Summary of reviews about therapeutic evidence associated with VitC.
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These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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Goethe University of Medicine in Frankfurt/Main, approbation in 2006, at J. Gutenberg University of Medicine in Mainz, specialty in internal medicine, cardiology and electrophysiology at Kerckhoff Heart and Thorax Center in Bad Nauheim, J.W. Goethe University of Medicine in Frankfurt/Main and J. Liebig University of Medicine in Gießen (all in Germany). Currently Dr. Erkapic is Cardiologist/Electrophysiologist at the University Clinic of Gießen and Kerckhoff Heart and Thorax Center. Fellow of the German Heartrhythm Fellowship (2008-2010). He is member of the German Society of Cardiology (DGK), European Society of Cardiology (ESC) and European Heart Rhythm Association (EHRA). 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Currently he is Consultant Cardiologist/Electrophysiologist at the Central Clinic of Suhl. Also, he is member of the Hungarian Society of Cardiology, German Society of Cardiology (DGK), and European Society of Cardiology (ESC). 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\r\n\tThe solution to many real-world problems lies in optimizing processes, parameters, or techniques, among many others. However, these optimizations usually mean dealing with immense search spaces, so exhaustive methods that may evaluate all possible solutions looking for the global optimum are intractable. Besides, many local optima may exist in the search space, so simple techniques may get stuck in them. Evolutionary algorithms and, more concrete, genetic algorithms are metaheuristic techniques inspired by Darwin's natural selection of species theory to solve search-based optimization problems, which has been demonstrated to effectively deal with complex search spaces. Genetic algorithms employ a population of individuals, each representing a full or partial solution to the problem, bred and reproduced looking for optimal individuals. Then, according to a fitness function, these individuals are evaluated, which determines how a given individual adapts to the problem at hand.
\r\n\r\n\tIn recent years, genetic algorithms have advanced by proposing novel algorithmic flows, representations, or specific techniques inside the main structure of the algorithm. As a result, genetic algorithms have been successfully applied to solve many real-world problems (engineering, smart cities, and energy). They have also helped to improve many machine learning (classification, regression, or hyperparameter optimization) and data mining (data preprocessing, pattern mining, or feature selection) techniques.
\r\n\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art and advances in genetic algorithms and present the fields in which they have been applied throughout the years.
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Furthermore, it stabilizes collagen and acts in iron absorption on the intestinal tract. Nevertheless, much is still discussed on its role in common cold, pneumonia, stress-related disorders, metabolic syndrome, and sepsis. Sepsis is a dysregulated host response to an infection that triggers the release of both pro and anti-inflammatory cytokines throughout its course. This “cytokine storm” is responsible for systemic septic symptoms such as vasodilatation, which leads to hypotension and hypoxia. Also, there is the activation of the clotting cascade leading to disseminated intravascular coagulation (DIC). This hemodynamic instability associated with high immune response makes sepsis a deadly disease. Having such nonspecific symptoms, treating sepsis is also problematic. However, the great majority of protocols include antimicrobial and fluid therapy, vasopressors, and inotropic agents. Using anticoagulants and corticosteroids is debated and varies according to symptoms and local protocols. The use of vitamin C in sepsis treatment is also a highly discussed subject, and there are many clinical trials ongoing trying to associate a better outcome with the help of vitamin C in high doses. Considering that sepsis leads to a depletion in vitamin C because of the increased need for reactive oxygen species (ROS) and the elevated cytokine release, it is fair to assume that supplementing it in high doses might help improve septic symptoms since it scavenges those oxygen-free radicals.
All things considered, this chapter intends to shed light on the pathophysiology of sepsis, and its current treatments, vitamin C’s biochemical and therapeutic properties, and the pieces of evidence from clinical trials that applied vitamin C to treat sepsis and its outcomes.
Sepsis is an overreaction to infections, resulting in multiple organ failure and septic shock, frequently leading to death [1]. Sepsis is commonly associated with a super systemic inflammatory condition followed by an immunosuppression phase in which secondary infections typically occur [2]. First sepsis models were developed using animal experiments after confirmation in human volunteers. Bacterial debris can stimulate an acute rise of pro-inflammatory cytokines, implying that this was the cause of the sepsis-associated organ failure. Guided by these results, several different proposed therapies failed to achieve a substantial positive outcome [3, 4]. Following the overwhelming inflammatory process, an intense anti-inflammatory reply leads to a lack of immune response, lymphopenia, and a high propensity for developing infections [5]. This information had provided the basis of the suppositions that the initial hyperinflammatory condition advances to a following immunosuppression [2]. Pro-inflammatory (as IL-6 and TNF) and anti-inflammatory (as IL-10) cytokines are elevated and death-related in septic patients [6].
After innate recognition of conserved microbial patterns, a substantial inflammatory response begins. The recognition, usually through Toll-Like receptors, leads to the activation of cytokines, growth factors and chemokines [7]. After CD4 T cells activation (Figure 1), both pro and anti-inflammatory cytokines are released [4]. The reason why CD4 T cells response is pro (Th1) or anti (Th2) inflammatory is supposed to be related to the size of the bacterial inoculum, pathogen type, and the infected organ [8, 9, 10, 11]. A more intense inflammatory response with higher cytokine levels is associated with severe sepsis situations. The spectrum of organic reactions is more intense, as well. General vasodilation, capillary leak, and lessened circulating fluid volume lead to blood clotting and multiple organ malfunction or failure [7].
Immune activation following microbial exposition or cellular damage. NF-κB: Nuclear Factor-κB; PAMP: Pathogen-associated molecular pattern; DAMP: Damage-associated molecular pattern; TLR: Toll-like Receptor; IL: Interleukin; TNF-α: Tumor Necrosis Factor-α; IFN-γ: Interferon-γ; PD-1: Programmed cell death protein 1.
The earlier the sepsis or septic shock diagnosis is achieved, the higher are the recovery chances. Broad-spectrum antibiotics (piperacillin/tazobactam, vancomycin, anidulafungin) are initiated while culture and antibiogram results are not available. Clindamycin associated with a β-lactam scheme can be recommended to avoid streptococcal toxic shock. Once the pathogen is identified and its susceptibility to antibiotics is defined, early interruption should be performed, depending on the patient’s improvement [2, 12].
Supportive therapy is needed in virtually all cases. Fluid resuscitation, inotropic (e.g., dobutamine), and vasopressor agents (e.g., norepinephrine) are the most common, effective, and widespread therapies [13].
