\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art on Theileriosis, Babesiosis, and Anaplasmosis, both in humans and domestic animals. Particularly this book aims to permit the researchers to enter into a critical focus on the biology of the parasites, eco-epidemiology of the diseases, clinical manifestations, risk factors, immunology, surveillance, diagnosis, identification, and management of risks as well as the potential economic impact on animal production.
",isbn:"978-1-80356-384-8",printIsbn:"978-1-80356-383-1",pdfIsbn:"978-1-80356-385-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"3d72ae651ee2a04b2368bf798a3183ca",bookSignature:"Prof. Elisa Pieragostini",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11577.jpg",keywords:"Zoonosis, Global Climate Change, Epidemiology, Risk Factors, Haemoparasites, Prevention & Control, Piroplasmosis, Anaplasmosis, Babesiosis, Theileriosis, Tick-Borne Diseases, Ticks",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 23rd 2022",dateEndSecondStepPublish:"April 29th 2022",dateEndThirdStepPublish:"June 28th 2022",dateEndFourthStepPublish:"September 16th 2022",dateEndFifthStepPublish:"November 15th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Professor of Animal genetics and breeding at Bari University, a researcher in animal genetics related to the resilience of Apulian livestock to enzootic tick-borne haemoparasites and to the involved functional effect of hemoglobin variants. 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1. Introduction
The short- and long-term benefits of breastfeeding for mother and baby have been well documented [1]. The short-term benefits of breastfeeding include a lower incidence of many childhood communicable diseases, childhood lymphocytic leukemia, inflammatory bowel disease, lower incidence of type 1 diabetes, and higher IQ [2]. The long-term benefits of breastfeeding include lower incidence of noncommunicable disorders (NCDs), obesity, diabetes type 2, and hypercholesterolemia resulting in cardiovascular diseases and hypertension [2–4]. Furthermore, breastfeeding results in improved maternal health by reducing the incidence of maternal premenopausal breast and ovarian cancer as well as lowering the incidence of maternal obesity and its complications [2].
World Health Organization (WHO) recommends exclusive breastfeeding for the first 6 months and to continue breastfeeding with addition of safe and nutritious complementary food up to 2 years of age and beyond.
In the past 10 years, the global exclusive breastfeeding rate improved only marginally from 33% in 1995 to 37% in 2014. Suboptimal breastfeeding results in higher health care expenses for pediatrics and maternal care, and global productivity-related economic losses of $302 billion or 0.49% of world gross income annually [4].
The impact of breastfeeding in lowering the incidence of mental health disorders has recently gained scrutiny. Neurodevelopmental disorders, especially autism and attention deficit disorder, are reported to be significantly associated with formula feeding [5–7]. The annual expenditure for the care of autistic children and adults in the United States is estimated to be in excess of $120 billion [8].
The short- and long-term benefits of breastfeeding for mother and baby have been well documented. In our study, we demonstrate the mental health benefits of breastfeeding and identify early weaning and formula feeding as possible risk factors for development of ASDs in genetically susceptible children.
2. What causes autism?
Autism was reported as a distinct entity by Leo Kanner, professor of psychiatry at Johns Hopkins University in 1943. In his article “Autistic Disturbances of Affective Contact” he described 11 cases, 3 girls and 8 boys as having infantile autism. He noted that the family members were intelligent but generally they were not warm-hearted, and that the parenting style might have contributed to the development of autism. Autism spectrum disorders consist of a group of neurodevelopmental disorders, characterized by a triad of impairments in social interaction, communications, and imagination, associated with narrow range of repetitive activities. Hans Asperger, a Viennese physician, also described a type of autism that he called autistic psychopathy in 1944, which later became to be known as Asperger syndrome. However, since the original article was written in German and was not translated into English until nearly 40 years later, there was no awareness until later when Asperger syndrome was included as a form of autism. However, a Russian neurologist, Grunya Sukharev, published an article in 1926 titled, the schzoid psychopathy in children with nearly identical description as Asperger syndrome.
