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Currently, he is an Associate Professor at Physics Department, Kasetsart University, Thailand. He is a specialist in the development of smart sensors and intelligent systems for food, agricultural and environmental applications. He has received over twenty-eight research awards such as TRF–OHEC–SCOPUS Young Researcher Award in physical science, Invention Award from National Research Council of Thailand, Highest Citation Award for the young researcher, etc. He has served as a reviewer, guest editor, and associate editor for several scientific journals. He is Top 2% World Ranking of Scientists in Electrical & Electronic Engineering in 2020 and 2021 ranked by the Stanford University researcher team. He has published several dozens of articles in reputed journals, proceedings, book chapters, patents, and copyrights. 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1. Introduction
Postoperative pain of all types is often under-treated and may lead to chronic postsurgical pain, a centralized painful condition that can be challenging to treat [1]. Reports of postimplant pain can vary. In a survey of pacemaker patients, most patients were satisfied overall with their device and not affected by pain, soreness, or discomfort [2]. Yet in another study, over 40% of surgical patients from a single-center Italian study (n = 235) reported still having mild postsurgical pain at six months [3]. Despite the frequency of device implants for cardiac conditions, there is little study on the incidence, intensity, or duration of pain associated with cardiac implantable electronic device (CIED) implantation.
There is a paucity of literature to inform clinicians about pain management for those undergoing an implantable cardioverter-defibrillator (ICD) or pacemaker implantation. A single-center study from Europe (n = 372) analyzed pain control retrospectively over the course of device implant [4]. The study found about a quarter of patients received analgesia or sedation in advance of surgery. During surgery, all patients received local lidocaine anesthesia. Upon completion of the surgery, less than one-third (31%) were given pain medication or sedated. Using a 0 to 10 numeric rating scale, the highest pain rating during the implantation was 8. Pain above 5 was reported one, three, six, eight, and 24 hours after surgery, with the most frequently reported pain sites being the surgical incision, shoulder area, and chest region [4].
2. Postoperative pain control
There has been a little systematic study of pain associated with CIED implantation even though, such procedures are increasingly prevalent. Further complicating the subject of postoperative pain control are differences between subcutaneous and transvenous devices and the fact that some implantation procedures are done on an outpatient basis.
2.1 Risk factors for postoperative pain
The BRUISE-CONTROL studies 1 and 2 used a visual analog scale to assess pain in 1308 patients who had a CIED implanted. Using multivariable regression analysis, the following were associated with clinically important postsurgical pain: clinically significant hematoma (odds ratio [OR] 3.8), de novo CIED implantation (OR 1.9), female sex (OR 1.6), age < 65 years (OR 1.5), and body mass index <20 (OR 2.1) [5].
In a study of 21 consecutive adult CIED patients (mean age 61 ± 11 years), patients were asked to rate their pain on a 0 to 100 visual analog scale, where 0 was no pain at all and 100 was the worst possible pain imaginable. Patients rate their pain 24 hours after surgery and again at one month postoperatively. At 24 hours postimplant, the mean VAS score was 34 ± 20. Only one patient in the study experienced severe pain, with the rest rating pain as moderate (48%) or mild (48%). Using regression analysis, it was found that the use of intraoperative fentanyl and a longer time spent in the procedure were significant predictors of more intense postoperative pain. The mean VAS score for pain at one month was 19 ± 18 and 17 out of 21 patients rated this pain as “mild” [6].
2.2 Inpatient versus outpatient pain control
Device implantation may be done on an inpatient or outpatient basis, depending on a variety of factors, including patient characteristics, comorbidities, physician preference, geography, patient frailty, and other factors. A retrospective chart review of 415 consecutive primary-prevention ICD patients found that same-day discharge was safe and feasible [7]. However, in real-world clinical practice, many such procedures are performed on inpatients. In a prospective study of 327 de novo ICD patients, 40.3% were implanted during acute hospitalization [8]. Of these inpatients, 57.6% were secondary-prevention patients [8]. Predictors of hospitalization include, a more complex device (non-single-chamber device), New York Heart Association (NYHA) class IV symptoms, low diastolic blood pressure, higher blood urea nitrogen levels, and lower hemoglobin [8].
2.3 Subcutaneous ICDs
Subcutaneous ICDs are often implanted under general anesthesia and postoperative pain may be managed with opioid analgesia. However, there is a trend toward moving away from general anesthesia and postoperative opioids to a different type of pain control [9]. Monitored anesthesia care (MAC) has been reported in the literature to be a safe and effective method for subcutaneous ICD implantation [10, 11]. The truncal plane block along with perioperative nonopioid analgesics is being considered and appears feasible and effective [12]. A study of 91 consecutive patients undergoing subcutaneous ICD implantation at 10 centers found ultrasound-guided serratus anterior plane block was effective for anesthesia during the procedure and postoperative analgesia [13].
The Subcutaneous Defibrillator and Send Home (DASH) study investigated the feasibility and safety of subcutaneous ICD implant in patients (mean age 47 ± 14 years) discharged on the same day [14]. In total, 49 patients were enrolled and all were discharged following the surgery without staying overnight at the hospital. The protocol called for preoperative acetaminophen 975 mg and oxycodone 10 mg, local bupivacaine during the surgery, and limited fixed-dose combination oral analgesic of oxycodone plus acetaminophen (5/325 mg) after surgery, every 6 hours as needed. Using a 0 to 10 numerical pain rating scale, severe pain (defined as a score ≥ 8) occurred in 14.3% of patients on the day of surgery, 14.3% on postoperative day 1, and 8.2% of patients on a postoperative day 3 [14].
In a study of 104 adult patients undergoing subcutaneous ICD implantation, 69% were administered intraprocedural liposomal bupivacaine but there were no statistically significant differences between those who received bupivacaine and those who did not in terms of inpatient opioid consumption, outpatient opioid prescriptions, or overall opioid consumption in the postoperative period [15]. Similar findings were observed in a study of liposomal bupivacaine in knee arthroplasty [16].
In a study of opioid use following CIED implantations, patients who underwent subcutaneous ICD implantation were more likely to be prescribed opioids than those implanted with transvenous devices (25% vs. 20%) [17]. In a retrospective single-center study of structured interviews with female patients who were implanted with a subcutaneous ICD (mean time since implant 4.6 ± 3.1 years) 54% said their postsurgical pain was worse than they expected [18]. About half (44%) said that they experienced daily discomfort with their bra and the implanted device [18]. Thus, while postoperative pain can be managed following subcutaneous ICD implant, there are important gaps to be recognized in how pain is treated. In particular, patients should be advised about the nature, duration, and intensity of pain anticipated and provided with an analgesic regimen with specific instructions.
2.4 Device revision
ICDs and other CIEDs require replacement upon battery depletion, and the incidence of any type of complication within 45 days of device revision is 4.3% [19]. Device infections are more common for ICD and CRT-D system revisions than initial implants (2.9% and 3.9% for revisions, respectively, and 1.6% for both ICD and CRT-D de novo systems) [20]. It should be noted in this context that a CRT-D system is a more complicated device than a transvenous ICD, even a dual-chamber ICD, and requires a left-ventricular lead. This risk for infection may be cumulative with subsequent device revisions; in fact, each intervention at the same implant site appears to double the risk for infection [21]. There are no studies, comparing postoperative pain intensity or characteristics of initial and revised procedures. Since up to 40% of ICD procedures involve a generator replacement [22], this represents a significant knowledge gap.
In an analysis of opioid prescribing for CIED implantation, patients undergoing device upgrades and generator change-outs were less likely to receive opioids than those getting a de novo implant (18.3%, 11.6%, and 20%, respectively) [17].
2.5 Special populations
2.5.1 Pediatric
The number of pediatric device patients is a relatively small subset of the device population, but babies, as well as children and adolescents, may be recipients of CIEDs. Nerve blocks have been effectively used in pediatric patients undergoing implantation of a subcutaneous ICD [23]. In this case series of 10 patients, the combination of bilateral parasternal blocks with a left erector spinae plane block provided good pain control. Pectoral nerve blocks have been shown to reduce perioperative anesthetic requirements and postoperative pain in children undergoing transvenous ICD implantation [24].
2.5.2 Women
A study of 180 men and 60 women, who had a de novo ICD implantation, found that women were statistically significantly more likely to be younger and less likely to be married or have a history of coronary artery disease than men [25]. However, women had lower functional status, reported more intense pain, and had more sleep problems than men. Men and women were similar in terms of symptoms of anxiety and depression [25]. A study of 179 consecutive ICD outpatients (mean age 60.5 ± 15.9 years) found women reported significantly more intense pain than men [26].
Women have been historically under-represented in ICD clinical trials and historically were sometimes overlooked in consideration for ICD implantation. In a retrospective study of 5156 outpatients with an ejection fraction ≤35%, 25.0% of women had received an ICD compared to 36.3% men (p < 0.01) [27]. In an observational study based on Get with the Guidelines-Heart Failure Program, 21,059 patients with an ejection fraction ≤35%, were evaluated in the time frame from 2011 to 2014. During this time, women were less likely to be counseled about ICD therapy than men (19.3% vs. 24.6%, p < 0.001) [28]. It may be that women who receive ICDs are not adequately counseled about what to expect from surgery or treated for pain.
2.5.3 Overweight
Studies suggest that obese patients, defined as a body mass index >30 kg/m2, are at an elevated risk for inappropriate shock and failed defibrillation testing when a subcutaneous device is implanted [29, 30]. Electrocardiographic testing before implant and appropriate patient selection may reduce such risks [10]. It is unknown whether obese patients experience more pain or more intense pain than normal-weight patients.
2.5.4 Racial/ethnic groups
In a retrospective analysis of 5156 outpatients with an ejection fraction ≤35%, 28.0% of Black compared to 33.2% of White patients had an ICD, p = 0.02 [27]. Although this difference was statistically significant, it was less pronounced than sex-based differences in ICD implantation, where men were more likely to receive an ICD than women [27]. Since Blacks Americans are less likely to have health insurance than Whites, it might be speculated that part of this difference can be traced back to differences in health coverage. However, a study from the United Kingdom found that despite free, universal healthcare, there were racial disparities in ICD implantations; ICDs in the United Kingdom were significantly more likely to be implanted in White than South Indian residents [31]. Although the population of Caucasians in the area of Leicestershire was 77.7% and South Asians made up 15.9% of the population, 91.9% of all ICDs in that areas were implanted in Caucasians compared to 8.1% South Asians. These differences persisted for primary- and secondary-prevention patients although the gap between Caucasians and South Asians was even wider for secondary-prevention treatment [31]. It is unclear, why this marked difference occurs. The lower rate of Black patients for ICD therapy is particularly concerning because Blacks are at greater risk than Whites for sudden cardiac death [32]. However, in the United States, Blacks also had a higher ICD refusal rate than other groups when ICD therapy was presented to them as a consideration [32]. Among patients who are at higher risk of sudden cardiac death, Blacks had significantly less probability of getting an ICD [33].
2.5.5 Geriatric
Advanced age and frailty have been associated with less-frequent use of ICD systems and indications require the patient have a reasonable expectation to live at least one more year after device implant [34]. This life expectancy requirement is not always taken into account. In a survey of 386 physicians who refer selected patients for possible ICD implantation, 23% said that they do not consider life expectancy and 13% have knowingly referred patients with a life expectancy of under one year [35]. However, there is no specific age cutoff for ICD indications. More than 40% of all first implants of ICD systems occur in patients over the age of 70, and de novo patients over age 80 are not uncommon [36]. Biological age may be more important than chronological age in this regard [37].
Postsurgical pain in geriatric device patients is not well studied; indeed, elderly patients are often under-represented in clinical trials, if they are included at all. In a study of 150,264 primary-prevention patients, there were significantly more adverse events in the oldest patients (4.5% in those ≥80 years) compared to the youngest group (2.8% in those <65 years) [38]. This rate of adverse events plateaued at about 4.5% at age 80 and beyond. Comorbid conditions were stronger predictors for complications than age [38]. However, the proportions of older and younger patients who specifically experienced pain were not reported.
The control of postsurgical pain in geriatric patients can be challenging due to comorbid conditions, concurrent drug therapies (polypharmacy), and age-related pharmacokinetic and pharmacodynamic alterations [39]. Pain assessment maybe even more challenging in elderly patients with impaired communication skills or cognitive deficits. Because elderly patients may get benefit from ICD therapy and may have special limitations with respect to pain therapy, further study is much needed.
2.6 Opioid considerations
Opioids have come under increasing scrutiny as routine analgesics since the Centers for Disease Control and Prevention (CDC) published guidance to limit their use because of growing concerns for their risks, opioid-associated side effects, and opioid use disorder (OUD). In addition, opioids may increase the risk of atrial fibrillation or other arrhythmias [40]. Nevertheless, opioids are effective analgesic agents and are often used for appropriate patients under clinical supervision to manage the acute pain associated with surgery.
In a retrospective analysis of all CIED procedures done at the three Mayo Clinics in Minnesota, Arizona, and Florida, from 2010 to early 2018, opioids were prescribed to 20.2% of the 16,517 patients (mean age 70 ± 15 years) after device implantation. Of this group, 80% were opioid naïve. Of the opioid-naïve patients, 9.4% refilled their opioid prescription at least once and 38.8% of patients received >200 oral morphine equivalents (ME) [17]. The mean amount of ME prescribed was 243 ± 346 overall. Opioid-experienced patients were prescribed significantly more opioids than opioid-naïve patients with 335 ME compared to 219 ME for the opioid-naïve patients (p < 0.001) [17].
Opioids are associated with many well-known side effects, including nausea, somnolence, mental fogginess, pruritus, and constipation [41]. In most cases, these side effects are mild to moderate although they can in some instances be severe and even treatment-limiting. A short course of postsurgical opioids typically does not result in treatment-limiting side effects, although some patients find opioid analgesics unpleasant. In a study of 250 surgical inpatients, who had a variety of different types of surgery, 25% of those who had received some form of analgesic reported having side effects, although 90% said that they were satisfied with the pain control medications they were administered [42].
Although this chapter deals with postoperative pain control following device implant, it is difficult to discuss pain management isolated to the specific postoperative period without describing preoperative and perioperative techniques, which can affect the pain experienced by the patient when the procedure has ended and the patient enters recovery.
2.7.1 Preoperative
The implant of an ICD or any CIED can be associated with severe acute pain. The pain is most intense immediately after the implant procedure and diminished gradually over the next few days as the implant site heals. Postoperative pain should be managed with preoperative, perioperative, and postoperative strategies. In discussing the device implant with the patient, the clinical team should educate the patient on pain control goals and available options with their risks and benefits. It is important to manage the patient’s expectations because complete pain eradication is likely not possible. It has been found that oral gabapentin (600–1200 mg) or pregabalin (150–300 mg) administered an hour or two before surgery can reduce postsurgical opioid consumption [43, 44]. Likewise, oral celecoxib (200–400 mg) 30 minutes to 1 hour before surgery can likewise diminish the need for postoperative opioids [43, 45]. Note that the individual patient must be considered in any analgesic regimen; nonsteroidal anti-inflammatory drugs such as celecoxib may be contraindicated in certain cardiology patients.