Other therapies have been studied over the years, but few or controversial results were obtained. Corticosteroids are frequently associated with septic shock therapy. Several randomized controlled trials focused on this issue, and some meta-analysis evaluated the outcomes. Considering all observed flaws of the trials (heterogeneity across studies, doses, the uncertainty of the statistical approach, time of observation, among others), the meta-analysis showed a small benefit using low doses of corticosteroids for a more extended period [14, 15, 16, 17, 18, 19, 20]. International Guidelines for Management of Sepsis and Septic Shock recommend corticosteroid therapy only if fluid resuscitation and vasopressor administration are not enough to restore patients’ stability. Intravenous hydrocortisone (200 mg/day) and continuous evaluation of blood glucose and sodium (corticosteroids may induce hyperglycemia and hypernatremia) are the clinical guidance in those cases [12].
Anticoagulant therapy would be beneficial to oppose the disseminated intravascular coagulation that happens in sepsis conditions. However, antithrombin use did not show evidence to lower the mortality rate and was more prone to bleeding development [12, 21, 22]. On the other hand, thrombomodulin and heparin showed some positive effects on the mortality rate and reduced bleeding risk [23, 24].
Immunoglobulins are still controversial in sepsis. Studies using intravenous immunoglobulins could not show benefits on septic shock or sepsis conditions [25, 26, 27, 28, 29]. However, the majority of studies use a small sample size, so more extensive studies are still needed to evaluate its effectiveness [12, 29].
To the present, numerous researches are trying to achieve a satisfactory result for septic shock or sepsis. However, a long list of failures is along with all the tries. There is a rationale behind Vitamin C usage in these cases, and this chapter will then discuss what is already known and what still needs investigation.
Vitamin C (VitC, ascorbate) is an antioxidant vitamin. This classification is based on the emission of solvated electrons in aqueous media. In organisms, this process can be enzymatically induced. VitC quickly loses electrons in aqueous media, forming ascorbate free radicals. This is why ascorbate is classified as a very potent electron donor. Peroxyl radicals may be formed under oxygenated conditions, by the reaction of solvated electrons with oxygen in aerated solutions [30].
Ascorbate can directly scavenge free radicals or restore other redox systems like α-tocopherol or glutathione (Figure 2). Simultaneously, it is vital to the activity of several iron and copper-dependent enzymes [31]. VitC and monodehydroascorbate radicals have low electron reduction potentials [32] to reduce more common radicals present in metabolic conditions.
Antioxidant network. Ascorbate plays a central role in the human antioxidant system. ROS: Reactive Oxygen Species; R·: Free Radical; DHAR: Dehydroascorbate Reductase; GPX: Glutathione Peroxidase; GSSG: Glutathione Disulfide; GR: Glutathione Reductase.
It is well established that a severe dietary undersupply of vitamin C will result in scurvy. But vitamin C has also a role as a cofactor in several enzymes. It takes part in carnitine synthesis, which is essential for the transport of fatty acids into mitochondria for ATP generation [33, 34]; in the biosynthesis of norepinephrine from dopamine [35, 36], peptide hormones [37, 38], and tyrosine metabolism [39, 40]; in collagen synthesis, increasing its stability [41, 42, 43]; finally, it acts in nonheme iron absorption on the intestinal tract [44].
However, ascorbic acid’s role in preventing or treating common and complex diseases is still uncertain. Even the widely held assumption that ascorbic acid is a significant biological antioxidant and has a prominent role in disease prevention has not been definitively validated [45, 46].
Hundreds of studies have been published over the years on vitamin C’s effects and its roles in preventing or treating several diseases. There have been many controversial outcomes from this association, whether they are positive or negative. Table 1 presents the reviews that summarize those outcomes.
Effect | Conclusion of the study | Reference |
---|---|---|
Cardiovascular protection | Vitamin C deficiency is associated with a higher risk of cardiovascular disease (CVD) mortality. | [47] |
High vitamin C intake from supplements is associated with an increased risk of CVD mortality in postmenopausal women with diabetes. | [48] | |
Population with optimal plasma levels of VitC has no benefit from supplementation. People with VitC deficiency have a higher risk of developing CVD. | [49] | |
Neurologic protection | Antiexcitotoxic, neuromodulator, and neurotrophic effects of ascorbic acid over the CNS are critical for neuroprotective strategies. Clinical trials have demonstrated that ascorbate supplementation produces beneficial results for depression and anxiety. More controlled clinical trials are still necessary to better understand the action mechanisms in stress-related disorders. | [50] |
Metabolic syndrome | A direct positive effect of vitamin C alone on Metabolic syndrome needs to be confirmed in animals and human populations. Combination of vitamin C with other antioxidants may be worthwhile in managing Metabolic syndrome. | [51] |
Common cold (CC) treatment and prevention | In adults, the duration of colds was reduced by 8% and in children by 14%. The severity of colds was also reduced by vitamin C administration during the cold process. No reliable effect of vitC was seen on the duration or severity of colds in the therapeutic trials. | [52] |
Regular supplementation has shown that ascorbate reduces the duration and severity of CC. | [53] | |
Supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections. | [54] | |
Pneumonia treatment and prevention | Due to the small number of included studies and the low quality of the existing evidence, data is uncertain about the effect of vitamin C supplementation on preventing and treating pneumonia. | [55] |
Exercise recovery | Vitamin C supplementation attenuates the oxidative stress (lipid peroxidation) and inflammatory response (IL-6) to a single exercise bout. No effects of vitamin C supplementation were found on creatine kinase (CK), C-reactive protein (CRP), cortisol levels, muscle soreness, and muscle strength. | [56] |
Cancer treatment | Ascorbate can be positive as a pro-oxidative factor as well. VitC would promote the removal of 8-Oxo-2′-deoxyguanosine from DNA by upregulation of repair enzymes due to pro-oxidative properties. Vitamin C showed protection against radiation-induced cell damage. | [57] |
No clinically relevant positive effect of vitamin C in cancer patients on the overall survival, clinical status, quality of life, and performance status. The quality of the evaluated studies, however, is low. Small advantages were more associated to intravenous than oral administration. | [58] |
Summary of reviews about therapeutic evidence associated with VitC.
Nevertheless, when they are critically analyzed, one can realize they show many inconsistencies regarding the methodology. Recently, Lykkesfeldt interestingly analyzed some more expressive clinical trials and unraveled many of the study’s limitations and flaws, as described below, which should be avoided in future researches in this field [59] (Table 2).
