacizumab in a subgroup of patients [50]. Ranibizumab given as needed was equivalent to bevacizumab given monthly. The comparison between bevacizumab given as needed and ranibizumab given monthly was also inconclusive.
The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance) Although not powered sufficiently to compare adverse event rates associated with the two drugs, the rates of death, arteriothrombotic events, and venous thrombotic events were similar for patients receiving bevacizumab or ranibizumab. The rate of serious systemic adverse events, primarily hospitalizations, was higher among the patients who had received bevacizumab, but rates of adverse events did not increase with increased exposure to the drug [49].
At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment[51] The 2 year results demonstrate that among patients receiving monthly injections for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). However mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion of patients without fluid on OCT ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment in the second year resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009), even thoughmost of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF) [51].
The first year results from an NIHR Health Technology Assessment (HTA) programmed funded trial, IVAN (Inhibit VEGF in Age related choroidal Neovascularization) were recently published [52]. The trial compared the efficacy of ranibizumab vs bevacizumab in 610 subjects with nvAMD from 23 hospitals and academic institutions in the UK. In addition blood samples were repeatedly evaluated for the VEGF concentration in the plasma. Patients received injections of the drug into the affected eye every month for the first three months. Groups were then subdivided to receive either injections at every visit thereafter namely the continuous group or only if the specialist decided there was persistent disease – namely the discontinuous group. Whenever re-treatment was performed the patient received a series of 3 monthly consecutive injections as opposed to 1 injection given in the CATT. After 12 months the comparison between the two drugs was inconclusive (-1.99 letters in favor of the Ranibizumab, 95% confidence interval [CI], -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (-0.35 letters; 95% CI, -2.40 to 1.70). Mena foveal total thickness did not differ by drug, but was 9% less using the continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants receiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion of subjects experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF levels were found to be significantly lower in subjects treated with bevacizuamb compared to ranibizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P<0.0001) and higher with discontinuous treatment compared to continuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42; P = 0.004). These results clearly indicate the higher systemic exposure to bevacizumab compared with ranibizumab. Researchers concluded that the comparison of VA at 1 year between bevacizumab and ranibizumab was inconclusive. Visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs and treatment regimens having similar efficacy and safety.
The results of the second year of the IVAN trial and others like the VIBERA (Germany), EQUAL (Netherlands) and MANTA (Austria) studies [53-55] are about to be published in the coming future.
As many as 10% of patients demonstrate a significant loss of vision in spite of 2 years of monthly anti-VEGF therapy [9, 20]. Within this group of individuals exist those who progress to disciform scar, RPE tear, massive subretinal hemorrhage, geographic atrophy, and in addition eyes that demonstrate persistent macular fluid/blood and leakage on OCT and fluorescein angiography associated with vision loss. This subgroup of patients is referred to as anti-VEGF non-responders. This variability in anti-VEGF treatment response can be attributed to more aggressive forms of nvAMD, including retinal angiomatous proliferation (RAP), tachyphylaxis to anti-VEGF drugs, mimics of wet AMD [56], and genetic differences among patients [57, 58].
The therapeutic approach in these patients include alternating bevacizumab and ranibizumab, switching to a newer anti VEGF drug- Eylea, combination therapy which is further discussed in the next section, or other treatment options such as brachytherapy and transpupillary thermotherapy.
Since the development and progression of nvAMD involve pro-angiogenic factors, vascular permeability molecules, and inflammatory proteins, targeting only one component of this process may be insufficient and temporary, as shown by the data presented above. Anti VEGF agents are very effective in halting vascular leakage, but it has shown to be a temporizing treatment, and there is an increased need for a treatment with longer efficacy duration..The ideal combination therapy regimen would provide a longer-lasting treatment effect in addition to potentially being more or equally efficacious to monotherapy alone.
The main combination therapies are further discussed.
SUMMIT is a clinical trial program that includes three similarly designed, controlled studies to further examine the safety, efficacy, and treatment burden of combination therapy with PDT and ranibizumab compared with ranibizumab alone: DENALI in the USA, and Canada, examining verteporfin PDT in combination at both standard- and reduced-fluence light doses; MONT BLANC in Europe, examining verteporfin PDT in combination at standard-fluence light dose only, and an Asian study (EVEREST) which is designed to compare standard fluence PDT combined with ranibizumab and ranibizumab monotherapy in the treatment of polypoidal choroidal vasculopathy (PCV). Twelve-month results of the MONTBLANC study showed that combining standard-fluence PDT with ranibizumab 0.5mg results in VA improvement that is noninferior to a ranibizumab monotherapy regimen with three ranibizumab-loading doses followed by injections on a monthly PRN basis (non-inferiority margin of 7 letters There was no significant difference between the two treatment arms with regard to proportion of patients with a treatment-free interval of at least three months duration after month 2. Adverse event incidence was similar between treatment groups [59].As monotherapy is not inferior to the combination; they concluded that monotherapy should be the preferred treatment.
Twelve-month results of the DENALI study showed that combining PDT with ranibizumab in a regimen that consists three ranibizumab loading doses followed by additional injections on a monthly PRN basis and PRN PDT every 3 months can improve VA at month 12 in patients with sub foveal CNV secondary to nvAMD [60]. However the combination treatment was found inferior to the monotherapy with ranibizumab alone. At month 12, patients in the standard fluence combination group and the reduced fluence combination group gained on average 5.3 and 4.4 letters from baseline, compared to a more significant gain of 8.1 letters in the ranibizumab monthly monotherapy group. DENALI did not demonstrate non-inferior visual acuity gain for PDT combination therapy compared with ranibizumab monthly monotherapy, meaning the monotherapy with monthly ranibizumab was found superior to the combination therapy.
Six months results of the EVEREST trial were recently published [61]. At Month 6, verteporfin PDT combined with ranibizumab or verteporfin PDT alone was superior to ranibizumab monotherapy in achieving complete polyp regression (77.8% and 71.4% vs. 28.6%; P < 0.01); mean change ± standard deviation in best-corrected visual acuity (letters) was the highest in the combination group although not statistically better than the ranibizumab monotherapy. There was a mean improvement of 10.9 ± 10.9 letters in the verteporfin PDT + ranibizumab, 7.5 ± 10.6 letters in the verteporfin PDT alone, and 9.2 ± 12.4 letters in the ranibizumab monotherapy. There were no new safety findings with either drug used alone or in combination. Based on the results of the EVERST we can conclude that combination therapy of reduced fluence PDT with ranibizumab should be applied in cases of PCV, because this combined treatment yields the best VA results and highest rate of anatomic closure of the polyps.
Augustin et al. described a combination therapy involving standard fluence PDT with reduced light duration (70 seconds instead of 83 seconds),with total light dose of 42J/ cm2. Sixteen hours after PDT administration patients were taken to the operating room, and underwent limited vitrectomy followed by intravitreal dexamethasone (800 mcg) and intravitreal bevacizumab (1.5 mg) injections [62]. Most patients treated with this triple therapy hadlong-lasting improvement in VA with only one treatment at final follow-up (The mean follow-up period was 40 weeks (range, 22-60 weeks). Less than one-fourth of the patients treated with this regimen required additional treatment either with repeat triple therapy or anti-VEGF alone during the follow-up period [62].
Bakri et al. retrospectively reviewed the treatment benefit in patients receiving a same-day combination of reduced fluence PDT, intravitreal dexamethasone (200mcg), and intravitreal bevacizumab (1.25 mg). Patients were either treatment naïve or previously treated. At final follow-up, patients treated with this regimen showed stable VA and decreased macular thickness [63].
An average of less than one additional treatment with either repeat triple therapy or anti-VEGF was required in the treatment of naive group while almost four additional treatments were required in previously treated patients [63]. No steroid-related complications were noted in either study [62, 63]. A prospective interventional case series of 17 patients treated with a same-day regimen of standard fluence PDT, intravitreal bevacizumab(1.25 mg), and intravitreal triamcinolone (IVTA) (2 mg), was recently published. Patients treated with this regimen also showed an improvement in VA and reduced central macular thickness [64].
The Reduced Fluence Visudyne Anti-VEGF Dexamethasone in Combination for AMD Lesions (RADICAL) trial is a prospective, multicenter, randomized trial of combination therapy for the treatment of wet AMD that began in 2008. Patients are randomized into four treatment arms including anti-VEGF monotherapy with ranibizumab, half-fluence PDT with ranibizumab, half-fluence PDT with ranibizumab and dexamethasone, or quarter-fluence PDT with ranibizumab and dexamethasone. The dose of ranibizumab used was 0.5 mg and dexamethasone 500 mcg. Patients enrolled in the trial were followed for a total of 24 months. For the first 12 months, patients were followed monthly with decision for retreatment made at each visit. After 12 months, patients were reassessed every 3 months or sooner at physician’s discretion. Patients in the anti-VEGF monotherapy arm received mandatory first 3 monthly consecutive injections followed by retreatment as needed thereafter. Retreatment with combination therapy was not administered prior to 8 weeks interval. Twelve-month data released by the sponsor [65], QLT incorporated, showed significantly fewer re-treatments in all combination therapy arms compared with the groups of patients treated with anti-VEGF monotherapy [65].
VA appears to equally improve among all groups, but confidence intervals varied. Of the three combination therapy arms, the triple therapy half-fluence PDT group shared similar mean visual improvement compared with monotherapy and had the fewest re-treatments. After 12 months, three retreatments of triple therapy with half-fluence PDT were required compared to 5.1 re-treatments of monotherapy (p<0.001). Adverse event incidence was similar amongst all treatment groups. The final results of the 24-months trial were not published yet.
Safety issues with anti VEGF intravitreal injections include local ocular adverse events (AEs) from the drug or the injection, as well as potential systemic AEs of the drug.
Ocular AEs may be categorized as common but not serious and rare but potentially serious. The AEs that are considered common but not serious include subconjunctival hemorrhage, vitreous floaters from medication or vitreous hemorrhage, and discomfort from antiseptic used to prepare the conjunctiva before the injection(9, 20, 21).
Repeated intravitreal injection of ranibizumab or bevacizumab, over extended time periods, has been demonstrated to result in a low incidence of serious ocular adverse events. In the CATT study, endophthalmitis developed after only two of 5449 injections (0.04%) in 599 patients treated with ranibizumab, and after only four of 5508 injections (0.07%) in 586 patients treated with bevacizumab. Uveitis, retinal detachment, retinal vascular occlusion or embolism, retinal tear, and vitreous hemorrhage each also occurred in less than 1% of patients [49, 50]. Efforts are underway in order to further reduce the incidence of these events, with studies evaluating the effect of needle type and injection technique on patient pain levels, vitreal reflux, and ocular complications [66].
