\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art novel imaging techniques by focusing on the most important evidence-based developments in this area.
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"d9159ce31733bf78cc2a79b18c225994",bookSignature:"Dr. Gabriel Cismaru",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11867.jpg",keywords:"Hypertrophic Cardiomyopathy, Dilated Cardiomyopathy, Restrictive Cardiomyopathy, Transesophageal Echocardiography, Intracardiac Echocardiography, 3-Dimensional Echocardiography, Adult Congenital Heart Disease, Tetralogy of Fallot, Transposition of the Great Vessels, Coronary Artery Disease, Risk Stratification, Revascularization",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 21st 2022",dateEndSecondStepPublish:"May 19th 2022",dateEndThirdStepPublish:"July 18th 2022",dateEndFourthStepPublish:"October 6th 2022",dateEndFifthStepPublish:"December 5th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Cismaru Gabriel is an Assistant Professor at the University of Medicine and Pharmacy Cluj-Napoca, certified in Cardiology. After completing his certification in cardiology, Dr. Cismaru began his electrophysiology fellowship at the Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu. He has authored or co-authored peer-reviewed articles and book chapters in the field of cardiac pacing, defibrillation, electrophysiological study, and catheter ablation.",coeditorOneBiosketch:"Raluca Tomoaia is an MD, Ph.D. in novel techniques in Echocardiography at the University of Medicine and Pharmacy in Cluj-Napoca, Romania., assistant professor, and a researcher in echocardiography and cardiovascular imaging.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"191888",title:"Dr.",name:"Gabriel",middleName:null,surname:"Cismaru",slug:"gabriel-cismaru",fullName:"Gabriel Cismaru",profilePictureURL:"https://mts.intechopen.com/storage/users/191888/images/system/191888.png",biography:"Dr. Cismaru Gabriel is an assistant professor at the Cluj-Napoca University of Medicine and Pharmacy, Romania, where he has been qualified in cardiology since 2011. He obtained his Ph.D. in medicine with a research thesis on electrophysiology and pro-arrhythmic drugs in 2016. Dr. Cismaru began his electrophysiology fellowship at the Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, France, after finishing his cardiology certification with stages in Clermont-Ferrand and Dinan, France. He began working at the Rehabilitation Hospital\\'s Electrophysiology Laboratory in Cluj-Napoca in 2011. He is an experienced operator who can implant pacemakers, CRTs, and ICDs, as well as perform catheter ablation of supraventricular and ventricular arrhythmias such as ventricular tachycardia and ventricular fibrillation. He has been qualified in pediatric cardiology since 2022, and he regularly performs device implantation and catheter ablation in children. Dr. Cismaru has authored or co-authored peer-reviewed publications and book chapters on cardiac pacing, defibrillation, electrophysiological studies, and catheter ablation.",institutionString:"Iuliu Hațieganu University of Medicine and Pharmacy",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"7",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}}],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:null},relatedBooks:[{type:"book",id:"5970",title:"Bedside Procedures",subtitle:null,isOpenForSubmission:!1,hash:"ba56d3036ac823a7155f40e4a02c030d",slug:"bedside-procedures",bookSignature:"Gabriel Cismaru",coverURL:"https://cdn.intechopen.com/books/images_new/5970.jpg",editedByType:"Edited by",editors:[{id:"191888",title:"Dr.",name:"Gabriel",surname:"Cismaru",slug:"gabriel-cismaru",fullName:"Gabriel Cismaru"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9064",title:"Epidemiology and Treatment of Atrial Fibrillation",subtitle:null,isOpenForSubmission:!1,hash:"1cd6bf2b3181eb82446347fbe478a2bc",slug:"epidemiology-and-treatment-of-atrial-fibrillation",bookSignature:"Gabriel Cismaru and Keith Andrew Chan",coverURL:"https://cdn.intechopen.com/books/images_new/9064.jpg",editedByType:"Edited by",editors:[{id:"191888",title:"Dr.",name:"Gabriel",surname:"Cismaru",slug:"gabriel-cismaru",fullName:"Gabriel Cismaru"}],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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1. Introduction
1.1. Use of agroindustrial waste in fermentation processes
Alcoholic fermentation is a process by which microorganisms convert hexoses, mainly glucose, fructose, mannose and galactose, in the absence of oxygen and get products as alcohol (ethanol), carbon dioxide and adenosine triphosphate (ATP) molecules. Approximately 70% of the energy is released as heat and the remainder is preserved in two terminal phosphate bonds of ATP, for use in transfer reactions, such as activation of glucose (phosphorylation) and amino acids before of the polymerization. In other words, fermentation is a set of chemical reactions carried out by microorganisms in which an organic compound is oxidized, partially in the absence of oxygen to obtain chemical energy and understood as a partial oxidation when all the carbon atoms of the compound are oxidized to form CO2. It is a process known since antiquity and is currently the only industrial process for the preparation of ethyl alcohol in all countries. The glucose as raw material is not only used, but other types of raw material much cheaper. However, the process of alcoholic fermentation occurs naturally, originated by the activity of some microorganisms through its anaerobic energy cell metabolism; for a large‐scale production process, it is necessary for microorganisms (bacteria, fungi and yeasts) to accelerate the process of alcoholic fermentation and increase the conversion rate [1]. During the twentieth century and until the beginning of the twenty‐first century, alcoholic fermentation has focused exclusively on the improvement of fermentation processes and specifically on the optimization of industrial performance through a good selection of yeast strains, which are the most used microorganisms for the production of ethanol by fermentation, due to its high productivity in the conversion of sugars and better separation of the biomass after fermentation. Yeasts are unicellular (usually spherical) microorganisms of size 2–4 μm and are present naturally in some products such as fruits, cereals and vegetables. Different species of fermentative microorganisms have been identified, among which are mainly Saccharomyces cerevisiae, Kluyveromy cesfragilis, Torulaspora and Zymomonas mobilis [2].
S. cerevisiae is a unicellular organism that is able to follow two metabolic routes to obtain the energy necessary to carry out its vital processes: alcoholic fermentation and aerobic respiration. The first is characterized by the evolution of CO2 and the production of ethanol out of contact with oxygen, obtaining the energy necessary to carry out its vital processes from metabolizing carbohydrates. The yeast requires glucose to be catalyzed by the glycolysis or Embden‐Meyerhof pathway, to obtain pyruvate that is then converted by anaerobically into ethanol and CO2 by the action of specific enzymes. Its optimal temperature of growth varies between 22 and 29°C and does not survive more than 53°C. It ferments a sugar solution with a concentration of less than 12% and is inactivated when the sugar concentration exceeds 15% due to the osmotic pressure of medium on the cell. On the other hand, Z. mobilis is a facultative anaerobic gram‐negative bacterium that can ferment certain sugars through a metabolic pathway producing bioethanol, sometimes, more efficiently than yeasts. It has an incomplete Krebs cycle, but it has characteristics to perform the pyruvic synthesis pathways from glucose or glyceraldehyde‐3‐phosphate. This organism also shows a high rate of sugar uptake and a yield of ethanol as fuel of the 97% [3].
The alcoholic fermentation processes using agroindustrial products present a great challenge given the inconveniences that could arise when using raw material for human consumption or edible vegetable crops for the production of ethanol, and, on the other hand, the change in the use of land destined for the cultivation of vegetables that will be used to produce ethanol and bioethanol, which would sometimes lead to deforestation, food shortages, increase of desert regions and greater inability of soils to retain water, thus disrupting the balance of the hydrological cycle [4].
On a global scale, the use of energy raw materials for energy purposes and in the production of ethanol has led to higher prices for products such as maize or barley, as well as making ethanol production economically unviable. Therefore, it is important to use raw materials that do not compete with food products and that are low cost in the production of biofuels, must also ensure a good profitability and are environmentally sustainable projects. In the energy sector, it has been estimated that the use of all world food surpluses could only produce bioethanol to replace 1% of the oil currently used. Concluding that if food crops were used to produce ethanol, a chain of food imbalances would be generated, which would be unsustainable [5].
An alternative to producing ethanol is through the use of other nontraditional raw materials, which arise as by‐products and/or waste from industrial processes. Propose new technologies that allow the production of ethanol from cane residues, solid waste and those materials containing cellulose and hemicellulose, which allows the revalorization of waste from various industries, converting them into raw material for the production of ethanol.
At present, efforts have been made mainly in the search for cheap raw materials, which replace the traditional ones, in order to achieve greater efficiency in the processes of fermentation, recovery and purification of alcohol produced. The importance of the production of bioethanol has as main interest to compete with the use of fossil fuels since ethanol can be used as fuel for motor vehicles increasing the octane number, and therefore the reduction of consumption and contaminants (10–15% less carbon monoxide and hydrocarbons). Ethanol can be mixed with unleaded gasoline from 10 to 25% without difficulty, although some engines have been able to incorporate 100% alcohol as fuel. Thus, ethanol could substitute for methyl tert‐butyl ether (MTBE), an oxygenation product with which gasolines have been reformulated in Mexico since 1989, which has reduced CO2 emissions. This action is very important since MTBE, being a very stable compound, with low degradation and very soluble in water.
The production of bioethanol lost importance at the end of the first half of the XX century, being replaced by the production of synthetic ethanol, from petroleum derivatives, which is cheaper, but cannot be used in food preparation, alcoholic beverages or medications. The rise in oil prices turned our eyes toward the fermentation route of ethanol production, and today, we work mainly in the search for cheap raw materials, replacing the traditional sugary materials. Studies carried out by different researchers suggest that the by‐products of mango juice, cane juice and molasses are an efficient alternative for the production of ethanol without affecting the food item, besides increasing the productivity and concentration of ethanol in the fermentation medium, and therefore reduce the costs of ethanol production [6].
Historically, the sugar industry in Mexico is one of the most important, characterized by sugarcane harvests throughout the year, with a production of cane of 46,231,229 tons per year, and the remaining residue derived of sugarcane has been exploited as energy biomass and for the production of different biotechnological products by fermentation. Other alternatives of raw material are mango juice and its residues, and the fruit is grown in all the countries of Latin America, Mexico being the main exporting country of this fruit, with an annual production of approximately 1 million 452 thousand tons of mango and of which more than 60% of this production is given to the South‐Southeast region of our country.
The alternative of using residues or products that can replace the raw materials normally used in ethanol production is now a highly promising possibility, because the cost of production of ethanol is closely related and dependent on the cost of the raw material, the volume and the composition of the same. The existing economy in Mexico related to cane cultivation (experience and sugar tradition) and the export of mango types offers technological alternatives that allow the fermentation of cane juice, molasses and mango juice through S. cerevisiae and Z. Mobilis as viable sources for the production of ethanol, whether in the manufacture of alcoholic beverages or for the production of biofuels.