Concern | Trouble | Resolution |
---|---|---|
Measurement of Vit C intake vs. status | Focus on VitC intake rather than its status. Even large cohort studies used estimates of micronutrient intakes from self-reported questionnaires or diaries. Lack of precision due to recall error, loss of vitamin from storage and preparation, diet change over time, and possible different polymorphisms. | Retrieving blood samples from fasted individuals. |
Lack of stability | Fasted blood samples can be obtained, but there are significant challenges in correlating vitamin C status to disease risk. This is due to the lability of ascorbate. Ascorbate is quickly oxidized ex vivo, and the resulting oxidation products are quickly degraded or metabolized | Process samples in a cold (4 °C) environment. Avoid hemolysis. Choose HPLC with electrochemical detection. |
Study Design | Random Controlled Trials may require very long intervention periods to accumulate sufficient disease endpoints. This perspective is needed to observe an accumulated preventive potential of a lifelong VitC intake of both placebo and intervention groups up to the trial. This issue has been completely neglected in the available literature. | Perform multicentric randomized follow-up clinical trials. |
Healthy Enrolee Effect | A tendency towards recruiting health-conscious, self-motivated subjects eating a healthy diet already rich in micronutrients, with higher exercise frequency and lower disease rate than the background population. | Work with more significant samples, baseline adjustment among groups, previous genetic evaluation |
Concerns about clinical trials performed to evaluate ascorbate efficacy on diseases, according to Lykkesfeldt [59] (modified by the authors).
Considering the lack of high-quality data to evaluate the efficacy of ascorbate in less severe or more chronic conditions, it is fair to assume that an acute and severe disease such as sepsis is a hard-to-evaluate condition. Vitamin C in sepsis has some particularities such as a diverse route of administration and a peculiar dose–response relationship. The scientific rationale behind this therapeutic proposal to sepsis is discussed in the rest of this chapter.
Sepsis is a condition associated with VitC deficiency because of its high consumption due to enhanced reactive oxygen species (ROS) production. Ascorbate supplementation is thus necessary, and the best results are thought to be achieved through high intravenous doses [60, 61]. The absorption, distribution, metabolism, and excretion (ADME) of vitC in humans are distinct from other small molecules.
In biological systems, VitC exists in two main chemical forms (Figure 3), the reduced and predominant ascorbate anion and the oxidized dehydroascorbate (DHA). Due to the DHA reductase activity (Figure 2), virtually every cell can recycle DHA. Therefore, total ascorbate is considered the sum of VitC and DHA. The membrane transport can be performed by three possible mechanisms: passive or facilitated diffusion and active transport, the most relevant of the three [62].
VitC chemical forms in biological systems – Redox cycle. MDHA: Monodehydroascorbate radical. DHA: Dehydroascorbate.
Orally, VitC is absorbed by the saturable mucosal sodium-dependent Vitamin C transporter 1 (SVCT1) [60]. Ascorbate oral absorption is limited, achieving a plateau after 200-300 mg (Figure 4). SVCT transporters are widely distributed throughout organs and are responsible for most VitC passage across membranes, even against a concentration gradient [63, 64, 65].
VitC oral absorption and distribution. ASC: Ascorbate, SVCT1 and 2: sodium-dependent Vitamin C transporter 1 and 2, DHA: Dehydroascorbate.
Some SVCT polymorphisms have already been identified, which may be associated with a critical pharmacokinetic variation. Some of those SVCT alleles are supposed to lead to permanent ascorbate deficiency (plasma concentrations <23 μM) [62].
Humans do not synthesize vitC, so the oral ingestion of food is the primary source of vitC. There is enough ascorbate for healthy individuals in the average diets that contain food rich in it. However, pathologic conditions associated with low ascorbate levels may need supplementation to achieve the minimum plasma concentrations [62].
Intravenously, plasma levels of ascorbic acid continuously increase, producing plasma levels up to 70-fold higher than the maximum oral doses, achieving the millimolar concentration [66]. A linear relationship between dose and Cmax (maximum concentration plasma level) was observed in doses up to about 70 g/m2, leading to nearly 50 mM plasma levels. Apparently, the pharmacokinetic of vitC changes from zero to first-order after high-dose intravenous administration [62].
Intracellular levels of ascorbate vary between 0.5 to 10 mM, which is much higher than the 50–80 μM usually found in healthy individuals’ plasma. Simultaneously, human erythrocytes can turn DHA to VitC and keep an intracellular ascorbate level similar to that of plasma. This recycling ability of the red blood cells is essential as an antioxidant reserve [62].
As it happens at the absorption phase, distribution depends on active transport as well. Ascorbate exits the bloodstream and crosses the organ’s cell membranes through SVCT2 carriers (Figure 4). Yet, even in the steady-state achieved concentration after regular ascorbate dosage, different tissues present highly diverse concentrations. This may happen because of distinct levels of SVCT2 expression [62].
Metabolism of VitC is essentially associated with the redox cycle involved with the antioxidant function (Figure 3). As previously cited, ascorbate is an electron donor, and it can reduce free radicals (Figure 2) by oxidizing itself to the stable radical monodehydroascorbate (MDHA). This radical can react to another equal, providing an ascorbate molecule and the DHA metabolite that can be reduced, as mentioned before, to ascorbate through DHA reductase activity [62].
VitC is a highly water-soluble (about 330 g/L) small molecule (about 8 Å large, 176.1 g/mol), it has a pKa of 4.2, and is almost insoluble in hydrophobic organic solvents [67]. Like other molecules with similar solubility, ascorbate is filtered through the glomerulus and is concentrated after water resorption. At this time, local pH drops to five, leading to an increase of the non-ionized ascorbic acid fraction. However, passive reabsorption does not occur because of the highly hydrophilic characteristic of the molecule. In the proximal tubules, the reuptake of ascorbate is controlled by the saturable active transporter SVCT1. In individuals with saturated plasma levels, supplemental vitC is excreted quantitatively [68].
After high-dose intravenous administration, vitC is rapidly eliminated through glomerular filtration. Reuptake is non-significant under this condition, and the half-life is constant, about two hours (after discontinuation of infusion), and first-order kinetic applies to this case. In about 16 h, physiological levels are back to normal [62, 69, 70, 71].
Critically ill patients, such as those in septic shock conditions, have an increased ascorbate turnover, needing a dose many folds higher (oral or intravenous) than would be expected to saturate a healthy person. Systemic inflammation and severe pressure due to oxidative stress increase VitC consumption [61, 72, 73]. Mathematically predicted plasmatic ascorbate values are much higher than what is achieved in critically ill patients, suggesting that pharmacokinetics in this group of patients is changed.
In sepsis conditions, the mitochondrial impairment may be a relevant route to cell death and organ collapse. Anomalies in the citric acid cycle and reduction of the fatty acid’s beta-oxidation seem to be a characteristic aspect of this mitochondrial disorder [74].
While ascorbate is transported across membranes through SVCT’s proteins, DHA can be transported by glucose transporters GLUT1, 3, and 4 [75]. DHA is transported into the mitochondria by GLUT1 and converted to ascorbate (Figure 5), where it works as an antioxidant, avoiding damage to the organelle [76]. Ascorbate can also act as a cofactor to the mitochondrial Trimethyllysine dioxygenase (TMLD) enzyme, responsible for the first L-carnitine synthesis, needed for the β-oxidation of fatty acids [77].