It is unknown if pretreatment antibiotics for several days prior to injection, or only on the procedure\'s day is necessary in order to reduce the risk of endophthalmitis. Furthermore, it is unknown if post treatment antibiotics are necessary on the day of the procedure or thereafter to reduce this risk furthermore. Although the product insert for ranibizumab indicates that the administration of the intravitreal injection should include the use of sterile gloves and a sterile drape, not all physicians agree that these items are necessary to maintain sterile conditions for the injection. However, all agree that the use of a lid speculum and administration of povidone-iodine to the lids, lashes, and conjunctiva are recommended [67].
Another concern is an allergic reaction to the drug. Since ranibizumab is a recombinant monoclonal antibody that contains both mouse and human derived segments, some patients treated with the drug may develop systemic antibodies [8, 20].
In the ANCHOR trial 3.9% of ranibizumab 0.5-mg subjects had developed antibodies to ranibizumab compared with 0% in the PDT group [20].
In the MARINA trial, after 24 months, 6.3% of subjects treated with ranibizumab 0.5 mg and 1.1% of those in the sham injection group developed antibodies to ranibizumab [8].
Systemic AEs are a concern, since inhibitors of VEGF injected intravitreally, can penetrate the general circulation and compromise functions that rely on VEGF outside of the eye, such as wound healing and the formation of new blood vessels around the heart or brain in cases of ischemia [68, 69]. Patients with AMD already are at higher risk of cardiovascular disease than the general population because of their age and the association of AMDwith systemic hypertension [70], consequently, participants in clinical trialsof VEGF inhibitors were carefully monitored for possible increases in blood pressure, occurrence of myocardial infarction/stroke, and nonocular hemorrhages [8, 20].
Among participants in the MARINA trial, approximately16% in both the ranibizumab 0.5 mg and sham injectiongroups developed hypertension [8] and in the ANCHOR treatment related hypertension was higher in the PDT group (8.4%) than in the ranibizumab group (6.4%) [20].
In the CATT trial there was no evidence that ranibizumab0.5 mg was associated with increases in either diastolic or systolic blood pressure [49, 50].
Nonocular hemorrhages include events such as cerebral or gastrointestinal bleeding. In the ANCHOR trial, non ocular hemorrhage was more frequent in the 0.5-mg ranibizumab group (6.4%) than in the PDT group (2.1%) [20]. In the MARINA trial, the cumulative frequency of nonocular hemorrhage by month 24 was 5.5% in the sham injection group compared with 8.8% in the 0.5-mgranibizumab group [8].
Among participants in the MARINA trial, approximately 16% in both the ranibizumab 0.5 mg and sham injection groups developed hypertension [3].
In the CATT trial Gastrointestinal disorders (e.g., hemorrhage, hernia, nausea, and vomiting), occurred in 11 (1.8%) ranibizumab-treated and in 28 (4.8%) bevacizumab-treated patients (
With respect to cardiovascular or cerebrovascular events, during the ANCHOR trial, 1 subject in the PDT group (0.7%) and 3 subjects in the ranibizumab 0.5-mg group (2.1%) developed nonfatal myocardial infarctions, although the events did not occurshortly after treatment. [20]. The frequency of stroke (1 in each group) and cerebral infarction (0 in each group) in the ANCHOR trial were too low to draw meaningful conclusion [20].
At 24 months, the overall frequency of cardiovascular systemic events in the MARINA trial was similar in the0.5-mg ranibizumab and sham injection groups [8]. Therewere only small differences in the frequency of thromboembolic events between the sham injection group (3.8%) and the ranibizumab 0.5-mg group (4.6%) [8]. The frequency of death (2.5%) was the same in the ranibizumab 0.5-mgand sham injection groups [8]. Two individuals in each group died of stroke.
There was no significant difference in the frequency of myocardial infarction between the 2 treatment groups in the SAILOR trial [36].
In the CATT trial at 2 years, 5.3% assigned to ranibizumab and 6.1% assigned to Bevacizumab had died (
One or more serious systemic adverse events occurred in 255 patients (21.5%), with 53 (17.6%) in the ranibizumab-monthly group, 64 (22.4%) in the bevacizumab-monthly group, 61 (20.5%) in the ranibizumab-as-needed group, and 77 (25.7%) in the bevacizumab-as-needed group (P = 0.11 by the chi-square test). Hospitalizations accounted for 298 of the 370 individual serious systemic adverse events (80.5%). When dosing-regimen groups were combined, the proportions of patients with serious systemic adverse events were 24.1% for bevacizumab and 19.0% for ranibizumab (P = 0.04). After adjustment for demographic features and coexisting illnesses at baseline, the risk ratio for bevacizumab, as compared with ranibizumab, was 1.29 (95% confidence interval, 1.01 to 1.66; P = 0.04). Patients treated as needed had higher rates than patients treated monthly (risk ratio, 1.20; 95% CI, 0.98−1.47;
Although event rates for these cerebrovascular or cardiovascular events seem to be low with ranibizumab, ophthalmologists should ensure that patients understand the theoretic potential for these risks. Additional studies over time may help to refine understanding of the magnitude, if any, of this risk.
In the recently published IVAN trial at 12 months, 6 participants (1.9%) in the ranibizumab group and 5 (1.7%) in the bevacizumab group (
Data on the safety of intravitreal bevacizumab are more limited than data on Ranibizumab safety, due to the lack of large multicenter trials performed with Bevacizumab. The results of the CATT and IVAN trials were previously presented.
SIRNA stands for short interfering RNA. SIRNAs are 21 to 25 nucleotide-long double-stranded RNA molecules capable of destroying a corresponding target messenger RNA with high selectivity and efficacy [71]. This leads to post transcriptional gene silencing (PTGS).
SIRNAs work intracellularly, where they are incorporated into a protein complex called RNA-induced silencing complex (RISC) [71]. The RISC has RNA helicase activity, which unwinds the two strands of RNA. The strand of the siRNA that becomes associated to the RISC leads the complex to selectively cleave and degrade messenger RNA molecules containing a complementary sequence. The siRNA is engineered to match the protein encoding nucleotide sequence of the target messenger RNA. Since the translation of messenger RNA into proteins is an amplification step, destroying it is a very potent method of inhibiting protein function.
SIRNA-027 (SIRNA Therapeutics, Inc.) is a short interfering RNA that targets the VEGF receptor 1 (VEGFR-1).Animal experiments have shown that both intravitreous and periocular injections of siRNA directed against VEGFR1 lead to a substantial reduction of VEGFR1 messenger RNA levels [71-72].
The siRNA suppressed the development of CNV at rupture sites in Bruch’s membrane and decreased retinal neovascularizationin mice with oxygen-induced ischemic retinopathy [72-73].
Acuity Pharmaceuticals has also produced a siRNA called Cand5 or Bevasiranib that targets the messenger RNA of the VEGF protein itself. Animal models have shown prevention of CNV development after laser-induced injury [72].
Bevasiranib sodium was developed for intravitreal administration. Following intravitreal injection, bevasiranib is well distributed within the eye and localizes to the retina [72, 73].
Preliminary results of Phases I and II clinical trials of bevasiranib have shown promising results for the treatment of nvAMD and diabetic macular edema. There are various studies of different phases underway (the COBALT studies although recruitment was stopped). A phase III study evaluating the combination of bevasiranib and ranibizumab in nvAMD (the CARBON study) is currently underway.
The purpose of this study is to compare intravitreal bevasiranib sodium as maintenance therapy for AMD following initiation with three monthly doses of ranibizumab. Preliminary clinical results indicate that the effects of bevasiranib do not appear until six weeks after the initiation of treatment, which suggests that combination therapy with anti VEGF drug might be justified. The late effect of bevasiranib might be linked to its mechanism of action, since bevasiranib inhibits the synthesis of new VEGF, and does not eliminate existing VEGF, a direct anti-VEGF agent may be required to neutralize VEGF already present in the eye before inhibition of new VEGF synthesis. Preliminary results of the carbon and cobalt studies suggested that over 30% of patients on combination ranibizumab-bevasiranib achieve an improvement of at least three additional lines of VA than those on ranibizumab alone. The safety and efficacy of this combination awaits the full results of the ongoing clinical trials.
However, the lack of available data from randomized placebo-controlled or comparative studies makes it difficult to evaluate the role of bevasiranib in nvAMD therapy. It is clear from experimental and preclinical studies that anti-VEGF siRNA is capable of down regulating VEGF production, a key goal of anti-VEGF therapy [72].
In summary, bevasiranib exploits an interesting technology [72, 73] and may be a useful addition to the currently available drugs used to treat wet AMD.
VEGF A signals through two VEGF receptors [7, 10]. VEGF R consist of protein-tyrosine kinases (VEGFR-1, VEGFR-2, and VEGFR-3) and two non-protein kinase coreceptors (neuropilin-1 and neuropilin-2) [10]. New drugs targeting these tyrosine kinases are being investigated.
Vatalanib (PTK787; Novartis)- Vatalanib [74] is a potent tyrosine kinase inhibitor with good oral bioavailability and activity against the VEGFR family, PDGFRβ and c-Kit receptor kinases. Preclinical studies [74] suggest that vatalanib induces dose-dependent inhibition of VEGF-induced angiogenesis. A phase I/II trial, ADVANCE [75], to evaluate the safety and efficacy of oral vatalanib combined with PDT with verteporfin in 50 patients has been completed, but the data have not yet been published in a peer-reviewed journal.
Pazopanib (GW786034; GlaxoSmithKline)- Pazopanib [76] is a second-generation tyrosine kinase inhibitor against all VEGFR, PDGFRα, PDGFRβ, and c-kit. A phase I clinical trial using pazopanib as eye drops in 38 healthy volunteers has successfully demonstrated its safety and tolerability. Subsequently, a phase II trial [77] to evaluate its pharmacodynamics, pharmacokinetics and safety has been completed, but the data have not yet been published in a peer-reviewed journal.