1.2. Tecnología de inmovilización
Research has been developed in order to increase the productivity of alcoholic fermentation processes. The productivity, expressed as grams of ethanol produced per hour per unit of fermentation volume, can be increased by optimizing the composition of the culture medium, by the selection of an appropriate microorganism strain or through the adaptation of the design of reactors [7]. One challenge today is to reduce ethanol production costs, and an alternative is to reduce the cost of the culture media, which can represent about 30% of the final production costs of ethanol [8].
Some fermentation technologies have been developed to improve the production of ethanol and its concentration in the culture media [9, 10]. Among these, the immobilization technology offers advantages in contrast to free cell cultures, such as increased retention time in bioreactors, high cellular metabolic activity, high cell load and protection for cells from stress [10, 11]. The immobilization cell technologies have been applied for different purposes as for the production of hydrogen [12] and compounds commercially used in the food industry [13]. Other studies have been developed with immobilized algal cells to remove nutrients (N and P) from wastewater, phenol and hexavalent chromium [14–17]. Similarly, the immobilization of Zymomonas and Saccharomyces have been used for the bio-ethanol production from waste materials [7–10, 18–20].
On the other hand, the immobilization technology provides the possibility of efficiently incorporating symbiotic bacteria [21, 22]. The interaction between two microorganisms in the same matrix is called coimmobilization, and this association can be positive with higher growth and production. However, there are relatively less applications in the ethanol production involving the immobilization of mixed‐culture systems and/or coimmobilized cultures.
In a petroleum deficiency situation, bioethanol from yeast and bacterial fermentation has become a promising alternative source for fuel. Agricultural and industrial waste containing sugar, starch and cellulose, such as cassava peels, fruit bunches, and the effluents from sugar and pineapple cannery productions have been successfully applied for the bioethanol production [23, 24]. In this context, the municipality of Ciudad del Carmen, Campeche, Mexico, has an annual production of about 2.868 ha mango (Mangifera indica), obtained through various forms of cultivation and orchard‐based technology, but the lack of local market and the poor product distribution to other locations cause much of the product be wasted, with significant losses in the locality. Hence, the need to seek alternatives to use these wastes and generate added value in the economy of the region.
This study was to determine whether the association between S. cerevisiae coimmobilized with Z. mobilis improved growth, and ethanol production using a culture medium equivalent to mango juice (M. indica) creates an opportunity for a regional fruit for exploitation in the production of ethanol. In this study, both microorganisms were confined in small alginate beads, a practical means of using microorganisms for environmental applications.
2. Materials and methods
2.1. Microorganism and medium
The yeast strain S. cerevisiae (ATCC® 2601) and bacteria Z. mobilis (ATCC® 8938) were obtained from the laboratory Microbiologis® and used for fermentation in coimmobilized and immobilized systems. Both microorganisms were cultured in a medium containing composition (g L−1), as described by Demirci et al. [25]: 20 g glucose, 6 g yeast extract, 0.23 g CaCl2•2H2O, 4g (NH4)2SO4, 1 g MgSO4•7H2O and 1.5 g of KH2PO4, previously sterilized by autoclave. Strains were maintained in 250 mL of culture at 30°C and pH 4.5 with manual shaking three times a day. Transfers of fresh medium were made every 24 h for three consecutive days prior to use in experiments.
2.2. Preparation of immobilized and coimmobilized cells
For the preparation of immobilized cells, we used the technique described by Tam and Wong [26]. Both microorganisms were harvested by centrifugation at 3500 rpm for 10 min. The bacteria and yeast cells were resuspended in 50 mL of distilled water to form a concentrated cell suspension. The suspension was then mixed with a 4% sodium alginate solution in 1:1 volume ratio to obtain a mixture of 2% microorganism–alginate suspension. The mixture was transferred to a 50‐mL burette, and drops were formed when “titrated” into a calcium chloride solution (2%). This method produced approximately 6500 uniform algal beads of approximately 2.5 mm in diameter with biomass content for Z. mobilis‐alginate of 0.0055 g bead−1 and for S. cerevisiae of 0.00317 g bead−1 for every 100 mL of the microorganism–alginate mixture (Figure 1).
Figure 1.
Microorganism–alginate beads suspension.
The beads were kept for hardening in the CaCl2 solution for 4 h at 25 ± 2°C and then rinsed with sterile saline solution (0.85% NaCl) and subsequently with distilled water. A concentration of 2.6 beads mL−1 of medium (equivalent to 1:25 bead: medium v/v) was placed in a Chemostat Ommi Culture Plus (Virtis) containing 2 L of culture medium. The reactor was maintained under stirring at 120 rpm and 30°C (Figure 2). A similar procedure was used for coimmobilization, with the difference that the concentrate of bacteria (25 mL) and yeast (25 mL) was mixed and then mixed with 50 mL of alginate; this procedure allowed retaining the same concentration of cells in all experiments.
Figure 2.
Chemostat Ommi Culture Plus (Virtis) used for fermentation experimental process.
2.3. Experimental setup and procedure
This study was divided into two parts: (1) the batch experiment consisted of evaluating the growth and ethanol production in a medium equivalent to mango juice in cultures with free cells, immobilized and coimmobilized, and (2) evaluate the effect of glucose concentration in the production of ethanol in the system previously selected in the first experimental part based on the ethanol productivity obtained. Fermentation was performed in a Chemostat Ommi Culture Plus (Virtis) with a volume of 2 L operation, adjusting stirring at 120 rpm and maintaining a temperature of 30°C. The medium equivalent to mango juice was similar to that described by Demirci et al. [25] by adjusting the composition of the medium to a concentration of 200 g L−1 glucose, equivalent to that observed in the mango juice (M. indica).
The experimental design consisted of triplicate cultures in a Chemostat reactor Ommi Culture Plus for S. cerevisiae and Z. mobilis in free cell culture, immobilized and coimmobilized. For each experiment, the biomass was collected, as well as samples of the culture medium to the end of the logarithmic phase every 20 h. For the determination of ash‐free dry weights, five beads were dissolved and filtered through a GF‐C glass fiber filter (2.5 cm diameter), previously rinsed with distilled water, and incinerated at 470°C for 4 h. The samples were dried at 120°C and put to constant weight for 2 h in a conventional oven and then in a muffle furnace at 450°C for 3 h. The soluble solids of each fermenting medium were determined every 20 h by taking 1 mL aliquot from each reactor and testing for the Brix level in an refractometer.
Ethanol content (% v/v) was obtained using the Anton Paar DMA 4100M instrument, which determines the density of the mixture in relation to the standard OIML‐STD‐90, which can determine the content of distillate ethanol (% v/v); according to the ethanol density recorded, it was possible to obtain an approximate of ethanol content (grams of ethanol per liter of culture) produced for each experiment. Prior to the determination of the ethanol content, a distillation of cultures was conducted with a plate column distiller PS‐DA‐005/PE of four plates, at small scale. The cooling water flow was 3 L h−1 at 15°C. An aliquot of 3 L was distilled for 4 h, maintaining the operating conditions at atmospheric pressure, without reflux and with a temperature ramp in the heating jacket of 30°C up to 80°C.
The STATISTICA 7.0 software for statistical analysis and calculated mean and standard deviation for each treatment were used. The covariance analysis (ANCOVA) with P ≤ 0.05 was used to evaluate the growth in free cell cultures, immobilized and coimmobilized. The Tukey test (P ≤ 0.05) was used when significant differences were observed.
3. Results
3.1. Growth
In free cell cultures, the growth was observed immediately after being inoculated in the reactor of 2 L. Growth kinetics shows an exponential phase for S. cerevisiae and Z. mobilis of 120 h. After this period of cultivation, both species showed a decline in the production of biomass, finalizing treatment after 200 h of culture. The maximum values of biomass concentration were 14.18 and 11.80 g L−1 dry weight for S. cerevisiae and Z. mobilis, respectively. Both microorganisms grew satisfactorily under the culture conditions used in this study (Figure 3A), with a higher growth rate (μ) for S. cerevisiae (0.0547 d−1) with respect to Z. mobilis (0.0418 d−1). Growth rates in free cell cultures for both microorganisms S. cerevisiae and Z. mobilis were not significantly different (P ≥ 0.05).
Figure 3.
Average increase of biomass for Saccharomyces cerevisiae and Zymomonas mobilis in free culture (A) and immobilized cells (B).
For immobilized cells, both yeast and bacteria presented immediate growth after adding the beads to the culture medium; in both treatments, the exponential phase of growth reached a maximum of 80 h. It is noteworthy that although both microorganisms were immobilized under the same procedure, the content of biomass per bead at the beginning of treatment was lower for Z. mobilis (0.0031 g bead−1) compared to S. cerevisiae (0.0039 g bead−1). Despite these differences, both microorganisms were able to tolerate immobilization (Figure 3B), reaching maximum biomass content values of 0.0055 and 0.0047 g bead−1 for S. cerevisiae and Z. mobilis, respectively. In relation to growth, Z. mobilis showed a higher growth rate (0.142 d−1) with respect to S. cerevisiae (0.106 d−1), but there were no significant differences (P ≤ 0.0001).
3.2. Glucose‐substrate removal
The decrease of substrate showed significant differences (P ≤ 0.0001) between treatments with free and immobilized cells for both species (Figure 4). However, the Tukey test analysis showed that the two species in free culture were not significantly different (P > 0.05) in 200 h of treatment. While for the immobilized and coimmobilized cell cultures, only the immobilized Z. mobilis bacteria showed no significant differences (P = 0.245) during removal of the substrate with the coimmobilized system during 140 h of culture (Figure 4B).
Figure 4.
Average reduction of glucose (g L−1) for Saccharomyces cerevisiae and Zymomonas mobilis in free culture (A) and immobilized culture (B). Different letters indicate significant differences (P ≤ 0.05).
It is a fact that consumed substrate was greater in free culture for S. cerevisiae and Z. mobilis from 200 to 80 g L−1 (60% removal) after the 200‐h treatment period (Figure 4A), compared to the immobilized system with 40% removal for S. cerevisiae (from 200 to 120 g L−1) and 30% removal for Z. mobilis (from 200 to 140 g L−1), while in those cultures of coimmobilized cells consumption ranged from 200 to 130 g L−1 (35% removal) (Figure 4B).
The average consumption analysis based on removal rates determined during the exponential growth for both species showed that free culture S. cerevisiae and Z. mobilis reached removal rates of 2.0 and 2.7 g‐substrate per g‐biomass d, respectively. This suggested greater productivity for the bacteria (5.76 g h−1) with respect to yeast (5.29 g h−1) (Table 1).
Uptake rate, productivity (Y) and ethanol mole produced per glucose mole for Saccharomyces cerevisiae and Zymomonas mobilis in free culture, immobilized and coimmobilized.
Indicate significant differences (P ≤ 0.05).