A structured plan to help to reduce the pain associated with CIED implantation and other related procedures, such as catheter ablation, could significantly reduce pain up to 8–24 hours after the procedure [46]. The elements of such programs include patient education, regular pain assessments, analgesic protocols, and prompt referrals to pain specialists if the pain becomes severe or cannot be managed.
It is concerning that many device patients do not receive any preoperative analgesics. In a study from Croatia, it was found that 75% of patients undergoing CIED implantation received no preoperative pain medications at all [4].
2.7.2 Perioperative
Perioperative pain control is typically managed by local medications and/or regional anesthesia [4]. Proper device placement in the fascia and good hemostasis during the procedure may reduce pain following the operation. Liposomal bupivacaine extended-release formulation may provide good anesthetic infiltration with an effect that can last up to 72 hours [47]. In some cases, general anesthesia is used but truncal plane blocks may also provide adequate anesthesia for difficult procedures or those involving a subcutaneous device [12]. For conventional ICDs and devices with transvenous lead systems, local anesthetic infiltration is probably adequate, but sometimes cervical or pectoral nerve block may be employed [48, 49]. Intravenous ketamine is not recommended because of the potential for myoclonus, which can interfere with device function and cause double-counting [17].
2.7.3 Postoperative
Following surgery, the patient may get benefit from oral analgesics to manage acute pain. Opioid analgesics may be considered for a short course in appropriate patients. A great concern about the use of opioids in any patient is the potential for OUD. Risk stratification tools exist that can help to determine which patients may be at elevated risk for opioid misuse and abuse [50] (see Table 1). Opioid overdose may result in potentially life-threatening respiratory depression; naloxone is a rapid-acting rescue drug. Patients taking opioids following CIED implantation may benefit from a prescription for naloxone and the family or caregivers should be trained in how to administer it in an emergency.
Diagnosis, Intractability, Risk, and Efficacy Inventory (DIRE)
Scoring system
More suitable for long-term therapy or ongoing therapy
Clinician does assessment
Opioid Risk Tool
Clinician-guided questionnaire-based interview; stratifies low, medium, and high risk for aberrant drug-taking behaviors
May be used before start of opioid therapy
High degree of sensitivity and specificity
Pain Medication Questionnaire (PMQ)
Questionnaire
Designed for chronic pain patients
Validated translated versions available
Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R)
Questionnaire
To identify those at low risk of OUD
Validated translated versions available
Table 1.
While there is no consensus as to the best opioid-screening tool, a variety of validated instruments exist [51, 52, 53]. In place of an assessment tool, a clinical interview with the patient may be conducted to assess past drug experiences, familial history of substance use disorders, and attitudes about pain control. Note that these tools are often used in the setting of long-term opioid therapy, rather than short-term postoperative use.
In a single-center retrospective study from Croatia (n = 372), 31% of patients being implanted with an ICD received pain medication following surgery; the highest intensity pain recorded in this study was 8 on a 0 to 10 scale [4]. The most frequently prescribed medications in this study were fixed-dose combination oral tramadol and acetaminophen 37.5/325 mg (29%), diazepam 5 mg (17%), tramadol 5 mg monotherapy (16%), and acetaminophen monotherapy 500 mg (12%) [4]. It should be noted that in this study 69% of patients received no postoperative analgesic medications at all [4]. This strongly suggests that many CIED patients have poorly controlled pain after surgery. Of course, postoperative pain control may be inadequate for many types of surgery. In USA survey of surgical inpatients, who had a variety of procedures, about 80% reported they suffered pain following surgery with 86% of them ranking this pain as “moderate” to “severe” [42]. Perhaps most important is that pain was reported to occur more frequently after discharge than before [42]. Patients may not always know what to expect and some may accept moderate to severe postoperative pain following surgery, not knowing that postoperative pain can often be safely and effectively managed.
An important analgesic strategy involves a combination of multimodal analgesia. Multimodal analgesia is based on the use of two or more analgesics with different mechanisms of action to offer a synergistic benefit to patients. Some fixed-dose combination products offer oral acetaminophen plus, a small amount of opioid, such as oxycodone, in a single oral dose. Adjuvant agents may also be helpful such as gabapentin or pregabalin to help with a neuropathic component to postsurgical pain.
A challenge in pain management following implant is the fact that most device patients do not spend prolonged periods of time in the hospital. Most CIED patients are discharged home shortly after surgery, whether they are outpatients or spend the night in the hospital. Thus, most device patients must manage the longest duration of their postsurgical pain at home. For this reason, patients and their families or caregivers must be educated about the pain medications they are to take, the appropriate doses and timing, and the risks as well as the benefits of these medications. Following transvenous device implant, patients should be educated about arm movements to prevent capsulitis (“frozen shoulder”) [54].
3. Conclusions
With millions of device patients around the world, it is important to develop good guidance in terms of how to manage postoperative pain in these patients. Most postoperative pain is moderate to severe but has a predictable trajectory in which the pain is most intense immediately after surgery and diminished day over day over the course of several days. A good strategy for pain control for CIED patients is to consider managing pain perioperatively and then offer the patient postoperative counseling for pain management at home along with appropriate analgesics. For appropriate patients, a short course of opioid analgesics may be appropriate but other nonopioid agents may be considered as well. Subcutaneous ICD implantation is likely associated with more severe or longer-duration postoperative pain although there are no specific head-to-head comparative pain studies. Barring complications, device patients recover over the course of days and weeks and should need analgesia only for a short duration of time.
Conflict of interest
Peter Magnusson has received speaker’s fees or grants from Abbott, Alnylam, Amicus Therapeutics, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Coala Life, Internetmedicin, Lilly, MSD, Novo Nordisk, Octopus Medical, Orion Pharma, Pfizer, Sanofi, Vifor Pharma, and Zoll.
Jo Ann LeQuang has no disclosures.
Joseph Pergolizzi is a consultant/speaker, owner, or researcher for Spirify, US World Meds, Salix, Enalare, Scilex, Pfizer, Lilly, Teva, Taketa, Regeneron, Grünenthal, Neumentum, NativeCardio, BDSI, and Bridge Therapeutics.
\n',keywords:"CIED implant, device surgery, ICD implant, ICD implant, implant pain control, implantable cardioverter defibrillator, pacemaker",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/79644.pdf",chapterXML:"https://mts.intechopen.com/source/xml/79644.xml",downloadPdfUrl:"/chapter/pdf-download/79644",previewPdfUrl:"/chapter/pdf-preview/79644",totalDownloads:86,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:0,impactScoreQuartile:0,hasAltmetrics:0,dateSubmitted:"September 9th 2021",dateReviewed:"November 5th 2021",datePrePublished:"December 12th 2021",datePublished:null,dateFinished:"December 12th 2021",readingETA:"0",abstract:"Postoperative pain following cardiac implantable electronic device (CIED) surgery may not always be adequately treated. The postoperative pain trajectory occurs over several days following the procedure with tenderness and limited arm range of motion lasting for weeks after surgery. Pain control typically commences in the perioperative period while the patient is in the hospital and may continue after discharge; outpatients may be given a prescription and advice for their analgesic regimen. It is not unusual for CIED patients to be discharged a few hours after implantation. While opioids are known as an effective analgesic to manage acute postoperative pain, growing scrutiny on opioid use as well as their side effects and potential risks have limited their use. Opioids may be considered for appropriate patients for a short course of treatment of acute postoperative pain, but other analgesics may likewise be considered.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/79644",risUrl:"/chapter/ris/79644",book:{id:"10863",slug:null},signatures:"Peter Magnusson, Jo Ann LeQuang and Joseph V. Pergolizzi",authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Postoperative pain control",level:"1"},{id:"sec_2_2",title:"2.1 Risk factors for postoperative pain",level:"2"},{id:"sec_3_2",title:"2.2 Inpatient versus outpatient pain control",level:"2"},{id:"sec_4_2",title:"2.3 Subcutaneous ICDs",level:"2"},{id:"sec_5_2",title:"2.4 Device revision",level:"2"},{id:"sec_6_2",title:"2.5 Special populations",level:"2"},{id:"sec_6_3",title:"2.5.1 Pediatric",level:"3"},{id:"sec_7_3",title:"2.5.2 Women",level:"3"},{id:"sec_8_3",title:"2.5.3 Overweight",level:"3"},{id:"sec_9_3",title:"2.5.4 Racial/ethnic groups",level:"3"},{id:"sec_10_3",title:"2.5.5 Geriatric",level:"3"},{id:"sec_12_2",title:"2.6 Opioid considerations",level:"2"},{id:"sec_13_2",title:"2.7 Clinical strategies: Preoperative, perioperative, postoperative",level:"2"},{id:"sec_13_3",title:"2.7.1 Preoperative",level:"3"},{id:"sec_14_3",title:"2.7.2 Perioperative",level:"3"},{id:"sec_15_3",title:"Table 1.",level:"3"},{id:"sec_18",title:"3. 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Department of Caring Services, Faculty of Health and Occupational Studies, University of Gävle, Sweden
Centre for Research and Development, Uppsala University/Region Gävleborg, Sweden
Cardiology Research Unit, Department of Medicine, Solna, Karolinska Institutet, Sweden
'},{corresp:"yes",contributorFullName:"Jo Ann LeQuang",address:"joannlequang@gmail.com",affiliation:'
NEMA Research, Inc., United States of America
'},{corresp:null,contributorFullName:"Joseph V. Pergolizzi",address:null,affiliation:'
NEMA Research, Inc., United States of America
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1. Introduction
Fungal infections are considered a serious health problem, especially in people with weakened immune systems, and are a main cause of morbidity and mortality worldwide [1].
However, the impact of these “opportunistic” diseases on human health is not widely highlighted [2]. Due to this, research related to fungi occurs slowly compared to those caused by other pathogens.
Among the different mycotic infections, those caused by Candida and Cryptococcus are the most threatening due to severity of the disease and higher worldwide occurrence [3]. The pathogenicity of fungal infections proceeds in well-organized steps. For example, Candida cell surface adhesion factors first promote its adherence to host surface, followed by releasing of various hydrolytic enzymes and other virulence factors for invasion and damage of the host tissues [4].
Candida species can cause a variety of infections from the mildest to the most severe being candidemia the most frequent hospital infection accounting for up to 15% of bloodstream infections. Candida species are the main causative agents in 50–70% of systemic fungal infections [5].
Cryptococcus species are other yeasts of medical importance, with more than 39 species, among which Cryptococcus gattii and Cryptococcus neoformans are the most clinically relevant [6, 7, 8]. However, other species such as Cryptococcus albidus and Cryptococcus laurentii are emerging pathogens involved in several types of infections [6, 9, 10, 11].
These yeasts are present in several environmental niches, such as woody sites (decomposing tree trunks, mainly eucalyptus, and soil), vegetable remains, domestic dust, and bird excrement, more precisely in Columba livia [12, 13, 14]. The source of the infection is exogenous and occurs primarily by inhalation or by direct inoculation into the tissue after trauma of desiccated spores or yeasts. It is believed that the only source of infection is environmental, since there are no reports of transmission between animals and humans or between humans [15].
The main virulence factors of Cryptococcus species are growth capacity at 37°C, polysaccharide capsule, melanin synthesis, and production of urease and antioxidant enzymes, causing primary or opportunistic cryptococcosis, such as pulmonary, cutaneous, and meningitis diseases [6, 8, 13, 16, 17, 18, 19]. Cryptococcosis is the third opportunistic infection associated with AIDS [20].
In addition to delays in yeast diagnosis, there is currently a limited antifungal armamentarium in use against yeast diseases including only four chemical classes: polyenes, triazoles, echinocandins, and flucytosine. Antifungals act by binding specific components of fungal plasma membrane or its biosynthetic pathways or even cell wall components [21]. However, most of the antifungal agents used in the clinic is fungistatic and often led to the development of resistance by fungal species. Modern early antifungal treatment strategies, such as prophylaxis and empirical and preemptive therapy, result in long-term exposure to antifungal agents, which is a major driving force for the development of resistance.
Among the available antifungal agents, azoles are the preferred and most frequently used drugs for treatment of Candida and Cryptococcus infections. Fluconazole (FLZ), a type of azole, is often preferred in treatments of Candida infections because of its low cost and toxicity, in addition to availability in varied formulations [22]. However, there are many reports that described resistance development among Candida species, especially in relation to azoles.
Infectious Diseases Society of America recommends the treatment of cryptococcosis through FLZ and amphotericin B (AMB) with or without combination with 5-flucytosine (5-FC), followed by prolonged maintenance with fluconazole. Other azole compounds such as itraconazole (ITC), voriconazole, and posaconazole may be used as an alternative to FLZ in cases of contraindication or inefficacy of the latter [23, 24]. However, there has been a progressive increase in isolates of Cryptococcus spp. resistant to FLZ, which complicates the management of cryptococcal meningitis [25]. On the other hand, AMB and 5-FC are not available in all countries and are, respectively, nephrotoxic and hepatotoxic, limiting the anti-cryptococcal therapeutic [24].
Considering the limited availability of antifungals in use and the emergence of resistance, the control of Candida and Cryptococcus infections is a challenge in the modern clinic. In this way there is a continuous need for the search for new substances with new mechanisms of action with the aim of developing novel broad spectrum antifungal drugs with better efficacy.
In this way, plants stand out as the major producers of promising substances, the phytochemicals. Identification of new molecules with antifungal potential for the manufacture of new drugs, more effective and less toxic, is essential to facing the challenge. The use of phytochemicals alone or in combination with traditional drugs represents an important alternative to conventional therapy. The combination of drugs usually requires lower doses of antimicrobials. This reduction might lead to a toxicity decrease, which results in a higher tolerance to the antimicrobial by the patient.
2. Pathogenic yeast infections: a serious health problem
In the last two decades, fungal infections have shown a significant increment. In addition to the increase in the number of patients with compromised immune system, factors such as increasing number of patients using catheters, the use of broad-spectrum antibiotics, the rising number of patients requiring organ transplantations, as well as those with hematological malignancies and diabetes also contribute to this phenomenon [26, 27].
Even though fungal infections cause significant amount of human morbidity and mortality, the impact of these “opportunistic” diseases on human health is not widely highlighted [2]. Due to this, the research into the pathophysiology of human fungal infections is slow in comparison to other disease-causing pathogens. Recently, an editorial published in the journal Nature Microbiology [28] ratified the importance of not neglecting fungi. The call proposed a reflection on fungi and how these microorganisms have been neglected, even with studies already consolidated showing their medical relevance.
The most frequent fungal diseases affecting populations in the world are candidiasis [29, 30, 31, 32, 33, 34] and cryptococcosis [8, 20, 25]. There are several types of candidiasis as mucosal candidiasis, cutaneous candidiasis, onychomycosis, systemic candidiasis [35, 36], and pulmonary candidiasis. An important fact is that candidiasis is an infection that can affect both immunocompromised and healthy people [37, 38]. Candidemia is the most relevant and prevalent nosocomial fungal infection associated with a high mortality rate (up to 49%) in patients with a compromised immune system [39, 40]. The association of Candida with bloodstream infections depends on patient’s condition, age, and geographic region. Candidemia is such an important infection that in 10–40% of cases, it is associated with sepsis or septic shock [41].