This is an immunologic approach to combat CNV. A recent report demonstrated CD8+ cytotoxic T lymphocyte (CTL)-mediated regression of physiologic and pathologic retinal neovascularization [78], thus a possible immunologic therapy for CNV was suggested. It was approved by an animal model [79] which showed that CNV can regress by inducing cellular immunity specific for VEGFR-2.
More recently, a phase I study [80] of anti-VEGFR vaccine therapy has been recruiting participants. The patients will be vaccinated once a week for 12 weeks. On each vaccination day, VEGFR-1 peptide (1 mg) and VEGFR-2 peptide (1 mg) mixed with Montanide ISA 51 will be administered by subcutaneous injection. The study will evaluate the safety and tolerability as well as the immunological and clinical response of the vaccine therapy to treatment of nvAMD.
As mentioned before, both angiogenic and inflammatory processes are involved in nvAMD, new therapeutics targeting the inflammatory process, besides steroids are being investigated
POT-4 (Potentia Pharmaceuticals)- POT-4 [81] is a peptide capable of binding to human complement factor C3 (C3). As C3 is a central component of all known complement activation pathways, its inhibition effectively shuts down all downstream complement activation that could otherwise lead to local inflammation, tissue damage and up-regulation of angiogenic factors such as VEGF.
A phase I single escalating dose study [82] has just released its first results, which indicate that POT-4 IVT is safe, and the data accumulated so far support the continued investigation of POT-4 for the treatment of both dry and wet AMD with a larger randomized phase II trial to further define its efficacy profile.
ARC1905 (Ophthotech Corp.) -ARC1905 [81] is an anti-C5 aptamer, which prevents the formation of key terminal fragments (C5a and C5b-9) by inhibiting human complement factor C5 (C5). C5a fragment is an important inflammatory activator inducing vascular permeability, recruitment and activation of phagocytes. C5b-9 is involved in the formation of membrane attack complex (C5b-9), which initiates cell lysis [81]. Thus by inhibiting these C5-mediated inflammatory, ARC1905 might be beneficial in wet AMD.
A phase I study [83] to evaluate the safety, tolerability, and pharmacokinetic profile of multiple doses of ARC1905 IVT in combination with multiple doses of Lucentis has been completed, but the data have not yet been published in a peer-reviewed journal.
OT-551 (Othera)- OT-551 [84], an Othera Pharmaceuticals\' Othera (OT)-551 antioxidant eye drop has the potential for chronic treatment of the dry form of age-related macular degeneration.
A phase I trial [84] demonstrated that when the compound is added to Lucentis or Avastin treatment, there is a synergistic effect in patients with wet AMD. A pilot study [85] of participants with bilateral geographic atrophy is designed to characterize the effect of 0.45% concentration of OT-551 eye drops on the progression of geographic atrophy area over a two-year period.
Pigment epithelium-derived factor (PEDF) is one of the most potent antiangiogenic proteins found in humans, which were shown to inhibit VEGF-induced proliferation, migration of microvascular endothelial cells, reduce VEGF-induced hypermeability and cause vessel regression in established neovascularization [86]. AdPEDF uses a DNA carrier, to deliver the PEDF gene, resulting in the local production of AdPEDF in the treated eye.
A phase I escalating-dose clinical trial [87] in patients with nvAMD was completed. Three to six months after a single injection, it suggested that 50–94% of patients had a stabilization or improvement in lesion size from baseline, suggesting that antiangiogenesis may last for several months after a single IVT. there were no dose-limiting toxicities or drug-related severe adverse events reported. Further studies investigating the efficacy of AdPEDF in patients with wet AMD are under way.
VISION | \n\t\t\t1186 | \n\t\t\tIVT every 6 weeks | \n\t\t\tPegaptanib; 0.3/1.0/3.0 mg-Sham | \n\t\t\t31%–37% stable vision, 4%–6%gained "/>3 lines (12 months) | \n
MARINA | \n\t716 | \n\tIVT monthly | \n\tRanibizumab; 0.3/0.5 mg-sham | \n\t95% stable vision, 26%–34% gained"/>3 lines (12 months) | \n
ANCHOR | \n\t423 | \n\tIVT monthly | \n\tRanibizumab; 0.3/0.5 mg-Sham + PDT every 3 months if needed | \n\t96%Stable vision,35%–40% gained"/>3lines (12 months) | \n
FOCUS | \n\t162 | \n\tIVT monthly+PDT | \n\tRanibizumab; 0.5 mg-PDT every 3 months | \n\t90% stable vision | \n
HORIZON | \n\t853 | \n\tIVT monthly | \n\tRanibizumab; 0.5 mg | \n\tMean loss of vision 2–5 letters, 3% gained "/>3 lines, 7%–14% lost "/>3 lines (12 months) | \n
PIER | \n\t183 | \n\tIVT monthly x 3, re-treatment every 3 months | \n\tRanibizumab; 0.3/0.5 mg-sham | \n\t83%–90% stable vision, 12%–13% gained "/>3lines (12 months) | \n
PRONTO | \n\t37 | \n\tIVT monthly x 3, re-treatment as needed (9.9 injections over 24 months) | \n\tRanibizumab; 0.5 mg | \n\t43% gained "/>3 lines (24 months) | \n
SUSTAIN | \n\t513 | \n\tIVT monthly x 3, re treatment as needed (5.3 injections for "naïve" patients over 12 months) | \n\tRanibizumab; 0.3/0.5 mg | \n\tMean BCVA increased steadily from baseline to month 3 to reach +5.8 letters, decreased slightly from month 3 to 6, and remained stable from month 6 to 12, reaching +3.6 at month 12 | \n
CLEAR-IT | \n\t51 | \n\tIVT single | \n\tAflibercept; 0.05/0.15/0.5/1.0/2.0/4.0 mg | \n\t95% stable vision, 50% of 2.0/4.0 mg group gained "/>3 lines (3 months) | \n
VIEW1 VIEW2 | \n\t1217 1240 | \n\tVTE 0.5 mg monthly (0.5q4wk), VTE 2 mg monthly (2q4wk),VTE 2 mg every two months (2q8wk), or ranibizumab 0.5mg monthly (Rq4wk) | \n\tAflibercept (VTE);0.5/2.0 mg-Ranibizumab;0.5 mg | \n\tAll VTE groups were noninferior to ranibizumab. | \n
Summary of main clinical trials on anti VEGF treatment for AMD
Over the past decade, the treatment of nvAMD improved dramatically with the discovery of anti-VEGF agents that have enabled patients not only to stabilize the vision but to improve and regain vision in this potentially blinding disease.
With the goal of maximizing VA and minimizing the frequency of intravitreal injections and associated risks of treatment, evidence-based management of wet AMD has evolved into individualized anti-VEGF therapy with frequent follow up and retreatment. As a safer and more cost-effective alternative to the traditional monthly treatments used in the ANCHOR and MARINA trials, two individualized anti-VEGF treatment regimens have been described, but neither has been proven superior to date: as-needed (or “PRN”) therapy and the treat-and-extend strategy. Despite a paucity of evidence comparing the as-needed versus the treat-and extend treatment regimens, a possibility exists that the treat and extend regimen will prove to be the most efficacious, cost-saving, and preferred protocol. The current evidence based treatment strategy for the management of wet AMD supports the use of either bevacizumab or ranibizumab either monthly or with a more individualized treatmentstrategy with close followup. As second generation anti-VEGF agents become available and the stress on our healthcaresystems intensifies, increasingly efficacious and costconscioustreatment strategies will be essential.
Because of their ability to move rapidly, mobilize large amounts of debris, and initiate spontaneously, landslides pose a threat to people and infrastructure [1, 2]. The danger is heightened by the fact that they can occur in wet or dry regions, and on steep or shallow slopes [3]. Synergistic effects between increasing urbanization, sustained deforestation, and increased rainfall variability caused by climate change portend an increase in the frequency of catastrophic landslides such as that experienced in recent years [4].
In Brazil, as elsewhere, the mechanism of slope saturation by rainwater represents the main cause of landslide triggering [5, 6, 7]. Their onset is related to exceptional rainfall events of short duration, such as intense precipitation associated with a thunderstorm, or events of long duration and low intensity [8]. Specifically, high-intensity, short-duration precipitation events are known to trigger shallow landslides [9] - landslides with a failure surface depth of less than two meters [10] - while long duration, low intensity precipitation events generally result in deep seated landslides [11]. However, the causal relationship between rainfall and landslides is not so simple [12]. Rather, their initiation is associated with the infiltration of water into the soil that causes an increase in hydraulic pressure and a decrease in resistance, ultimately leading to failure of the affected surface [13]. The effectiveness of the process therefore depends on the hydraulic, physical and mechanical properties of the terrain, in addition to other factors such as slope steepness, vegetation cover and climatic characteristics [12]. In this regard, mountainous regions are particularly favorable to landslides because of the steep slopes, but especially because of the orographic uplift of humid air masses that cause significant precipitation at high elevations and on slopes exposed to prevailing winds [14, 15].
In the Brazilian municipality of Angra dos Reis, located in the Serra do Mar Mountain Range, heavy summer precipitation has historically triggered several landslides, causing a significant number of casualties and considerable damage, especially in the last decade. As an example, the catastrophic events of December 2002 and January 2010 resulted in 93 casualties, forced the evacuation of more than 2,500 residences and generated economic losses of approximately R$120 million. In this tropical environment, the frequency of rainfall-induced landslides is particularly high due to the rugged terrain, heavy summer rainfall, and improper land use regarding the physical and climatic environment [7]. The risk posed by this geomorphological hazard is particularly high due to the fact that almost 60% of the population lives in slope areas [16] and more than 25% (44,000 inhabitants) live where a high risk of landslides is considered [17].
However, since the beginning of the research on rain-triggered landslides in Brazil, no suitable threshold has been proposed for the Angra dos Reis territory. In fact, the thresholds of Guidicini and Iwasa [18] were established for the whole Serra do Mar, whose area is four times larger than that of Angra dos Reis, while the one elaborated by Soares [19] is not representative of the triggering conditions due to the use of an inadequate database. Thus, despite the recurrence of this natural hazard and the socioeconomic risks it poses, the relationships between rainfall characteristics and landslide occurrence remain poorly studied and partly misunderstood in this rugged region of Southeast Brazil. Therefore, the establishment of rainfall thresholds at local and regional scales is of great interest for the municipality of Angra dos Reis and could be an effective tool of prevention and mitigation in the landslide risk management perspective.