In cultures with immobilized cells, the removal rate in the exponential phase (80 h) was greater for S. cerevisiae (0.165 g‐substrate per g‐biomass d) with respect to Z. mobilis (0.056 g‐substrate per g‐biomass d), but in coimmobilized culture it was greater (0.235 g‐substrate per g‐biomass d) since both species contribute to reducing glucose and increasing the removal rate. Similar results were observed in the productivity, where the coimmobilized cell culture showed higher values (8.80 g L−1 h−1) with respect to the immobilized cells of S. cerevisiae (8.45 g L−1 h−1) and Z. mobilis (8.70 g L−1 h−1 (Table 1). In general, the highest productivity levels were recorded in coimmobilized and immobilized cultures with respect to free cell cultures because shorter ethanol production time (80 h) compared to free cultures (120 h).
3.3. Effect of initial concentration of glucose on ethanol production
It is a fact that most cultures from fruits may contain a high concentration of fiber solids that cause problems of mixture in the reactor, and consequently a low contact between cells and substrate. Mango juice is no exception. In this study, we evaluated the growth and alcohol production of Z. mobilis coimmobilized with S. cerevisiae in cultures with dilutions of 200 and 50 g L−1 of substrate in equivalent medium.
For the coimmobilized of Z. mobilis and S. cerevisiae within alginate beads, an immediate increase in biomass content was observed. Although the biomass content for both treatment showed significant differences (P ≤ 0.0024), the results suggest that the concentration of substrate was not a limiting factor for the growth for bacteria and yeast (Figure 5). The maximum biomass content in the treatment of glucose to 50 g L−1 (Gl50) was obtained in the first 100 h of culture with about 0.0063 g beads−1; while for the treatment of 200 g L−1 glucose (Gl200) was of 0.053 g beads−1 during a period of 80 h (Figure 5).
Figure 5.
Growth (g biomass bead−1) in coimmobilized system at different substrate concentrations.
The content of alcohol produced had no significant differences (P ≤ 0.05) with respect to glucose concentration. However, uptake rates exhibit a decline as the glucose content in the reactor decreases (Table 2). The highest uptake rate occurred at a concentration of 200 g L−1 glucose (0.235 g‐substrate per g‐biomass d) with a 76.5% removal, compared to 50 g L−1 glucose (0.08 g‐substrate per g‐biomass d). Although the production of alcohol was similar in both treatments, the ratio mol‐ethanol produced per consumed mol‐glucose was higher in cultures of 50 g L−1 glucose with a value of 6.91, with respect to 200 g L −1 glucose with a ratio of 5.82 mol‐ethanol produced per consumed mol‐glucose (Table 2). Similarly, higher productivity was obtained (8.85 g L−1 h−1) at a lower glucose concentration compared to a medium with high glucose content (8.80 g L−1 h−1).
C0
Ethanol formed (% v/v)
Y (g L−1 h−1)
Glucose consumed (g L−1)
Uptake rate (g‐substrate removed per g‐biomass d)
molesEthmoleGlc
50
89.63
8.85
40.0
0.08
6.91
200
88.70
8.80
47.0
0.235
5.82
Table 2.
Productivity (Y), uptake rate and ethanol mole produced per glucose with minimum content of glucose for coimmobilized Z. mobilis and S. cerevisiase.
C0: Initial concentration of glucose (g L−1 ).
4. Growth and productivity
To evaluate the capacity of growth in free and immobilized culture, two microorganisms, yeast and bacteria, were subjected to the same culture conditions (Figure 3A). In free culture, the yeast S. cerevisiae showed a higher cell density and specific growth rate (0.0547 d−1) with respect to bacteria Z. mobilis (0.0418 d−1) in a treatment time of 120 h. The immobilized systems are known to have a greater capacity of cell growth and high metabolic activity [27, 28], which is consistent with the results obtained in this study. The result showed a high growth rates for immobilized Z. mobilis (0.142 d−1) and S. cerevisiae (0.106 d−1) with respect to free cell cultures, suggesting that immobilization did not affect growth in both microorganisms and increased biomass content favorably. Furthermore, the high activity in immobilized cell was observed with in a decrease of substrate in a shorter time of treatment (80 h) compared to free cell cultures (120 h). The short time of treatment for immobilized cell could be attributed to the increase of biomass within the beads and consequently an immediate decay of the substrate; however, this indicates that increasing cell population within the beads can cause a limited effects of nutrients on the cells located at the center of the beads, causing a decrease in cellular activity [28, 29].
Another factor that probably favors the rapid decline in cell density is attributed to the production of CO2 as result of fermentation activity. Studies suggest the adverse effect of CO2 gas, because if the diffusion of CO2 is lower compared to its production, it will accumulate inside of alginate bead [30]. In this study, the CO2 is observed in the reactor as bubbles attached on the surface of the beads, suggesting that the spread of CO2 gas in the first 80 h was not a factor that inhibited growth and the production of alcohol; however, after this time, gas saturation in the reactor was probably high, affecting the diffusion of CO2. This coupled with a limitation in the transport of nutrients and subsequent inhibition of microorganisms and may have caused glucose consumption to be lower compared to free cells (Table 1).
In particular, in free cell culture, the lower percentage of alcohol obtained by yeast during the increasing fermentation culture commonly relates to the fact that this is affected by the high concentration of ethanol in the solution, which may inhibit metabolism and decrease efficiency [31], unlike bacteria Z. mobilis [30]. In the present study, the lowest biomass produced by the bacteria (0.0047 g L−1) with respect to yeast (0.0055 g L−1) may be practical from the standpoint of waste generation. Similarly, observations were reported by Amin and Verachtert [9] for Z. mobilis and Saccharomyces bayanus immobilized in carrageenan with 5.6 and 9.9 g L−1, respectively.
It is evident that ethanol production was not inhibited in immobilized or coimmobilized systems, and even showed higher productivity with respect to free cells (Table 1), suggesting that they are more efficient in the conversion of sugar with respect to time. Krishnan et al. [19] reported lower productivity for Z. mobilis immobilized in carrageenan (1.6 g L−1 h−1) compared to that obtained in this study (8.7 g L−1 h−1); this difference may be attributed to the lower amount of glucose content in the culture medium of 32 g L−1 with respect to that used in the present study of 200 g L−1.
Interestingly, the immobilized systems showed a higher conversion of substrate of 4.42 and 6.29 mole of ethanol per mole of glucose for yeast and bacteria, respectively, compared to the obtained by free cells, from 2.7 to 3.3 mole of ethanol per mole of glucose. In general, treatments with immobilized cells showed a higher output of ethanol per mole of glucose with respect to that reported by Amin and Verachtert [9] for Z. mobilis and S. bayanus immobilized in carrageenan with values of 1.8–1.9 mole of ethanol produced per mole of consumed glucose. Gunasekaran et al. [32] and Krishnan et al. [19] suggest that Z. mobilis is a good candidate to obtain alcohol with approximately 1.9 mole ethanol per mole of glucose; similarly, Rogers et al. [33] reported that specific productivity of ethanol (g ethanol g−1 biomass dry weight) is greater for Zymomonas than for Saccharomyces uvarum.
According to the results, immobilization and coimmobilization exhibited a lower uptake rate compared to free cells; this shows that there was less consumption of substrate (Table 1). Nevertheless, there was greater productivity, which indicates that it is possible to obtain high alcohol content with a lower requirement of substrate, but with the disadvantage of residual glucose in the medium; this problem can be solved with sequenced systems, as suggested by Demirci et al. [25]. Another alternative of solving this problem is to increase the cell number or inoculum size within the reactor. This is reasonable because a high number of cells could create a greater sorption of substrate (glucose) into the cell and eventually consumed substrate. However, Siripattanakul‐Ratpukdi [10] suggested that with different cell yeast loads, the same reduction (>90%) of substrate is obtained at the end of a treatment period of 10 h.
The low glucose reduction observed in this study in alginate beads can be attributed to the decline in cell density, but it is likely that the diffusion of substrate could have been prevented. Studies have reported that the adsorption of substrate by the matrix was observed in the first hours of treatment, with a possible decrease of substrate diffusion within the matrix in a continuous process [34].
On the other hand, Robinson et al. [35] suggest that the diffusion rate within the alginate matrix depends on the concentration gradient between the culture medium and matrix; this is, when the nutrient concentration in the culture medium decreases, the diffusion rate occurs within the matrix and therefore the removal rate. In this study, during the first hours of treatment, the matrix is probable a partial saturation with substrate (glucose), because the substrate is decreased during the culture time, and cell growth for both microorganisms was continuous. Clearly, the immobilized cell system successfully decreased glucose by adsorption of the matrix (immobilized glucose) and biodegradation (bioconversion of glucose), being the main process the biodegradation. This suggests that the main factor that could limit glucose removal may have been the high concentration of CO2 in the reactor.
4.1. Coimmobilization of Z. mobilis and S. cerevisiae at different glucose concentrations
The biomass content in alginate beads shows that a high concentration of glucose (200 g L−1) leads to a rapid decrease compared to cultures with a low glucose concentration (50 g L−1). This confirms the fact that the high concentration of glucose saturates beads faster, reducing the diffusion between beads and the culture medium; consequently, the diffusion of CO2 produced can be reduced and remains trapped inside the bead, causing a decrease in growth and substrate consumption.
Conversely, the low concentration of substrate of the culture medium indicates the presence of a soft transport and substrate accumulation within the matrix, allowing a proper consumption and growth of bacteria and yeast. Therefore, a low concentration of substrate may actually increase the production of alcohol with minimal residual glucose, reaching values of 6.91 mol of ethanol per mole of glucose, with respect to a high glucose concentration (Table 2).
Previous studies in our laboratories have shown that the fermentation process of mango juice for a coimmobilized system can produce a production ratio of 1.4 L of alcohol (79% v/v ethanol) for every 3 L of mango juice.
5. Conclusions
The present study has shown the existing potential of using coimmobilized systems in the production of ethanol. The association of Z. mobilis and S. cereviase was positive, obtaining a higher ethanol content and high conversion of substrate compared to free and immobilized cells.
In general, the immobilization technology offers an alternative by increasing productivity and conversion of substrate compared to culture systems with free cells. In the present study, the immobilized systems showed high conversion capacity to obtain high alcohol content with a lower requirement of substrate.
The possible substrate inhibition was not a factor affecting cell growth in both organisms; it is clear that the immobilized cell system successfully reduced glucose by the matrix adsorption (immobilized glucose) and biodegradation (bioconversion of glucose), being biodegradation the main process. This suggests that the main factor that could limit further growth was the high concentration of CO2 in the reactor. Furthermore, although no significant differences were detected in the alcohol content in immobilized culture in diluted medium, the conversion from glucose to ethanol is greater in those media with a glucose concentration of 50 g L−1. For practical purposes, it is desirable that the fermentation of waste organic be performed through dilutions to increase the homogeneity of alginate beads within the reactor and consequently allow the diffusion of CO2 and substrate through the beads.