Candida albicans continues to be the most prevalent species isolated from fungal infections [27, 42, 43, 44]. However, the prevalence of other Candida species has increase substantially. These species are C. parapsilosis, C. tropicalis, C. krusei, C. glabrata, C. guilliermondii, C. orthopsilosis, C. metapsilosis, C. famata, and C. lusitaniae [44, 45, 46].
Candida species presents high degree of flexibility, being able to grow in extremely different environments regarding to the availability of nutrients, temperature variation, pH, osmolarity, and amount of available oxygen [47]. This fact associated with the high resistance capacity of species to antifungals, their virulent features, and capability of forming biofilms with other species [48, 49] makes the genus Candida a serious risk to human health [50]. Thus, Candida species are highly adaptable and possess numerous strategies to survive in conditions that can affect their overgrowth and alter their susceptibility profiles.
Cryptococcus spp. may remain latent in the lungs, leading to asymptomatic infection, or may cause multifocal lung disease. The latency period of Cryptococcus can range from 6 weeks to more than 1 year after inhalation [51]. The fungus presents neurotrophism and can migrate to the central nervous system (CNS) through hematogenous dissemination and, when crossing the blood-brain barrier, can cause meningoencephalitis [13, 18]. Episodes of mental confusion in patients with cryptococcosis have been described [52, 53]. Neurocryptococcosis is the most severe form of the disease with high mortality rates in the absence of adequate treatment [18, 23]. The mortality due to cryptococcosis is higher than the mortality caused by tuberculosis and similar to that caused by malaria [54].
Another clinical manifestation is cutaneous cryptococcosis, which is rare and usually secondary to hematogenous dissemination. Cutaneous lesions are characterized by an infiltrative plaque of a solid tumor mass that can present ulcerative and necrotic lesion [17]. Pulmonary and cutaneous lesions due to nodular features may be misdiagnosed as tumor lesions [55]. In addition to the respiratory tract, CNS and skin, other sites may be affected: prostate, eyes, adrenal glands, lymph nodes, bone marrow, and liver [51].
Until now, there are three proposals to explain fungal neurotropism. The first is that neuronal substrates present in the basal ganglia promote cryptococcal growth and survival, and, thus, perivascular spaces may serve as a niche for Cryptococcus, as described by [56] in a healthy female patient who had evidence of Cryptococcus infection within the perivascular spaces of the parenchyma. The second proposal describes that it is possible that there are specific neuronal receptors that can attract Cryptococcus to the CNS [57]. The third hypothesis, one of the most widespread, is that the fungus uses neurotransmitters such as dopamine that aids in the synthesis of melanin [19, 57, 58].
Besides the clinical importance of fungal infections caused by theses pathogenic yeasts, interestingly, climatic abnormalities due to phenomena such as La Niña and El Niño have recently been described as important in the distribution and occurrence of mycoses in countries influenced by them [59].
3. Traditional antifungal agents against yeasts
In the last two decades, there has been an increasing, but limited, discovery of antifungal agents [47]. These include azoles, such as fluconazole, itraconazole, ketoconazole (KTC), miconazole, and clotrimazole, polyenes (amphotericin B [AMB] and nystatin), allylamines, thiocarbamates, morpholines, 5-fluorocytosine, and echinocandins (for instance, caspofungins) [21]. However, fungal cells and human cells are eukaryotic, so antifungal compounds target both cell types, resulting in considerable side effects in patients and fewer available targets for drug action. Antifungals target three cellular components of fungi (Figure 1). Azoles inhibit ergosterol biosynthesis by interfering with the enzyme lanosterol 14-α-demethylase in endoplasmic reticulum of the fungal cell. This enzyme is involved in the transformation of lanosterol into ergosterol, a component that is part of the plasma membrane structure of the fungus (Figures 1 and 2). Thus, as the concentration of ergosterol is reduced, the cell membrane structure is altered, thereby inhibiting fungal growth [60].
Figure 1.
Mechanisms of action of some traditional antifungal agents on cellular targets. Azoles inhibit the ergosterol synthesis in the endoplasmic reticulum of the fungal cell by interfering with the enzyme lanosterol 14-α-demethylase. Polyenes act by binding to ergosterol present at the cell membrane. Echinocandins inhibit (1,3) β-d-glucan synthase, thereby preventing glucan synthesis.
Figure 2.
Specific point of action of antifungal drugs in the ergosterol biosynthesis pathway.
Azoles comprise a five-member azole ring containing two (imidazole) or three nitrogen atoms (triazole) attached to a complex side chain [61, 62]. Imidazoles include KTC, miconazole, econazole, and clotrimazole, and triazoles include FLZ, ITC, voriconazole (synthetic triazole derivative of FLZ of second generation), and posaconazole (hydroxylated analog of itraconazole) [63].
AMB and nystatin bind to ergosterol causing the disruption of the membrane structure and promoting extravasation of intracellular constituents such as ions and sugars and, consequently, cell death [21] (Figure 1).
Pyrimidine analogs include 5-fluorocytosine and 5-fluorouracil (5FU). The first has fungistatic properties and enters the fungal cell through cytosine permease, inhibiting the thymidylate-synthetase enzyme and interfering with DNA. 5-fluorouracil, which in turn can be phosphorylated to 5-fluorodeoxyuridine monophosphate, can be incorporated into RNA molecules [63]. Due to toxicity [64]; stronger side effects, such as hepatic impairment; interference with bone marrow function; and rapid occurrence of resistance especially among Candida species, the clinical use of 5-FC is preferred in association with AMB [65, 66]. In addition, the nephrotoxicity and hepatotoxicity of AMB and 5-FC, respectively, and the unavailability of these antifungals in many countries have limited their use in cryptococcal therapeutic [24].
Host’s immunity, type of infection, site of origin of the samples, toxicity, bioavailability of the drug, and the sensitivity/resistance profile of the isolates interfere in the choice of the type of agent to be used [22]. AMB is considered the gold standard drug for most mycoses that affect patients at risk [67], although it has high toxicity. Azoles have fungistatic properties that affect cell growth and proliferation [65]. Among azoles, KTC was one of the firsts to emerge and was the first alternative to AMB [68]. Currently, FLZ is the drug of choice for most Candida and Cryptococcus infections [64] and is the most recommended antifungal agent for use in invasive candidiasis [47, 49].
For cryptococcosis, the choice of treatment depends on the patient’s immunological status and mainly on the clinical of the disease, if it is just a pulmonary manifestation or if the infection is systemic. Fluconazole is recommended in cases of lung disease with mild to moderate symptoms. Amphotericin B with or without combination with 5-flucytosine is the recommended therapy for more serious infections such as meningoencephalitis, followed by prolonged maintenance with fluconazole [23, 24].
Although azoles are generally well-tolerated, they have limitations such as hepatotoxicity and the emergence of resistance among fungal isolates [69] which provide motivation for improving this class of antifungal agents [68]. For instance, alterations in triazole molecule gave rise to voriconazole (structurally related to FLZ) and posaconazole (related to ITC), both available for systemic therapy [66].
Echinocandins, which include caspofungin, micafungin, and anidulafungin, are a new class of antifungals and have fungicidal effects in all Candida species [66]. They inhibit (1,3) β-d-glucan synthase, thereby preventing glucan synthesis, which is present in the cell membrane of fungi (Figure 1). As this drug acts on the wall structure of the fungus, it has the advantage of a lower side effect in animal cells [47].
Allylamines (terbinafine and naftifine) and thiocarbamates inhibit the enzyme squalene epoxidase, which participates in the synthesis of ergosterol and is encoded by the ERG1 gene (Figure 2). This activity leads to membrane rupture and accumulation of squalene. Allylamine effects can also prevent the production of other sterol derivatives.
To minimize toxicity and resistance, some pharmacological strategies were developed. The preparation and use of new antifungal formulas (liposomal AMB (Ambisome®), AMB lipid complexes (Abelcet®), AMB colloidal dispersions (Amphocil®/Amphotech®), and AMB lipid nanosphere formulations and β-cyclodextrin itraconazole) are one strategy [68]. Others include combination therapies of antifungal compounds (e.g., AMB + 5-FC, FLZ + 5-FC, AMB + FLZ, caspofungin + liposomal AMB, and caspofungin + FLZ) and nanostructuring of conventional antifungal agents [70, 71, 72, 73].
However, all traditional antimycotic drugs have at least one restriction related to their use. Some do not have a broad spectrum of action or are fungistatic. Others have high toxicity and low bioavailability with significant side effects [74]. Therefore, limitations of treatment and drug resistance associated with pathogenicity of the clinical isolates support the urgent need to identify substances that are more effective, with new mechanisms of action in the fight against Candida and Cryptococcus infections.
4. Resistance in pathogenic yeasts: a significant problem
Most antifungals target sterols or the enzymes that synthesize them. However, the fungistatic nature of many of these antifungals and emergence of clinical drug resistance limits their success. Increased drug resistance in fungi is a problem that cannot be avoided, particularly for FLZ, which is the preferred antifungal for treating yeast infections [75].
The number of people at risk for fungal infections has been increasing, resulting in an increased use of antifungal agents, even as prophylaxis. Thus, besides the existence of some non-albicans Candida (NAC) species presenting inherent resistance to azoles, higher minimum inhibitory concentrations (MICs) for antifungals against C. albicans strains have been observed [76]. The World Health Organization (2014) categorizes antimicrobial resistance as that developed by the microorganism to an antimicrobial drug, which was initially effective in treatment of such infections. Low-dose prophylactic administration of azole derivatives, such as FLZ, for prolonged periods to prevent the occurrence of opportunistic infections in immunosuppressed patients also results in resistant phenotypes [27, 75]. Therapeutic failures and empiric treatment are facts which are likely to collaborate to the increased incidence of fungal infections.
In the last decade, a number of new clinical problems have arisen, requiring new guidelines regarding the treatment of cryptococcosis, mainly because clinical data have suggested that cryptococcal strains have become more resistant to drugs [23, 25]. Some relates say that clinical Cryptococcus isolates are frequently less susceptible to fluconazole than environmental isolates. However, Chowdhary et al. [77] evaluated the susceptibility profile of environmental and clinical strains of C. gattii and observed that environmental samples were less susceptible to fluconazole, itraconazole, and voriconazole in comparison to clinical isolates.
Heteroresistance is also a worrying phenomenon. It consists of the ability of a subpopulation of microorganism to adapt to high concentrations of the drug, resulting in resistant homogenous populations. However, heteroresistant strains return to the initial phenotype when the stimulus with the drug is withdrawn [78].
Some mechanisms for cellular and molecular resistance to FLZ in yeasts are described. In Candida and Cryptococcus, the first is related to the induction of multidrug pumps, which decrease the concentration of drug available in the intracellular compartment of yeast cells. Various genes belonging to the ATP-binding cassette superfamily or to the major facilitator superfamily encode efflux pumps were identified in C. albicans. Overexpression of some transporter genes or of their regulated genes can confer cross-resistance to various azoles [21]. In C. gattii and C. neoformans, AFR1, MDR1, and AFR2 genes encode ABC transporters that expel the azole out of the fungal cell, thereby causing resistance to these drugs [79].
A second mechanism of resistance involves modification of the target enzyme encoded by the ERG11 gene, also known as cytochrome P450 lanosterol 14-α-demethylase (Cyp51). Mutations in this gene prevent azoles from binding to enzyme sites. Another mechanism of resistance is related to mutations in the ERG3 gene which does not convert 14-α-methylfecosterol into 14-α-methyl-3,6-diol in the ergosterol synthesis pathway. This substitution causes azoles to have no fungistatic effects on the fungal cell membrane [21].
Transcriptional regulation is also important for the development of resistance mechanisms. YAP1, a protein, is important for the mechanism of C. neoformans heteroresistance to fluconazole and oxidative stress. Mutant strains of C. neoformans that lost protein YAP1 became hypersensitive to a variety of oxidizing agents and mainly to fluconazole [80].
Resistance to polyenes (AMB) in fungus is less common and in C. albicans is associated with the substitution of ergosterol with a precursor molecule or a general reduction of sterols in the plasma membrane [81]. Reduction of membrane ergosterol renders Cryptococcus neoformans and Aspergillus spp. less susceptible to amphotericin B [82]. Enzymes encoded by ERG3 and ERG2 genes participate in ergosterol biosynthesis and have the main alterations related to AMB resistance because mutations in their genes modify ergosterol content required for the action of polyenes [83].
The main resistance mechanism to echinocandins is related with point mutations in gene that encodes the major subunit of the glucan synthase enzyme (Fks subunit) (Figure 1) and can provide resistance to all echinocandin [84]. Other Candida species also present this resistance mechanism such as C. tropicalis, C. parapsilosis, C. glabrata, C. krusei, C. guilliermondii, and C. dubliniensis [85, 86].
Resistance to 5-FC can be of two types: primary, occurring via cytosine permease (encoded by the FCY2 gene) whose mutation decreases drug uptake [87], and secondary, related to alterations in cytosine deaminase (encoded by FCY1) or uracil phosphoribosyltransferase (encoded by FUR1) activities. Cytosine permease is responsible by conversion of 5-FC to 5-fluorouridine or to 5-fluorouridine monophosphate (5-FUMP) [88]. Resistance is easily developed in fungal isolates from patients who are receiving the drug. However, other molecular mechanisms related to resistance to 5-FC must exist because most of them have not been observed in C. albicans [89].
The increase in the drug-resistant Candida and Cryptococcus strains to commercial antifungals has caught the attention of clinicians and researchers to medicinal plant products (commonly referred as phytochemicals). The use of phytochemicals with greater antifungal potential and different mechanisms of action may be useful in reducing the phenomenon of resistance. Lately, they have become a significant alternative for discovery of commercially viable, economically cheaper, and safe phytomedicines.
5. Medicinal plants as a source of antifungal agents
Global Action Fund for Fungal Infections (GAFFI), an international organization working to reduce infections and deaths associated with fungi, has reported that approximately 300 million people in the world suffer from a serious fungal infection every year and that among them over 1.35 million deaths are registered [90].
Despite the introduction of new and novel antifungal drugs, their production and impact are slow, and the development of antifungal resistance has forced the attention of researchers toward herbal products, mainly phytochemicals, in search of development of safe and economically viable antifungals.
Populations around the world have used folk medicine as an alternative therapy for various disorders. Currently, many species have been extensively studied in an attempt to discover new biologically active compounds with novel structures and mechanism of action for the development of new drugs.
Medicinal plants are commonly preferred because of their wide level of functional chemical groups with comparatively poor toxic substances, low-cost extracts, fewer side effects, and easy accessibility to people. Various bioactive compounds have been abundantly found such as phytochemicals.
Leaves, as well as the seeds and fruits of plants, have higher levels of phenolic compounds. The concentration of these compounds also depends on the nature of the chemical used as solvent in the extraction process as well as on the growth and storage conditions [91].
The biological activity of plant products has been evaluated against fungi. The ethanol extract, Lonicera japonica aerial parts, a medicinal plant of folk medicine of China that used to treat some diseases, showed a very strong antimicrobial activity against Candida species and potent wound healing capacity [92]. Methanolic extract of Lannea welwitschii leaves was antimicrobial against clinical yeasts. A preliminary phytochemical screening of extracts revealed tannins, flavonoids, alkaloids, and glycosides as compounds [93]. Pyrostegia venusta crude flower extracts, fractions, and pure compounds showed an effective broad spectrum antifungal activity [94].