The Brazilian municipality of Angra dos Reis is located in the western part of the state of Rio de Janeiro. It represents an area of 825 km2 composed of four districts (Angra dos Reis, Cunhambebe, Ilha Grande and Mambucaba) comprising 116 neighborhoods. The urban center of the Angra dos Reis district covers an area of 6.5 km2, or 0.84% of the territory covered by the Angra dos Reis region, and includes 21 neighborhoods.
The geology is composed of 30% granites, 27% orthogneiss, 33% paragneiss with a minor proportion of contemporary sediments (Neogene-Quaternary). In terms of soils in the area, they are characterized by the presence of rock outcrops, fluvio-marine deposits, colluvium, and saprolites [20]. Superficial saprolites are less than two meters thick, have a large amount of boulders, and are generally located on very steep slopes where bedrock outcrops. The thick saprolites, associated with the upper and lower slopes, are more than two meters thick and result from a significant chemical alteration of the rocks in situ favored by the high heat and humidity.
The western part of the state of Rio de Janeiro belongs to the physiographic region of the Serra do Mar, which extends for just over 1,000,000 km along the southern and southeastern Brazilian coastline [21]. The Serra do Mar originated from tectonic movements that began ~80 million years ago (Late Cretaceous) with epirogenic uplift of the crystalline shield throughout southeastern Brazil [22]. Today, this mountain range forms an enormous tectonic barrier parallel to the coast.
Angra dos Reis is located more precisely in the southern part of the Atlantic Plateau, which corresponds to the Bocaína Plateau region and includes the escarpments of the Serra do Mar and the narrow coastal plain of Ilha Grande Bay. In the Bocaína Plateau, the slopes are moderately inclined (10 to 35o), but can exceed 35o in places. The strong geomorphological activity is visible by landslide scars and scree slopes [23]. The urban center of Angra dos Reis, with a summit at 571 m above sea level and very steep slopes, is part of this geomorphological unit. The area of Ilha Grande Bay with its mountainous massif oriented East–West, which culminates at 1031 m of altitude, is also included in this geomorphological unit. The massif has steep slopes, rocky walls, and well incised river channels [23]. Finally, due to the East–West alignment of the Serra do Mar in this area, the slopes are mainly oriented to the North and South, both regionally and locally.
The climate is particularly variable due to the proximity of the Atlantic Ocean and the rugged terrain associated with the Serra do Mar. According to the Köppen-Geiger classification, the region is characterized by an Af-type climate; a humid tropical climate without a well-defined dry season corresponding to average monthly temperatures above 18°C and average monthly rainfall above 60 mm. Annual rainfall varies between 2000 and 2500 mm [24]. Typical of tropical regions, there is heavy rainfall in the summer (December to March; with average rainfall exceeding 250 mm and about 16 rainy days/month) and a period of lesser rainfall in the winter (June to August; with total rainfall around 80 mm and less than 10 rainy days/month) [15, 18]. During the rainy season, which concentrates nearly 60% of the annual precipitation [15], rainfall of 200 to 300 mm in 24 to 48 hours is frequent [5]. This intense rainfall is furthermore largely responsible for the high frequency of landslides in this part of Brazil [7, 25].
The intensity and distribution of precipitation is influenced by various static and dynamic factors [26]. Dynamic factors refer to the different air masses and their circulation patterns such as, among others, frontal systems, the South Atlantic Subtropical Anticyclone and the South Atlantic Convergence Zone. The static factors correspond rather to the geographical location (latitude, maritime proximity that facilitates solar radiation, evaporation and cloud formation) as well as to the topographical characteristics (elevation and perpendicular orientation of the Serra do Mar Mountain Range with respect to atmospheric currents that favor the development of intense thunderstorms through the orographic lifting of polar humid air masses blowing in the northwest direction) [24]. Therefore, coastal areas and windward-facing slopes (south-facing) tend to be wetter (2000-2500 mm/year) due to orographic precipitation, while leeward-facing slopes (north-facing) are generally drier (1400-1700 mm/year) due to moisture loss from advection of air masses over the Mountain Range [27].
The high population growth since the early 1970s in Angra dos Reis, related to the construction of the Governor Mario Covas highway (Br-101) and the Angra 1 and Angra 2 nuclear plants [16], has generated significant pressure on the physical environment. However, the rugged topography (7% plains and 93% hills/mountains), which limits the amount of land available and suitable for human settlement, as well as the lack of land-use planning regulations have caused chaotic development of the territory [28]. This development has led to deforestation, surface sealing, transformation of plateaus into pastures and residential development on steep slopes, generating furthermore an accumulation of waste, a change in natural drainage conditions and anthropic filling and excavation activities that have affected the stability of the slopes and increased the likelihood of landslide occurrence [5]. As a result, the biophysical cover of the municipality of Angra dos Reis, which was once entirely Atlantic Forest (
The landslide inventory includes all the landslides that occurred in the territory of the municipality of Angra dos Reis. The information’s included are the geographical coordinates of the landslides and the date of occurrence. However, the inventory does not allow distinguishing between different mass movements (landslide, debris flow, etc.). Therefore, all types of landslides are considered here, without any particular distinction. This is a well-established approach [30, 31] and advantageous considering the fact that the typology of landslides is unknown, unspecified or uncertain since many reports come from citizens, journalists or technicians without adequate scientific training. Duplicate landslides, those with identical geographic coordinates and date of occurrence, were removed from the database. The same is true for cases with erroneous locations. All the recorded landslides were georeferenced and compiled into a geographic database using ArcGIS software [32].
Finally, each of the landslides was associated with a rainfall region according to its location (see Section 3.2), in order to associate or not the cases of landslides with the occurrence of rainfall episodes in the municipality. Subsequently, the landslides were matched to the rainfall data series according to the date of occurrence. This allowed each landslide to be assigned a daily precipitation value (R), 3-, 5-, 10-, 15-, and 30-day antecedent precipitation values, as well as duration (D) and cumulative precipitation values during the rainfall event (E).
The rainfall data were collected from a regional network consisting of two rain gauges administered by the State Institute of the Environment (SIE) and 19 rain gauges managed by the Civil Defense of Angra dos Reis. In the case of the SIE rain gauges, automatic recordings were made every 15 minutes, 96 times a day. In the case of the rain gauges of the Civil Defense, the data were daily and the reading was done manually every morning at 9:00 am. However, the period covered by the data sets varies considerably depending on the rain gauge station. In order to estimate the amount of rainfall responsible for the occurrence of each of the recorded landslides, the regional study area was first partitioned and an area of influence was calculated for each rainfall station using the Thiessen polygon technique [33] with ArcGIS software [32]. Next, the databases associated with the 21 rainfall stations were agglomerated based on geographic proximity to obtain complete time series for the 6-years period considered.
First, the daily data (R) from each station were associated (or not) with a rainfall event, i.e. a more or less continuous period of rainfall. A rainfall event begins when at least two millimeters of rain have been accumulated in 24 hours and ends at the beginning of a period of at least 24 hours without rainfall. Once the rainfall events were identified, the duration (D) in hours of each episode and the associated total rainfall (E) in millimeters could be calculated. These values were then used to establish thresholds based on the duration of rainfall events (ED).
In a second step, each daily precipitation (R) was associated with antecedent precipitation values. The antecedent precipitation values correspond to the daily totals accumulated over 3, 5, 10, 15 and 30 days before the daily precipitation considered (A (3d), (5d), (10d), (15d), (30d)). These data will allow to evaluate the role of the previous precipitation in the landslide triggering and to determine the most significant previous period.
The thresholds (ED) were developed from the combination of the variables D and E obtained for each landslide that was triggered during a rainfall event and are defined respectively as the duration (h) and cumulative precipitation (mm) from the start of the rainfall event to the occurrence of the landslide. ED thresholds were developed at the regional and local scales, as well as for the North and South aspects and also for the wet and dry seasons. In the latter case, the considered duration of the dry and wet seasons has been extended to simplify the analyses. Therefore, the dry season is from May to October and the wet season is from November to April.
In all cases, the E (cumulated event rainfall) and D (duration of the rainfall event) values were first plotted in a line graph (log–log coordinates), based on the frequentist method assuming that the threshold curve is a power law such as reported by Guzzetti et al. [34] and Peruccacci et al. [35]:
where α and γ are the scaling and the shape parameters that control the slope of the power law threshold curve.
The intercept α and the slope γ were then determined through a frequency analysis of the empirical rainfall conditions that have triggered landslides. The large number of landsides recorded over a 6-years period in the study area appears sufficiently complete and representative to determine the 1% and the 5% exceedance probability levels. The mean values of α (intercept) and γ (slope) and their uncertainties (
Using the Thiessen polygon technique, six rainfall regions were identified at the regional scale: three in the South (Japuiba, Angra dos Reis, and Jacuecanga – JAJ) and three in the North (Mambucada, Bracui, and Serra d’Agua – MBS). Then, the 1640 landslides recorded were associated with one of the 1434 rainfall events compiled (≥2 mm). In that regards, only 33% (484 out of 1434) of these rainfall events have triggered landslides (Table 1).
Extent | RE | LE | D (h) | E (mm) | |||||
---|---|---|---|---|---|---|---|---|---|
(km2) | Min | Max | Mean | Min | Max | Mean | |||
Municipality | 825 | 484 | 1640 | 24 | 624 | 101,3 | 2 | 542,9 | 111,9 |
South: JAJ | 374 | 357 | 1276 | 24 | 624 | 102,2 | 2 | 542,9 | 112,8 |
North: MBS | 451 | 127 | 364 | 24 | 432 | 97,9 | 2 | 400,8 | 108,7 |
Urban Center | 6,5 | 129 | 526 | 24 | 528 | 108,4 | 2 | 540,5 | 114,9 |
Statistics of rainfall events (RE), landslide events (LE), duration (D) and accumulation of rainfall (E) that initiated landslides at the regional scale (municipality, north, south) and local scale of the urban center of Angra dos Reis.
A North–South disparity appears in the number of rainfall events recorded in the North (127) and South (357) of the municipality (Table 1). The number of recorded landslides is significantly higher in the South (1274) compared to the North (364). Therefore, 78% of the landslides occurred in the South (JAJ) of the region (Figure 1), where the majority of the population and urban areas are concentrated. On the other hand, few landslides were recorded in the North (MBS) and in the vegetated areas of the Bocaína Plateau (Figure 1).