The etiology of autism had been quite elusive, although there is common belief that autism has a genetic basis; however, the gene expression may be influenced by environmental factors. The genetic influence in development of autism has been shown by twin studies, where there is a high probability that monozygotic twins, who have identical genes, develop autism at a high rate. Heritability index, a measure of genetic transmission of neurobehavioral disorders, autism, hyperactivity, schizophrenia, and major depression are 0.95, 0.8, 0.8, and 0.75, respectively [9].
In the past 40 years, a number of environmental toxins were considered to be the main culprit in the development of autism. Prenatal factors, including maternal folate deficiency and short interpregnancy intervals, do not appear to be causal factors [10]. Perinatal factors, newborn jaundice, breech presentation, and prematurity do not seem to be responsible for autism development. Multiple gene theory and second hit theory which advocate ASD genes induce increased susceptibility to environmental toxins have also been refuted as a cause of autism.
The fraudulent report of finding measles viruses in the guts of 12 children with autism, published in Lancet in 1998, therefore linking autism to MMR vaccine was retracted by the coauthors in 2004 and by the journal’s editor in 2010. Allegations that vaccine’s ingredients (thimerosal, aluminum) are responsible for the epidemic of autism have been soundly refuted by epidemiological studies and there is no scientific basis that there is a causal association between vaccines and autism [11].
In the past 20 years, multidisciplinary research has resulted in better understanding of the complex nature of ASDs. The multicenter study reported by Sanders et al. on the association of copy number variations, characterized by submicroscopic deletions or duplications on chromosomes in the individuals with ASDs, demonstrate the genetic etiology of this disorder [12–14]. However, there is evidence that a number of individuals with CNV genotype have normal phenotypes, indicating incomplete gene penetrance and the influence of environmental factors [12].
3. The role of oxytocin in infant’s brain development
There is significant evidence that oxytocin plays a major role in the development of the mammalian brain [1]. Oxytocin, a neuropeptide is secreted by the paraventricular (PVN) and supraventricular (SON) nuclei in the hypothalamus. Oxytocin was thought to be only a parturition hormone, which initiates the uterine contractions during childbirth and the myoepithelial cells in the breast, pushing breast milk from the alveoli through the milk ducts during breastfeeding. However, animal experiments have generated significant evidence that oxytocin plays a major role in the development of the mammalian’s central nervous system. Oxytocin is implicated in both romantic and maternal love and all aspects of reproduction and breastfeeding. Romantic and maternal love are some of the most inspiring manifestations of human behavior and responsible for the survival of our species. Additionally, oxytocin is a neurotransmitter and neuromodulator and implicated in neuroplasticity of the infant’s central nervous system. There are numerous oxytocin receptors in the central nervous system and the peripheral tissues. However, there are separate oxytocin receptors for romantic and maternal love [1].
Oxytocin is generated by the specialized neuroendocine cells in the hypothalamus, which are activated by the sensory nerves in the infants’ oral mucosa and released during breastfeeding. Additionally, oxytocin is released during skin-to-skin contact with the mother due to sensory nerves responding to warmth, touch, and stroking by the mother [15]. The sensory nerves enter the spinal cord or brain stem and connect to the nucleus tractus solitarius (NTS). Furthermore, oxytocin release is triggered by the breast milk/food in the infant’s stomach, which results in the release of cholecystokinine in the gut. Cholecystokinine stimulates the release of oxytocin by activating the sensory vagal nerve fibers, which results in central and peripheral oxytocin release [1, 15].
The endogenous release of oxytocin results in behavioral changes in both mother and baby, including bonding and attachment. Additionally, oxytocin stimulates the sense of well-being and suppresses the HPA axis [10, 15].