Vitamin C multiple anti-inflammatory mechanisms. DHA: Dehydroascorbate, ASC: Ascorbate, GLUT: Glucose Transporter, (H)TML(D): (Hydroxy) Trimethyllysine (Dioxygenase), CPT1: Carnitine Palmitoyltransferase 1, LCFA: Long-Chain Fatty Acids; LACS: Long-Chain Acyl-CoA Synthetase, TNFR: Tumor Necrosis Factor Receptor, NF-κB: Nuclear Factor Kappa-light-chain-enhancer of activated B cells, NIK: NF-κB-Inducing Kinase, NEMO: NF-κB Essential Modulator, IKKα and β: IκBα and β kinases, PI3K: Phosphoinositide 3-Kinase, Nrf2: Nuclear Factor Erythroid 2-Related Factor 2, HO-1: Heme Oxygenase 1, HMGB1 - High Mobility Group Box 1.
The heart is a vital organ that may be affected by sepsis. Proteolysis, mitochondrial injury, and calcium homeostasis dysfunction are expected consequences of the oxidative myocyte damage. Experimental models show that supplementation of the redox scavengers can diminish cardiac disorder [78]. Ascorbate can decrease apoptosis and improve mitochondrial integrity in myocytes through the blockage of the mitochondrial permeability transition pore opening, limiting calcium profusion [79].
VitC can achieve high concentrations in leukocytes, especially lymphocytes and macrophages. In other defense cells, VitC acts to improve chemotaxis, stimulating interferon expression, and promoting lymphocyte proliferation. In neutrophils, ascorbate increases phagocytic capacity and oxidative burst, and decreases NET (neutrophil-extracellular-trap) formation [61, 80].
VitC can mediate immune modulation. VitC inhibits nuclear Factor Kappa-B (NF-κB) activation. The mechanism that underlies this suppression involves the blockade of the TNFα-induced activation of NIK (NFκB-inducing kinase) and IKKβ kinases (Figure 5) [81]. Further modulation is provided by the VitC induced decrease in the late pro-inflammatory cytokine HMGB1 (high mobility group box 1) secretion and through the lowering of histamine levels [82, 83].
Table 1 shows studies that were performed to evaluate VitC efficacy in many pathological conditions. In critically ill patients, several clinical trials have already been completed or are still ongoing. Until December 2020, 39 studies involving ascorbate and some critically ill conditions were registered at the United States National Library of Medicine (NLM) databank clinicaltrials.gov. The list with all referred studies and links to the clinicaltrials.gov forms are available at the end of this chapter.
To the present date, 25 of the cited trials are already finished, 12 are ongoing, and two will begin in 2021. Twelve of these studies tested VitC alone, with no other experimental therapeutics except the usually applied in sepsis cases (i.e., antimicrobial and fluid therapy, vasopressors, and inotropic agents). Seventeen trials used a combination of hydrocortisone, ascorbate, and thiamine (HAT).
Ten studies experimented a combination of VitC with a corticosteroid only (2 trials) or VitC with VitB1 (5 trials) or VitC in combination with some other therapeutic agent (3 trials). Even if there is no consensus about intravenous doses to be used in critically ill patients, 23 of the 39 trials employed 6 g/day doses, mostly in a 6 h-interval regimen (1.5 g each). Five studies used doses below 6 g/day, and nine studies used doses above 6 g/day, mostly in a protocol of 200 mg/kg/day in a 6 h interval regimen (about 14 g/day to a 70 kg patient).
Sadly, from the 25 already finished trials, only 5 reported their results to clinicaltrials.gov or published them in a peer-reviewed journal. One of those was a pharmacokinetic study [84], so no outcomes were evaluated. The other four studies that reported results were called REDOXS [85], ORANGES [86], VITAMINS [87], and CITRIS-ALI [88].
REDOXS used ascorbate in 1.5 g/day dose administered enterally associated with glutamine and other antioxidants. The study was planned to evaluate glutamine associated with a pool of antioxidants effect on critically ill patients. Results reported no difference when compared to placebo for the primary endpoint (28-day mortality rate).
ORANGES was a study intended to evaluate the HAT protocol in septic patients. They evaluated almost 70 patients (in each group) in a protocol that involved 6 g/day ascorbate (1.5 g per dose) for a maximum of 4 days after ICU admission. The study concluded that HAT could decrease the duration of shock, but not the 28-day mortality rate in patients with sepsis, probably due to ascorbate administration (they had an arm of the study that received only corticosteroids).
VITAMINS used the same HAT and ascorbate dosage as described above. They evaluated about 100 patients (in each group). The difference between the ORANGES trial is the control group. While ORANGES intervention in control was essentially placebo, the VITAMINS used a corticoid and thiamine (when clinicians evaluated its need). VITAMINS results indicate that treatment with intravenous ascorbate, hydrocortisone, and thiamine, did not significantly improve the duration of mortality rate and discontinuation of vasopressor administration over seven days.
The CITRIS-ALI trial evaluated the administration of VitC alone in sepsis, associated with acute respiratory distress syndrome (ARDS) patients, in a dose of 200 mg/kg/day (about 14 g/day to a 70 kg patient). The primary outcome evaluated the change in the Sequential Sepsis Related Organ Failure Score (SOFA) and two plasma biomarkers (C-reactive protein and thrombomodulin). The study assessed groups of about 80 patients. Circa 65% of patients (from both control and treatment groups) received corticosteroids during the study, and the mortality rate was significantly lower in the VitC group. However, since this outcome was not a primary outcome, the authors did not consider it in this study. Authors concluded that patients with sepsis and ARDS did not have an improvement in organ dysfunction scores, nor did they have altered markers of inflammation and vascular injury after a 96-hour infusion of vitamin C compared with placebo.
Outside the clinicaltrial.gov, several studies have investigated the use of IV ascorbate in critically ill patients. Cases of trauma, severe burn, and septic shock were evaluated, in various dosage schemes, from 7 g until 110 g/day. No severe adverse effects related to the vitamin C infusion were reported in any of the studies. A decrease in the incidence of multiple system organ failure, trends to reduced mortality, and ICU stay length was the usual results achieved [89, 90, 91].
One of the most commented studies about the effects of the HAT approach, and maybe the reference for several of the clinical trials, was published by Dr. Marik from Eastern Virginia Medical School in 2017 [92]. This study proposed the early HAT protocol using ascorbate IV (1.5 g every 6 h for 4 days or until ICU discharge), hydrocortisone (50 mg every 6 h for 7 days or until ICU discharge), as well as IV thiamine (200 mg every 12 h for 4 days or until ICU discharge). VitC is administered as an infusion over 30 to 60 min and mixed in a 100 mL solution of either dextrose 5% in water or normal saline. Dr. Marik’s results showed that early use of intravenous VitC, with hydrocortisone and thiamine, would be used effectively to prevent progressive organ impairment, including acute kidney damage, and reduce patients’ mortality with severe sepsis and septic shock. However, the published work evaluated a small sample, and as the authors say at the end of the manuscript, additional studies are required to confirm their preliminary findings [92].