Map of the study area (825 km2), Municipality of Angra dos Reis in the state of Rio de Janeiro, Brazil. Red dots show location of the 1640 landslides recorded and the black dashed line represents the limit between north (Mambucada, Bracui, and Serra d’Agua – MBS) and south (Japuida, Angra dos Reis, and Jacuecanga – JAJ) regions.
Regarding the inter-annual variability of rainfall events triggering landslides for the 6-years period analyzed indicates that landslides occur every year. On an intra-annual basis, the average number of triggering events and the ratios of triggering versus non-triggering events vary primarily with the seasonality. Indeed, the average numbers and ratios are 9 and 40% in the wet season (January to April), 5 and 25% in the dry season (May to August), and 8 and 32% in the transition season (September to November).
The 484 rainfall events that likely triggered landslides lasted approximately 4 days (101 hours; Table 1), with a minimum and maximum duration of 24 and 624 hours (26 days), and initiated an average of three landslides. Specifically, 45% (219 out of 484) of the triggering events initiated a single slide, 75% (365 out of 484) triggered three or fewer slides, and only 8% (37 out of 484) generated ten or more failures, with a maximum of 38 landslides per episode. In this regard, two rainfall events recorded in the region of Angra dos Reis triggered exactly 38 landslides. The first one started on December 27, 2012 and ended on January 4, 2013, accumulating 540.5 mm of rain in nine days, while the second one started on January 9, 2013 and ended on January 22, 2013 after dumping 372.9 mm in 14 days. While the first of the two rainfall events had accumulated only 46.5 mm in the previous 30 days, the second had accumulated 565 mm of antecedent rainfall over 30 days. Therefore, the soils of the region had received 937.9 mm in 44 days as of January 22, 2013. Angra dos Reis was specifically the region the most affected by landslides during the study period, accounting for 39% (638 out of 1640) of all landslides recorded. This corresponds to an average of four landslides per triggering rainfall event, which is slightly higher than the regional average of three at the municipal level.
On a seasonal basis, 69% of the landslides (1130 of 1640) were initiated during the wet season. This significantly outweighs the amount of landslides that were initiated during the dry season and the transition season, both of which accounted for approximately 15%. On a monthly basis, January had the most landslides initiated, followed by March, April and December in relatively equal proportions. This average of 69 landslides per month in January is almost twice as the amount recorded in the other wet months (December, February, March, and April), which average 33, and five times more than in drier months (May to October), which average 13. Finally, the month of May represents the least likely period for landslide occurrence with only six landslides recorded on average. This data is nevertheless significant and indicates that landslides can occur in any month of the year, despite less precipitation in the winter period (May to August).
With respect to slope steepness, 71% of the cases occurred on gentle slopes (0 to 20o), 27% on slopes between 20 and 35 o and only 2% on steep slopes (>35 o). Regarding slope orientation, more than a third of the landslides (34%) were initiated on south facing slopes, i.e. facing the prevailing winds, while 24% were initiated on north facing slopes. The remaining cases were associated with west (18%) and east (16%) facing slopes and relatively flat terrain (8%). Finally, 58% of the landslides were triggered in urban areas compared to 27% in forested areas and 8% in pastures.
At the urban center scale of Angra dos Reis, 526 landslides were linked to one of 234 rainfall events compiled. The geographic distribution of landslides is relatively heterogeneous despite a fairly large clustering (155 cases; 30%) in the colluviums of the Sapinhatuba I and Monte Castelo neighborhoods in the east-central part of the urban center (Figure 2). The landslides were initiated during 129 of the 234 (55%) rainfall events compiled (Table 1). These 129 rainfall events lasted a little more than 4 days, or 108 hours, with a minimum and maximum duration of 24 and 528 hours (22 days). The minimum and maximum number of landslides initiated by these episodes are 1 and 38, for an average of four landslides per triggering rainfall event. More specifically, 36% (47 of 131) of the triggering rainfall events initiated a single slide, 63% (83 of 131) initiated three or fewer slides, and only 9% (12 of 131) generated ten or more ruptures.
Map of the urban center of Angra dos Reis. Red dots show location of the 526 landslides recorded over an area of 6.5 km2.
On a seasonal basis, two-thirds of the 526 slides (66%) were initiated during the wet season. Indeed, the average number of rainfall triggering events and the ratios of triggering versus non-triggering events are 2 and 64% in the wet season (January to April), 1 and 37% in the dry season (May to August), and 2 and 59% in the transition season (September to November). On a monthly basis, January was the most significant month with an average of 25 landslides compared to only seven for all other months. 42% of the landslides occurred on gentle slopes (0 to 20o), 39% on slopes between 20 and 35 o and 19% on steep slopes >35 o. In this respect, more landslides were recorded on steep slopes at the local scale compared to the regional scale. The slopes facing south were the most affected with 53% of the landslides, compared to 21% on slopes facing north, 13% on the east and 14% on the west facing slopes (Figure 2). Finally, a high proportion of landslides (76%) occurred in urban areas, while only 22% occurred in forest and pasture areas.
As we mentioned in the methodological section, several ED thresholds were defined at the regional and local scales based on the overall database, but also with different subsets for the seasonality (wet and dry seasons), and the southern (JAJ) and northern (MBS) parts of the study area.
Figure 3 shows, in log–log coordinates, the distribution of rainfall conditions (D, E) that have resulted in landslides at both scales; the municipality of Angra dos Reis (1640 landslides) and the urban center (526 landslides), with the 1% and 5% ED thresholds curves. The urban center shows a quite similar 1% ED threshold (T1 UC-ADR) and 5% ED threshold (T5 UC-ADR) to those calculated at the regional scale (T1 ADR and T5 ADR). See Table 1 for more details about the scale and intercept parameters.
Rainfall duration D (x-axis) and cumulated event rainfall E (y-axis) conditions that have resulted in landslides at the regional scale of the municipality of Angra dos Reis (upper panel) and at the local scale of the urban center (lower panel). 1% and 5% ED power law thresholds are shown with their equations (solid lines) as well as 50% (dashed line) for reference. Inset shows the study area and the localization of the three major deadly events (red dots) at the regional scale.
The ED rainfall thresholds shown in Figure 4 indicate lower 5% thresholds for the extended dry season (T5 M-O-ADR and T5-M-O-UC) by comparison to the wet season (T5-N-A-ADR and T5 N-A-UC) at both scales. Indeed, the insets clearly indicate the high monthly variability in occurrence of landslides recorded, showing obvious differences between the dry and wet season. In this case, the 5% ED thresholds were quite similar for the municipality and urban center, particularly for the dry season and with a very small difference for the wet season (Table 1). However, the rainfall events triggering landslides during the wet season appears of shorter duration at the local scale (24 to 336 hours) compared to the regional scale (24 to 624 hours). No difference was reported for the dry season.
Rainfall duration D (x-axis) and cumulated event rainfall E (y-axis) conditions that have resulted in landslides in the period May–October (dry season; blue dots) and for the period November–April (wet season; gray dots). Colored lines are the 5% power law thresholds and insets show the distribution of recorded landslides on a monthly basis. Upper panel shows the dataset at the regional scale and lower panel shows the dataset at the local scale of urban center.
Finally, the Figure 5 shows the similar tendency of the 5% thresholds for the southern and northern regions, although the latter shows a slightly higher value. However, it is worth mentioning the significant difference between the two regions regarding the number of recorded landslides; 1276 in the southern part and 364 in the northern part of the municipality. A significant appears also in the duration of rainfall events triggering landslides, which is limited to 432 hours in the north by comparison to 624 hours in the south (Table 2 and Figure 5).
Rainfall duration D (x-axis) and cumulated event rainfall E (y-axis) conditions that have resulted in landslides in the southern region (JAJ; yellow dots) and the northern region (MBS; red dots). Colored lines are the 5% power law thresholds and inset shows the geographical area covers by both regions as well as the number of landslides recorded.
Label | Area | RE | LE | Threshold | Range (h) | Uncertainty |
---|---|---|---|---|---|---|
T1, ADR | R | 484 | 1640 | 24-624 | ||
T5, ADR | R | 484 | 1640 | 24-624 | ||
T1, UC-ADR | L | 129 | 526 | 24-528 | ||
T5, UC-ADR | L | 129 | 526 | 24-528 | ||
T5, N-A-ADR | R-Wet | 1240 | 1240 | 24-624 | ||
T5, M-O-ADR | R-Dry | 400 | 400 | 24-528 | ||
T5, N-A-UC | L-Wet | 393 | 393 | 24-336 | ||
T5, M-O-UC | L-Dry | 133 | 133 | 24-528 | ||
T5, JAJ-ADR | R-South | 357 | 1276 | 24-624 | ||
T5, MBS-ADR | R-North | 451 | 364 | 24-432 |
Rainfall ED thresholds for the possible initiation of landslides in Angra dos Reis.
Label: label of the thresholds defined in this study. Area: regional scale (R) of the municipality or local scale (L) of the urban center. RE: number of rainfall events. LE: number of landslide events. Threshold: D rainfall duration, in hours; E, cumulated event rainfall, in mm. Range: range of the validity for the threshold. Uncertainty: associated with the intercept α and the slope γ of the threshold model based on a power law.
Several factors of a geological (volcanic activity, earthquake, lithologic faults and discontinuities, etc.), meteorological (precipitation, temperature), and human (land use) nature influence slope stability [36]. Therefore, the dynamic relationships in time and space between these different factors greatly complicate the objective assessment of landslide susceptibility and probability of occurrence for a given region and time period [37].
In the humid tropics, the majority of precipitation and its extremes are concentrated during the summer period. To this end, the warm and humid climate of southeastern Brazil favors the chemical alteration of rock and the development of saprolites, especially in hilly and mountainous environments. During major rainfall events, these are reworked by mass movements such as debris flows, superficial slides, rotational, and deep-seated landslides [38]. It is therefore not surprising that in the past several catastrophic events occurred [39, 40, 41], for example and among others in 1967 [42], 1988 and 1996 [43, 44, 45], and more recently in 2008, 2010 and 2011 [46, 47, 48]. The rapid growth of urbanization in the last decades with an improper land use [38] is certainly responsible, at least partially, for the tragic outcome of these recent disasters.