\n',keywords:"Mangifera indica, immobilization, coimmobilization, ethanol, Zymomonas mobilis, Saccharomyces cerevisiae",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/56400.pdf",chapterXML:"https://mts.intechopen.com/source/xml/56400.xml",downloadPdfUrl:"/chapter/pdf-download/56400",previewPdfUrl:"/chapter/pdf-preview/56400",totalDownloads:1722,totalViews:624,totalCrossrefCites:1,totalDimensionsCites:2,totalAltmetricsMentions:0,introChapter:null,impactScore:0,impactScorePercentile:10,impactScoreQuartile:1,hasAltmetrics:0,dateSubmitted:"December 6th 2016",dateReviewed:"June 2nd 2017",datePrePublished:null,datePublished:"November 8th 2017",dateFinished:"July 11th 2017",readingETA:"0",abstract:"Fermentation technologies have been developed to improve the production of ethanol and an alternative is the immobilization technology, which offers the possibility of efficiently incorporating symbiotic bacteria in the same matrix. This study analyzes the potential use of immobilized and coinmobilized systems on beads of calcium alginate for ethanol production used mango waste (Mangifera indica) by Zymomonas mobilis and Saccharomyces cerevisiae compared with free cells culture and evaluate the effect of glucose concentration on productivity in coimmobilized system using a Chemostat reactor Ommi Culture Plus. For free cell culture, the productivity was higher for Z. mobilis (5.76 g L-1 h-1) than for S. cerevisiae (5.29 g L-1 h-1); while in coimmobilized culture, a higher productivity was obtained (8.80 g L-1 h-1) with respect to immobilized cultures (8.45 g L-1 h-1 - 8.70 g L-1 h-1). The conversion of glucose to ethanol for coimmobilized system was higher (6.91 mol ethanol) with 50 g L-1 of glucose compared to 200 g L-1 of glucose (5.82 mol ethanol); suggesting the immobilized and coimmobilized cultures compared with free cells offer an opportunity for the reuse of organic residues and high alcohol production.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/56400",risUrl:"/chapter/ris/56400",book:{id:"6293",slug:"yeast-industrial-applications"},signatures:"Alejandro Ruiz Marin, Yunuen Canedo Lopez, Asteria Narvaez\nGarcia, Juan Carlos Robles Heredia and Jose del Carmen Zavala\nLoria",authors:[{id:"109423",title:"Dr.",name:"José",middleName:"Del Carmen",surname:"Zavala Loría",fullName:"José Zavala Loría",slug:"jose-zavala-loria",email:"jzavala62@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Autonomous University of Carmen",institutionURL:null,country:{name:"Mexico"}}},{id:"116684",title:"MSc.",name:"Asteria",middleName:null,surname:"Narváez García",fullName:"Asteria Narváez García",slug:"asteria-narvaez-garcia",email:"anarvaez@pampano.unacar.mx",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Autonomous University of Carmen",institutionURL:null,country:{name:"Mexico"}}},{id:"194857",title:"Dr.",name:"Alejandro",middleName:null,surname:"Ruiz",fullName:"Alejandro Ruiz",slug:"alejandro-ruiz",email:"aruiz@pampano.unacar.mx",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"194858",title:"Dr.",name:"Yunuen",middleName:null,surname:"Canedo",fullName:"Yunuen Canedo",slug:"yunuen-canedo",email:"ycanedo@pampano.unacar.mx",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"210537",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Robles Heredia",fullName:"Juan Carlos Robles Heredia",slug:"juan-carlos-robles-heredia",email:"jrobles@pampano.unacar.mx",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Autonomous University of Carmen",institutionURL:null,country:{name:"Mexico"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1. Use of agroindustrial waste in fermentation processes",level:"2"},{id:"sec_2_2",title:"1.2. Tecnología de inmovilización",level:"2"},{id:"sec_4",title:"2. Materials and methods",level:"1"},{id:"sec_4_2",title:"2.1. Microorganism and medium",level:"2"},{id:"sec_5_2",title:"2.2. Preparation of immobilized and coimmobilized cells",level:"2"},{id:"sec_6_2",title:"2.3. Experimental setup and procedure",level:"2"},{id:"sec_8",title:"3. Results",level:"1"},{id:"sec_8_2",title:"3.1. Growth",level:"2"},{id:"sec_9_2",title:"3.2. Glucose‐substrate removal",level:"2"},{id:"sec_10_2",title:"3.3. Effect of initial concentration of glucose on ethanol production",level:"2"},{id:"sec_12",title:"4. Growth and productivity",level:"1"},{id:"sec_12_2",title:"4.1. Coimmobilization of Z. mobilis and S. cerevisiae at different glucose concentrations",level:"2"},{id:"sec_14",title:"5. 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Fermentation pattern of Zymomonas mobilis strains on different substrate: A comparative study. Journal of Biosciences. 1986;10(2):181-186'},{id:"B33",body:'Rogers PL, Jon JL, Tribe DE. Kinetics of alcohol production by Zymomonas mobilis at high sugar concentration. Biotechnology Letters. 1979;1:165'},{id:"B34",body:'Siripattanakul S, Khan E. Fundamentals and applications of entrapped cell bioaugmentation for contaminant removal. In: Shah V, editor. Emerging Environmental Technologies. Vol. 2. Berlin: Springer; 2010. pp. 147-169'},{id:"B35",body:'Robinson PK, Reeve JO, Goulding KH. Phosphorus uptake kinetics of immobilized Chlorella in bath and continuous‐flow culture. Enzyme and Microbial Technology. 1989;11:590-596'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Alejandro Ruiz Marin",address:"aruiz@pampano.unacar.mx",affiliation:'
Environmental Sciences Laboratory, Faculty of Chemistry, Autonomous University of Carmen, Ciudad del Carmen, Mexico
Environmental Sciences Laboratory, Faculty of Chemistry, Autonomous University of Carmen, Ciudad del Carmen, Mexico
'},{corresp:null,contributorFullName:"Juan Carlos Robles Heredia",address:null,affiliation:'
Environmental Sciences Laboratory, Faculty of Chemistry, Autonomous University of Carmen, Ciudad del Carmen, Mexico
'},{corresp:null,contributorFullName:"Jose del Carmen Zavala Loria",address:null,affiliation:'
Environmental Sciences Laboratory, Faculty of Chemistry, Autonomous University of Carmen, Ciudad del Carmen, Mexico
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1. Introduction
Thromboembolic diseases are a leading source of morbidity and death in the United States. Thrombosis can happen in either the arteries or the veins. Acute myocardial infarction (MI), ischemic stroke, and limb gangrene are all caused by arterial thrombosis. Deep vein thrombosis (DVT), which can cause post-thrombotic syndrome, and pulmonary embolism (PE), which can be fatal or cause thromboembolic pulmonary hypertension, are both examples of venous thromboembolism (VTE). Arterial thrombosis is usually managed using antiplatelet therapy. On the other hand, VTE episodes are typically managed using anticoagulant therapy [1].
Anticoagulant drugs are the mainstay of therapy for many thrombotic disorders. The selection of one agent over the other is usually guided by balancing the risks versus the benefits of these anticoagulants. Also, it requires deep knowledge and understanding of the clinical pharmacology, efficacy, safety, and clinical outcomes for each of these anticoagulants.
Historically. Jay McLean and William Henry Howell discovered heparin a century ago, in 1914. However, it was first used in clinical practice in the 1940s. It’s given subcutaneously or intravenously, and it binds to antithrombin. This will improve its capacity to inactivate several clotting factors such as thrombin, factor Xa, and factor IXa [2]. Later on, several oral and parenteral antithrombotic agents are used to prevent and treat thrombotic episodes. In 1940, Karl Link and colleagues discovered warfarin which is a vitamin-k antagonist. Warfarin was first marketed as a rodenticide. Later on, it was adopted for therapeutic usage as an anticoagulant [3].
In 2003, the discovery of ximelagatran showed that a particular oral thrombin inhibitor might be safe and effective in a range of thrombotic diseases, paving the way for introducing a new class of anticoagulants [4]. Following these advancements, a major millstone was declared in the field of anticoagulation. Several direct oral anticoagulants (DOACs) targeting factors Xa and II were introduced from 2007 to 2014. According to several landmark randomized studies, they were shown to be equally safe and efficacious as warfarin in preventing and treating venous thromboembolism and stroke prevention in atrial fibrillation. These advancements led to an enormous change in the landscape of managing thrombotic events [5].
This chapter is intended to review the currently available oral anticoagulants, including vitamin K antagonists (VKA), such as warfarin, and the (DOACs) such as dabigatran, apixaban, rivaroxaban, and edoxaban. In addition, it will discuss periprocedural management of anticoagulants, reversal modalities and highlight the major future advancements in the field of anticoagulation.
2. Vitamin K Antagonists
Warfarin is a vitamin K antagonist that was approved by the US Food and Drug Authority (FDA) in 1954 for stroke prevention. It is approved in many other indications such as managing and preventing VTE. Until recently, it was the only oral agent approved for these indications. However, more oral anticoagulants have been approved that possess more advantages and better pharmacokinetic properties. However, warfarin still a widely used medication to prevent blood clotting disorders. Warfarin administration remains a challenge despite being used for more than 60 years. Warfarin has a narrow therapeutic index and monitored regularly using international normalized ratio (INR). Duo to it inter and intra individual variation in response and multiple drug and food interactions, warfarin was replaced as a first line anticoagulant agent [6].
2.1 Mechanism of action
Warfarin exerts it anticoagulant effect by interfering with vitamin K epoxide reductase in the liver which serve as a cofactor for the carboxylation of glutamate to γ-carboxyglutamates. This process leads to the inhibition of vitamin K–dependent γ-carboxylation of factors II, VII, IX, and X. However, Vitamin K antagonist does not inhibit the existing γ-carboxyglutamates that can lead to delay in its anticoagulant effect [6].
2.2 Pharmacology
Warfarin consists of a racemic mixture of S-warfarin and R-warfarin, in which the S- form being more active. It has high bioavailability with rapid absorption from the gastrointestinal tract. After drug administration, warfarin reaches maximum concentration within 90 mins. Warfarin is highly albumin bound with a half-life of 36–42 hours. Warfarin is metabolized mainly in the liver through the cytochrome P450 (CYP) enzymes. However, the two isomers and metabolized through a different pathway in the liver. CYP2C9 is associated with the metabolism of the more potent S-warfarin whereas R-warfarin mainly metabolized by CYP1A2 and CYP3A4 [6].