4. Environmental influence on the infant’s brain development
Anthropological studies clearly demonstrate the necessity of the closeness of the mother-baby dyads. The statement by famous anthropologist, Sarah Blaffer Hrdy that “for species such as primates, the mother is the environment” holds very true. Primates such as monkeys, apes, and humans are referred to by scientists as the “carrying mammals” versus the “nested mammal” because of the difference in the sugar and the fat contents of their breast milk and feeding frequency. The human infant’s central nervous system depends on the microenvironment that is similar to the maternal uterine environment, which is full of sensory exchanges involving warmth, sound, movement, transportation, feeling, touch, smell, and access to the nutrients in the mother’s breast milk.
Anthropological studies indicate that the mammalian brain development requires an enriched environment with the mother providing breast milk, emotional and physical support and protection. This is in contrast to a mother who is formula-feeding her infant with little or no emotional and physical support. The infant is not held by the mother or the caretaker, she is frequently ignored and sometimes is physically or emotionally abused. This type of environment which we call a toxic environment frequently results in developmental delay, lower IQ, and neurodevelopmental disorders. The elegant experiments by Volkmar and Grenough demonstrate the effect of environmental enrichment in laboratory rats, which resulted in more complexity and dentritic branching of the visual cortex [16]. Furthermore, Weaver et al. [17] have shown that epigenetic factors can induce gene activation by histone acetylation without changing the DNA sequence. Therefore, histone acetylation results in gene activation in the offspring when they reach maturity.
Imaging studies (Figure 1) comparing the activation of oxytocin receptor sites in formula and breastfeeding mothers demonstrate significant enhancement of oxytocin receptors in breastfeeding mothers, which correlates with greater neural response [1]. Furthermore, higher plasma and salivary oxytocin levels are reported in breastfeeding compared to formula feeding mothers, 36% in plasma and 23% in saliva, respectively [18]. We hypothesize that an increase in brain oxytocin level may improve learning, speech, cognition, parental attachment, and emotional ties. Additional support for the beneficial effect of oxytocin in premature infants is reported from the University of Chicago hospitals. Premature infants, who received sensory stimulations, including auditory, tactile, visual, and vestibular, gained more weight and were discharged home sooner than the control group who did not receive any sensory or only tactile stimulation. Measurements of salivary cortisol levels in the infants showed a decline in the infants associated with ATVV (auditory, tactile, visual, and vestibular) stimulation corresponding to the rise in blood oxytocin level (Figure 2).
Figure 1.
Comparison of the functional MRI studies of breastfeeding and formula feeding mothers after viewing the pictures of their own infants. Oxytocin receptors are significantly enhanced in breastfeeding mothers.
Figure 2.
Salivary cortisol levels in three groups of premature infants, showing a decline associated with ATVV sensory stimulation, which corresponds to a rise in serum oxytocin.
In the past decade, there has been credible evidence that ASDs are associated with oxytocin dysfunction [19]. Modahl et al. [20] reported lower serum oxytocin in children with ASDs. Additionally, oxytocin infusion to adults with ASD resulted in temporary improvement in some of their symptoms [21, 22]. However, it is generally believed that oxytocin does not cross the blood-brain barrier. Therefore, trials of oxytocin nasal spray, which would bypass the blood-brain barrier was attempted for a period of 6 weeks to adults with ASD, which resulted only in temporary improvements in some of the autistic symptoms [23]. These findings indicate that oxytocin has a critical function during the first 5 years of life when the accelerated brain growth occurs.
Population genetic studies have shown that structural alteration of oxytocin are responsible for development of autism [24]. Finally, genetic alterations in oxytocin receptor protein are reported to be associated with ASDs [25].
5. Industrialization, global conflicts, the rise of formula feeding, and autism
It is commonly believed that the rate of breastfeeding in the industrialized nations sank to its lowest level after the 1950s and began to climb in the past 20–30 years. We assume that autism has always existed, but not recognized until the 1940s when it was described independently by Leo Kanner and Hans Asperger. However, it is clear that throughout our history, the prevalence of ASDs was quite low, due to the high rate of breastfeeding and sensory interaction between the mother and her infant. There is clear evidence that there is an increase in the prevalence of ASDs, especially in the United States that in recent years has reached alarming numbers. However, expansion of diagnostic criteria and diagnostic substitution may explain the increase in ASDs diagnosis in the United States. Furthermore, the prevalence of autism is lower in other industrialized nations because of higher rates of breastfeeding and paid maternity leave. In parts of Africa and the Middle East, infants are breastfed for 4 years and they report lower rates of autism.