In this context, several approaches have subsequently been used to assess landslide risk: landslide susceptibility zonation using GIS-based fuzzy logic [49], electric and electromagnetic methods with geotechnical soundings [50], structural geology and kinematic analysis with stereographic projections [51, 52], analysis of morphological parameters (drainage efficiency index, slope geometry, slope angles, etc.) [53], laboratory and fields observations [54], and modeling with SHALSTAB (shallow landsliding stability model), SINMAP (stability index mapping), GEO-SLOPE (slope stability analysis), and TRIGRS (transient rainfall infiltration) software’s [55, 56, 57]. Despite the limited effectiveness of these modeling procedures and the interest in mapping and vulnerability of populations to landslides, e.g. [58, 59, 60], there is still little work on the determination of rainfall thresholds favorable to landslide occurrence. Indeed, the few authors who have focused on defining rainfall thresholds in southeastern Brazil and the Serra do Mar at the regional scale, are rather thresholds based on total precipitation during major events [19, 61].
The ED thresholds presented in this study at regional and local scales highlight the statistical dependency of the cumulated rainfall E to the rainfall duration D. In that regards, they represent appropriate rainfall thresholds for the possible occurrence of 1640 landslides in the municipality of Angra dos Reis and 526 landslides at the local scale of the urban center over a 6-year period. However, because these thresholds result of statistical modeling applied to an empirical dataset, uncertainties have been quantified using a bootstrap approach.
Figure 4 indicates a significant difference in seasonal thresholds for all duration analyzed. Surprisingly, less cumulated rainfall appear required to initiate landslides during the dry season (May–October) by comparison to the wet summer season (November–April). This result was not expected considering that usually the antecedent rainfall conditions of the wet season, and the resulting increased moisture in the soil, reduce the amount of event rainfall required to triggering landslides [30]. Unfortunately, the absence of details about the landslides recorded does not allow a better discrimination in landslide classification or typology regarding their temporal occurrence. However, the significant difference between the northern and southern regions in number of landslides triggered by rainfall events (Figure 5), attests for the likely influence of other environmental factors such as slope aspect, land cover type, lithological types, etc. Slope steepness does not appear to be a very important factor given the amount of landslides recorded on gentle slopes. On the other hand, even considering the size of the dataset analyzed (484 rainfall events resulting in 1640 landslides), we acknowledge that further studies are required to better understand the role of land use, land cover types, urbanization, and human induced changes that may affect the amount of rain necessary to trigger landslides locally and regionally. Finally, as mentioned by [62], the bootstrapping technique may result in optimistic estimates of the uncertainties in the thresholds determined, to which we suggest conducting similar analyses over longer time series.
In the Brazilian municipality of Angra dos Reis, heavy summer rainfall has historically triggered several landslides, causing a significant number of victims and considerable damage. The risk posed by this geomorphic hazard is particularly high due to the fact that almost 60% of the population lives in slope areas [16] and more than 25% live in areas considered to be at high risk of landslides [17]. In that regards, our data indicate that 58% of the 1640 landslides recorded occurred in urban areas, 71% on gentle slope, and 34% on south facing slopes, reflecting the exposure and risk to the population. Therefore, the interest of the municipal authorities of Angra dos Reis in establishing rainfall thresholds (i.e. Table 2) should allow a better anticipation of spatial and temporal occurrence of the phenomenon. The thresholds in this study could ultimately be integrated into a landslide monitoring and warning system and serve as a necessary component of hazard assessment. This is particularly pertinent considering that since the beginning of research on rain-triggered landslides in Brazil, no suitable thresholds have been proposed for the Angra dos Reis territory.
In fact, the thresholds of Guidicini and Iwasa [18] were established for the whole Serra do Mar, whose area is four times larger than that of Angra dos Reis, while the one developed by Soares [19] is not representative of the triggering conditions due to the use of an inadequate database. The thresholds proposed and to come in the near future according to the characteristics of the territory and from recent and reliable data could be an effective tool for landslide risk management.
In the mountainous and tropical environment of the municipality of Angra dos Reis in Brazil, the high frequency of intense rainfall generates several landslides that recurrently interfere with human activities and infrastructures. Lithology, land use and vegetation cover are biophysical parameters that remain to be explored in relation to the spatial and temporal dynamics of landslides, especially in a context of climate change and increasing urbanization.
The establishment of quantitative rainfall thresholds that, when reached or exceeded, are likely to trigger landslides (e.g. Figures 3–5) therefore appears to be a valid approach for risk management. The thresholds reported in this study could provide a relevant management tool for municipal authorities. Moreover, the establishment of thresholds based on the duration of rainfall events (ED) should be regarded as a research axis whose development is essential in risk management, particularly in order to set up a landslide monitoring and warning system. The detailed study of rainfall conditions that led to the initiation of 1640 landslides in the municipality of Angra dos Reis and 526 landslides in the urban center revealed that very small amounts of water accumulated over periods of up to 26 days are sufficient to initiate landslides (Table 2). These precipitations represent barely 1 to 4% of the annual average rainfall depending on the duration of the events considered. The rainfall limits appear low when compared to some of the thresholds proposed in the literature for Brazil and other tropical regions.
Special thanks to the municipal authorities of Angra dos Reis for providing us the data on the occurrence of landslides as well as the data from the rainfall stations in their territory. Finally, thanks also to the Scientific Council of the Brazilian Government for granting research funding in the context of this Canada-Brazil cooperation, particularly with the department of Geography of the State University of Rio de Janeiro.
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Developing nations are a broad term that includes countries that are less industrialised and have lower per capita income levels than developed countries. This chapter will discuss clean water for drinking water purposes. Pollution concerns of water in developing countries will be categorised in terms of physical, chemical and biological pollutants such as turbidity, organic matter and bacteria. Natural and anthropogenic pollution concerns linking with seasonal factors will be outlined. The multi-barrier approach to drinking water treatment will be discussed. Abstraction points used will be researched. Water treatment systems, medium- to small-scale approaches, will be discussed. The processes involved in removing the contaminants including physical processes such as sedimentation, filtration such as slow-sand filtration, coagulation and flocculation, and disinfectant processes such as chlorination will be reviewed. Other important methods including solar disinfection, hybrid filtration methods and arsenic removal technologies using innovative solid phase materials will be included in this chapter. Rainwater harvesting technologies are reviewed. Safe storage options for treated water are outlined. Challenges of water treatment in rural and urban areas will be outlined.",book:{id:"6682",slug:"the-relevance-of-hygiene-to-health-in-developing-countries",title:"The Relevance of Hygiene to Health in Developing Countries",fullTitle:"The Relevance of Hygiene to Health in Developing Countries"},signatures:"Josephine Treacy",authors:[{id:"238173",title:"Dr.",name:"Josephine",middleName:null,surname:"Treacy",slug:"josephine-treacy",fullName:"Josephine Treacy"}]},{id:"44219",doi:"10.5772/54973",title:"Disaster Management Discourse in Bangladesh: A Shift from Post-Event Response to the Preparedness and Mitigation Approach Through Institutional Partnerships",slug:"disaster-management-discourse-in-bangladesh-a-shift-from-post-event-response-to-the-preparedness-and",totalDownloads:4124,totalCrossrefCites:4,totalDimensionsCites:28,abstract:null,book:{id:"3054",slug:"approaches-to-disaster-management-examining-the-implications-of-hazards-emergencies-and-disasters",title:"Approaches to Disaster Management",fullTitle:"Approaches to Disaster Management - Examining the Implications of Hazards, Emergencies and Disasters"},signatures:"C. Emdad Haque and M. Salim Uddin",authors:[{id:"163390",title:"Dr.",name:"C. Emdad",middleName:null,surname:"Haque",slug:"c.-emdad-haque",fullName:"C. Emdad Haque"},{id:"168399",title:"Mr.",name:"Mohammed S",middleName:null,surname:"Uddin",slug:"mohammed-s-uddin",fullName:"Mohammed S Uddin"}]},{id:"59705",doi:"10.5772/intechopen.74943",title:"Augmented Reality Trends in Education between 2016 and 2017 Years",slug:"augmented-reality-trends-in-education-between-2016-and-2017-years",totalDownloads:2513,totalCrossrefCites:19,totalDimensionsCites:27,abstract:"The aim of this chapter is to review literature regarding using augmented reality (AR) in education articles published in between 2016 and 2017 years. The literature source was Web of Science and SSCI, SCI-EXPANDED, A&HCI, CPCI-S, CPCI-SSH, and ESCI indexes. Fifty-two articles were reviewed; however, 14 of them were not been included in the study. As a result, 38 articles were examined. Level of education, field of education, and material types of AR used in education and reported educational advantages of AR have been investigated. All articles are categorized according to target groups, which are early childhood education, primary education, secondary education, high school education, graduate education, and others. AR technology has been mostly carried out in primary and graduate education. “Science education” is the most explored field of education. Mobile applications and marker-based materials on paper have been mostly preferred. The major advantages indicated in the articles are “Learning/Academic Achievement,” “Motivation,” and “Attitude”.",book:{id:"6543",slug:"state-of-the-art-virtual-reality-and-augmented-reality-knowhow",title:"State of the Art Virtual Reality and Augmented Reality Knowhow",fullTitle:"State of the Art Virtual Reality and Augmented Reality Knowhow"},signatures:"Rabia M. 