2.3 Indication and dosing
Warfarin has multiple indications including venous thrombosis, prosthetic heart valves and more commonly arterial fibrillation. Usually, the starting dose for warfarin is 5–10 mg daily. However, lower doses can be initiated for patients at high risk of bleeding. Patients with known genetic polymorphism in CYP2C9 or VKORC1 can be more sensitive to warfarin. Also, elderly patients, patients with chronic kidney disease or patients on other medications that can cause bleeding can be initiated at a lower dose and up titrated to INR goal. Duo to its delayed antithrombotic effect, patients with established clot or high risk for thrombosis are bridged with a fast-acting parenteral anticoagulant. Commonly, heparin or enoxaparin are given concomitantly with warfarin until INR is at goal for 2 consecutive days with a minimum of 5 days on parenteral anticoagulant [6].
2.4 Monitoring
Warfarin is a drug known for its narrow therapeutic index as well as having multiple drug and food interactions. Therefore, continuous monitoring is important to ensure anticoagulation efficacy is achieved and severe side effects are avoided. INR is calculated from prothrombin time which is a test that measures how long a clot is formed in a blood sample is performed when patients are on warfarin. Mostly, warfarin is given to achieve an INR goal of 2–3. However, patients with a mechanical mitral valves or mechanical aortic valve replacement with Starr-Edwards or disc valves have a higher INR target of 2.5–3.5 duo to higher thromboembolic risk [6].
2.5 Side effects
One of the major risks associated with using warfarin is bleeding and the severity of bleeding can vary. Majority of bleeding side effect is seen when INR supratherapeutic. Therefore, INR monitored and maintained at target is essential to minimize bleeding risk. There are several approaches to manage a supratherapeutic INR and the choice usually depends on the present or absent of bleeding, severity of bleeding and magnitude in which INR increased. Skin necrosis is a rare complication associated with warfarin administration in patients with protein C or S deficiency [6].
2.6 Drug interaction
Warfarin can interact with large number of medications. Drugs can cause pharmacodynamic or pharmacokinetic interaction with warfarin. Pharmacokinetic interactions involve medications that inhibit or induce CYP2C9, CYP1A2 or CYP3A4 which can alter warfarin concentration. Inhibitors of the CYP enzymes can interfere with warfarin metabolism that leads to higher warfarin concentration. However, CYP enzyme inducers can increase warfarin removal, therefore, decrease its effect. Pharmacodynamic interaction can occur when warfarin given with other anticoagulants, antiplatelet, non-steroidal anti-inflammatory drugs, or serotonin Reuptake Inhibitors. In which, these drugs can increase risk of bleeding [6].
3. Direct Oral Anticoagulants
Direct oral anticoagulants (DOACs) have been introduced to the market initially in 2010 as a potential alternative for warfarin. They possess many advantages over warfarin that placed them as the first-line anticoagulant option for many indications. These agents include apixaban, rivaroxaban, edoxaban, and dabigatran. All of these agents do not require regular monitoring of their anticoagulant effect and they achieve the target anticoagulation level shortly given their fast onset of action compared to warfarin. These significant advantages placed these agents as the preferred anticoagulant option by patients and clinicians [7].
3.1 Mechanism of action
Factor Xa is a crucial coagulation factor in the coagulation cascade that leads to the formation of thrombin and clot generation. Apixaban, rivaroxaban, and edoxaban, bind directly and reversibly to factor Xa and inhibit its action leading to a strong anticoagulation activity. On the other side, dabigatran inhibits directly factor IIa (thrombin), leading to the prevention of clot formation [8].
3.2 Pharmacology
Apixaban binds directly to factor Xa when free and when thrombin bound. It has a bioavailability of approximately 50% and reaches a plasma peak in about 2 hours with maximum plasma concentration in about 3 to 4 hours. It has a half-life of approximately 12 hours after oral administration necessitating twice-daily dosing. It is metabolized mainly by CYP3A4 and eliminated in both urine and feces. Renal elimination accounts for 27% of total clearance. Apixaban has no interaction with food but is a substrate of P-glycoprotein (P-gp) and CYP3A4 requiring vigilant review of concurrent medications for possible drug–drug interactions [9].
Dabigatran is the active form of the prodrug dabigatran etexilate, which binds thrombin directly and competitively inhibiting its activity. The approximate bioavailability of dabigatran after oral administration is 3–7%, with peak plasma concentration achievement within 2 hours. The bioavailability increased to 75% after the pellets were taken without the capsule. Therefore, the capsules should not be broken, chewed, or opened before administration. The half-life of dabigatran is approximately 12–17 hours, necessitating twice-daily dosing. Dabigatran is mainly eliminated in the urine with a renal clearance of roughly 80%. It is a substrate of P-gp and therefore, it carries a risk for drug–drug interactions [9].
Edoxaban binds selectively to factor Xa and inhibits its action without the need for a cofactor (i.e., antithrombin III). It has a bioavailability of approximately 62% and reaches a peak plasma concentration in about 1 to 2 hours. It has a half-life of approximately 10–14 hours, and 50% of the total clearance is through urine. Therefore, edoxaban blood levels are increased or decreased in patients with poor or good renal function. Edoxaban is a substrate for P-gp and CYP3A4, increasing the risk for drug–drug interactions [9].
Rivaroxaban is a selective inhibitor of factor Xa with no requirement for a cofactor (i.e., antithrombin III) with no direct effect on platelet aggregation. It has a very high bioavailability following oral administration of 2.5 mg and 10 mg doses reaching 80–100%. Administration with food increases the bioavailability of rivaroxaban. Therefore, it should be taken with food. Peak plasma concentration is achieved in about 2 to 4 hours. It has a renal clearance of up to 30%. Rivaroxaban is a substrate for P-gp increasing the risk of drug–drug interactions [9]. Table 1 summarizes the pharmacological properties of DOACs.
Apixaban
Dabigatran
Edoxaban
Rivaroxaban
Mechanism of action
Factor Xa
Thrombin
Factor Xa
Factor Xa
Pro-drug
No
Yes
No
No
Bioavailability
50%
3%-7%
62%
66%-80%
Time to peak
2 hours
2 hours
1-2 hours
2-4 hours
Half-life
12 hours
12-17 hours
12-14 hours
9-13 hours
Protein binding
87%
35%
55%
90%
Renal elimination
27%
80%
50%
30%
Substrate of CYP3A4
Yes
No
Yes
Yes
Substrate of P-gp
Yes
Yes
Yes
Yes
Dialyzable
No
Yes
No
No
Table 1.
Pharmacological properties of DOACs.
3.3 Indications and dosing
DOACs are currently used in different indications, including reducing the incidence of stroke in patients with NVAF, treatment of acute VTE, and reducing the risk of recurrent VTE. Finally, apixaban, rivaroxaban, and dabigatran have been approved by US FDA and European Medical Agency (EMA) for thromboprophylaxis post orthopedic surgeries (i.e., knee and hip replacements). Apixaban and rivaroxaban are approved for post-knee and hip replacement surgeries, and dabigatran is only approved for post-hip replacement surgery. In addition, rivaroxaban is also approved for VTE prophylaxis in acutely ill medical patients at risk for thromboembolic complications, not at high risk of bleeding [9]. Table 2 illustrates the usual dosing recommendations for the various indications.
Apixaban
Dabigatran
Edoxaban
Rivaroxaban
Stroke prevention in nonvalvular atrial fibrillation (NVAF)
5 mg PO BID 2.5 mg PO BID if two of the following occurs:
Age ≥ 80 years
Scr ≥ 1.5 mg/dl
Weight ≤ 60 kg
150 mg PO BID
60 mg PO once daily
Not recommended with CrCl > 95 ml/min
20 mg PO once daily
Treatment of acute venous thromboembolism (VTE)
10 mg PO BID for 7 days, then 5 mg PO BID
Following 5-10 days of initial parenteral therapy: 150 mg PO BID
Following 5-10 days of initial parenteral therapy:
Weight > 60 kg: 60 mg PO once daily
Weight ≤ 60 kg: 30 mg PO once daily
15 mg PO BID for 21 days, then 20 mg PO once daily
Reduction in the risk of recurrent VTE
2.5 mg PO BID
150 mg PO BID
Not approved
10 mg PO once daily
Post-knee/hip replacement DVT prophylaxis
2.5 mg PO BID 12-24 hours post-op
Hip replacement duration: 35 days
Knee replacement duration: 12 days
Hip replacement only: 110 mg PO 1-4 hours post-surgery, then 220 mg PO once daily for 28-35 days
Not approved
10 mg PO once daily 6-10 hours post-op
Hip replacement duration: 35 days
Knee replacement duration: 12 days
VTE prophylaxis in acutely ill medical patients at risk for thromboembolic complications, not at high risk of bleeding
Not approved
Not approved
Not approved
10 mg PO once daily in the hospital and after hospital discharge for a total duration of 31-39 days
Table 2.
DOACs approved indications and recommended doses for normal kidney patients.
3.4 Monitoring
DOACs possess the advantage of having predictable pharmacokinetic and pharmacodynamic properties making their regular monitoring of blood levels or coagulation factors not necessary. This provides a great advantage and more convenience to patients than the traditional anticoagulant warfarin. Currently, there are no validated and clinically feasible tests to measure the anticoagulant effect of DOACs on daily basis. Besides, routine monitoring of kidney function is necessary to ensure appropriate clearance of DOACs as all of them have varying degrees of renal elimination. This becomes of high importance when dealing with end-stage renal disease patients or patients on hemodialysis. Monitoring hepatic function every 6 to 12 months is recommended as all DOACs except dabigatran are metabolized by the liver. Regular follow-up on patient adherence is also encouraged to ensure the safety and efficacy of the anticoagulation given their short duration of action [9].
3.5 Side effects
As with all anticoagulants, the main severe and concerning side effect is bleeding. Careful watching of signs and symptoms of bleeding and proper patient education on identifying them is crucial. Dyspepsia is another reported side effect more linked to dabigatran. Taking dabigatran with food should help with minimizing dyspepsia as the body tolerates the medication with time [10].
3.6 Choosing an anticoagulant agent
Warfarin could be an appealing anticoagulant option in many cases. For example, it could be an adequate option to be sued in patients with an estimated creatinine clearance (CrCl) of less than 30 mL/min as those individuals were excluded from many clinical trials that compared warfarin to the DOACs. Also, it could be used in patients with poor medication adherence. This is mainly because many of the currently available DOACs are dosed to be taken twice daily. This could affect patient adherence. In addition, the presence of laboratory assessment modalities like the INR can identify poor medication adherence. Despite the long list of interacting medications with warfarin, the use of warfarin could be preferred as dose adjustments based on INR monitoring can facilitate titration of the anticoagulant response. Warfarin remains the least expensive anticoagulant currently available. This could make it a reasonable option for individuals who cannot afford the more costly options [11].