Historically, the first description of autism was reported independently by three physicians, Grunya Sukharev from Russia, Leo Kanner from the United States, and Hans Asperger from Austria at about the same time. The authors do not describe possible cause(s) for autism and no mention of the type of feedings during infancy. However, we know of the desperate conditions of populace in Russia and Austria. In the United States, many women were working in the factories and the infants were fed cow’s milk or powdered milk. There are no reliable statistics on the breastfeeding rates in the mid-twentieth century. However, cow’s milk or powdered milk feeding became very popular in Europe and the United States. Many women chose injection of a prolactin inhibitor after childbirth to prevent producing any breast milk. In the 1980s, the formula companies began aggressive marketing of infant formulas directly to the consumers. This resulted in World Health Organization’s campaign to counter the formula industry by the passage of the Code of Ethics of Marketing of Breast Milk Substitutes, followed by Baby-Friendly Hospital Initiative.
In the past 20 years, improved public awareness of many benefits of breastfeeding for mother-baby dyads has resulted in higher breastfeeding initiations [3]. This is especially true in college-educated mothers and middle-class families. The rates of breastfeeding in the United States vary greatly by race, ethnicity, parents’ income, parents’ education, and the community support. Many college-educated mothers elect to breastfeed their babies and exclusive breastfeeding rates in this population at 6 months stands at 16%. The rate of breastfeeding is inversely associated with families’ income. Therefore the breastfeeding rates for the families at or above 6 times poverty line at 6 months is 21%, for those at 4.2 times poverty line is 20% and for those below the poverty line is 12%. Accordingly, the breastfeeding rates by mothers at six times above the poverty line, those between 4.2 times, and those below the poverty line are at 21, 20, and 12%, respectively [26]. Breastfeeding rates also vary greatly among the racial groups, whites are at 19%, Hispanics at 16%, and African Americans are at 9% at 6 months [26].
The United States WIC program, Women, Infants and Children, which funds nutrition program for pregnant mothers and children, who are below the 180% poverty level, began providing infant formulas beginning in 1974 to the WIC recipients. The WIC program was enacted in 1972 following a White House Conference on the ill-effects of poverty on pregnancy and the well-being of breastfed infants. During the first 2 years, the program was very successful in eliminating malnutrition in pregnant women and their babies.
However, for the past three generations the great majority of WIC recipients have received free formula for their infants for 1 year. The WIC population has the lowest breastfeeding rates in the United States and numerous interventions to improve breastfeeding rates in this population have not been effective.
There are numerous benefits of exclusive breastfeeding to both mother and her infant, which are attributed to the ingredients of breast milk [2]. However, recent research and genomic studies demonstrate that the infant’s social environment may play a significant role in her brain development. The environmental factors may be positive, including high socioeconomic status (SES), high maternal IQ, breastfeeding, and mother-infant sensory interactions. Negative environmental factors include poverty, formula feeding, lack of high school and college education, absence of mother-baby sensory interaction, neglect, and abuse.
Fragile X syndrome is the most common inherited cause of intellectual disability and the focus of intense research on multiple levels from molecular to the cognitive functions and the IQ of the individuals. Fragile X syndrome is caused by CGC (dinucleotide) repeats on the X chromosome, replacing the FMRP (fragile X mental retardation protein) gene, which results in autism. However, environmental enrichment results in a favorable outcome in some of these children. The IQ of the boys with fragile X syndrome is known to be higher in association with parental responsiveness to the child, having educational material in the home and parental efforts to provide developmental enrichment [27]. The association of home environment with IQ is larger than any other variables, including the child’s level of FMRP and mean parental IQ.