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Therefore, this chapter deals with the philosophical systems and paradigms of scientific research, the epistemology, evaluating understanding and application of various theories and practices used in the scientific research. The key components of the scientific research paradigm are highlighted. Theories on the basis of which this research was focused on identification of the level of development of the management culture in order to implement corporate social responsibility are identified, and the stages of its implementation are described.",book:{id:"5791",slug:"management-culture-and-corporate-social-responsibility",title:"Management Culture and Corporate Social Responsibility",fullTitle:"Management Culture and Corporate Social Responsibility"},signatures:"Pranas Žukauskas, Jolita Vveinhardt and Regina Andriukaitienė",authors:[{id:"179629",title:"Prof.",name:"Jolita",middleName:null,surname:"Vveinhardt",slug:"jolita-vveinhardt",fullName:"Jolita Vveinhardt"}]},{id:"74550",title:"School Conflicts: Causes and Management Strategies in Classroom Relationships",slug:"school-conflicts-causes-and-management-strategies-in-classroom-relationships",totalDownloads:2328,totalCrossrefCites:1,totalDimensionsCites:10,abstract:"Conflicts cannot cease to exist, as they are intrinsic to human beings, forming an integral part of their moral and emotional growth. Likewise, they exist in all schools. The school is inserted in a space where the conflict manifests itself daily and assumes relevance, being the result of the multiple interpersonal relationships that occur in the school context. Thus, conflict is part of school life, which implies that teachers must have the skills to manage conflict constructively. Recognizing the diversity of school conflicts, this chapter aimed to present its causes, highlighting the main ones in the classroom, in the teacher-student relationship. It is important to conflict face and resolve it with skills to manage it properly and constructively, establishing cooperative relationships, and producing integrative solutions. Harmony and appreciation should coexist in a classroom environment and conflict should not interfere, negatively, in the teaching and learning process. This bibliography review underscore the need for during the teachers’ initial training the conflict management skills development.",book:{id:"7827",slug:"interpersonal-relationships",title:"Interpersonal Relationships",fullTitle:"Interpersonal Relationships"},signatures:"Sabina Valente, Abílio Afonso Lourenço and Zsolt Németh",authors:[{id:"324514",title:"Ph.D.",name:"Sabina",middleName:"N.",surname:"Valente",slug:"sabina-valente",fullName:"Sabina Valente"},{id:"326375",title:"Prof.",name:"Abílio Afonso",middleName:"Afonso",surname:"Lourenço",slug:"abilio-afonso-lourenco",fullName:"Abílio Afonso Lourenço"},{id:"329177",title:"Dr.",name:"Zsolt",middleName:null,surname:"Németh",slug:"zsolt-nemeth",fullName:"Zsolt Németh"}]},{id:"52475",title:"Teenage Pregnancies: A Worldwide Social and Medical Problem",slug:"teenage-pregnancies-a-worldwide-social-and-medical-problem",totalDownloads:8293,totalCrossrefCites:6,totalDimensionsCites:8,abstract:"Teenage pregnancies and teenage motherhood are a cause for concern worldwide. From a historical point of view, teenage pregnancies are nothing new. For much of human history, it was absolutely common that girls married during their late adolescence and experienced first birth during their second decade of life. This kind of reproductive behavior was socially desired and considered as normal. Nowadays, however, the prevention of teenage pregnancies and teenage motherhood is a priority for public health in nearly all developed and increasingly in developing countries. For a long time, teenage pregnancies were associated with severe medical problems; however, most of data supporting this viewpoint have been collected some decades ago and reflect mainly the situation of per se socially disadvantaged teenage mothers. According to more recent studies, teenage pregnancies are not per se risky ones. A clear risk group are extremely young teenage mothers (younger than 15 years) who are confronted with various medical risks, such as preeclampsia, preterm labor, and small for gestational age newborns but also marked social disadvantage, such as poverty, unemployment, low educational level, and single parenting. In the present study, the prevalence and outcome of teenage pregnancies in Austria are focused on.",book:{id:"5392",slug:"an-analysis-of-contemporary-social-welfare-issues",title:"An Analysis of Contemporary Social Welfare Issues",fullTitle:"An Analysis of Contemporary Social Welfare Issues"},signatures:"Sylvia Kirchengast",authors:[{id:"188289",title:"Prof.",name:"Sylvia",middleName:null,surname:"Kirchengast",slug:"sylvia-kirchengast",fullName:"Sylvia Kirchengast"}]},{id:"58060",title:"Pedagogy of the Twenty-First Century: Innovative Teaching Methods",slug:"pedagogy-of-the-twenty-first-century-innovative-teaching-methods",totalDownloads:8832,totalCrossrefCites:17,totalDimensionsCites:22,abstract:"In the twenty-first century, significant changes are occurring related to new scientific discoveries, informatization, globalization, the development of astronautics, robotics, and artificial intelligence. This century is called the age of digital technologies and knowledge. How is the school changing in the new century? How does learning theory change? Currently, you can hear a lot of criticism that the classroom has not changed significantly compared to the last century or even like two centuries ago. Do the teachers succeed in modern changes? The purpose of the chapter is to summarize the current changes in didactics for the use of innovative teaching methods and study the understanding of changes by teachers. In this chapter, we consider four areas: the expansion of the subject of pedagogy, environmental approach to teaching, the digital generation and the changes taking place, and innovation in teaching. The theory of education, figuratively speaking, has two levels. At the macro-level, in the “education-society” relationship, decentralization and diversification, internationalization of education, and the introduction of digital technologies occur. At the micro-level in the “teacher-learner” relationship, there is an active mix of traditional and innovative methods, combination of an activity approach with an energy-informational environment approach, cognition with constructivism and connectivism.",book:{id:"5980",slug:"new-pedagogical-challenges-in-the-21st-century-contributions-of-research-in-education",title:"New Pedagogical Challenges in the 21st Century",fullTitle:"New Pedagogical Challenges in the 21st Century - Contributions of Research in Education"},signatures:"Aigerim Mynbayeva, Zukhra Sadvakassova and Bakhytkul\nAkshalova",authors:[{id:"201997",title:"Dr.",name:"Aigerim",middleName:null,surname:"Mynbayeva",slug:"aigerim-mynbayeva",fullName:"Aigerim Mynbayeva"},{id:"209208",title:"Dr.",name:"Zukhra",middleName:null,surname:"Sadvakassova",slug:"zukhra-sadvakassova",fullName:"Zukhra Sadvakassova"},{id:"209210",title:"Dr.",name:"Bakhytkul",middleName:null,surname:"Akshalova",slug:"bakhytkul-akshalova",fullName:"Bakhytkul Akshalova"}]},{id:"58894",title:"Research Ethics",slug:"research-ethics",totalDownloads:3371,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Research ethics is closely related to the ethical principles of social responsibility. This research covers a wide context of working with people, so the researchers raised a task not only to gain confidence in the respondents’ eyes, to receive reliable data, but also to ensure the transparency of the science. This chapter discusses the theoretical and practical topics of research, after evaluation of which ethical principles of organization and conducting the research are presented. There is a detailed description of how and what ethical principles were followed on the different stages of the research.",book:{id:"5791",slug:"management-culture-and-corporate-social-responsibility",title:"Management Culture and Corporate Social Responsibility",fullTitle:"Management Culture and Corporate Social Responsibility"},signatures:"Pranas Žukauskas, Jolita Vveinhardt and Regina Andriukaitienė",authors:[{id:"179629",title:"Prof.",name:"Jolita",middleName:null,surname:"Vveinhardt",slug:"jolita-vveinhardt",fullName:"Jolita Vveinhardt"}]}],onlineFirstChaptersFilter:{topicId:"23",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"83053",title:"Apologies in L2 French in Canadian Context",slug:"apologies-in-l2-french-in-canadian-context",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.106557",abstract:"This article presents the results of an analysis of apology strategies in native and non-native French in Canadian context. The data used were obtained through a Discourse Completion Task questionnaire that was completed by a group of native French speakers (FL1) and a group of learners of French as a second language (FL2). The goal was to identify and compare pragmatic and linguistic choices made by both groups when apologizing in three different situations. Several differences and similarities emerged between the two groups regarding the use of exclamations to introduce apologies, direct apologies, indirect apologies, and supportive acts. For instance, it was found that the FL1 speakers used “expressions of regret”, “offers of apology” 15 and “requests for forgiveness” to apologize directly, while the FL2 speaking informants used 16 only “expressions of regret” and “offers of apology”. While the respondents of both groups 17 mostly chose “offers of repair” to apologize indirectly, they displayed divergent preferences 18 regarding the use of other indirect apology strategies. Differences were also documented 19 with respect to the use of intensification devices in direct apologies and the use of supportive acts. Implications of the findings for L2 French pedagogy were also discussed.",book:{id:"11480",title:"Second Language Acquisition - Learning Theories and Recent Approaches",coverURL:"https://cdn.intechopen.com/books/images_new/11480.jpg"},signatures:"Bernard Mulo Farenkia"},{id:"83049",title:"An Ethnographic Study on Sense of a Community: The “Awramba” Experience",slug:"an-ethnographic-study-on-sense-of-a-community-the-awramba-experience",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.105953",abstract:"The study was conducted on “Awramba” Community who are living in “Amhara” region, south “Gondor” Zone, Ethiopia. The general objective of this study was to capture an understanding of sense of community in “Awramba” community. The study tried to answer the following questions: How the community was established? What are the criteria to be part of the community? What are the shared values of social practice that has survived for the test of time? What is the historical background of the “Awramba” Community? The researcher used realist ethnography method to achieve the above objective and to answer the questions. In-depth interview and observational guide techniques were applied to collect reliable data for the study. The observation and in-depth interview data were analyzed qualitatively. The study showed the following themes: Membership criteria of the community are based on adhering to the community norm. They have a strong sense of community based on shared story, cooperative work, marriage and mourning values, religious view, gender equality, commitment to be honest, and solving their problem by themselves. The emotional connection of the “Awramba” community is strengthened by their common celebration of the yearly anniversary of New Year and scheduled meeting.",book:{id:"11429",title:"Sustainability, Ecology, and Religions of the World",coverURL:"https://cdn.intechopen.com/books/images_new/11429.jpg"},signatures:"Nassir-Maru Yesuf"},{id:"83014",title:"Culture: A Pillar of Organizational Sustainability",slug:"culture-a-pillar-of-organizational-sustainability",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.106523",abstract:"Sustainability is a concern that permeates all levels of society and is premised on meeting the needs of the present without compromising the ability of future generations to meet theirs. More recently, policies and research have emerged that guide organizations to align their activities with the broader sustainable development agendas, including cultural issues, not just economic, social, and environmental ones. Culture is the material and immaterial attribute of society. It incorporates social organizations, literature, religion, myths, beliefs, behaviors and entrepreneurial practices of the productive segment, use of technology, and expressive art forms on which future generations depend. Thus, cultural sustainability is a fundamental issue and is configured as the fourth pillar of sustainability, equal to social, economic, and environmental issues, which has to do with the ability to sustain or continue with cultural beliefs and practices, preserve cultural heritage as its entity, and try to answer whether any culture will exist in the future. The importance of cultural sustainability lies in its power to influence people. Their beliefs are in the decisions made by society. Thus, there can be no sustainable development without including culture.",book:{id:"11429",title:"Sustainability, Ecology, and Religions of the World",coverURL:"https://cdn.intechopen.com/books/images_new/11429.jpg"},signatures:"Clea Beatriz Macagnan and Rosane Maria Seibert"},{id:"82949",title:"Corruption and Deterioration of Democracy: The Brazilian Lesson",slug:"corruption-and-deterioration-of-democracy-the-brazilian-lesson",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.106194",abstract:"Although it has emerged, nationally and internationally, as one of the largest investigations against political corruption, Operation Car Wash—at its peak of popular prestige—cleared the path for the political rise of Jair