High doses of IV ascorbate, thiamine, and glucocorticoids can reduce pro-inflammatory mediators, ROS, and decrease immunosuppression. Thiamine is useful to energy production as a precursor of thiamine pyrophosphate and acts as an antioxidant. Thiamine is essential because ascorbate may cause oxalate accumulation in the kidneys, and the concomitant use can prevent it since thiamine pyrophosphate is a cofactor required for the oxidation of glyoxylate to carbon dioxide by the enzyme glyoxylate aminotransferase. Thiamine deficiency increases the conversion of glyoxylate to oxalate. At the same time, thiamine deficiency is common in septic patients and is associated with an increased risk of death [61, 93].
The VitC in critically ill patients is still a dilemma to be solved. There is a rationale behind its use that seems to be optimal. HAT therapy’s premise is the use of a combination of drugs that aim at multiple sectors of the patient’s response to an infectious agent, synergistically restoring the impaired immune system, avoid damage due to oxidants, and restore mitochondrial activity. However, to evaluate the clinical features and impact of this scheme, most of the studies performed were small, doses used between trials were highly different, and the risk of bias was usually uncertain or high. Secondary outcomes need bigger sample sizes, and so were yet harder to evaluate. The studies’ duration was not uniform, so the follow-up and comparison analysis were possible only to the longest available time in each trial. Finally, the heterogeneity between treatment schemes made comparisons hard. Isolated analysis of VitC ignores any synergistic effects that could be seen with HAT therapy [94].
Vitamin C is a powerful antioxidant that takes part in many vital biological processes. Due to its properties, it has been proposed that VitC could improve sepsis and septic shock symptoms. Because of its pharmacokinetics, it is imperative that ascorbic acid is administered IV in high dosage to explore its full potential in sepsis. Furthermore, the inclusion of hydrocortisone and thiamine to compose the HAT protocol has shown to improve patients outcomes in some clinical trials. Nevertheless, there is still much debate on whether the HAT protocol can actually exert this improvement. To further investigate this proposal, trials should increase sample sizes and come to an agreement on treatment schemes so they can be accurately compared, in addition to sharing the results of the research on Clinical Trials.
JChem for Word was used for Figure 3, Product version 20.21.0.768, ChemAxon (https://www.chemaxon.com). All other images were created with BioRender.com
The authors declare no conflict of interest.
Trial name | Internet link to the trial |
---|---|
High-dose Intravenous Vitamin C as an Adjunctive Treatment for Sepsis in Rwanda | https://clinicaltrials.gov/ct2/show/NCT04088591 |
Outcome Following Vitamin C Administration in Sepsis | https://clinicaltrials.gov/ct2/show/NCT01590303 |
VICTAS Vitamin C, Thiamine, and Steroids in Sepsis | https://clinicaltrials.gov/ct2/show/study/NCT03509350 |
Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Sepsis and Septic Shock | https://clinicaltrials.gov/ct2/show/NCT03258684 |
Therapy With Hydrocortisone, Ascorbic Acid, Thamine in Patients With Sepsis | https://clinicaltrials.gov/ct2/show/NCT04160676 |
Vitamin C & Thiamine in Sepsis | https://clinicaltrials.gov/ct2/show/NCT03592277 |
Vitamin C Infusion for Treatment in Sepsis and Alcoholic Hepatitis | https://clinicaltrials.gov/ct2/show/NCT03829683 |
Vitamin C, Vitamin B1 and Steroid in Sepsis | https://clinicaltrials.gov/ct2/show/NCT04039815 |
Effect of Intravenous Vitamin Con SOFA Score Among Septic Patients | https://clinicaltrials.gov/ct2/show/NCT04137276 |
Ascorbic Acid, Corticosteroids, and Thiamine in Sepsis (ACTS) Trial | https://clinicaltrials.gov/ct2/show/NCT03389555 |
Pilot Study on the Use of Hydrocortisone, Vitamin c and Thiamine in Patient With Sepsis and Septic Shock | https://clinicaltrials.gov/ct2/show/NCT04111822 |
Vitamin C, Thiamine, Cyanocobalamine, Pyridoxine and Hydrocortisone in Sepsis | https://clinicaltrials.gov/ct2/show/NCT04197115 |
High Dose of Vitamin C on Mechanically Ventilated Septic Patients in Intensive Care Unit | https://clinicaltrials.gov/ct2/show/NCT04029675 |
Ascorbic Acid (Vitamin C) Infusion in Human Sepsis | https://clinicaltrials.gov/ct2/show/NCT01434121 |
The Effect of Vitamin C, Thiamine and Hydrocortisone on Clinical Course and Outcome in Patients With Severe Sepsis and Septic Shock | https://clinicaltrials.gov/ct2/show/NCT03335124 |
Effect of Anti-inflammatory and Anti-microbial Cosupplementations in Traumatic ICU Patients at High Risk of Sepsis | https://clinicaltrials.gov/ct2/show/NCT04216459 |
Ascorbic Acid and Thiamine Effect in Septic Shock | https://clinicaltrials.gov/ct2/show/NCT03756220 |
ASTER (Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery) | https://clinicaltrials.gov/ct2/show/study/NCT04291508 |
ViCiS (Vitamin C to Reduce Vasopressor Dose in Septic Shock) | https://clinicaltrials.gov/ct2/show/NCT03835286 |
Vitamin C and Septic Shock | https://clinicaltrials.gov/ct2/show/NCT03338569 |
Comparative, Between Triple Therapy Regimen to Hydrocortisone Monotherapy in Reducing the MR in Septic Shock Patients | https://clinicaltrials.gov/ct2/show/study/NCT04508946 |
Outcomes of Septic Shock Patients Treated With a Metabolic Resuscitation Bundle Consisting of Intravenous Hydrocortisone, Ascorbic Acid and Thiamine | https://clinicaltrials.gov/ct2/show/NCT03913468 |
LOVIT (Lessening Organ Dysfunction With Vitamin C) | https://clinicaltrials.gov/ct2/show/NCT03680274 |
Vitamin C, Thiamine and Hydrocortisone for the Treatment of Septic Shock | https://clinicaltrials.gov/ct2/show/NCT03872011 |
CORVICTES (Vitamin C, Hydrocortisone and Thiamine for Septic Shock) | https://clinicaltrials.gov/ct2/show/NCT03592693 |
CORVICTES-ΥΜ (Vitamin C, Steroids, and Thiamine, and Cerebral Autoregulation and Functional Outcome in Septic Shock) | https://clinicaltrials.gov/ct2/show/NCT03649633 |
Effect of IV Vitamin C, Thiamine, and Steroids on Mortality of Septic Shock | https://clinicaltrials.gov/ct2/show/NCT03828929 |
Thiamine, Vitamin C and Hydrocortisone in the Treatment of Septic Shock | https://clinicaltrials.gov/ct2/show/NCT03540628 |
Effects of Glucocorticoid Combined With Vitamin C and Vitamin B1 on Microcirculation in Severe Septic Shock | https://clinicaltrials.gov/ct2/show/NCT03821714 |
Clinical Trial of Antioxidant Therapy in Patients With Septic Shock | https://clinicaltrials.gov/ct2/show/NCT03557229 |
STASIS (Steroids, Thiamine and Ascorbic Acid in Septic Shock) | https://clinicaltrials.gov/ct2/show/NCT04134403 |
HYVITS (Evaluation of Hydrocortisone, Vitamin C and Thiamine for the Treatment of Septic Shock) | https://clinicaltrials.gov/ct2/show/NCT0338050 |
AVoCaDO (Administration of Intravenous Vitamin C in Novel Coronavirus Infection (COVID-19) and Decreased Oxygenation) | https://clinicaltrials.gov/ct2/show/NCT04357782 |
REDOXS (Trial of Glutamine and Antioxidant Supplementation in Critically Ill Patients) | https://clinicaltrials.gov/ct2/show/study/NCT00133978 |
Pharmacokinetics of Two Different High-dose Regimens of Intravenous Vitamin C in Critically Ill Patients | https://clinicaltrials.gov/ct2/show/study/NCT02455180 |