An extract of Piper betle leaves inhibited the growth of Candida species [95], and four different extracts of Strychnos spinosa showed anti-Candida activity [96]. Hydro-methanolic extracts of leaves from Juglans regia and Eucalyptus globulus and methanol extract of Cynomorium coccineum demonstrated excellent antimycotic property against Candida strains [91, 97]. Akroum [98] showed antifungal activity in an acetylic extract of Vicia faba against C. albicans in vitro and reduced mortality rates in Candida-infected mice that were treated with the extract.
Berberine, a protoberberine-type isoquinoline alkaloid isolated from the roots, rhizomes, and stem bark of natural herbs, such as Berberis aquifolium, Berberis vulgaris, Berberis aristata, Hydrastis canadensis, Phellodendron amurense, Coptis chinensis, and Tinospora cordifolia, was described as powerful reducer of the viability of in vitro biofilms formed by fluconazole-resistant Candida tropicalis cells [99].
Ethanolic and aqueous extracts from different plants from Brazilian Cerrado commonly used in folk medicine such as Eugenia dysenterica and Pouteria ramiflora were promising against C. tropicalis, C. famata, C. krusei, C. guilliermondii, and C. parapsilosis. A phytochemical screening of active extracts from these plants disclosed as main components flavonoids and catechins [100]. Crude extract and fractions (n-butanolic and ethyl acetate ones) from Terminalia catappa leaves showed antifungal properties against Candida spp.; hydrolysable tannins (punicalin, punicalagin), gallic acid (GA), and flavonoid C-glycosides were the active components found in butanolic fraction [101].
Bottari et al. [102] determined the antimicrobial activity of the aqueous and ethanolic leaf extracts of Carya illinoensis. Both extracts had MIC values against seven Candida reference strains between 25 and 6.25 mg/mL. Phenolic acids (gallic acid and ellagic acid), flavonoids (rutin), and tannins (catechins and epicatechins) were likely responsible, in part, for the activity against Candida strains. Further, the extracts inhibited the production of C. albicans germ tubes.
5.1 Phytochemicals: polyphenols as substances most found in plants
Several woody plant produce medicinal phytochemicals such as polyphenols that are low molecular weight naturally occurring organic compounds containing one or more phenolic groups [103]. Further, polyphenols perform various substantial functions in plant physiology and, therefore, can be found, in lesser or greater quantity, in all of them.
Phenolic acids, flavonoids, tannins, and coumarins are some examples of phenolic compounds found in and extracted from medicinal plants [104] (Table 1). Research has shown that polyphenols have potentially healthy effects in humans, working primarily as anticancer, antihypertensive, anti-allergen, anti-inflammatory, antioxidant, and antimicrobial agents. The antimicrobial activity of polyphenols has been extensively investigated mainly against bacteria [104]. Nevertheless, the antifungal activity of most of the phenolic compounds remains unknown. There are few studies on the mechanism of action of the substance, cytotoxicity, the synergism with traditional antifungals drugs, and their anti-virulence activities.
Phytochemicals
Bioactive compounds
Properties
Plant sources
Flavonoids
Flavan-3-ol
Against Candida
Syzygium cordatum
Baicalein, gallotannin
Against Candida
Scutellaria baicalensis
Coumarins
Ulopterol
Against M. canis
Skimmia laureola
Prenyletin; prenyletin-methyl-ether
Against T. rubrum; T mentagrophytes
—
Osthenol
C. albicans, Fusarium solani, A. fumigatus
—
5,8-Dihydroxyumbelliprenin
T. interdigitale, M. gypseum
Ferula foetida
Saponins
Colchiside
Phytopathogenic fungi
Dipsacus asper roots
Terpenes or terpenoids
Triterpenes
Against dermatophytes
Ethyl acetate leaf extract of Satureja khuzestanica
Lectins
Lectins
Fusarium oxysporum
Seed from native Amazon species
Tannins
Punicalagin Punicalin
Against Candida spp.
Terminalia catappa
Punicalagin
T. mentagrophytes; T. rubrum; M. canis; M. gypseum
C. albicans, Cryptococcus neoformans, Aspergillus fumigatus
Punica granatum
Lambertianin C, sanguiin H-6
Geotrichum candidum
Rubus idaeus
Table 1.
Phytochemicals with antifungal compounds derived from plants.
Those with the most promising antifungal activity isolated from natural sources include flavonoids, tannins, coumarins, quinones, lignans, and neolignans [105] (Table 1).
Flavan-3-ols, flavonols, and tannins have received the most attention among the known polyphenols, attributable to their large spectrum of efficacy and high antimicrobial property. Structurally, flavonoids are aromatic compounds with 15 carbon atoms (C15) on their basic skeleton; they consist in tricyclic phenolic compounds with two aromatic rings on their structure (C6–C3–C6) [105]. Flavonoids are a class of natural compounds with several known protective activities, including antifungal activity. The flavonoids include subclasses such as chalcones, flavones, isoflavones, flavonols, flavanols (flavan-3-ol), and anthocyanidins [106].
The activity of flavonols such as quercetin, myricetin, and kaempferol has been described in C. albicans. For instance, quercetin, myricetin, and kaempferol from propolis have showed activity against Candida species [107]. The flavanol subclass (flavan-3-ol) and gallotannin, extracted from Syzygium cordatum, also showed inhibitory properties on the growth of C. albicans [108]. Serpa et al. [109] isolated baicalein, belonging to a subclass of flavones, from Scutellaria baicalensis, and induced apoptosis in C. albicans (Table 1), and apigenin, a flavone isolated from propolis, showed antifungal potential. Flavonoids as much as coumarins and lignans have shown an antifungal potential against several species of dermatophytes [105].
Other important groups of polyphenolic compounds present in various plant parts, such as the roots, flowers, leaves, fruits, and seeds, are tannins. They are divided into hydrolyzable (ellagitannins) and condensed tannins (proanthocyanidins) and gallotannins [110]. They have the ability to precipitate macromolecules such as proteins [111] as well as have antimicrobial properties. However, the mechanisms underlying the antimicrobial action of tannins in different microorganisms are still under investigation [111].
Ellagitannins constitute a complex class of polyphenols characterized by one or more hexahydroxydiphenoyl (HHDP) which can be linked in various ways to the glucose molecule [112]. Ellagic acid, gallagic acid, punicalins, and punicalagins isolated from ethyl acetate and butanolic fractions of Punica granatum revealed antifungal activity against C. albicans, Cryptococcus neoformans, and Aspergillus fumigatus [113] (Table 1).
Ellagitannins isolated from Ocotea odorifera, a plant commonly used in Brazil in folk medicine, have a potential against C. parapsilosis [114]. Two ellagitannins isolated from raspberry (Rubus idaeus L.) fruit, lambertianin C and sanguiin H-6, showed fungistatic activity both in vitro and in situ against Geotrichum candidum [115]. Dos Santos et al. [111] verified that encapsulated tannins from Acacia mearnsii have moderate activity against Aspergillus niger (ATCC 9642) and C. albicans (ATCC 34147).
Coumarins have a C6-C3 skeleton, possessing an oxygen heterocycle as part of the C3 unit [105]. These compounds are known to play a role in disease and pest resistance, as well as UV tolerance. The antifungal activity of 40 coumarins was tested against reference strains of Candida albicans, Aspergillus fumigatus, and Fusarium solani, but among them only osthenol showed the most effective antifungal activity (Table 1). The authors argue that the action of osthenol can be related to the presence of an alkyl group at C-8 position [116].
Another coumarin derivative, 4-acetetatecoumarin, was effective in inhibiting Aspergillus spp., acting on the factors of virulence and affecting the structure of the fungal wall. Diversinin, a coumarin isolated from the petroleum ether extract of Baccharis darwinii, demonstrated antifungal activity against T. rubrum, T. mentagrophytes, and M. gypseum, being fungicidal. Another coumarin derivative, 5,8-dihydroxyumbelliprenin, isolated from Ferula foetida, was active against M. gypseum and Trichophyton interdigitale [105] (Table 1).
Phenylpropanoids are other naturally occurring compounds categorized as coumarins, phenylpropanoic acid, and lignans frequently studied for their anti-Candida properties [117]. Navarro-Garcia et al. [118] and Raut et al. [119] found that a coumarin (scopoletin) and two phenylpropanoic acids (salicylaldehyde and anisyl alcohol) have antifungal property against C. albicans, with MICs of 25, 31, and 31 μg/mL, respectively.
Shahzad et al. [103] observed the effectiveness of pyrogallol and curcumin (CUR) against various C. albicans clinical isolates. In addition, curcumin inhibited the adhesion capability of cells and demonstrated anti-biofilm activity. Curcumin is a flavonoid found in turmeric (Curcuma longa L.). Pure curcumin had potential activity against Cryptococcus gattii both in vitro and in vivo [120]. According to Ferreira et al. [121], the essential oil from Curcuma longa L. can reduce the colony diameter, germination, and sporulation of Aspergillus flavus.
Alalwan et al. [122] undertook a series of adsorption experiments with varying concentrations of curcumin and showed that 50 μg/mL could prevent adhesion of C. albicans SC5314 to denture materials. Curcumin-silver nanoparticles also showed potential anticandidal activity against fluconazole-resistant Candida species isolated from HIV patients with MIC range of 31.2–250 μg/mL [123].
Gallic acid is a polyphenol natural compound found in many medicinal plant species that has been shown to have anti-inflammatory and antibacterial properties. GA was found to have a broad spectrum of antifungal activity against dermatophyte and Candida strains. Authors verified that GA reduced the activity of sterol 14-α-demethylase P450 (CYP51) and squalene epoxidase in the T. rubrum membrane.
Teodoro et al. [124] demonstrated that acetone fraction from Buchenavia tomentosa aqueous extract and its major compound gallic acid had the ability to inhibit reference strains C. albicans ATCC 18804 and Candida albicans SC 5314 adherence and to disrupt 48 h-biofilm.
5.2 Essential oils as potential antifungal
In the eagerness to research and develop new substances to suppress the development of pathogenic fungi from natural plant substances, knowledge about the biological activities of essential oils has been growing. Essential oils’ pharmacological activities, mainly related to their complex chemical composition and high concentrations of phenols, make these compounds particularly interesting for both the treatment and the prevention of fungal infections. Natural phenolic substances are among the most antifungal active substances present in essential oils, generally showing low toxic effects in animals [125]. They consist in a complex mixture of monoterpene and sesquiterpene hydrocarbons and oxygenated derivatives such as alcohols, aldehydes, ketones, and phenylpropanoids.
Essential oils are also called volatile oils or ethereal oils, as they have a high degree of evaporation when exposed to air. The presence of terpenes contributes to the complex constitution with the action against microorganisms being directly related to this characteristic [126]. Since ancient times, Mondello et al. [127] proposed that tea tree oil could be used in antifungal therapy, because it showed efficacy against multidrug-resistant Candida species in vitro and against mucosal candidiasis in vivo; they have also showed that terpinen-4-ol was the main substance presented in the oil which contribute to the anticandidal activity.
Several oils have demonstrated activity against Candida species. Sharifzadeh et al. [128] observed that essential oils from Trachyspermum ammi have anticandidal effects against isolates resistant to FLZ. Herbal essences from Foeniculum vulgare, Satureja hortensis, C. cyminum, and Zataria multiflora were tested against C. albicans. Essential oils from Z. multiflora showed the best anticandidal activity [129].
Carica papaya essential oils have inhibitory effects against Candida species, detected by agar diffusion and microdilution assays [130]. Minooeianhaghighi et al. [131] verified that a combination of essential oils from Cuminum cyminum and Lavandula binaludensis showed growth inhibition of C. albicans isolates, at very low concentrations (between 3.90 and 11.71 μg/mL). Essential oils from Cymbopogon nardus have also shown antimicrobial potential against Candida species, with inhibition of hyphal growth in C. albicans at concentrations between 15.8 and 1000 μg/mL. This oil also inhibited growth of filamentous fungus from the environment. Main compounds of C. nardus essential oil were the oxygen-containing monoterpenes: citronellal, geranial, geraniol, citronellol, and neral [126]. In addition to inhibiting biofilm formation [132], essential oils from Artemisia judaica have been shown to inhibit the formation of germination tubes in C. albicans and have shown that at a very low concentration (0.16 μL/mL), it inhibited 80% of Candida filamentation. Kose et al. [133] demonstrated the fungicidal potential of essential oils from Centaurea baseri against Candida species, with an MIC of 60 μg/mL.
Among the monoterpenes there is thymol (2-isopropyl-5-methylphenol) [134]. It is the most abundant constituent in essential oils from Thymus vulgaris (thyme) [135] and the major component of essential oils from Origanum vulgare (oregano) [136]. Thymol showed antifungal activity, fungistatic and fungicidal one, against Candida strains. Authors verified an MIC of 39 μg/mL against C. albicans and C. krusei and MIC of 78 μg/mL against C. tropicalis. Probably thymol acts by binding to ergosterol in the plasma membrane, thereby increasing ion permeability and resulting in cell death because an eightfold increase (from 39.0 to 312.5 μg/mL) in thymol MIC values against C. albicans was seen in the presence of exogenous ergosterol. A combination of thymol and nystatin resulted in synergy [137].
Terpenoids have shown synergistic effects with FLZ, so it may be useful as a candidate antifungal chemotherapeutic agent. In addition, terpenoids exhibit a very good antimycotic activity of filamentous-form growth of C. albicans at nontoxic concentrations [138]. Further, in experiments realized by [139], rubiarbonol G, a triterpenoid from Rubia yunnanensis, showed potent antimicrobial activity against C. albicans, with an MIC of 10.5 μg/mL.
The antifungal potential of terpenes, geraniol, and citronellol has been investigated previously, with effective inhibitory activity against C. albicans [138] and filamentous fungi of the Aspergillus species [140]. In addition, Mesa-Arango et al. [67] showed that oxygenated monoterpenes in the citral chemotype, such as geraniol, citral, and citronellal, have antifungal activity against C. parapsilosis, C. krusei, Aspergillus flavus, and Aspergillus fumigatus.
Terpenes’ anti-biofilm activity and the efficacy of thymol, geraniol, and carvacrol in the treatment of Candida infections associated with the use of hospital devices have been related [141]. Effects of carvacrol on Candida cells can be associated with alterations in the cytoplasmic membrane and induction of apoptosis [108].
Although the process of discovering bioactive molecules is complex and time-consuming, involving isolation, identification, and optimization of pharmacokinetic and pharmacodynamic properties, as well as the selection of lead compounds for further drug development, data related here showed that plants are a promising source of active molecules with antifungal properties. Biological assays have shown that plant extracts or essential oils and their bioactivity molecules inhibit ATCC and clinical strains of fungi species, including those with resistance to drugs employed in medical practice. In addition, some are able to inhibit and control the main virulence factors of fungi species, such as the formation and proliferation of hyphae and filamentation and, more importantly, the eradication of mature biofilms.