DOACs are considered the first line option in many indications given their predicted pharmacokinetics and pharmacodynamics which minimizes the need for regular drug monitoring compared to warfarin. They are dosed either once daily or twice daily and do not have significant drug-food interactions. Patients with various degrees of renal impairment (i.e. CrCL <30 ml/min) were excluded from the DOACs’ pivotal trials, therefore their use in this certain population is debatable. However, apixaban, for example has good pharmacokinetic data supporting its use in hemodialysis (HD) patients as it has very low renal clearance that accounts for only 25%. Currently, apixaban is recommended for stroke prevention in atrial fibrillation patients with end stage renal disease (ESRD) on HD. On the other hand, patients with poor compliance may benefit more from being on warfarin rather than DOACs as the effect of warfarin stays longer than DOACs. If a patient misses one dose of warfarin, the INR would still be in the therapeutic range for one or more days. Finally, the need to monitor kidney function with DOACs still exists and crucial to assess the need for renal dose adjustments [12, 13].
3.7 Periprocedural management of anticoagulation
Management of anticoagulation before and after surgeries such as thrombectomy is very crucial safety step to ensure safe and effective surgical interventions with minimal chances for bleedings. The appropriate knowledge of anticoagulants pharmacokinetics properties and the degree of bleeding risk of the procedure are two essential factors to formulate an appropriate periprocedural anticoagulation plan. Special considerations should be taken with individuals with impaired renal or liver functions [14].
In patients who are on a DOAC and going into a minimal risk procedure, omitting one dose of the anticoagulant on the day of the procedure is sufficient. However, in low or moderate risk procedures, the anticoagulant should be omitted for one day before the procedure and restart one day after the procedure. In high-risk procedures, omitting the DOAC agent two days before and after the procedure would reasonable. Table 3 summarizes the periprocedural management of anticoagulants.
Procedure Bleeding Risk
DOAC
Warfarin
Minimal
Omit anticoagulant on the day of procedure
No interruption needed
Low
Omit anticoagulant one day before the procedure
Reinitiate anticoagulant one day after the procedure
For individuals receiving dabigatran with CrCl 30 to 50 mL/min: omit two days before procedure.
Assess thromboembolic risk:
Low – moderate risk: interrupt 5 days before the procedure without parenteral anticoagulant bridging
High risk: interrupt 5 days before the procedure with parenteral anticoagulant bridging
Moderate
Omit anticoagulant one day before the procedure
Reinitiate anticoagulant one day after the procedure
Assess thromboembolic risk:
Low – moderate risk: interrupt 5 days before the procedure without parenteral anticoagulant bridging
High risk: interrupt 5 days before the procedure with parenteral anticoagulant bridging
Reinitiate warfarin postoperatively once hemostasis is attained
High
Omit anticoagulant two day before the procedure
Reinitiate anticoagulant two day after the procedure
For individuals receiving dabigatran with CrCl 30 to 50 mL/min: omit four days before procedure
interrupt 5 days before the procedure with parenteral anticoagulant bridging
Reinitiate warfarin postoperatively once hemostasis is attained
Table 3.
Periprocedural management of anticoagulants.
On the other side, patients who are on warfarin and undergoing minimal risk procedures, interruption of anticoagulation is not necessary. However, in other low and moderate risk procedures, warfarin should be interrupted with mostly no need for bridging. In high risk, interruption of anticoagulation is needed with bridging. Discontinuation of warfarin should be done five days before the procedure. When bridging is required, starting enoxaparin three days before the procedure is reasonable with last dose being given 24 hours before the procedure. In patients with various degrees of renal impairments may require longer interruption periods as clearance of the anticoagulant may become delayed. Table 3 summarizes the periprocedural management of anticoagulants.
4. Reversal Agents
4.1 Warfarin reversal modalities
Holding or discontinuing warfarin as a solo strategy may be adequate in asymptomatic patients with an elevated INR value and a low risk for bleeding. Certain patient may require further agents to be administered such as, Vitamin K (phytonadione), Prothrombin Complex Concentrate (PCC), and Fresh frozen plasma (FFP) [15].
4.1.1 Vitamin K (Phytonadione)
Exogenous vitamin K level helps reestablishing the hepatic formation of vitamin K–dependent clotting factors. When exogenous vitamin K is given, it can continue to be reduced and converted to its active form, KH2, which results with functional clotting factors despite recent warfarin administration. Vitamin K dose and route of administration vary depends on the bleeding magnitude. It can be given as 2–5 mg PO/IV for minor bleeding events and 5–10 IV for major bleed. Although they are rare, anaphylactic reactions and temporary warfarin resistance have been reported with vitamin K use IV vitamin K normalizes the INR quicker than PO. It only takes 8–12 hours with IV administration and might take up to 24–48 hours following oral administration [15].
4.1.2 Prothrombin Complex Concentrate (PCC)
Clotting factor replenishing, and it can enchase platelet activation. These clotting factors are 25-fold more concentrated than blood. Recombinant activated factor VII (FVIIa) (NovoSeven®) contains activated factor VII can directly activate thrombin generation by binding to tissue factor. PCC products are differentiated by the type of clotting factors they consist of. The 3-factor PCC consist of clotting factors II, IX, and X. The 4-factor PCC 4 consist of clotting factors II, IX, X, and VII (4PCC). Activated 4-factor PCC consist of II, IX, X, and VIIa. All PCC products have natural anticoagulants protein C and protein S. and all PCC products contain heparin, except Profilnine® (3-factor PCC)[15].
PCC dosing is based on factor IX and activated versus non-activated pertains to factor VII. Normally each single-dose vial of PCC is mixed with 10–40 mL of sterile water. Fixed dose PCC for non-intracranial hemorrhagic (ICH) bleed is usually 1000 units while in ICH, it is 1500–2000 units. The other modality to dose PCC is INR and weight driven dose. In patients with INR of 2 to less than 4, the dose is 25 units/kg. In patients with INR of 4–6, the dose is 35 units/kg. In patients with INR of more than 6, the dose is 50 units/kg. PCC dose might need to be rounded up or down to the nearest available vial size. The acceptable dose adjusting margin is institution dependent (usually 5–10%). Infusion related allergic reactions, heparin-induced thrombocytopenia (with exception of Profilnine®) and low acceptable risk of thrombosis have been reported in patients receiving PCC therapy [15].
4.1.3 Fresh frozen plasma (FFP)
FFP is not a specific reversal agent. It contains all coagulation factors, including II, VII, IX, and X in diluted inactive form. Moreover, it contains fibrinogen and platelet. There is no specific recommendation when it comes to FFP dosing, but usually it is given as 10–30 mL/kg (1-unit FFP has a volume of 250 mL). Transfusion reactions, volume overload, infection, and transfusion-related lung injury have been reported in patients receiving FFP therapy [15].
4.2 Direct thrombin inhibitors reversal agents
4.2.1 Idarucizumab
Idarucizumab is a humanized monoclonal antibody fragment that has been developed specifically to reverse the anticoagulation effect of dabigatran [9]. Idarucizumab is indicated for emergent surgery/urgent procedures In life-threatening or uncontrolled bleeding. It is given as a total dose of 5 grams (two separate doses of 2.5 g diluted in 50 mL vials) intravenous infusion over 5 minutes. Idarucizumab carries a warning for inducing thromboembolic events. The thrombotic rate in REVERSE-AD trial was 4.8% at 1 month. The risks of hypersensitivity and severe adverse reactions in patients with hereditary fructose intolerance are reported in the packaging insert due to sorbitol excipient. Among patients who received Idarucizumab, 5% or more experienced hypokalemia, pneumonia, pyrexia, and delirium [9].
4.2.2 Prothrombin Complex Concentrates (PCC)
Inconsistent data was reported regarding the efficacy of PCC in reversing dabigatran based on its laboratory abnormalities. When PCC is used, aPCC such as FEIBA may be preferred. The thrombin generation following PCC administration is dose dependent. Currently most guidelines recommend aPCC 50 units/kg to be given when an emergent reversal is needed for dabigatran. Because of the presence of activated clotting factors, and higher prothrombin and thrombin content in aPCC, the risk of thrombosis is expected to be higher with aPCC than with PCC [9].
4.3 Anti-Xa inhibitors reversal agents
4.3.1 Andexanet alfa
Andexanet alpha is a recombinant modified human “decoy” factor Xa protein, and it works through a competitive binding mechanism with high specificity to direct and indirect anti-Xa agents; to restore the activity of factor Xa and reverses the anticoagulant effect. In May 2018, the FDA approved Andexxa® for the reversal of apixaban and rivaroxaban in the setting of life-threatening or uncontrolled major bleeding. Later, the European Medicine Agency (EMA) gave it a ‘conditional authorization’ in 2019 using the trade name of (Ondexxya®)[9].
Andexanet alpha dosing is either 400 mg IV bolus followed by continuous IV infusion or 800 mg IV bolus followed by 960 mg continuous IV infusion, based on drug, dose, and timing. Treatment with the high dose would cost $49,500 for the drug alone. It is available as 100-mg dry powder vials. It needs to be reconstituted with 10 mL SWFI with typical dissolution time of 3 minutes. Most common reported issues related to andexanet alfa include flushing and fever which may be an infusion related side effect in study performed in healthy volunteers. Albeit the decoy mechanism of action of this drug, the most common side effects in patients with major bleeding events were thromboembolism including DVTs, myocardial infarction and ischemic stroke which was reported in 10% in the ANEXXA-4 trial.
4.3.2 Prothrombin Complex Concentrates (PCCs)
Variable data have been reported on the role of PCC in anti-Xa as potential reversal strategies. Multiple guidelines suggest using PCCs as alternative method to andexanet alfa. However, multiple reports demonstrated similar efficacy and safety profile for PCCs when used for major bleed induced by rivaroxaban, apixaban, or edoxaban. Many clinicians may prefer PCCs over andexanet alfa based on the cost difference in addition to the lack of high-quality head-to-head comparisons. Dosing may have a range between 25 and 50 units/kg based on actual body weight [9].
5. Ongoing research on anticoagulant therapy
The anti-factor Xa inhibitors have achieved so many milestones and currently are recommended by most well-respected clinical guidelines. This mechanism of action is becoming so appealing for many manufacturers to design new agents that specifically target factor Xa. Darexaban and nokxaban are two new potential agents that may see the light soon and attain the guidelines recommendations for many clinical indications. They have still not been approved by neither the US FDA nor the EMA but their Phase II trials are promising with comparable safety and efficacy data to current approved DOACs. On the other side, currently approved DOACs are being tested for many other indications and we may see further utilization of these agents on a wider range of patient population. Drugs targeting other coagulation factors such as factor XI and XII are also being developed [16, 17, 18, 19].