High Dose Intravenous Ascorbic Acid in Severe Sepsis | https://clinicaltrials.gov/ct2/show/results/NCT02734147 |
ORANGES - Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in Sepsis. | https://clinicaltrials.gov/ct2/show/NCT03422159 |
VITAMINS The Vitamin C, Hydrocortisone and Thiamine in Patients With Septic Shock Trial | https://clinicaltrials.gov/ct2/show/NCT03333278 |
CITRIS-ALI Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury | https://clinicaltrials.gov/ct2/show/study/NCT02106975 |
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Thus, IKS must be validated, exploited and integrated into AT innovation and development.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"John Tharakan",authors:[{id:"198534",title:"Prof.",name:"John",middleName:null,surname:"Tharakan",slug:"john-tharakan",fullName:"John Tharakan"}]},{id:"56510",doi:"10.5772/intechopen.69890",title:"Role of Traditional Ethnobotanical Knowledge and Indigenous Institutions in Sustainable Land Management in Western Highlands of Kenya",slug:"role-of-traditional-ethnobotanical-knowledge-and-indigenous-institutions-in-sustainable-land-managem",totalDownloads:2576,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"The objective of this chapter is to elucidate the relevance of indigenous knowledge and institutions in natural resource management using western highlands of Kenya as a case study. The research design was a mixed method, combining qualitative and quantitative methods. 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Shisanya",authors:[{id:"200734",title:"Prof.",name:"Chris",middleName:null,surname:"Shisanya",slug:"chris-shisanya",fullName:"Chris Shisanya"}]},{id:"68484",doi:"10.5772/intechopen.88118",title:"Journey to America: South Asian Diaspora Migration to the United States (1965–2015)",slug:"journey-to-america-south-asian-diaspora-migration-to-the-united-states-1965-2015-",totalDownloads:1203,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"This chapter examines the immigration of South Asian and Indian populations to the United States between 1820 and 2015. More specifically, this effort scrutinizes legislative changes in immigration policy enabling this group to become the second largest immigrant group after Mexicans in the United States. These changes include the following: the removal of national origin quotas, the introduction of temporary skilled worker programs, and the creation of employment-based permanent visas. Because of these policy changes, by 2015, South Asian immigrants, primarily Indians, had become the top recipients of high-skilled H-1B temporary visas and were the second-largest group of international students in the United States. All told, this study will answer the following questions: What are the origins and demographics of these emigrants who make up the South Asia diaspora? What fields of endeavor are they drawn to by their prior education and skill sets? To what geographic locations have they migrated? And how successful are they in assimilating into their new surroundings?",book:{id:"8522",slug:"indigenous-aboriginal-fugitive-and-ethnic-groups-around-the-globe",title:"Indigenous, Aboriginal, Fugitive and Ethnic Groups Around the Globe",fullTitle:"Indigenous, Aboriginal, Fugitive and Ethnic Groups Around the Globe"},signatures:"John P. Williams",authors:[{id:"264648",title:"Prof.",name:"John",middleName:null,surname:"Williams",slug:"john-williams",fullName:"John Williams"}]},{id:"56426",doi:"10.5772/intechopen.70104",title:"Indigenous Resource Management Practices and the Local Social-Cultural Context: An Insight towards Self-Directed Resource Management by People who ‘Coexist’ with Supernatural Agents",slug:"indigenous-resource-management-practices-and-the-local-social-cultural-context-an-insight-towards-se",totalDownloads:1744,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"In recent arguments in the governance of natural resource management, effectiveness and desirability of collaborative management among various stakeholder including indigenous people has been recognized. In the context of Indonesia, the reformation movement has stimulated the growth of a new perception of indigenous people’s rights to their land in the country. This recent transition presents a growing opportunity for indigenous people who live in nature-rich areas (national parks, etc.) to collaborate with ‘outside stakeholders’ such as governmental agencies, scholars and environmental NGOs in natural resource management. In such situations, it is necessary to deeply understand the value of indigenous resource management (IRM) practices to promote self-directed and effective resource management. This chapter focuses on local forest resource management and its suitability in the local social-cultural context in central Seram, east Indonesia. First, I describe how the well-structured forest resource use is constructed and maintained through the indigenous resource management practices based on ‘supernatural enforce mechanism’. After that, I investigate what social-ecological roles the IRM in Amanioho has, and how IRM practices relate to the social-cultural context of an upland community in central Seram. Then, I discuss the possible future applications for achieving self-directed resource management by people who ‘coexist’ with supernatural agents.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"Masatoshi Sasaoka",authors:[{id:"198898",title:"Dr.",name:"Masatoshi",middleName:null,surname:"Sasaoka",slug:"masatoshi-sasaoka",fullName:"Masatoshi Sasaoka"}]},{id:"56601",doi:"10.5772/intechopen.69887",title:"Revisiting Indigenous Biotic and Abiotic Weather Forecasting for Possible Integration with Scientific Weather Prediction: A Case from the Borana People of South Ethiopia",slug:"revisiting-indigenous-biotic-and-abiotic-weather-forecasting-for-possible-integration-with-scientifi",totalDownloads:1643,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"This study assesses how Borana herders make weather forecast using abiotic and biotic indicators. Survey questionnaire, observations, focus group discussions, and key informant interview were employed to obtain data. Field data were analyzed and interpreted using appropriate analytical tools and procedures. The result revealed that the Borana herders have time-tested weather forecasting experience of using astrological, intestinal, plant, and animal body language indicators. Astrological and intestinal readings that need special training and local expertise are known as Urgii Elaltus and Uchuu, respectively. Forecast information is disseminated using the Borana sociocultural institutions. Based on the disseminated forecast information, the Borana herders take measures such as strengthening enclosure, storing hay, migrating with animals, destocking, and changing schedules of social and cultural festivities such as wedding. The precision and credibility of traditional weather forecast steadily declined and led to repeated faulty predictions. Poor documentation and knowledge transfer system, influence of religion and modern education, premature death of forecast experts, and expansion of alcoholism were identified as causes undermining the vitality of Borana indigenous weather forecast. It is high time that the tenets of indigenous weather forecasting be assessed scientifically and be integrated into the modern science of weather forecasting before they vanish.