Eugenol (4-allyl-2-methoxyphenol) is a phenolic compound and the main constituent of the essential oil isolated from the Eugenia caryophyllata. There are reports of some pharmacological effects of eugenol, such as antifungal and antibacterial agent, and its anti-Candida action seems to be related to the generation of oxidative stress concomitantly with lipid peroxidation of the cell membrane of Candida albicans yeast and the generation of reactive oxygen species [142]. Eugenol also showed antifungal effects against both Cryptococcus gattii and C. neoformans cells by causing morphological alterations, changes of cellular superficial charges, and oxidative stress. Thymol and carvacrol can represent alternative, efficient, and cost effective drugs for anti-biofilm therapy for Cryptococcus species.
Eugenol showed activity against Alternaria spp. and P. chrysogenum, by agar diffusion method [143] and, along with other monoterpenes such as carvacrol and isoeugenol, exhibited strong antifungal activity against Rhizopus stolonifer and Absidia coerulea [144].
5.3 Synergistic action between phytochemicals and antifungals
Resistance mechanisms are developed by fungi to the treatment with conventional drugs in addition to toxic side effects to human cells showed by these drugs; researchers’ efforts in developing new strategies to improve treatment effectiveness of fungal infection are growing, with an interest in plants and folklore medicine.
The knowledge about synergistic effects of plant extracts or their compounds with traditional agents is nowadays a type of study that has aroused interest. Some in vitro screening assays have evidenced that plant extracts are less toxic than existing antifungal agents and, in combination with them, could reduce toxicity and increase antifungal potential [21, 145].
Accordingly, combination antifungal therapy offers the possibility of broadening the spectrum of drug activity, reducing toxicity, and decreasing fungal resistance [146].
Although combination of medications requires a careful evaluation of the synergistic, antagonistic, and agonist properties of the drugs involved [147], the use of drug combinations in treatment of infections by fungi is a common preferred strategy clinically. In many cases of fungal infection, combination therapy has been used successfully [21]. For some examples, see Table 2.
Combination of antifungals
Target
References
AMP B + posaconazole AMP B + caspofungin AMP B + fluconazole
Candida biofilms Candida biofilms Cryptococcosis in murine model
Various regimes of combinatorial antifungal therapy showing better efficacy in combination than that of independent drugs (adapted from [21]).
AMP B: amphotericin B.
There are two main hypotheses about the type of interaction resulting from the combination of fluconazole and amphotericin B, based on the mechanisms of action of these drugs. In the theory of depletion, the interaction between fluconazole and amphotericin B would result in antagonism due to pre-exposure to fluconazole, which would lead to depletion of the membrane ergosterol, and thus there would be a decrease in the available sites for amphotericin B. In the second theory, the synergism, amphotericin B would lead to the formation of pores, which would facilitate the greater access of azole to the intracellular space, which by inhibiting the enzymes involved in ergosterol biosynthesis would increase the antimicrobial efficacy. According to these theories, the combination of fluconazole and amphotericin B could involve different interactions [160, 161, 162].
Considering the difficulties regarding to the treatment of candidiasis and cryptococcosis, the combination of antifungals represents an important alternative to conventional therapy. The synergistic effects of drugs are primarily attributable to cell wall damage by one antifungal. Thus, this component potentiates the activity of other drugs exactly against some constituent of plasma membrane. Alternatively, compromised cell wall with an increased permeability could facilitate movement of drugs across the cell membrane to their targets. Or, the synergistic action of different drugs occurs because they act on different targets of the same pathway, which can happen, for example, with the combination of azoles and allylamines.
The objective of this strategy is to maximize the antifungal effects. Tangarife-Castaño et al. [163] reported synergy between essential oils or plant extracts associated with antifungal drugs when used as anti-C. albicans agents. The best synergistic effects were obtained from the combination between itraconazole and P. bredemeyeri extract against C. albicans.
Synergistic potential was observed when methanolic extract of T. catappa leaves was combined with nystatin or AMB against reference strains of C. albicans, Candida neoformans, C. glabrata, Candida apicola, and Trichosporon beigelii [164]. The combination showed maximum synergy against C. apicola.
Santos et al. [165] related synergistic antifungal activity of an ethanol extract of Hyptis martiusii in combination with metronidazole against C. albicans, C. krusei, and C. tropicalis. Avijgan et al. [166] reported a potent synergistic effect between an Echinophora platyloba ethanolic extract and itraconazole or FLZ against isolates of C. albicans from vaginal secretions of patients with recurrent vulvovaginitis, significantly lowering the concentrations of both substances.
A combination between thymol and nystatin was found to have synergistic effects against Candida species [137], reducing the MICs of both products by 87.4%. Synergism was observed between a water insoluble fraction from U. tomentosa bark and terbinafine, as well as between it and FLZ against seven resistant isolates of C. glabrata and C. krusei [167]. Synergistic effects led to cell damage, and authors demonstrated, through differential scanning calorimetry and infrared analysis, that intermolecular interactions between the extract components and either terbinafine or FLZ occurring outside the cell wall are likely responsible for synergistic effects observed between substances.
Subfraction combinations of Terminalia catappa, Terminalia mantaly, and Monodora tenuifolia showed synergistic interactions against C. albicans, C. glabrata, C. parapsilosis, and C. neoformans isolates. Synergistic combination between M. tenuifolia and T. mantaly subfractions also showed fungicidal effects against most tested strains [168].
The combination therapy with curcumin and fluconazole was the most effective among the treatments tested against Cryptococcus gattii. The association was able to reduce the fungal burden and damage on lung tissues of infected mice and to eliminate the fungal burden in the brain, enhancing the survival of mice with C. gattii-induced cryptococcosis [120].
Methanolic extract of Buchenavia tetraphylla is a great source of antimicrobial compounds and enhanced the action of FLZ against different C. albicans isolates from vaginal secretions as well as azole-resistant isolates. The extract increased the action of FLZ in most strains through additive (20% of strains) or synergistic (60% of strains) effects [169].
Kumari et al. [170] investigated the effect of six essential oil compounds sourced from oregano oil (carvacrol), cinnamon oil (cinnamaldehyde), lemongrass oil (citral), clove oil (eugenol), peppermint oil (menthol), and thyme oil (thymol) against three infectious forms: planktonic cells, biofilm formation, and preformed biofilm of C. neoformans and C. laurentii. The anti-biofilm activity of the tested compounds was in the order thymol > carvacrol > citral > eugenol = cinnamaldehyde > menthol. The three most potent compounds thymol, carvacrol, and citral showed best anti-biofilm activity at a much lower concentration against C. laurentii. In the presence of these potent compounds, assays revealed the absence of extracellular polymeric matrix, reduction in cellular density, and alteration in the surface morphology of biofilm cells. In addition they were the most efficient in terms of human safety in keratinocyte-Cryptococcus spp. co-culture infection model suggesting that thymol, carvacrol, and citral can be further exploited as cost-effective and nontoxic anti-cryptococcal drugs.
The lectin pCramoll from Cratylia mollis, a native forage plant endemic to the semiarid region of Brazil (caatinga biome), showed an immunomodulatory effect and a synergism in combination with fluconazole, increasing the survival of animals with cryptococcosis caused by C. gattii and improving aspects of morbidity present in the progression of cryptococcosis [171].
Thymol exhibited synergistic effects when combined with fluconazole against clinical species of Candida, enhancing the antifungal potential of the drug and decreasing the concentration required for the effect [172]. Zaidi et al. [173] found that methanolic extract of leaves of Ocimum sanctum in combination with fluconazole showed higher antifungal potential and synergistic activity against resistant Candida spp. than methanolic extract or fluconazole when used alone.
Essential oils were also recently proposed to increase drug effectiveness. Lavandula and Rosmarinus essential oils were selected as antiproliferative agents to compound lipid nanoparticles for clotrimazole delivery in treatment of Candida skin infections. Authors confirmed the potential anti-Candida activity of the selected oils due to their interaction with membrane permeabilization. In addition, in vitro studies against Candida albicans, Candida krusei, and Candida parapsilosis showed an increase of the antifungal activity of clotrimazole-loaded nanoparticles prepared with Lavandula or Rosmarinus, thus confirming that nanostructured lipid carriers (NLC) containing these essential oils represent a promising strategy to improve drug effectiveness against topical candidiasis [174].
A novel therapeutic strategy that has been adopted is photodynamic therapy (PDT). It is based on the interaction between a nontoxic photosensitizer and a safe source of visible light at a low intensity; the combination of these two factors in the presence of oxygen leads to the development of reactive oxygen species (ROS) which are toxic and cause oxidative damage to microorganism cells [175]. Curcumin associated with LED light was an efficient strategy against biofilms of C. dubliniensis isolates [176]. The uptake of CUR by yeast cells and its penetration through the biofilm were accompanied by confocal laser scanning microscopy. Daliri et al. [177] have assessed the effect of curcumin- and methyl blue-mediated PDT in combination with different laser exposure parameters on C. albicans colonies. They verified that the 460-nm laser in combination with CUR has the maximum antifungal efficiency against C. albicans.
Although we have described herein many in vitro studies examining synergistic effects among potential antifungal biomolecules and traditional antifungal agents, the mechanisms underlying these synergistic effects are poorly understood. Randomized and controlled analyses have been performed with the objective of verifying the efficacy and risks of using traditional antifungal combinations; however, the results are poor and contradictory. High cost to conduct these strategies, reduced number of clinical cases, and the existence of confusing variables are factors that contribute to the obtaining of vague and non-reproducible results.
Therefore, it is extremely relevant to examine carefully possible synergism between new phytocompounds and conventional antimycotic drugs in order to obtain more insight. Understanding the cellular action of each substance in the combination process is also a key step in inferring ways to employ strategy in the clinic. A lack of consensus in the medical clinic emphasizes the need to conduct further clinical trials using combinations of antifungals. The experiments and results addressed herein support further investigation of new plant constituents with antifungal properties and the efficacy of combination therapies involving phytocomponents and traditional antifungal agents as an important start for the development of unusual and original antifungal therapies.
6. Conclusions
The increase in Candida and Cryptococcus infections is alarming leading to high rates of morbidity and mortality worldwide. Concomitantly with the increase in fungal infections, species emerged, and the resistance phenomenon increased so that the available antifungal arsenal becomes irrelevant in the face of the problem. In addition, there are limitations manifested by some antifungal agents such as fungistatic character, severe toxicity, and renal dysfunction. Therefore, it is crucial to develop new drugs as alternative therapies that are potentially active against Cryptococcus and Candida. Plants are considered abundant and safe sources of phytochemicals endowed with many biological activities. Several polyphenols have been isolated and studied in relation to their anti-yeast and anti-virulence activities and may be useful in obtaining promising, efficient, and cost-effective drugs for the inhibition of Candida and Cryptococcus infections. Many phytosubstances are extremely effective in combination therapy with traditional or other phytochemicals, which can be further exploited to lead to novel drug therapies against recalcitrant infections.
Acknowledgments
Authors thank Ceuma University for their contribution to the work.
Conflict of interest
The authors declare no competing interests.