There is clear and convincing evidence that oxytocin has a major role in the development of oxytocin system, connecting the periaqueductal gray matter (PAG), the limbic system and the lateral orbitofrontal cortex, which are identified with maternal behavior [1]. Furthermore, the oxytocin system appears to include a number of pathways, especially in the limbic system, which are affected in various degrees in individuals with ASDs.
6. Association of early weaning and formula feeding with autism
Tanoue and Oda [28] first reported the association of early weaning and autism over 25 years ago. The authors also noted that in their study population, autism was more common in the lower socioeconomic class. The result of a survey comparing the rates of autism in three groups of children was reported by Schultz et al. [29]. The children who were breastfed for 6 months had a lower incidence of autism than the group who were fed formula without DHA&ARA supplementation. However, the group of children who were given formulas supplemented with DHA&ARA also had a lower rate of autism. We strongly believe that the study was flawed because it was conducted in 2004, only 2 years after DHA&ARA supplementation of infant formulas. The diagnosis of autism is usually confirmed in children who are older than 3–4 years old.
6.1. Methods
In this communication, we hypothesize that breastfeeding and nurturing result in a decrease in autism diagnosis. In order to explore this hypothesis, we conducted a confidential written survey of parents to ascertain the association of parent’s reported ASD diagnosis with the duration of breastfeeding, breast milk, or formula feeding. The study focused on the children who were 2–8 years old at the time of the survey and to include only formulas supplemented with DHA and ARA. The survey did not include any questions regarding the brand of the formulas used, because of possible frequent formula changes as well as difficulty recalling the brand name of formulas. Our study was based on an anonymous written retrospective survey which was conducted from our offices. The survey forms were made available from our offices. The completed survey forms were returned through fax to our office. Statistical analysis was performed using binary logistic regression analysis on the data of the children who were breastfed or formula-fed and those who received breast milk via a bottle. In each group there were a number of children who did not have autism. The children without ASD diagnosis were used as the “control group.” The odds ratios, P-values, and confidence intervals were calculated in relation to the duration of breastfeeding, formula feeding, or breast milk feeding using binary regression analysis.
6.2. Results
One hundred and forty-five parents responded to our survey. Eighty-five parents reported no ASD diagnosis and 60 parents reported that their child had ASD diagnosis. The children were divided into three groups. The infants who were formula-fed from birth were placed in the formula-fed group. The infants who were breastfed from birth were placed in the group of breastfed children, regardless of the length of breastfeeding. Twelve of the 60 children who were formula-fed from birth had ASD diagnosis as shown in Table 1. Twenty-six were reported to have been breastfed from less than 2 weeks to greater than 2 years and reported to have a diagnosis of autism as shown in Table 1. The survey results demonstrate that increasing the duration of breastfeeding is associated with a decline in ASD diagnosis as shown in Table 2. The statistical data reveal that children who were breastfed longer than 12 months are 6.67 times less likely to have autism diagnosis than children who were breastfed less than 12 months as shown in Table 3. Breastfeeding of less than 6 months duration was significantly associated with autism diagnosis. Twenty-two out of 64 children who were fed breast milk through a bottle were reported to have ASD diagnosis as shown in Table 4. The odds ratio analysis of the association of breast milk feeding and ASD diagnosis is shown in Table 5. This survey indicates that increasing the duration of breast milk feeding was not associated with a significant decrease in autism diagnosis. We believe that the infants who are bottle-fed with breast milk or formula have little sensory interaction with the mother or caregiver during the feeding Table 6. We hypothesize that breast milk feeding is associated with lower oxytocin release and oxytocin receptors in the infant’s central nervous system. Similarly, in children who were formula-fed and had ASD diagnosis, less sensory interaction between mother-baby during bottle feeding and absence of maternal hormones, especially estrogens, in the infant’s feeding result in lower oxytocin and its receptors in the infant’s brain [30]. The presence of estrogens as well as other maternal hormones in the breast milk has been well documented. Johnson et al. and Champagne et al. have reported that estrogens are transcriptional promoters of oxytocin and oxytocin receptor’s gene in experimental animals [31, 32]. The absence of estrogens in the infant’s feeding or the use of oxytocin blockers in experimental animals results in lower endogenous oxytocin and oxytocin receptors [30–32]. Oxytocin and estrogens have regulatory influence on the oxytocinergic system and have been shown to alter many aspects of cellular function and differentiation as well as potential to remodel the nervous system [33, 34]. Additionally, oxytocin is a neurotransmitter and neuromodulator and may increase neuroplasticity, synaptic connections, and alter ASD genes expression.