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"Desalegn Yayeh Ayal",authors:[{id:"198164",title:"Dr.",name:"Desalegn",middleName:"Yayeh",surname:"Ayal",slug:"desalegn-ayal",fullName:"Desalegn Ayal"}]}],mostDownloadedChaptersLast30Days:[{id:"56426",title:"Indigenous Resource Management Practices and the Local Social-Cultural Context: An Insight towards Self-Directed Resource Management by People who ‘Coexist’ with Supernatural Agents",slug:"indigenous-resource-management-practices-and-the-local-social-cultural-context-an-insight-towards-se",totalDownloads:1737,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"In recent arguments in the governance of natural resource management, effectiveness and desirability of collaborative management among various stakeholder including indigenous people has been recognized. In the context of Indonesia, the reformation movement has stimulated the growth of a new perception of indigenous people’s rights to their land in the country. This recent transition presents a growing opportunity for indigenous people who live in nature-rich areas (national parks, etc.) to collaborate with ‘outside stakeholders’ such as governmental agencies, scholars and environmental NGOs in natural resource management. In such situations, it is necessary to deeply understand the value of indigenous resource management (IRM) practices to promote self-directed and effective resource management. This chapter focuses on local forest resource management and its suitability in the local social-cultural context in central Seram, east Indonesia. First, I describe how the well-structured forest resource use is constructed and maintained through the indigenous resource management practices based on ‘supernatural enforce mechanism’. After that, I investigate what social-ecological roles the IRM in Amanioho has, and how IRM practices relate to the social-cultural context of an upland community in central Seram. Then, I discuss the possible future applications for achieving self-directed resource management by people who ‘coexist’ with supernatural agents.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"Masatoshi Sasaoka",authors:[{id:"198898",title:"Dr.",name:"Masatoshi",middleName:null,surname:"Sasaoka",slug:"masatoshi-sasaoka",fullName:"Masatoshi Sasaoka"}]},{id:"56259",title:"Indigenous Knowledge Systems for Appropriate Technology Development",slug:"indigenous-knowledge-systems-for-appropriate-technology-development",totalDownloads:4043,totalCrossrefCites:6,totalDimensionsCites:7,abstract:"Indigenous knowledge systems (IKS) comprises knowledge developed within indigenous societies, independent of, and prior to, the advent of the modern scientific knowledge system (MSKS). Examples of IKS such as Ayurveda from India and Acupuncture from China are well known. IK covers diverse areas of importance for society, spanning issues concerned with the quality of life - from agriculture and water to health. The IK resident in India and China have high relevance to rural life, especially given the level of engagement with agricultural and health technologies. The goal is to establish a heuristic whereby IK can be reviewed and evaluated within particular contexts to determine if the IKS can lead to the development of appropriate technology (AT) addressing that need sustainably. Although much work on cataloguing and documenting IKS has been completed in these two countries, a paucity of attention has been paid to the scientific rationale and technological content of these IKS. Evaluation of many indigenous technologies reveal that many of these technologies can be classified as ‘appropriate’, focused on basic needs of water, sanitation and agriculture, and many have origins in IKS that survived. Thus, IKS must be validated, exploited and integrated into AT innovation and development.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"John Tharakan",authors:[{id:"198534",title:"Prof.",name:"John",middleName:null,surname:"Tharakan",slug:"john-tharakan",fullName:"John Tharakan"}]},{id:"67017",title:"Late Antiquity: Then and Now",slug:"late-antiquity-then-and-now",totalDownloads:804,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Late Antiquity as a period has a complex history with moments when the issues pertaining to it seem to intensify. One of these was without a doubt the aftermath of World War I and reached its apex in 1923 during the International Congress of Historical Sciences in Brussels. The tragic events that had shaken Europe had a deep impact on historiography. In the aftermath of World War II, this trend was reversed on account of a progressive change of perspective and sensibility. In the last decades the favored epithets applied to Late Antiquity were “transformation”, “change”, “transition” and “evolution”. The idea of a “long” Late Antiquity has eventually superseded the previous discourse on when and why the Roman Empire declined. Instead of a caesura, the historical continuum, the longue durée, is stressed. The continuities between Christian Rome, Sasanian Iran, and Islam are being explored. Late Antiquity has become a popular subject of a historical research that is characterized by a wide variety of methods and a paradigm shift.",book:{id:"8893",slug:"antiquity-and-its-reception-modern-expressions-of-the-past",title:"Antiquity and Its Reception",fullTitle:"Antiquity and Its Reception - Modern Expressions of the Past"},signatures:"Arnaldo Marcone",authors:[{id:"287376",title:"Prof.",name:"Arnaldo",middleName:null,surname:"Marcone",slug:"arnaldo-marcone",fullName:"Arnaldo Marcone"}]},{id:"70226",title:"Introductory Chapter: The Importance of Reception Studies for Ancient History",slug:"introductory-chapter-the-importance-of-reception-studies-for-ancient-history",totalDownloads:748,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"8893",slug:"antiquity-and-its-reception-modern-expressions-of-the-past",title:"Antiquity and Its Reception",fullTitle:"Antiquity and Its Reception - Modern Expressions of the Past"},signatures:"Helena Trindade Lopes, Isabel Gomes de Almeida and Maria de Fátima Rosa",authors:[{id:"202246",title:"Prof.",name:"Helena",middleName:null,surname:"Trindade Lopes",slug:"helena-trindade-lopes",fullName:"Helena Trindade Lopes"},{id:"203967",title:"Prof.",name:"Isabel",middleName:null,surname:"Almeida",slug:"isabel-almeida",fullName:"Isabel Almeida"},{id:"315029",title:"Dr.",name:"Fátima",middleName:null,surname:"Rosa",slug:"fatima-rosa",fullName:"Fátima Rosa"}]},{id:"56510",title:"Role of Traditional Ethnobotanical Knowledge and Indigenous Institutions in Sustainable Land Management in Western Highlands of Kenya",slug:"role-of-traditional-ethnobotanical-knowledge-and-indigenous-institutions-in-sustainable-land-managem",totalDownloads:2574,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"The objective of this chapter is to elucidate the relevance of indigenous knowledge and institutions in natural resource management using western highlands of Kenya as a case study. The research design was a mixed method, combining qualitative and quantitative methods. A total of 350 individuals (comprising farmers, herbalists and charcoal burners) from households were interviewed using a structured questionnaire, 50 in-depth interviews and 35 focus group discussions. The results show that indigenous knowledge and institutions play a significant role in conserving natural resources in the study area. There was gender differentiation in knowledge attitude and practice (KAP) of indigenous knowledge as applied to sustainable land management. It is recommended that deliberate efforts should be put in place by the County Governments to scale up the roles of indigenous institutions in managing natural resources in the study area.