\n',keywords:"medicinal plants, yeast infections, antifungal agents, antifungal activity, phytochemicals",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67874.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67874.xml",downloadPdfUrl:"/chapter/pdf-download/67874",previewPdfUrl:"/chapter/pdf-preview/67874",totalDownloads:1268,totalViews:0,totalCrossrefCites:4,dateSubmitted:"March 14th 2019",dateReviewed:"June 5th 2019",datePrePublished:"July 2nd 2019",datePublished:"February 12th 2020",dateFinished:"June 26th 2019",readingETA:"0",abstract:"The rate of fungal infections is increasing rapidly, and pathogenesis of their species is poorly understood. Among fungi, Candida species are a major cause of morbidity and mortality worldwide and thus represent a serious threat to public health. In addition, Cryptococcus spp. are yeasts responsible for serious lung infections and meningitis. Polyenes, fluoropyrimidines, echinocandins, and azoles are used as commercial antifungal agents to treat fungal infections. However, the presence of intrinsic and developed resistance against azole antifungals has been extensively documented. The re-emergence of classical fungal diseases has occurred because of the increment of the antifungal resistance phenomenon. In this way, the development of new satisfactory therapy for fungal diseases persists as a major challenge of present-day medicine. The urgent need includes the development of alternative drugs that are more efficient and tolerant than those traditional already in use. The identification of new substances with potential antifungal effect at low concentrations or in combination is also a possibility. This chapter briefly examines the infections caused by Candida and Cryptococcus species and focuses on describing some of the promising alternative molecules and/or substances that could be used as antifungal agents, their mechanisms of action, and their use in combination with traditional drugs.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67874",risUrl:"/chapter/ris/67874",signatures:"Cristina de Andrade Monteiro and Julliana Ribeiro Alves dos Santos",book:{id:"8077",type:"book",title:"Phytochemicals in Human Health",subtitle:null,fullTitle:"Phytochemicals in Human Health",slug:"phytochemicals-in-human-health",publishedDate:"February 12th 2020",bookSignature:"Venketeshwer Rao, Dennis Mans and Leticia Rao",coverURL:"https://cdn.intechopen.com/books/images_new/8077.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78985-588-3",printIsbn:"978-1-78985-587-6",pdfIsbn:"978-1-83968-413-5",isAvailableForWebshopOrdering:!0,editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",middleName:null,surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Pathogenic yeast infections: a serious health problem",level:"1"},{id:"sec_3",title:"3. Traditional antifungal agents against yeasts",level:"1"},{id:"sec_4",title:"4. Resistance in pathogenic yeasts: a significant problem",level:"1"},{id:"sec_5",title:"5. Medicinal plants as a source of antifungal agents",level:"1"},{id:"sec_5_2",title:"5.1 Phytochemicals: polyphenols as substances most found in plants",level:"2"},{id:"sec_6_2",title:"5.2 Essential oils as potential antifungal",level:"2"},{id:"sec_7_2",title:"5.3 Synergistic action between phytochemicals and antifungals",level:"2"},{id:"sec_9",title:"6. Conclusions",level:"1"},{id:"sec_10",title:"Acknowledgments",level:"1"},{id:"sec_13",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Vallabhaneni S, Chiller TM. Fungal infections and new biologic therapies. Current Rheumatology Reports. 2016;18:29. 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Molecules. 2016;21:908. DOI: 10.3390/molecules21070908'},{id:"B116",body:'Montagner C, Souza SM, Groposoa C, Monacheb FD, Smaniaa EFA, Smania A Jr. Antifungal activity of coumarins. Zeitschrift für Naturforschung. 2008;63:21-28. DOI: 10.1515/znc-2008-1-205'},{id:"B117",body:'Lu M, Li T, Wan J, Li X, Yuan L, Sun S. Antifungal effects of phytocompounds on Candida species alone and in combination with fluconazole. International Journal of Antimicrobial Agents. 2017;49(2):125-136. DOI: 10.1016/j.ijantimicag.2016.10.021'},{id:"B118",body:'Navarro-García VM, Rojas G, Avilés M, Fuentes M, Zepeda G. In vitro antifungal activity of coumarin extracted from Loeselia mexicana Brand. Mycoses. 2011;54(5):e569-e571. DOI: 10.1111/j.1439-0507.2010.01993.x'},{id:"B119",body:'Raut JS, Shinde RB, Chauhan NM, Karuppayil SM. Phenylpropanoids of plant origin as inhibitors of biofilm formation by Candida albicans. Journal of Microbiology and Biotechnology. 2014;24(9):1216-1225. 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Antifungal activity of curcumin-silver nanoparticles against fluconazole-resistant clinical isolates of Candida species. Ayu. 2019;39(3):182-186. DOI: 10.4103/ayu.AYU_24_18'},{id:"B124",body:'Teodoro GR, Gontijo AVL, Salvador MJ, Tanaka MH, Brighenti FL, Delbem ACB, et al. Effects of acetone fraction from Buchenavia tomentosa aqueous extract and gallic acid on Candida albicans biofilms and virulence factors. Frontiers in Microbiology. 2018;9:647. DOI: 10.3389/fmicb.2018.00647'},{id:"B125",body:'Zabka M, Pavela R. Antifungal efficacy of some natural phenolic compounds against significant pathogenic and toxinogenic filamentous fungi. Chemosphere. 2013;93:1051-1056'},{id:"B126",body:'De Toledo LG, Ramos MADS, Spósito L, Castilho EM, Pavan FR, Lopes EDO, et al. Essential oil of Cymbopogon nardus (L.) Rendle: A strategy to combat fungal infections caused by Candida species. International Journal of Molecular Sciences. 2016;17(8):E1252. 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Chemical composition and antifungal activity of Carica papaya Linn. seeds essential oil against Candida spp. Letters in Applied Microbiology. 2017;64(5):350-354. DOI: 10.1111/lam.12711'},{id:"B131",body:'Minooeianhaghighi MH, Sepehrian L, Shokri H. Antifungal effects of Lavandula binaludensis and Cuminum cyminum essential oils against Candida albicans strains isolated from patients with recurrent vulvovaginal candidiasis. Journal de Mycologie Médicale. 2017;27(1):65-71. DOI: 10.1016/j.mycmed.2016.09.002'},{id:"B132",body:'Abu-Darwish MS, Cabral C, Gonçalves MJ, Cavaleiro C, Cruz MT, Zulfiqar A, et al. Chemical composition and biological activities of Artemisia judaica essential oil from southern desert of Jordan. Journal of Ethnopharmacology. 2016;191:161-168. DOI: 10.1016/j.jep.2016.06.023'},{id:"B133",body:'Köse YB, İşcan G, Göger F, Akalın G, Demirci B, Başer KHC. Chemical composition and biological activity of Centaurea baseri: New species from Turkey. 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Brazilian Archives of Biology and Technology. 2006;49:867-871'},{id:"B144",body:'Zhou L, Zhang Z, Wei M, Xie Y, He S, Shi H, et al. Evaluation of the antifungal activity of individual and combined monoterpenes against Rhizopus stolonifer and Absidia coerule. Environmental Science and Pollution Research. 2019;26:7804-7809. DOI: 10.1007/s11356-019-04278-z'},{id:"B145",body:'Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. Journal of Natural Products. 2012;75:311-335. DOI: 10.1021/np200906s'},{id:"B146",body:'Johnson MD, Perfect JR. Use of antifungal combination therapy: Agents, order, and timing. Current Fungal Infection Reports. 2010;4:87-95'},{id:"B147",body:'Lewis RE, Kontoyiannis DP. Rationale for combination antifungal therapy. Pharmacotherapy. 2001;21:149S-164S. DOI: 10.1592/phco.21.12.149S.34505'},{id:"B148",body:'Bink A, Pellens K, Cammue B, Thevissen K. Antibiofilm strategies: How to eradicate Candida biofilms. The Open Mycology Journal. 2011;5:29-38. DOI: 10.2174/1874437001105010029'},{id:"B149",body:'Santos JRA, Ribeiro NQ, Bastos RW, Holanda RA, Silva LC, Queiroz ER, et al. High-dose fluconazole in combination with amphotericin B is more efficient than monotherapy in murine model of cryptococcosis. Scientific Reports. 2017;7:4661'},{id:"B150",body:'Serena C, Fernández-Torres B, Pastor FJ, Trilles L, Lazéra MS, Nolard N, et al. In vitro interactions of micafungin with other antifungal drugs against clinical isolates of four species of Cryptococcus. Antimicrobial Agents and Chemotherapy. 2005;49:2994-2996. DOI: 10.1128/AAC.49.7.2994-2996.2005'},{id:"B151",body:'Espinel-Ingroff A. Novel antifungal agents, targets or therapeutic strategies for the treatment of invasive fungal diseases: A review of the literature (2005–2009). Revista Iberoamericana de Micología. 2009;26:15-22. DOI: 10.1016/S1130-1406(09)70004-X'},{id:"B152",body:'Katragkou A, McCarthy M, Meletiadis J, Hussain K, Moradi PW, Strauss GE, et al. In vitro combination therapy with isavuconazole against Candida spp. Medical Mycology. 2017;55:859-868. DOI: 10.1093/mmy/myx006'},{id:"B153",body:'Chen YL, Lehman VN, Averette AF, Perfect JR, Heitman J. Posaconazole exhibits in vitro and in vivo synergistic antifungal activity with caspofungin or FK506 against Candida albicans. PLoS One. 2013;8(3):e57672. DOI: 10.1371/journal.pone.0057672'},{id:"B154",body:'Chaturvedi V, Ramani R, Andes D, Diekema DJ, Pfaller MA, Ghannoum MA, et al. Multilaboratory testing of two-drug combinations of antifungals against Candida albicans, Candida glabrata, and Candida parapsilosis. Antimicrobial Agents and Chemotherapy. 2011;55(4):1543-1548. DOI: 10.1128/AAC.01510-09'},{id:"B155",body:'Barchiesi F, Falconi DFL, Scalise G. 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Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clinical Infectious Diseases. 2016;62:e1-e50. DOI: 10.1093/cid/civ1194'},{id:"B159",body:'Rees CA, Baoa R, Zegansa ME, Cramera RA. Natamycin and voriconazole exhibit synergistic interactions with non-antifungal ophthalmic agents against Fusarium species ocular isolates. Antimicrobial Agents and Chemotherapy. 2019. DOI: 10.1128/AAC.02505-18'},{id:"B160",body:'Mukherjee PK, Sheehan DJ, Hitchcock CA, Ghannoum MA. Combination treatment of invasive fungal infections. Clinical Microbiology Reviews. 2005;18:163-194. DOI: 10.1128/CMR.18.1.163-194.2005'},{id:"B161",body:'Carrillo-Muñoz AJ, Finquelievich J, Tur-Tur C, Eraso E, Jauregizar N, Quindós G, et al. Combination antifungal therapy: A strategy for the management of invasive fungal infections. Revista Española de Quimioterapia. 2014;27(3):141-158'},{id:"B162",body:'Musiol R, Mrozek-Wilczkiewicz A, Polanski J. Synergy against fungal pathogens: Working together is better than working alone. Current Medicinal Chemistry. 2014;21(7):870-893'},{id:"B163",body:'Tangarife-Castaño V, Correa-Royero C, Zapata-Londoño B, Duran C, Stanshenko E, Mesa-Arango AC. Anti-Candida albicans activity, cytotoxicity and interaction with antifungal drugs of essential oils and extracts from aromatic and medicinal plants. Infectio. 2011;15:160-167. DOI: 10.1016/S0123-9392(11)70080-7'},{id:"B164",body:'Chanda S, Rakholiya K, Dholakia K, Baravalia Y. Antimicrobial, antioxidant, and synergistic properties of two nutraceutical plants: Terminalia catappa L. and Colocasia esculenta L. Turkish Journal of Biology. 2013;37:81-91. DOI: 10.3906/biy-1203-41'},{id:"B165",body:'Santos KKA, Matias EFF, Sobral-Souza CE, Tintino SR, Morais-Braga MFB, Guedes GMM, et al. Trypanocide, cytotoxic, and anti-Candida activities of natural products: Hyptis martiusii Benth. European Journal of Integrative Medicine. 2013;5:427-431. DOI: 10.1016/j.eujim.2013.06.001'},{id:"B166",body:'Avijgan M, Mahboubi M, Nasab MM, Nia EA, Yousefi H. Synergistic activity between Echinophora platyloba DC ethanolic extract and azole drugs against clinical isolates of Candida albicans from women suffering chronic recurrent vaginitis. Journal de Mycologie Médicale. 2014;24:112-116. DOI: 10.1016/j.mycmed.2014.01.116'},{id:"B167",body:'Moraes RC, Lana AJD, Kaiser S, Carvalho AR, Oliveira LFS, Fuentefria AM, et al. Antifungal activity of Uncaria tomentosa (Willd.) D.C. against resistant non-albicans Candida isolates. Industrial Crops and Products. 2015;69:7-14. DOI: 10.1016/j.indcrop.2015.01.033'},{id:"B168",body:'Ngouana TK, Mbouna CDJ, Kuipou RMT, Tchuenmogne MAT, Zeuko’o EM, Ngouana V, et al. Potent and synergistic extract combinations from Terminalia catappa, Terminalia mantaly and Monodora tenuifolia against pathogenic yeasts. Medicine. 2015;2:220-235. DOI: 10.3390/medicines2030220'},{id:"B169",body:'Cavalcanti Filho JR, Silva TF, Nobre WQ, Oliveira De Souza LI, Silva E Silva FCS, Figueiredo RC, et al. Antimicrobial activity of Buchenavia tetraphylla against Candida albicans strains isolated from vaginal secretions. Pharmaceutical Biology. 2017;55(1):1521-1527. DOI: 10.1080/13880209.2017.1304427'},{id:"B170",body:'Kumari P, Mishra R, Arora N, Chatrath A, Gangwar R, Roy P, et al. Antifungal and anti-biofilm activity of essential oil active components against Cryptococcus neoformans and Cryptococcus laurentii. Frontiers in Microbiology. 2017;8:2161. DOI: 10.3389/fmicb.2017.02161'},{id:"B171",body:'Jandu JJB, Costa MC, Santos JRA, Andrade FM, Magalhães TFF, Gomes AG, et al. Treatment with pCramoll alone and in combination with fluconazole provides therapeutic benefits in C. gattii infected mice. Frontiers in Cellular and Infection Microbiology. 2017;7:211. DOI: 10.3389/fcimb.2017.00211'},{id:"B172",body:'Sharifzadeh A, Khosravi AR, Shokri H, Shirzadi H. Potential effect of 2-isopropyl-5-methylphenol (thymol) alone and in combination with fluconazole against clinical isolates of Candida albicans, C. glabrata and C. krusei. Journal de Mycologie Médicale. 2018;28(2):294-299. DOI: 10.1016/j.mycmed.2018.04.002'},{id:"B173",body:'Zaidi KU, Shah F, Parmar R, Thawani V. Anticandidal synergistic activity of Ocimum sanctum and fluconazole of azole resistance strains of clinical isolates. Journal de Mycologie Médicale. 2018;28(2):289-293. DOI: 10.1016/j.mycmed.2018.04.004'},{id:"B174",body:'Carbone C, Teixeira MC, Sousa MC, Martins-Gomes C, Silva AM, Souto EMB, et al. Clotrimazole-loaded Mediterranean essential oils NLC: A synergic treatment of Candida skin infections. Pharmaceutics. 2019;11:231. DOI: 10.3390/pharmaceutics11050231'},{id:"B175",body:'Konopka K, Goslinski T. Photodynamic therapy in dentistry. Journal of Dental Research. 2007;86:694-707'},{id:"B176",body:'Sanitá PV, Pavarina AC, Dovigo LN, Ribeiro APD, Andrade MC, Mima E. Curcumin-mediated anti-microbial photodynamic therapy against Candida dubliniensis biofilms. Lasers in Medical Science. 2018;33:709-717. DOI: 10.1007/s10103-017-2382-8'},{id:"B177",body:'Daliria F, Azizia A, Goudarzib M, Lawafc S, Rahimid A. In vitro comparison of the effect of photodynamic therapy with curcumin and methylene blue on Candida albicans colonies. Photodiagnosis and Photodynamic Therapy. 2019;26:193-198. DOI: 10.1016/j.pdpdt.2019.03.017'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Cristina de Andrade Monteiro",address:"cristina.monteiro@ceuma.br",affiliation:'
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Department of Ecology and Sustainable Economic Development (DECOS), Tuscia University.\nProfessor of: Biological Oceanography, Applied Marine Ecology with Laboratory, Applied Oceanography; Marine Environmental Sciences, University of Tuscia\nProfessor of: Management and protection of marine resources and fisheries resources; Naval Academy, Italian Navy.\nMember of University for Civitavecchia Consortium's board\nVicePresident of Italian FEE (Foundation for Environmental Education). \nGraduated in Geological Sciences at University of Rome La Sapienza . In Seattle (USA) achieve the Biosonics Certificate Course of: underwater electroacoustic and bioacoustic (evaluation of biological resources).\n1987-89) He began working for Generale Prospezioni of Rome for the characterization of marine areas facing power plants under the PEN (National Energy Plan). Secondments: 2 years Ministry of Environment , part of the “Crisis Unit†of the Ministry of Environment for the sinking of the “Havenâ€; 5 years working at the Laboratory of Experimental Ecology and Aquaculture of the Tor Vergata University of Rome. Was part of the Italian delegation to the work of the World Climate Conference in Rio de Janeiro (1992). \n2 years collaborating with the Stazione Zoologica Anton Dohrn of Naples. 1998-2001) Works for ENEL (Environmental section) Since 1999 contract professor, Faculty of Science, University of Tuscia. \n2001-2011) Becomes Associate Professor at the Faculty of Science of Tuscia University. Based and coordinates in Civitavecchia the Laboratory of Experimental Oceanology and Marine Ecology. \nMain scientific expertise: \nExperimental and numerical study of pelagic ecosystems: primary productivity, interaction between physical phenomena and ecological processes; development and application of oceanographic measurement techniques, with particular reference to bio-optical measures, bio-optical mathematical models. \nHe participated in over 35 oceanographic cruises. Author of about 120 between scientific and technical publications on Italian and international magazines and scientific technical reports all concerning oceanography. \nParticipates in numerous national and European research projects and applied research. Has coordinated several national research projects and two subtasks of a European program (MFSTEP). \nCreator of Oceanographic instruments and platforms for the study of physical and ecological processes at meso and macro-scale.",institutionString:null,institution:{name:"Tuscia University",institutionURL:null,country:{name:"Italy"}}},{id:"50280",title:"Dr.",name:"Viviana",surname:"Piermattei",slug:"viviana-piermattei",fullName:"Viviana Piermattei",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"68387",title:"Dr.",name:"Ingrid",surname:"Puillat",slug:"ingrid-puillat",fullName:"Ingrid Puillat",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"76903",title:"Dr.",name:"Yves",surname:"Auffret",slug:"yves-auffret",fullName:"Yves Auffret",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"76904",title:"MSc.",name:"Jérôme",surname:"Blandin",slug:"jerome-blandin",fullName:"Jérôme Blandin",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"79491",title:"MSc.",name:"Jean-François",surname:"Rolin",slug:"jean-francois-rolin",fullName:"Jean-François Rolin",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"79492",title:"Prof.",name:"Louis",surname:"Géli",slug:"louis-geli",fullName:"Louis Géli",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"French Research Institute for Exploitation of the Sea",institutionURL:null,country:{name:"France"}}},{id:"79496",title:"MSc.",name:"Nadine",surname:"Lantéri",slug:"nadine-lanteri",fullName:"Nadine Lantéri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"79497",title:"Mr.",name:"Yannick",surname:"Aoustin",slug:"yannick-aoustin",fullName:"Yannick Aoustin",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Nantes",institutionURL:null,country:{name:"France"}}},{id:"79498",title:"Dr.",name:"Roland",surname:"Person",slug:"roland-person",fullName:"Roland Person",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"translation-policy",title:"Translation Policy",intro:"
All Works published by IntechOpen prior to October 2011 are licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported license (CC BY-BC-SA 3.0). Works published after October 2011 are licensed under a Creative Commons Attribution 3.0 Unported license (CC BY 3.0), the latter allowing for the broadest possible reuse of published material.