Children with ASD diagnosis
Children without ASD diagnosis
Total
Number of formula-fed children
12
22
34
Number of breastfed children
21
26
47
Number of breast milk fed children
22
42
64
55
90
145
Table 1.
Number of breastfed children with ASD diagnosis should be 21 and without ASD diagnosis should be 26 autism relative to the feeding methods, breastfeeding, breast milk, or formula feeding.
Duration of breastfeeding
Number of children with ASD diagnosis
Number of children without ASD diagnosis
<2 months
8
2
2–3.99 months
4
1
4–5.99 months
2
2
6–8.99 months
4
0
9–11.99 months
2
2
12–14.99 months
2
8
15–17.99 months
2
3
18–23.99 months
2
0
>24 months
0
3
Table 2.
Number of children with and without ASD diagnosis relative to the duration of breastfeeding.
Months of breastfeeding
Odds ratio
P-value
95% confidence intervals
<6
0.27
0.04
(0.08–0.95)
6–11.99 months
0.93
0.94
(0.14–6-23)
>12 months
6.67
0.009
(1.61–26.47)
Table 3.
Odds ratios of association of breastfeeding duration and ASD diagnosis.
Duration of breast milk feeding
With ASD diagnosis
Without ASD diagnosis
<2 months
4
8
2–3.99 months
4
6
4–5.99 months
4
4
6–8.99 months
4
8
9–11.99 months
4
5
12–14.99 months
0
5
15–23.99 months
2
2
>24 months
0
4
Table 4.
Number of children with and without ASD relative to the duration of breast milk feeding.
Months of breast milk feeding
Odds ratios
P-value
95% confidence interval
<6 months
0.67
0.37
(0.11–4.31)
6–11.99 months
1.08
0.08
(0.35–3.40)
>12 months
3.67
0.12
(0.69–19.56)
Table 5.
Odds ratios of association of breast milk feeding duration and prevalence of ASD diagnosis.
Table 6.
Cascade of oxytocin system activation in the newborn infants.
There is clear and convincing evidence that links the ingredients of breast milk and infant’s sensory stimulation during breastfeeding to lowering the prevalence of autism. However, there are questions raised that infants who are later diagnosed to have autism may have dysregulated breastfeeding behavior [35]. A small retrospective study of the association of autism and dysregulated breastfeeding behavior revealed that the majority of infants in this study who developed autism were breastfeeding well and a few who were identified as having dysregulated breastfeeding behavior were breastfeeding more often and quite vigorously [35].
In this communication, we demonstrate the association between breastfeeding and decline in prevalence of ASD. We further believe that this effect is mediated by an increase in the endogenous oxytocin in the infant’s central nervous system [1, 13, 15]. The elegant experiments by Krol et al. demonstrate the significance of breastfeeding and oxytocin increase in the central nervous system of infants with CD-38 gene variation. CD-38 gene encodes the enzyme system that releases the oxytocin from the hypothalamic neuroendocrine cells. The individuals who have two copies of the C allele of the enzyme release less oxytocin than the individuals with the A (normal) allele and therefore are at risk of developing ASD [36]. Furthermore, the infants with CC allele of the enzyme who were not breastfed showed less eye contact with their caregiver at 6 months, an early sign of autism, while the infants who were exclusively breastfed continued to maintain normal eye contact with their mother. The author state that oxytocin in the breast milk is absorbed in the infant’s intestinal tract and cross the blood-brain barrier. However, this appears to be very unlikely because breast milk contains small amounts of oxytocin, 8 pg/ml in the first few days, and decreases with increased milk production. It is believed that oxytocin is digested in the infant’s digestive tract and even if it is absorbed into the blood stream, it does not cross the blood-brain barrier [10]. We postulate that the rise of oxytocin in the infant’s central nervous system is due to the presence of estrogens in the breast milk acting as transcriptional promoter of oxytocin gene. We believe that the finding is further indication that breastfeeding provides protection against autism development.