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"Chris A. Shisanya",authors:[{id:"200734",title:"Prof.",name:"Chris",middleName:null,surname:"Shisanya",slug:"chris-shisanya",fullName:"Chris Shisanya"}]}],onlineFirstChaptersFilter:{topicId:"275",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{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"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517",scope:"Paralleling similar advances in the medical field, astounding advances occurred in Veterinary Medicine and Science in recent decades. These advances have helped foster better support for animal health, more humane animal production, and a better understanding of the physiology of endangered species to improve the assisted reproductive technologies or the pathogenesis of certain diseases, where animals can be used as models for human diseases (like cancer, degenerative diseases or fertility), and even as a guarantee of public health. Bridging Human, Animal, and Environmental health, the holistic and integrative “One Health” concept intimately associates the developments within those fields, projecting its advancements into practice. This book series aims to tackle various animal-related medicine and sciences fields, providing thematic volumes consisting of high-quality significant research directed to researchers and postgraduates. It aims to give us a glimpse into the new accomplishments in the Veterinary Medicine and Science field. By addressing hot topics in veterinary sciences, we aim to gather authoritative texts within each issue of this series, providing in-depth overviews and analysis for graduates, academics, and practitioners and foreseeing a deeper understanding of the subject. Forthcoming texts, written and edited by experienced researchers from both industry and academia, will also discuss scientific challenges faced today in Veterinary Medicine and Science. In brief, we hope that books in this series will provide accessible references for those interested or working in this field and encourage learning in a range of different topics.",coverUrl:"https://cdn.intechopen.com/series/covers/13.jpg",latestPublicationDate:"May 18th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:10,editor:{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"19",title:"Animal Science",coverUrl:"https://cdn.intechopen.com/series_topics/covers/19.jpg",editor:{id:"259298",title:"Dr.",name:"Edward",middleName:null,surname:"Narayan",slug:"edward-narayan",fullName:"Edward Narayan",profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",biography:"Dr. Edward Narayan graduated with Ph.D. degree in Biology from the University of the South Pacific and pioneered non-invasive reproductive and stress endocrinology tools for amphibians - the novel development and validation of non-invasive enzyme immunoassays for the evaluation of reproductive hormonal cycle and stress hormone responses to environmental stressors. \nDr. Narayan leads the Stress Lab (Comparative Physiology and Endocrinology) at the University of Queensland. A dynamic career research platform which is based on the thematic areas of comparative vertebrate physiology, stress endocrinology, reproductive endocrinology, animal health and welfare, and conservation biology. \nEdward has supervised 40 research students and published over 60 peer reviewed research.",institutionString:null,institution:{name:"University of Queensland",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",institutionString:null,institution:{name:"Universidade Paulista",institutionURL:null,country:{name:"Brazil"}}},{id:"191123",title:"Dr.",name:"Juan José",middleName:null,surname:"Valdez-Alarcón",slug:"juan-jose-valdez-alarcon",fullName:"Juan José Valdez-Alarcón",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBfcQAG/Profile_Picture_1631354558068",institutionString:"Universidad Michoacana de San Nicolás de Hidalgo",institution:{name:"Universidad Michoacana de San Nicolás de Hidalgo",institutionURL:null,country:{name:"Mexico"}}},{id:"161556",title:"Dr.",name:"Maria Dos Anjos",middleName:null,surname:"Pires",slug:"maria-dos-anjos-pires",fullName:"Maria Dos Anjos Pires",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS8q2QAC/Profile_Picture_1633432838418",institutionString:null,institution:{name:"University of Trás-os-Montes and Alto Douro",institutionURL:null,country:{name:"Portugal"}}},{id:"209839",title:"Dr.",name:"Marina",middleName:null,surname:"Spinu",slug:"marina-spinu",fullName:"Marina Spinu",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLXpQAO/Profile_Picture_1630044895475",institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",institutionURL:null,country:{name:"Romania"}}},{id:"92185",title:"Dr.",name:"Sara",middleName:null,surname:"Savic",slug:"sara-savic",fullName:"Sara Savic",profilePictureURL:"https://mts.intechopen.com/storage/users/92185/images/system/92185.jfif",institutionString:'Scientific Veterinary Institute "Novi Sad"',institution:{name:'Scientific Veterinary Institute "Novi Sad"',institutionURL:null,country:{name:"Serbia"}}}]},{id:"20",title:"Animal Nutrition",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. He teaches various degree courses in zootechnics, sheep production, and agricultural sciences and natural resources.\n\nDr. Ronquillo’s research focuses on the evaluation of sustainable animal diets (StAnD), using native resources of the region, decreasing carbon footprint, and applying meta-analysis and mathematical models for a better understanding of animal production.",institutionString:null,institution:{name:"Universidad Autónoma del Estado de México",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"175762",title:"Dr.",name:"Alfredo J.",middleName:null,surname:"Escribano",slug:"alfredo-j.-escribano",fullName:"Alfredo J. 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Science",value:19,count:5}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:3},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:1},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:148,paginationItems:[{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:null},{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:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{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:null},{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. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. 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Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356823",title:"MSc.",name:"Seonghee",middleName:null,surname:"Min",slug:"seonghee-min",fullName:"Seonghee Min",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Daegu University",country:{name:"Korea, South"}}},{id:"353307",title:"Prof.",name:"Yoosoo",middleName:null,surname:"Oh",slug:"yoosoo-oh",fullName:"Yoosoo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Yoosoo Oh received his Bachelor's degree in the Department of Electronics and Engineering from Kyungpook National University in 2002. 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