Bolsonaro to the Presidency of the Republic of Brazil. And by doing so, to a certain extent, it paved the way for a set of arbitrary practices that today threaten and weaken the main Brazilian democratic institutions. Brazilian democracy today pays a high price for the Judiciary’s lethargic and condescending response to the unorthodox and illegal practices of Federal Judge Sérgio Moro during the golden years of Operation Car Wash (2014–2018). The lesson that the Brazilian episode brings to the international legal community is that the constant disrespect for the rules of due criminal procedure in large cases of corruption erodes the institutional bases that support the proper confrontation of this type of crime. The pertinent fight against corruption in a democracy can only take place in strict obedience to the law.",book:{id:"11772",title:"Corruption - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11772.jpg"},signatures:"Fabio Roberto D’Avila and Theodoro Balducci de Oliveira"},{id:"82903",title:"Walking Accessibility to Primary Healthcare Services: An Inequity Factor for Olders in the Lisbon Metropolitan Area (Portugal)",slug:"walking-accessibility-to-primary-healthcare-services-an-inequity-factor-for-olders-in-the-lisbon-met",totalDownloads:4,totalDimensionsCites:0,doi:"10.5772/intechopen.106265",abstract:"This chapter discusses the walking accessibility to primary healthcare by the olders in Lisbon Metropolitan Area (LMA), Portugal, and its contribution for age-friendly environments as a factor of inequity. Constrains emerged from the collation of the supply approach, represented by service catchment areas based on walking distance time, and the demand approach, through a survey. The location and density of primary health network are a major factor, as it is related to distinct land use patterns within the LMA. The settlement structure influences the potential walkability to primary healthcare. The discrepancy between the potential walking accessibility and the real options is notorious, as olders` choices are diversified in terms of transportation modes and destinations, but mostly keeping relatively short time distances. This phenomenon is also influenced by factors such as personal preference, difficulty to walk, negative perceptions about the surroundings, and insufficient care support. This debate is already an effective concern of local authorities with spatial planning, social and health competences, insofar as solutions in terms of service flexibility and new travel solutions adapted to the specific needs of the olders are a growing reality in the LMA, promoting more age-friendly, health, and inclusive environments, and hence an equitable metropolis.",book:{id:"11479",title:"Social Aspects of Ageing - Selected Challenges, Analyses, and Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11479.jpg"},signatures:"Eduarda Marques da Costa, Ana Louro, Nuno Marques da Costa, Mariana Dias and Marcela Barata"},{id:"82834",title:"Perspective Chapter: Social Work Education in University Curricula for Sustainable Development",slug:"perspective-chapter-social-work-education-in-university-curricula-for-sustainable-development",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.106246",abstract:"Universities of both global North and South have been changing from the traditional teaching-learning centers to cater to sustainability issues of those countries. Yet, there is a remarkable difference between the universities in the developed and the developing world. It has been found out that the different disciplines of university curricula can be integrated to address and minimize the adverse effects of unsustainability issues. The graduates of the universities will be the future leaders who have to cater to the needs and cope with the challenges of the next generation. There is a dearth of professional social workers to provide the necessary services as numerous catastrophes occur. The global society needs individuals who are equally sound in the knowledge of theory and the experience of practice. As the contemporary global issues become complex, the world needs competent social workers who can serve in different fields of practice. Social work could be the pivotal discipline in understanding common tragedies of the people to apply problem-solving model with the practitioners who are equipped with twenty-first century skills. Social work has to take a transition from a unidisciplinary to a multi- and trans-disciplinary perspective in achieving this objective.",book:{id:"11095",title:"Social Work - Perspectives on Leadership and Organisation",coverURL:"https://cdn.intechopen.com/books/images_new/11095.jpg"},signatures:"Upul Lekamge"}],onlineFirstChaptersTotal:146},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"86",title:"Business and Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/86.jpg",isOpenForSubmission:!0,annualVolume:11970,editor:{id:"128342",title:"Prof.",name:"Vito",middleName:null,surname:"Bobek",slug:"vito-bobek",fullName:"Vito Bobek",profilePictureURL:"https://mts.intechopen.com/storage/users/128342/images/system/128342.jpg",biography:"Dr. Vito Bobek works as an international management professor at the University of Applied Sciences FH Joanneum, Graz, Austria. He has published more than 400 works in his academic career and visited twenty-two universities worldwide as a visiting professor. 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Dr. Bobek is also a co-founder of the Academy of Regional Management in Slovenia.",institutionString:"Universities of Applied Sciences FH Joanneum, Austria",institution:{name:"Universities of Applied Sciences Joanneum",institutionURL:null,country:{name:"Austria"}}},editorTwo:{id:"293992",title:"Dr.",name:"Tatjana",middleName:null,surname:"Horvat",slug:"tatjana-horvat",fullName:"Tatjana Horvat",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hXb0hQAC/Profile_Picture_1642419002203",biography:"Tatjana Horvat works as a professor for accountant and auditing at the University of Primorska, Slovenia. She is a Certified State Internal Auditor (licensed by Ministry of Finance RS) and Certified Internal Auditor for Business Sector and Certified accountant (licensed by Slovenian Institute of Auditors). At the Ministry of Justice of Slovenia, she is a member of examination boards for court expert candidates and judicial appraisers in the following areas: economy/finance, valuation of companies, banking, and forensic investigation of economic operations/accounting. 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His teaching interests revolve around global economies and markets while his research focuses on topics related to development and growth, global business decisions, and the economics of technical innovation.",institutionString:null,institution:{name:"University of Houston",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},{id:"88",title:"Marketing",coverUrl:"https://cdn.intechopen.com/series_topics/covers/88.jpg",isOpenForSubmission:!0,annualVolume:11972,editor:{id:"203609",title:"Associate Prof.",name:"Hanna",middleName:null,surname:"Gorska-Warsewicz",slug:"hanna-gorska-warsewicz",fullName:"Hanna Gorska-Warsewicz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSD9pQAG/Profile_Picture_2022-06-14T11:58:32.jpeg",biography:"Hanna Górska-Warsewicz, Ph.D. is Associate Professor at Warsaw University of Life Sciences and Head of Department of Food Market and Consumption Research. She specializes in the subject of brands, brand equity, and brand management in production, service, and trade enterprises. She combines this subject with marketing and marketing management in both theoretical and practical aspects. Prof. Hanna Górska-Warsewicz also analyzes brands in the context of trademarks, legal regulations and the protection of intangible. She is an author or co-author of over 200 publications in this field, including 8 books. 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(Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}}]},{type:"book",id:"7726",title:"Swarm Intelligence",subtitle:"Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/7726.jpg",slug:"swarm-intelligence-recent-advances-new-perspectives-and-applications",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Javier Del Ser, Esther Villar and Eneko Osaba",hash:"e7ea7e74ce7a7a8e5359629e07c68d31",volumeInSeries:2,fullTitle:"Swarm Intelligence - Recent Advances, New Perspectives and Applications",editors:[{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\r\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\r\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Orthodontist, Assoc Prof in the Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"344229",title:"Dr.",name:"Sankeshan",middleName:null,surname:"Padayachee",slug:"sankeshan-padayachee",fullName:"Sankeshan Padayachee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"315727",title:"Ms.",name:"Kelebogile A.",middleName:null,surname:"Mothupi",slug:"kelebogile-a.-mothupi",fullName:"Kelebogile A. Mothupi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"337613",title:"Mrs.",name:"Tshakane",middleName:null,surname:"R.M.D. Ralephenya",slug:"tshakane-r.m.d.-ralephenya",fullName:"Tshakane R.M.D. Ralephenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}}]}},subseries:{item:{id:"10",type:"subseries",title:"Animal Physiology",keywords:"Physiology, Comparative, Evolution, Biomolecules, Organ, Homeostasis, Anatomy, Pathology, Medical, Cell Division, Cell Signaling, Cell Growth, Cell Metabolism, Endocrine, Neuroscience, Cardiovascular, Development, Aging, Development",scope:"Physiology, the scientific study of functions and mechanisms of living systems, is an essential area of research in its own right, but also in relation to medicine and health sciences. The scope of this topic will range from molecular, biochemical, cellular, and physiological processes in all animal species. Work pertaining to the whole organism, organ systems, individual organs and tissues, cells, and biomolecules will be included. Medical, animal, cell, and comparative physiology and allied fields such as anatomy, histology, and pathology with physiology links will be covered in this topic. Physiology research may be linked to development, aging, environment, regular and pathological processes, adaptation and evolution, exercise, or several other factors affecting, or involved with, animal physiology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",hasOnlineFirst:!1,hasPublishedBooks:!1,annualVolume:11406,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null,series:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261"},editorialBoard:[{id:"306970",title:"Mr.",name:"Amin",middleName:null,surname:"Tamadon",slug:"amin-tamadon",fullName:"Amin Tamadon",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002oHR5wQAG/Profile_Picture_1623910304139",institutionString:null,institution:{name:"Bushehr University of Medical Sciences",institutionURL:null,country:{name:"Iran"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón Poggi",slug:"juan-carlos-gardon-poggi",fullName:"Juan Carlos Gardón Poggi",profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",institutionString:null,institution:{name:"Valencia Catholic University Saint Vincent Martyr",institutionURL:null,country:{name:"Spain"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",institutionString:null,institution:{name:"Miguel Hernandez University",institutionURL:null,country:{name:"Spain"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",institutionString:null,institution:{name:"Alexandria University",institutionURL:null,country:{name:"Egypt"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",institutionString:"Kafkas University",institution:{name:"Kafkas University",institutionURL:null,country:{name:"Turkey"}}}]},onlineFirstChapters:{paginationCount:10,paginationItems:[{id:"82196",title:"Multi-Features Assisted Age Invariant Face Recognition and Retrieval Using CNN with Scale Invariant Heat Kernel Signature",doi:"10.5772/intechopen.104944",signatures:"Kamarajugadda Kishore Kumar and Movva Pavani",slug:"multi-features-assisted-age-invariant-face-recognition-and-retrieval-using-cnn-with-scale-invariant-",totalDownloads:14,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"82063",title:"Evaluating Similarities and Differences between Machine Learning and Traditional Statistical Modeling in Healthcare Analytics",doi:"10.5772/intechopen.105116",signatures:"Michele Bennett, Ewa J. 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Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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