In this communication, we demonstrate the evidence supporting our hypothesis that breastfeeding for 1 year or more is highly associated with reduced prevalence of autism and identify the lack of breastfeeding as a risk factor for the development of ASD in genetically susceptible children.
Acknowledgments
The opinions stated in this communication are only the opinions of the authors. The authors declare no competing interest.
\n',keywords:"autism, neuroplasticity, oxytocin, epigenetics, breastfeeding, enriched environment",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/54644.pdf",chapterXML:"https://mts.intechopen.com/source/xml/54644.xml",downloadPdfUrl:"/chapter/pdf-download/54644",previewPdfUrl:"/chapter/pdf-preview/54644",totalDownloads:2112,totalViews:3829,totalCrossrefCites:2,totalDimensionsCites:4,totalAltmetricsMentions:23,impactScore:3,impactScorePercentile:85,impactScoreQuartile:4,hasAltmetrics:1,dateSubmitted:"January 11th 2017",dateReviewed:"January 26th 2017",datePrePublished:null,datePublished:"April 12th 2017",dateFinished:"April 1st 2017",readingETA:"0",abstract:"There is strong and convincing evidence that infant’s sensory stimulation, which is associated with breastfeeding, contributes significantly to the infant’s neurodevelopment. Our study compared the prevalence of autism spectrum disorder (ASD) in children who were breastfed, given breast milk through a bottle (breast-milk fed), or formula-fed. We reported significant association of ASD in children who were formula-fed from birth or weaned early from the breast. The statistical data revealed that increasing the duration of breastfeeding resulted in a decrease in prevalence of ASD. The odds ratio of a child not having autism was 0.27, 0.93, and 6.67 for breastfeeding for less than 6, 6–12, or longer than 12 months, respectively. There is significant evidence that this association is mediated by the ingredients of the breast milk and infant’s endogenous oxytocin. Oxytocin is a neurotransmitter and neuromodulator and we postulate that oxytocin may increase neuroplasticity, synaptic connections, and alter ASD genes’ expression. Animal experiments and imaging studies demonstrate the central role of oxytocin in maternal love and bonding. Currently, there are no specific treatments for patients diagnosed with autism; therefore, it is imperative to identify the risk factors that contribute to the development of ASD. In this communication, we demonstrate that lack of breastfeeding is highly associated with ASD development in children with genetic susceptibility.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/54644",risUrl:"/chapter/ris/54644",book:{id:"5498",slug:"autism-paradigms-recent-research-and-clinical-applications"},signatures:"Touraj Shafai, Monika Mustafa, Jeffrey Mulari and Antonio Curtis",authors:[{id:"192429",title:"M.D.",name:"Touraj",middleName:null,surname:"Shafai",fullName:"Touraj Shafai",slug:"touraj-shafai",email:"shafaidocs@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Georgetown University",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. What causes autism?",level:"1"},{id:"sec_3",title:"3. The role of oxytocin in infant’s brain development",level:"1"},{id:"sec_4",title:"4. Environmental influence on the infant’s brain development",level:"1"},{id:"sec_5",title:"5. Industrialization, global conflicts, the rise of formula feeding, and autism",level:"1"},{id:"sec_6",title:"6. Association of early weaning and formula feeding with autism",level:"1"},{id:"sec_6_2",title:"6.1. Methods",level:"2"},{id:"sec_7_2",title:"6.2. Results",level:"2"},{id:"sec_9",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Bartel A, Zeki S, The neural correlates of maternal and romantic love, Elsevier, Neuroimage, 21;2004:1155–1165.'