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All Works licensed under CC BY-BC-SA 3.0 can be freely translated and used for non-commercial purposes. Works licensed under CC BY 3.0 license can be freely translated and used for both commercial and non-commercial purposes.
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Book Chapters
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All translated Chapters have to be properly attributed in accordance with the requirements included in IntechOpen's Attribution Policy. Besides proper attribution translated sections of Works must include the following sentence: "This is an unofficial translation of a work published by IntechOpen. The publisher has not endorsed this translation".
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Books and all other compilations
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All rights to Books and other compilations are reserved by IntechOpen. The copyright to Books and other compilations is subject to a Copyright separate from any that exists in the included Works.
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A Book in its entirety, or a significant part of a Book, cannot be translated freely without specific written consent by the publisher. Requests for permission can be made at permissions@intechopen.com.
All Works licensed under CC BY-BC-SA 3.0 can be freely translated and used for non-commercial purposes. Works licensed under CC BY 3.0 license can be freely translated and used for both commercial and non-commercial purposes.
\n\n
Book Chapters
\n\n
All translated Chapters have to be properly attributed in accordance with the requirements included in IntechOpen's Attribution Policy. Besides proper attribution translated sections of Works must include the following sentence: "This is an unofficial translation of a work published by IntechOpen. The publisher has not endorsed this translation".
\n\n
Books and all other compilations
\n\n
All rights to Books and other compilations are reserved by IntechOpen. The copyright to Books and other compilations is subject to a Copyright separate from any that exists in the included Works.
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A Book in its entirety, or a significant part of a Book, cannot be translated freely without specific written consent by the publisher. Requests for permission can be made at permissions@intechopen.com.
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Policy last updated: 2016-06-09
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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. 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From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. 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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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Life",subtitle:null,isOpenForSubmission:!1,hash:"f6000bc0eeed7fcf0277a2f8d75907d9",slug:"quality-of-life-and-quality-of-working-life",bookSignature:"Ana Alice Vilas Boas",coverURL:"https://cdn.intechopen.com/books/images_new/5761.jpg",editedByType:"Edited by",editors:[{id:"175373",title:"Dr.",name:"Ana Alice",middleName:null,surname:"Vilas Boas",slug:"ana-alice-vilas-boas",fullName:"Ana Alice Vilas Boas"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:6,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"66422",doi:"10.5772/intechopen.85463",title:"Vulnerability and Social Exclusion: Risk in Adolescence and Old Age",slug:"vulnerability-and-social-exclusion-risk-in-adolescence-and-old-age",totalDownloads:1121,totalCrossrefCites:8,totalDimensionsCites:10,abstract:"Vulnerability can be defined as the quality or state of being exposed to the possibility of being attacked or harmed, either physically or emotionally. In this chapter, it is defined as a possible ability of an individual or a group to face, manage, and anticipate a possible problem. This concept of vulnerability is associated with that of risk factor for social isolation, and therefore to situations that can also lead to illness and lack of mental and physical health. It can have its roots in poverty, in social exclusion, in ethnicity, in disability or simply in disease or specific developmental phases in life. All these aspects reflect very important vulnerability factors among biological, psychological, social, and behavioral variables. To date, no one has highlighted together two critical moments in life in which this brain area undergoes important variations: adolescence, in which its development occurs, and old age, in which this area goes into cognitive decline with the relative loss of many higher cognitive functions. This knowledge can help to better understand the forms of exclusion due to vulnerability in order to develop new forms of social inclusion.",book:{id:"8262",slug:"the-new-forms-of-social-exclusion",title:"The New Forms of Social Exclusion",fullTitle:"The New Forms of Social Exclusion"},signatures:"Rosalba Morese, Sara Palermo, Matteo Defedele, Juri Nervo and Alberto Borraccino",authors:[{id:"214435",title:"Dr.",name:"Rosalba",middleName:null,surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese"},{id:"218983",title:"BSc.",name:"Juri",middleName:null,surname:"Nervo",slug:"juri-nervo",fullName:"Juri Nervo"},{id:"218984",title:"MSc.",name:"Matteo",middleName:null,surname:"Defedele",slug:"matteo-defedele",fullName:"Matteo Defedele"},{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"},{id:"266453",title:"Prof.",name:"Alberto",middleName:null,surname:"Borraccino",slug:"alberto-borraccino",fullName:"Alberto Borraccino"}]},{id:"55349",doi:"10.5772/intechopen.68596",title:"The Development of a Human Well-Being Index for the United States",slug:"the-development-of-a-human-well-being-index-for-the-united-states",totalDownloads:1986,totalCrossrefCites:3,totalDimensionsCites:9,abstract:"The US Environmental Protection Agency (EPA) has developed a human well-being index (HWBI) that assesses the over-all well-being of its population at the county level. The HWBI contains eight domains representing social, economic and environmental well-being. These domains include 25 indicators comprised of 80 metrics and 22 social, economic and environmental services. The application of the HWBI has been made for the nation as a whole at the county level and two alternative applications have been made to represent key populations within the overall US population—Native Americans and children. A number of advances have been made to estimate the values of metrics for counties where no data is available and one such estimator—MERLIN—is discussed. Finally, efforts to make the index into an interactive web site are described.",book:{id:"5761",slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"J. Kevin Summers, Lisa M. Smith, Linda C. Harwell and Kyle D. Buck",authors:[{id:"197485",title:"Dr.",name:"J. Kevin",middleName:null,surname:"Summers",slug:"j.-kevin-summers",fullName:"J. Kevin Summers"},{id:"197486",title:"Ms.",name:"Lisa",middleName:null,surname:"Smith",slug:"lisa-smith",fullName:"Lisa Smith"},{id:"197487",title:"Ms.",name:"Linda",middleName:null,surname:"Harwell",slug:"linda-harwell",fullName:"Linda Harwell"},{id:"197488",title:"Dr.",name:"Kyle",middleName:null,surname:"Buck",slug:"kyle-buck",fullName:"Kyle Buck"}]},{id:"55323",doi:"10.5772/intechopen.68873",title:"Positive Psychology: The Use of the Framework of Achievement Bests to Facilitate Personal Flourishing",slug:"positive-psychology-the-use-of-the-framework-of-achievement-bests-to-facilitate-personal-flourishing",totalDownloads:1674,totalCrossrefCites:3,totalDimensionsCites:8,abstract:"The Framework of Achievement Bests, which was recently published in Educational Psychology Review, makes a theoretical contribution to the study of positive psychology. The Framework of Achievement Bests provides an explanatory account of a person’s optimal best practice from his/her actual best. Another aspect emphasizes on the saliency of the psychological process of optimization, which is central to our understanding of person’s optimal functioning in a subject matter. Achieving an exceptional level of best practice (e.g. achieving excellent grades in mathematics) does not exist in isolation, but rather depends on the potent impact of optimization. This chapter, theoretical in nature, focuses on an in‐depth examination of the expansion of the Framework of Achievement Bests. Our discussion of the Framework of Achievement Bests, reflecting a methodical conceptualization, is benchmarked against another notable theory for understanding, namely: Martin Seligman’s PERMA theory. For example, for consideration, one aspect that we examine entails the extent to which the Framework of Achievement Bests could explain the optimization of each of the five components of PERMA (e.g. how does the Framework of Achievement Bests explain the optimization of engagement?).",book:{id:"5761",slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Huy P. Phan and Bing H. Ngu",authors:[{id:"196435",title:"Prof.",name:"Huy",middleName:"P",surname:"Phan",slug:"huy-phan",fullName:"Huy Phan"}]},{id:"56529",doi:"10.5772/intechopen.70237",title:"Well-being and Quality of Working Life of University Professors in Brazil",slug:"well-being-and-quality-of-working-life-of-university-professors-in-brazil",totalDownloads:1649,totalCrossrefCites:2,totalDimensionsCites:6,abstract:"This chapter presents a study about the perceptions on quality of working life (QWL) regarding factors and indicator in two public universities in Brazil. It aimed also to analyze their perceptions about university working conditions. This exploratory study is based on quantitative and qualitative analyses. A sample of 715 university professors participated on the research. Data collection was carried out in two steps: online survey and focus groups. There is a moderate negative correlation between psychological well-being and work-related stress. Emotional charge also presents a moderate positive correlation with work-related stress, as well as physical charge and psychological distress. Work-life balance is negatively correlated with physical charge, emotional charge, work-related stress, psychological distress, and burnout. We observed also that 43.6% of the professors reported high levels of work-related stress in their everyday work. The precariousness of university teaching is associated with three main elements, which we defined as the tripod of the precarization of university teaching work. It consists of academic productivism, excess of administrative work and bureaucratic activities, and inadequate working conditions. The operating dynamics of this tripod effect professors’ well-being, their QWL, and even the quality of the work they develop in public universities.",book:{id:"5761",slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Alessandro Vinicius de Paula and Ana Alice Vilas Boas",authors:[{id:"175373",title:"Dr.",name:"Ana Alice",middleName:null,surname:"Vilas Boas",slug:"ana-alice-vilas-boas",fullName:"Ana Alice Vilas Boas"},{id:"196534",title:"Dr.",name:"Alessandro Vinicius",middleName:null,surname:"De Paula",slug:"alessandro-vinicius-de-paula",fullName:"Alessandro Vinicius De Paula"}]},{id:"71723",doi:"10.5772/intechopen.91705",title:"Characterizing Rapists and Their Victims in Select Nigeria Newspapers",slug:"characterizing-rapists-and-their-victims-in-select-nigeria-newspapers",totalDownloads:1052,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"While offender and victim characterization offers clues to devising preventive strategies and victim therapy, existing studies in Nigeria are yet to capture this empirically. Using two national dailies, about 331 rape cases have been analyzed. The rapists were found to be of the age group 18–55 years. The victims’ age has been reported to be between 1 and 20 years. Rape victims were mostly females (>90%) compared to males. Most of the rapists are labeled as familiar foes meaning, father, relatives, or neighbors. Third-party guardianship is mentioned as predatory.",book:{id:"6934",slug:"psycho-social-aspects-of-human-sexuality-and-ethics",title:"Psycho-Social Aspects of Human Sexuality and Ethics",fullTitle:"Psycho-Social Aspects of Human Sexuality and Ethics"},signatures:"Oludayo Tade and Collins Udechukwu",authors:[{id:"316697",title:"Dr.",name:"Oludayo",middleName:null,surname:"Tade",slug:"oludayo-tade",fullName:"Oludayo Tade"},{id:"318220",title:"Dr.",name:"Collins",middleName:"Obinna",surname:"Udechukwu",slug:"collins-udechukwu",fullName:"Collins Udechukwu"}]}],mostDownloadedChaptersLast30Days:[{id:"76968",title:"In the Darkness of This Time: Wittgenstein and Freud on Uncertainty",slug:"in-the-darkness-of-this-time-wittgenstein-and-freud-on-uncertainty",totalDownloads:434,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Both Wittgenstein and Freud experienced the crisis of humanism resulting from the first and second world wars. Although they were both considered to be influential figures, they hardly investigated the ways in which people could cope with the consequences of these crises. However, Wittgenstein and Freud did suggest ways of understanding uncertainties caused by real life events, as well as by the nature of human thought processes. This article will explore the therapeutic ways of dealing with uncertainties common to both thinkers and the different concepts facilitating their methodologies. The central contention of this article is that both Wittgenstein and Freud developed a complex methodology, acknowledging the constant and unexpected changes humans have deal with, whilst also offering the possibility of defining “hinge propositions” and “language-games” which can stabilize our consciousness.",book:{id:"10814",slug:"anxiety-uncertainty-and-resilience-during-the-pandemic-period-anthropological-and-psychological-perspectives",title:"Anxiety, Uncertainty, and Resilience During the Pandemic Period",fullTitle:"Anxiety, Uncertainty, and Resilience During the Pandemic Period - Anthropological and Psychological Perspectives"},signatures:"Dorit Lemberger",authors:[{id:"325725",title:"Dr.",name:"Dorit",middleName:null,surname:"Lemberger",slug:"dorit-lemberger",fullName:"Dorit Lemberger"}]},{id:"76565",title:"Introductory Chapter: The Transition from Distress to Acceptance of Human Frailty - Anthropology and Psychology of the Pandemic Era",slug:"introductory-chapter-the-transition-from-distress-to-acceptance-of-human-frailty-anthropology-and-ps",totalDownloads:350,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"10814",slug:"anxiety-uncertainty-and-resilience-during-the-pandemic-period-anthropological-and-psychological-perspectives",title:"Anxiety, Uncertainty, and Resilience During the Pandemic Period",fullTitle:"Anxiety, Uncertainty, and Resilience During the Pandemic Period - Anthropological and Psychological Perspectives"},signatures:"Fabio Gabrielli and Floriana Irtelli",authors:[{id:"174641",title:"Dr.",name:"Floriana",middleName:null,surname:"Irtelli",slug:"floriana-irtelli",fullName:"Floriana Irtelli"},{id:"259407",title:"Prof.",name:"Fabio",middleName:null,surname:"Gabrielli",slug:"fabio-gabrielli",fullName:"Fabio Gabrielli"}]},{id:"77214",title:"The Impact of the COVID-19 Pandemic on the Mental Health of Dentists",slug:"the-impact-of-the-covid-19-pandemic-on-the-mental-health-of-dentists",totalDownloads:357,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Since March 2020, the COVID-19 disease has declared a pandemic producing a worldwide containment. For months, many people were subjected to strict social isolation away from family and loved ones to prevent disease transmission, leading to anxiety, fear, and depression. On the other hand, many had to close down their businesses and stop working, resulting in financial issues. Previous studies have reported that pandemics, epidemics, and some diseases can lead to mental disorders such as fear, anxiety, stress, and depression. Among those most affected, healthcare workers (HCWs), especially those on the front line, often develop mental health problems. Although there is data available on the management and care of HCWs, little attention has been paid to the mental health and well-being of dentists during the COVID-19 pandemic. Therefore, this chapter aims to review the impact of the COVID-19 pandemic on dentists’ mental health and mental health-related symptoms. Finally, to recommend specific measures to avoid consequent potential implications for dentists, dental students, and dental patients.",book:{id:"10814",slug:"anxiety-uncertainty-and-resilience-during-the-pandemic-period-anthropological-and-psychological-perspectives",title:"Anxiety, Uncertainty, and Resilience During the Pandemic Period",fullTitle:"Anxiety, Uncertainty, and Resilience During the Pandemic Period - Anthropological and Psychological Perspectives"},signatures:"Andrea Vergara-Buenaventura and Carmen Castro-Ruiz",authors:[{id:"346660",title:"M.Sc.",name:"Andrea",middleName:null,surname:"Vergara-Buenaventura",slug:"andrea-vergara-buenaventura",fullName:"Andrea Vergara-Buenaventura"},{id:"419814",title:"MSc.",name:"Carmen",middleName:null,surname:"Castro-Ruiz",slug:"carmen-castro-ruiz",fullName:"Carmen Castro-Ruiz"}]},{id:"55323",title:"Positive Psychology: The Use of the Framework of Achievement Bests to Facilitate Personal Flourishing",slug:"positive-psychology-the-use-of-the-framework-of-achievement-bests-to-facilitate-personal-flourishing",totalDownloads:1674,totalCrossrefCites:3,totalDimensionsCites:8,abstract:"The Framework of Achievement Bests, which was recently published in Educational Psychology Review, makes a theoretical contribution to the study of positive psychology. The Framework of Achievement Bests provides an explanatory account of a person’s optimal best practice from his/her actual best. Another aspect emphasizes on the saliency of the psychological process of optimization, which is central to our understanding of person’s