6. Conclusion
Several anticoagulant agents could be used to manage thrombotic events. However, it is essential to consider thrombectomy over anticoagulant therapy in acute settings. This is mainly due to the fact that limited data exist on the use of VKA or DOACs in the acute treatment of patients with ischemic stroke. Anticoagulants could be reserved as a secondary prevention strategy in many thrombotic disorders.
Conf lict of interest
The authors declare no conflict of interest.
Notes/thanks/other declarations
None.
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Introduction",level:"1"},{id:"sec_2",title:"2. Vitamin K Antagonists",level:"1"},{id:"sec_2_2",title:"2.1 Mechanism of action",level:"2"},{id:"sec_3_2",title:"2.2 Pharmacology",level:"2"},{id:"sec_4_2",title:"2.3 Indication and dosing",level:"2"},{id:"sec_5_2",title:"2.4 Monitoring",level:"2"},{id:"sec_6_2",title:"2.5 Side effects",level:"2"},{id:"sec_7_2",title:"2.6 Drug interaction",level:"2"},{id:"sec_9",title:"3. Direct Oral Anticoagulants",level:"1"},{id:"sec_9_2",title:"3.1 Mechanism of action",level:"2"},{id:"sec_10_2",title:"3.2 Pharmacology",level:"2"},{id:"sec_11_2",title:"3.3 Indications and dosing",level:"2"},{id:"sec_12_2",title:"3.4 Monitoring",level:"2"},{id:"sec_13_2",title:"3.5 Side effects",level:"2"},{id:"sec_14_2",title:"3.6 Choosing an anticoagulant agent",level:"2"},{id:"sec_15_2",title:"3.7 Periprocedural management of anticoagulation",level:"2"},{id:"sec_17",title:"4. Reversal Agents",level:"1"},{id:"sec_17_2",title:"4.1 Warfarin reversal modalities",level:"2"},{id:"sec_17_3",title:"4.1.1 Vitamin K (Phytonadione)",level:"3"},{id:"sec_18_3",title:"4.1.2 Prothrombin Complex Concentrate (PCC)",level:"3"},{id:"sec_19_3",title:"4.1.3 Fresh frozen plasma (FFP)",level:"3"},{id:"sec_21_2",title:"4.2 Direct thrombin inhibitors reversal agents",level:"2"},{id:"sec_21_3",title:"4.2.1 Idarucizumab",level:"3"},{id:"sec_22_3",title:"4.2.2 Prothrombin Complex Concentrates (PCC)",level:"3"},{id:"sec_24_2",title:"4.3 Anti-Xa inhibitors reversal agents",level:"2"},{id:"sec_24_3",title:"4.3.1 Andexanet alfa",level:"3"},{id:"sec_25_3",title:"4.3.2 Prothrombin Complex Concentrates (PCCs)",level:"3"},{id:"sec_28",title:"5. Ongoing research on anticoagulant therapy",level:"1"},{id:"sec_29",title:"6. Conclusion",level:"1"},{id:"sec_30",title:"Conf lict of interest",level:"1"},{id:"sec_31",title:"Notes/thanks/other declarations",level:"1"}],chapterReferences:[{id:"B1",body:'Dahlbäck B. Blood coagulation. Lancet. 2000;355(9215):1627-1632.'},{id:"B2",body:'Lim GB. Milestone 1: Discovery and purification of heparin. Nat Rev Cardiol. 2017 Dec 14.'},{id:"B3",body:'Lim GB. Milestone 2: Warfarin: from rat poison to clinical use. Nat Rev Cardiol. 2017 Dec 14.'},{id:"B4",body:'Cully M. Milestone 9: Ximelagatran sets the stage for NOACs. Nat Rev Cardiol. 2017 Dec 14.'},{id:"B5",body:'Huynh K. Milestone 10: Era of the NOACs. Nat Rev Cardiol. 2017 Dec 14.'},{id:"B6",body:'Harter K, Levine M, Henderson SO. Anticoagulation drug therapy: a review. West J Emerg Med. 2015 Jan;16(1):11-17.'},{id:"B7",body:'Badreldin H, Nichols H, Rimsans J, Carter D. Evaluation of anticoagulation selection for acute venous thromboembolism. J Thromb Thrombolysis. 2017 Jan;43(1):74-78.'},{id:"B8",body:'Weitz JI. Factor Xa and thrombin as targets for new oral anticoagulants. Thromb Res. 2011 Jan;127 Suppl:S5-12.'},{id:"B9",body:'Chaudhary R, Sharma T, Garg J, Sukhi A, Bliden K, Tantry U, et al. Direct oral anticoagulants: a review on the current role and scope of reversal agents. J Thromb Thrombolysis. 2020 Feb;49(2):271-286.'},{id:"B10",body:'Connors JM. Testing and monitoring direct oral anticoagulants. Blood. 2018;132(19):2009-2015.'},{id:"B11",body:'Wadsworth D, Sullivan E, Jacky T, Sprague T, Feinman H, Kim J. A review of indications and comorbidities in which warfarin may be the preferred oral anticoagulant. J Clin Pharm Ther. 2021 Jun;46(3):560-570.'},{id:"B12",body:'January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart R. J Am Coll Cardiol. 2019;74(1):104-132.'},{id:"B13",body:'Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the Europea. 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Clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban, an oral direct factor Xa inhibitor, in healthy Caucasian and Japanese subjects. Biopharm Drug Dispos. 2013 Nov;34(8):431-441.'},{id:"B18",body:'Choi HY, Choi S, Kim YH, Lim HS. Population Pharmacokinetic and Pharmacodynamic Modeling Analysis of GCC-4401C, a Novel Direct Factor Xa Inhibitor, in Healthy Volunteers. CPT pharmacometrics Syst Pharmacol. 2016;5(10):532-543.'},{id:"B19",body:'Weitz JI, Chan NC. Advances in Antithrombotic Therapy. Arterioscler Thromb Vasc Biol. 2019;39(1):7-12.'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Mohammed Aldhaeefi",address:null,affiliation:'
Department of Pharmacy Practice, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
Department of Pharmacy Practice, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
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Please note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at funders@intechopen.com
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Please be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
\n\n
In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
\n\n
\n\t
Does your institution already have a budget for covering Open Access publication costs?
\n\t
Does your grant list Open Access publication fees as legitimate direct/indirect costs?
\n
\n\n
If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
\n\n
Please note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at funders@intechopen.com
\n\n
Please be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
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The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:"2753-6580",scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
\r\n
\r\n\t
\r\n
\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t
\r\n
\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
\r\n
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
\r\n
\r\n\t
\r\n
\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
\r\n
\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
\r\n
\r\n\t
\r\n
\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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He was elected a Yangtze River Scholars Distinguished Professor in 2013, a member of the International Statistical Institute (ISI) in 2016, a member of the board of the International Chinese Statistical Association (ICSA) in 2018, and a fellow of the Institute of Mathematical Statistics (IMS) in 2021. He received the ICSA Outstanding Service Award in 2018 and the National Science Foundation for Distinguished Young Scholars of China in 2012. He serves as a member of the editorial board of Statistics and Its Interface and Journal of Systems Science and Complexity. He is also a field editor for Communications in Mathematics and Statistics. His research interests include biostatistics, empirical likelihood, missing data analysis, variable selection, high-dimensional data analysis, Bayesian statistics, and data science. He has published more than 190 research papers and authored five books.",institutionString:"Yunnan University",institution:{name:"Yunnan University",country:{name:"China"}}},{id:"1177",title:"Prof.",name:"António",middleName:"J. R.",surname:"José Ribeiro Neves",slug:"antonio-jose-ribeiro-neves",fullName:"António José Ribeiro Neves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1177/images/system/1177.jpg",biography:"Prof. António J. R. Neves received a Ph.D. in Electrical Engineering from the University of Aveiro, Portugal, in 2007. Since 2002, he has been a researcher at the Institute of Electronics and Informatics Engineering of Aveiro. Since 2007, he has been an assistant professor in the Department of Electronics, Telecommunications, and Informatics, University of Aveiro. He is the director of the undergraduate course on Electrical and Computers Engineering and the vice-director of the master’s degree in Electronics and Telecommunications Engineering. He is an IEEE Senior Member and a member of several other research organizations worldwide. His main research interests are computer vision, intelligent systems, robotics, and image and video processing. He has participated in or coordinated several research projects and received more than thirty-five awards. He has 161 publications to his credit, including books, book chapters, journal articles, and conference papers. He has vast experience as a reviewer of several journals and conferences. As a professor, Dr. Neves has supervised several Ph.D. and master’s students and was involved in more than twenty-five different courses.",institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"11317",title:"Dr.",name:"Francisco",middleName:null,surname:"Javier Gallegos-Funes",slug:"francisco-javier-gallegos-funes",fullName:"Francisco Javier Gallegos-Funes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/11317/images/system/11317.png",biography:"Francisco J. Gallegos-Funes received his Ph.D. in Communications and Electronics from the Instituto Politécnico Nacional de México (National Polytechnic Institute of Mexico) in 2003. He is currently an associate professor in the Escuela Superior de Ingeniería Mecánica y Eléctrica (Mechanical and Electrical Engineering Higher School) at the same institute. His areas of scientific interest are signal and image processing, filtering, steganography, segmentation, pattern recognition, biomedical signal processing, sensors, and real-time applications.",institutionString:"Instituto Politécnico Nacional",institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"428449",title:"Dr.",name:"Ronaldo",middleName:null,surname:"Ferreira",slug:"ronaldo-ferreira",fullName:"Ronaldo Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428449/images/21449_n.png",biography:null,institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"165328",title:"Dr.",name:"Vahid",middleName:null,surname:"Asadpour",slug:"vahid-asadpour",fullName:"Vahid Asadpour",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/165328/images/system/165328.jpg",biography:"Vahid Asadpour, MS, Ph.D., is currently with the Department of Research and Evaluation, Kaiser Permanente Southern California. He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. 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. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,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. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. 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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",keywords:"Physiology, Comparative, Evolution, Biomolecules, Organ, Homeostasis, Anatomy, Pathology, Medical, Cell Division, Cell Signaling, Cell Growth, Cell Metabolism, Endocrine, Neuroscience, Cardiovascular, Development, Aging, Development"},{id:"11",title:"Cell Physiology",scope:"
\r\n\tThe integration of tissues and organs throughout the mammalian body, as well as the expression, structure, and function of molecular and cellular components, is essential for modern physiology. The following concerns will be addressed in this Cell Physiology subject, which will consider all organ systems (e.g., brain, heart, lung, liver; gut, kidney, eye) and their interactions: (1) Neurodevelopment and Neurodevelopmental Disease (2) Free Radicals (3) Tumor Metastasis (4) Antioxidants (5) Essential Fatty Acids (6) Melatonin and (7) Lipid Peroxidation Products and Aging Physiology.