optimal functioning in a subject matter. Achieving an exceptional level of best practice (e.g. achieving excellent grades in mathematics) does not exist in isolation, but rather depends on the potent impact of optimization. This chapter, theoretical in nature, focuses on an in‐depth examination of the expansion of the Framework of Achievement Bests. Our discussion of the Framework of Achievement Bests, reflecting a methodical conceptualization, is benchmarked against another notable theory for understanding, namely: Martin Seligman’s PERMA theory. For example, for consideration, one aspect that we examine entails the extent to which the Framework of Achievement Bests could explain the optimization of each of the five components of PERMA (e.g. how does the Framework of Achievement Bests explain the optimization of engagement?).",book:{id:"5761",slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Huy P. Phan and Bing H. Ngu",authors:[{id:"196435",title:"Prof.",name:"Huy",middleName:"P",surname:"Phan",slug:"huy-phan",fullName:"Huy Phan"}]},{id:"77908",title:"Anxiety, Uncertainty and Resilience during the Pandemic Period-Anthropological and Psychological Perspectives",slug:"anxiety-uncertainty-and-resilience-during-the-pandemic-period-anthropological-and-psychological-pers",totalDownloads:288,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Following any natural disaster, tragedy, calamities, there are upsurge of mental health issues found worldwide. COVID 19 is no exception to them. Public health and infection control domains were the first hit at the peak of pandemic. The news and information were bombarded in traditional print and electronic Medias as well as in social Medias. The tsunami of infodemic was a recent topic of discussion. The responsible reporting, media role, role of Government and Non Government organizations are immense. To combat these challenges and ensuring peace and tranquillity are the biggest task of the policymakers ahead.",book:{id:"10814",slug:"anxiety-uncertainty-and-resilience-during-the-pandemic-period-anthropological-and-psychological-perspectives",title:"Anxiety, Uncertainty, and Resilience During the Pandemic Period",fullTitle:"Anxiety, Uncertainty, and Resilience During the Pandemic Period - Anthropological and Psychological Perspectives"},signatures:"Ranjan Bhattacharyya",authors:[{id:"347365",title:"Associate Prof.",name:"Ranjan",middleName:null,surname:"Bhattacharyya",slug:"ranjan-bhattacharyya",fullName:"Ranjan Bhattacharyya"}]}],onlineFirstChaptersFilter:{topicId:"278",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:8,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:286,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:105,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:9,numberOfPublishedChapters:101,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:11,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:9,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"May 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:8,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). In addition to a number of research articles, he has written two books, Computational Intelligence: An Introduction and Fundamentals of Computational Swarm Intelligence.",institutionString:null,institution:{name:"Stellenbosch University",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",isOpenForSubmission:!0,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. 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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. 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He received his Ph.D. in Molecular Biology with his thesis “Genetic variability of the tick-borne encephalitis virus in natural foci of Novosibirsk city and its suburbs.” His primary field is molecular virology with research emphasis on vector-borne viruses, especially tick-borne encephalitis virus, Kemerovo virus and Omsk hemorrhagic fever virus, rabies virus, molecular genetics, biology, and epidemiology of virus pathogens.",institutionString:"Russian Academy of Sciences",institution:{name:"Russian Academy of Sciences",country:{name:"Russia"}}},{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.png",biography:"László Babinszky is Professor Emeritus, Department of Animal Nutrition Physiology, University of Debrecen, Hungary. He has also worked in the Department of Animal Nutrition, University of Wageningen, Netherlands; the Institute for Livestock Feeding and Nutrition (IVVO), Lelystad, Netherlands; the Agricultural University of Vienna (BOKU); the Institute for Animal Breeding and Nutrition, Austria; and the Oscar Kellner Research Institute for Animal Nutrition, Rostock, Germany. In 1992, Dr. Babinszky obtained a Ph.D. in Animal Nutrition from the University of Wageningen. His main research areas are swine and poultry nutrition. He has authored more than 300 publications (papers, book chapters) and edited four books and fourteen international conference proceedings.",institutionString:"University of Debrecen",institution:{name:"University of Debrecen",country:{name:"Hungary"}}},{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201830/images/5017_n.jpg",biography:"I am a professor at UANL since 1988. My research lines are the development of reproductive techniques in small ruminants. We also conducted research on sexual and social behavior in males.\nI am Mexican and study my professional career as an engineer in agriculture and animal science at UANL. Then take a masters degree in science in Germany (Animal breeding). Take a doctorate in animal science at the UANL.",institutionString:null,institution:{name:"Universidad Autónoma de Nuevo León",country:{name:"Mexico"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",slug:"miguel-quaresma",fullName:"Miguel Quaresma",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309250/images/9059_n.jpg",biography:"Miguel Nuno Pinheiro Quaresma was born on May 26, 1974 in Dili, Timor Island. He is married with two children: a boy and a girl, and he is a resident in Vila Real, Portugal. He graduated in Veterinary Medicine in August 1998 and obtained his Ph.D. degree in Veterinary Sciences -Clinical Area in February 2015, both from the University of Trás-os-Montes e Alto Douro. He is currently enrolled in the Alternative Residency of the European College of Animal Reproduction. He works as a Senior Clinician at the Veterinary Teaching Hospital of UTAD (HVUTAD) with a role in clinical activity in the area of livestock and equine species as well as to support teaching and research in related areas. He teaches as an Invited Professor in Reproduction Medicine I and II of the Master\\'s in Veterinary Medicine degree at UTAD. Currently, he holds the position of Chairman of the Portuguese Buiatrics Association. He is a member of the Consultive Group on Production Animals of the OMV. He has 19 publications in indexed international journals (ISIS), as well as over 60 publications and oral presentations in both Portuguese and international journals and congresses.",institutionString:"University of Trás-os-Montes and Alto Douro",institution:{name:"University of Trás-os-Montes and Alto Douro",country:{name:"Portugal"}}},{id:"38652",title:"Dr.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",position:null,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",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón",slug:"juan-carlos-gardon",fullName:"Juan Carlos Gardón",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:"Catholic University of Valencia San Vicente Mártir, Spain",institution:null},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain. She is a Full Professor at the Department of Medicine and Animal Surgery at the same University. She developed her research activity in the field of Endocrinology, Hematology, Biochemistry and Immunology of horses. She is a scientific reviewer of several international journals : American Journal of Obstetrics and Gynecology, Comparative Clinical Pathology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology. Since 2014, she has been the Head of the Clinical Analysis Laboratory of the Hospital Clínico Veterinario from the Faculty of Veterinary, CEU-Cardenal Herrera University.",institutionString:"CEU-Cardenal Herrera University",institution:{name:"CEU Cardinal Herrera University",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",country:{name:"United Kingdom"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",biography:"Samir El-Gendy is a Professor of anatomy and embryology at the faculty of veterinary medicine, Alexandria University, Egypt. Samir obtained his PhD in veterinary science in 2007 from the faculty of veterinary medicine, Alexandria University and has been a professor since 2017. Samir is an author on 24 articles at Scopus and 12 articles within local journals and 2 books/book chapters. His research focuses on applied anatomy, imaging techniques and computed tomography. Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",biography:"Dr. Fonseca-Alves earned his DVM from Federal University of Goias – UFG in 2008. He completed an internship in small animal internal medicine at UPIS university in 2011, earned his MSc in 2013 and PhD in 2015 both in Veterinary Medicine at Sao Paulo State University – UNESP. Dr. Fonseca-Alves currently serves as an Assistant Professor at Paulista University – UNIP teaching small animal internal medicine.",institutionString:null,institution:{name:"Universidade Paulista",country:{name:"Brazil"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",biography:"María de la Luz García Pardo is an agricultural engineer from Universitat Politècnica de València, Spain. She has a Ph.D. in Animal Genetics. Currently, she is a lecturer at the Agrofood Technology Department of Miguel Hernández University, Spain. Her research is focused on genetics and reproduction in rabbits. The major goal of her research is the genetics of litter size through novel methods such as selection by the environmental sensibility of litter size, with forays into the field of animal welfare by analysing the impact on the susceptibility to diseases and stress of the does. Details of her publications can be found at https://orcid.org/0000-0001-9504-8290.",institutionString:null,institution:{name:"Miguel Hernandez University",country:{name:"Spain"}}},{id:"41319",title:"Prof.",name:"Lung-Kwang",middleName:null,surname:"Pan",slug:"lung-kwang-pan",fullName:"Lung-Kwang Pan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41319/images/84_n.jpg",biography:null,institutionString:null,institution:null},{id:"201721",title:"Dr.",name:"Beatrice",middleName:null,surname:"Funiciello",slug:"beatrice-funiciello",fullName:"Beatrice Funiciello",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201721/images/11089_n.jpg",biography:"Graduated from the University of Milan in 2011, my post-graduate education included CertAVP modules mainly on equines (dermatology and internal medicine) and a few on small animal (dermatology and anaesthesia) at the University of Liverpool. After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". Master\\\'s degree in Ecology and Biodiversity Conservation at Federal University of Mato Grosso with a scholarship by CAPES/REUNI program: Project \\"Reproductive biology of Melanorivulus punctatus\\". PhD\\\'s degree in Science (Cell and Tissue Biology Area) \n at University of Sao Paulo with scholarship granted by FAPESP; Project \\"Development of morphofunctional changes in ovary of Astyanax altiparanae Garutti & Britski, 2000 (Teleostei, Characidae)\\". She has experience in Reproduction of vertebrates and Morphology, with emphasis in Cellular Biology and Histology. 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developments are based on the knowledge generation on applied intelligence. The motor of the society is the industry and the research of this topic has to be empowered in order to increase and improve the quality of our lives.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",keywords:"Machine Learning, Intelligence Algorithms, Data Science, Artificial Intelligence, Applications on Applied Intelligence"},{id:"23",title:"Computational Neuroscience",scope:"Computational neuroscience focuses on biologically realistic abstractions and models validated and solved through computational simulations to understand principles for the development, structure, physiology, and ability of the nervous system. This topic is dedicated to biologically plausible descriptions and computational models - at various abstraction levels - of neurons and neural systems. This includes, but is not limited to: single-neuron modeling, sensory processing, motor control, memory, and synaptic plasticity, attention, identification, categorization, discrimination, learning, development, axonal patterning, guidance, neural architecture, behaviors, and dynamics of networks, cognition and the neuroscientific basis of consciousness. Particularly interesting are models of various types of more compound functions and abilities, various and more general fundamental principles (e.g., regarding architecture, organization, learning, development, etc.) found at various spatial and temporal levels.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",keywords:"Single-Neuron Modeling, Sensory Processing, Motor Control, Memory and Synaptic Pasticity, Attention, Identification, Categorization, Discrimination, Learning, Development, Axonal Patterning and Guidance, Neural Architecture, Behaviours and Dynamics of Networks, Cognition and the Neuroscientific Basis of Consciousness"},{id:"24",title:"Computer Vision",scope:"The scope of this topic is to disseminate the recent advances in the rapidly growing field of computer vision from both the theoretical and practical points of view. Novel computational algorithms for image analysis, scene understanding, biometrics, deep learning and their software or hardware implementations for natural and medical images, robotics, VR/AR, applications are some research directions relevant to this topic.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",keywords:"Image Analysis, Scene Understanding, Biometrics, Deep Learning, Software Implementation, Hardware Implementation, Natural Images, Medical Images, Robotics, VR/AR"},{id:"25",title:"Evolutionary Computation",scope:"Evolutionary computing is a paradigm that has grown dramatically in recent years. This group of bio-inspired metaheuristics solves multiple optimization problems by applying the metaphor of natural selection. It so far has solved problems such as resource allocation, routing, schedule planning, and engineering design. Moreover, in the field of machine learning, evolutionary computation has carved out a significant niche both in the generation of learning models and in the automatic design and optimization of hyperparameters in deep learning models. This collection aims to include quality volumes on various topics related to evolutionary algorithms and, alternatively, other metaheuristics of interest inspired by nature. For example, some of the issues of interest could be the following: Advances in evolutionary computation (Genetic algorithms, Genetic programming, Bio-inspired metaheuristics, Hybrid metaheuristics, Parallel ECs); Applications of evolutionary algorithms (Machine learning and Data Mining with EAs, Search-Based Software Engineering, Scheduling, and Planning Applications, Smart Transport Applications, Applications to Games, Image Analysis, Signal Processing and Pattern Recognition, Applications to Sustainability).",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",keywords:"Genetic Algorithms, Genetic Programming, Evolutionary Programming, Evolution Strategies, Hybrid Algorithms, Bioinspired Metaheuristics, Ant Colony Optimization, Evolutionary Learning, Hyperparameter Optimization"},{id:"26",title:"Machine Learning and Data Mining",scope:"The scope of machine learning and data mining is immense and is growing every day. It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. It is not limited to any particular applications, but contributions are encouraged from all disciplines.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence"},{id:"27",title:"Multi-Agent Systems",scope:"Multi-agent systems are recognised as a state of the art field in Artificial Intelligence studies, which is popular due to the usefulness in facilitation capabilities to handle real-world problem-solving in a distributed fashion. The area covers many techniques that offer solutions to emerging problems in robotics and enterprise-level software systems. Collaborative intelligence is highly and effectively achieved with multi-agent systems. Areas of application include swarms of robots, flocks of UAVs, collaborative software management. Given the level of technological enhancements, the popularity of machine learning in use has opened a new chapter in multi-agent studies alongside the practical challenges and long-lasting collaboration issues in the field. It has increased the urgency and the need for further studies in this field. We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:{title:"Artificial Intelligence",id:"14"},selectedSubseries:null},seriesLanding:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. This series is intended for doctors, engineers, and scientists involved in biomedical engineering or those wanting to start working in this field.",coverUrl:"https://cdn.intechopen.com/series/covers/7.jpg",latestPublicationDate:"May 7th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:3,numberOfPublishedChapters:96,numberOfPublishedBooks:12,editor:{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},subseries:[{id:"7",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:null,institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda",middleName:"R.",surname:"Gharieb",fullName:"Reda Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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