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Because of the close relationship between structure and function, studies in human physiology and anatomy seek to understand the mechanisms that help the human body function. The series on human physiology deals with the various mechanisms of interaction between the various organs, nerves, and cells in the human body.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",keywords:"Anatomy, Cells, Organs, Systems, Homeostasis, Functions"},{id:"13",title:"Plant Physiology",scope:"Plant Physiology explores fundamental processes in plants, and it includes subtopics such as plant nutrition, plant hormone, photosynthesis, respiration, and plant stress. In recent years, emerging technologies such as multi-omics, high-throughput technologies, and genome editing tools could assist plant physiologists in unraveling molecular mechanisms in specific critical pathways. The global picture of physiological processes in plants needs to be investigated continually to increase our knowledge, and the resulting technologies will benefit sustainable agriculture.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/13.jpg",keywords:"Plant Nutrition, Plant Hormone, Photosynthesis, Respiration, Plant Stress, Multi-omics, High-throughput Technology, Genome Editing"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"August 18th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:126,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},subseries:[{id:"3",title:"Bacterial Infectious Diseases",keywords:"Antibiotics, Biofilm, Antibiotic Resistance, Host-microbiota Relationship, Treatment, Diagnostic Tools",scope:"
\r\n\tThe era of antibiotics led us to the illusion that the problem of bacterial infection is over. However, bacterial flexibility and adaptation mechanisms allow them to survive and grow in extreme conditions. The best example is the formation of a sophisticated society of bacteria defined as a biofilm. Understanding the mechanism of bacterial biofilm formation has changed our perception of the development of bacterial infection but successfully eradicating biofilm remains a challenge. Considering the above, it is not surprising that bacteria remain a major public health threat despite the development of many groups of antibiotics. Additionally, increasing prevalence of acquired antibiotic resistance forces us to realize that we are far from controlling the development of bacterial infections. On the other hand, many infections are endogenous and result from an unbalanced relationship between the host and the microorganism. The increasing use of immunosuppressants, such as chemotherapy or organ transplantation, increases the incidence of patients highly susceptible to bacterial infections in the population.
\r\n
\r\n\tThis topic will focus on the current challenges and advantages in the diagnosis and treatment of bacterial infections. We will discuss the host-microbiota relationship, the treatment of chronic infections due to biofilm formation, and the development of new diagnostic tools to rapidly distinguish between colonization and probable infection.
",annualVolume:11399,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",editor:{id:"205604",title:"Dr.",name:"Tomas",middleName:null,surname:"Jarzembowski",fullName:"Tomas Jarzembowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKriQAG/Profile_Picture_2022-06-16T11:01:31.jpg",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorTwo:{id:"484980",title:"Dr.",name:"Katarzyna",middleName:null,surname:"Garbacz",fullName:"Katarzyna Garbacz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003St8TAQAZ/Profile_Picture_2022-07-07T09:45:16.jpg",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorThree:null,editorialBoard:[{id:"190041",title:"Dr.",name:"Jose",middleName:null,surname:"Gutierrez Fernandez",fullName:"Jose Gutierrez Fernandez",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"University of Granada",institutionURL:null,country:{name:"Spain"}}},{id:"156556",title:"Prof.",name:"Maria Teresa",middleName:null,surname:"Mascellino",fullName:"Maria Teresa Mascellino",profilePictureURL:"https://mts.intechopen.com/storage/users/156556/images/system/156556.jpg",institutionString:"Sapienza University",institution:{name:"Sapienza University of Rome",institutionURL:null,country:{name:"Italy"}}},{id:"164933",title:"Prof.",name:"Mónica Alexandra",middleName:null,surname:"Sousa Oleastro",fullName:"Mónica Alexandra Sousa Oleastro",profilePictureURL:"https://mts.intechopen.com/storage/users/164933/images/system/164933.jpeg",institutionString:"National Institute of Health Dr Ricardo Jorge",institution:{name:"National Institute of Health Dr. Ricardo Jorge",institutionURL:null,country:{name:"Portugal"}}}]},{id:"4",title:"Fungal Infectious Diseases",keywords:"Emerging Fungal Pathogens, Invasive Infections, Epidemiology, Cell Membrane, Fungal Virulence, Diagnosis, Treatment",scope:"Fungi are ubiquitous and there are almost no non-pathogenic fungi. Fungal infectious illness prevalence and prognosis are determined by the exposure between fungi and host, host immunological state, fungal virulence, and early and accurate diagnosis and treatment. \r\nPatients with both congenital and acquired immunodeficiency are more likely to be infected with opportunistic mycosis. Fungal infectious disease outbreaks are common during the post- disaster rebuilding era, which is characterised by high population density, migration, and poor health and medical conditions.\r\nSystemic or local fungal infection is mainly associated with the fungi directly inhaled or inoculated in the environment during the disaster. The most common fungal infection pathways are human to human (anthropophilic), animal to human (zoophilic), and environment to human (soilophile). Diseases are common as a result of widespread exposure to pathogenic fungus dispersed into the environment. \r\nFungi that are both common and emerging are intertwined. In Southeast Asia, for example, Talaromyces marneffei is an important pathogenic thermally dimorphic fungus that causes systemic mycosis. Widespread fungal infections with complicated and variable clinical manifestations, such as Candida auris infection resistant to several antifungal medicines, Covid-19 associated with Trichoderma, and terbinafine resistant dermatophytosis in India, are among the most serious disorders. \r\nInappropriate local or systemic use of glucocorticoids, as well as their immunosuppressive effects, may lead to changes in fungal infection spectrum and clinical characteristics. Hematogenous candidiasis is a worrisome issue that affects people all over the world, particularly ICU patients. CARD9 deficiency and fungal infection have been major issues in recent years. Invasive aspergillosis is associated with a significant death rate. Special attention should be given to endemic fungal infections, identification of important clinical fungal infections advanced in yeasts, filamentous fungal infections, skin mycobiome and fungal genomes, and immunity to fungal infections.\r\nIn addition, endemic fungal diseases or uncommon fungal infections caused by Mucor irregularis, dermatophytosis, Malassezia, cryptococcosis, chromoblastomycosis, coccidiosis, blastomycosis, histoplasmosis, sporotrichosis, and other fungi, should be monitored. \r\nThis topic includes the research progress on the etiology and pathogenesis of fungal infections, new methods of isolation and identification, rapid detection, drug sensitivity testing, new antifungal drugs, schemes and case series reports. It will provide significant opportunities and support for scientists, clinical doctors, mycologists, antifungal drug researchers, public health practitioners, and epidemiologists from all over the world to share new research, ideas and solutions to promote the development and progress of medical mycology.",annualVolume:11400,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"302145",title:"Dr.",name:"Felix",middleName:null,surname:"Bongomin",fullName:"Felix Bongomin",profilePictureURL:"https://mts.intechopen.com/storage/users/302145/images/system/302145.jpg",institutionString:null,institution:{name:"Gulu University",institutionURL:null,country:{name:"Uganda"}}},{id:"45803",title:"Ph.D.",name:"Payam",middleName:null,surname:"Behzadi",fullName:"Payam Behzadi",profilePictureURL:"https://mts.intechopen.com/storage/users/45803/images/system/45803.jpg",institutionString:"Islamic Azad University, Tehran",institution:{name:"Islamic Azad University, Tehran",institutionURL:null,country:{name:"Iran"}}}]},{id:"5",title:"Parasitic Infectious Diseases",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology",scope:"Parasitic diseases have evolved alongside their human hosts. In many cases, these diseases have adapted so well that they have developed efficient resilience methods in the human host and can live in the host for years. Others, particularly some blood parasites, can cause very acute diseases and are responsible for millions of deaths yearly. Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. Therefore, it is important to conduct studies that examine parasitic infections in the context of the coronavirus pandemic for the benefit of all communities to help foster more informed decisions for the betterment of human and animal health.",annualVolume:11401,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"188881",title:"Dr.",name:"Fernando José",middleName:null,surname:"Andrade-Narváez",fullName:"Fernando José Andrade-Narváez",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRIV7QAO/Profile_Picture_1628834308121",institutionString:null,institution:{name:"Autonomous University of Yucatán",institutionURL:null,country:{name:"Mexico"}}},{id:"269120",title:"Dr.",name:"Rajeev",middleName:"K.",surname:"Tyagi",fullName:"Rajeev Tyagi",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRaBqQAK/Profile_Picture_1644331884726",institutionString:"CSIR - Institute of Microbial Technology, India",institution:null},{id:"336849",title:"Prof.",name:"Ricardo",middleName:null,surname:"Izurieta",fullName:"Ricardo Izurieta",profilePictureURL:"https://mts.intechopen.com/storage/users/293169/images/system/293169.png",institutionString:null,institution:{name:"University of South Florida",institutionURL:null,country:{name:"United States of America"}}}]},{id:"6",title:"Viral Infectious Diseases",keywords:"Novel Viruses, Virus Transmission, Virus Evolution, Molecular Virology, Control and Prevention, Virus-host Interaction",scope:"The Viral Infectious Diseases Book Series aims to provide a comprehensive overview of recent research trends and discoveries in various viral infectious diseases emerging around the globe. The emergence of any viral disease is hard to anticipate, which often contributes to death. A viral disease can be defined as an infectious disease that has recently appeared within a population or exists in nature with the rapid expansion of incident or geographic range. This series will focus on various crucial factors related to emerging viral infectious diseases, including epidemiology, pathogenesis, host immune response, clinical manifestations, diagnosis, treatment, and clinical recommendations for managing viral infectious diseases, highlighting the recent issues with future directions for effective therapeutic strategies.",annualVolume:11402,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",fullName:"Emmanuel Drouet",profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",institutionString:null,institution:{name:"Grenoble Alpes University",institutionURL:null,country:{name:"France"}}},{id:"188219",title:"Prof.",name:"Imran",middleName:null,surname:"Shahid",fullName:"Imran Shahid",profilePictureURL:"https://mts.intechopen.com/storage/users/188219/images/system/188219.jpeg",institutionString:null,institution:{name:"Umm al-Qura University",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"214235",title:"Dr.",name:"Lynn",middleName:"S.",surname:"Zijenah",fullName:"Lynn Zijenah",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSEJGQA4/Profile_Picture_1636699126852",institutionString:null,institution:{name:"University of Zimbabwe",institutionURL:null,country:{name:"Zimbabwe"}}},{id:"178641",title:"Dr.",name:"Samuel Ikwaras",middleName:null,surname:"Okware",fullName:"Samuel Ikwaras Okware",profilePictureURL:"https://mts.intechopen.com/storage/users/178641/images/system/178641.jpg",institutionString:null,institution:{name:"Uganda Christian University",institutionURL:null,country:{name:"Uganda"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/92422",hash:"",query:{},params:{id:"92422"},fullPath:"/profiles/92422",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()