},{id:"B2",body:'Breastfeeding and Maternal and Infant Health Outcomes in Developed Countries, Evidence Report, Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, 2007, Rockville, MD.'},{id:"B3",body:'Infant and young child feeding, Fact Sheet, World Health Organization on global rates of breastfeeding Bulletin, February 2015.'},{id:"B4",body:'Victora C et al., Breastfeeding in 21st century, epidemiology, mechanism and lifelong effect, Lancet, 2016,387:10017;475–490.'},{id:"B5",body:'Shafai T, Mustafa M, Hild T, Mulari J, Curtis A, Influence of infant feeding methods: breastfeeding, breast milk or formula feeding on the prevalence of autism spectrum disorders, The Journal of Southern California Clinicians, 2013;7:1;33–38.'},{id:"B6",body:'Shafai T, Mustafa M, Hild T, Mulari J, Curtis A, Association of early weaning and formula feeding with autism spectrum disorders, Breastfeeding Medicine, 2014; 9:5;275–276.'},{id:"B7",body:'Sabuncuoglu O, Orengul C, Bikmazer A et al., Breastfeeding and parafunctional oral habits in children with and without attention deficit/hyperactivity disorder, Breastfeeding Medicine, 2014;9:244–250.'},{id:"B8",body:'Ganz ML, The life-time distribution of the incremental societal cost of autism, Archives of Pediatrics and Adolescent Medicine, 2007;61:343–349.'},{id:"B9",body:'McGuffin P, Riley B, Plomon R, Toward behavioural genomics, Science, 2001;291:1132–1249.'},{id:"B10",body:'Gardener H, Speigelman D, Buka L, Prenatal risk factors for autism: comprehensive meta-analysis, The British Journal of Psychiatry, 2009;195:7–14.'},{id:"B11",body:'Bulletin, Institute of Medicine, Immunization Safety Committee, Vaccines and Autism, Washington D.C., National Academic Press, 2004.'},{id:"B12",body:'Sanders JS, et al., Multiple recurrent de novo CNVs, including duplication of the 7q 11.23 Williams syndrome region, are strongly associated with autism, Neuron, 2011;70:863–885.'},{id:"B13",body:'Gilman SR, Iossifov, Levy D, Ronemus M, Vitkup D, Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses, Neuron, 2011;70:898–907.'},{id:"B14",body:'Levy D et al., Rare de novo and transmitted copy number variation in autistic spectrum disorders, Neuron, 2011;70:886–897.'},{id:"B15",body:'Uvnas Moberg K, Prime DK, Oxytocin effects in mothers and infants during breastfeeding, Infant, 2013;9:201–206.'},{id:"B16",body:'Volkmar FG, Greenough WT, Rearing complexity affects branching of dendrites in the visual cortex of the rat, Science, 1972;176:1445–1447.'},{id:"B17",body:'Weaver ICG, Cervoni N, Champagne FA, et al., Epigenetic programming by maternal behaviour, Nature Neuroscience, 2004;7:848–854.'},{id:"B18",body:'Grewen KM, Davenport RE, Light KC, An investigation of plasma and salivary oxytocin responses in breast and formula feeding mothers of infants, Psychophysiology, 2010;47:285–332.'},{id:"B19",body:'Insel TR, O’Brien DJ, Leckman JF, Oxytocin, vasopressin and autism, is there a connection, Biological Psychiatry, 1999;45:145–157.'},{id:"B20",body:'Modahl C, Green L, Fein D, et al., Plasma oxytocin levels in autistic children, Biological Psychiatry, 1998;43:270–277.'},{id:"B21",body:'Hollander E, Novotney S, Hanratty M, Oxytocin infusion reduces repetitive behaviour in adults with autistic and Asperger disorder, Neuropsychopharmacology, 2003;28:193–198.'},{id:"B22",body:'Hollander E, Bartz J, Chaplin W, Oxytocin increases the retention of social cognition in autism, Biological Psychiatry, 2007;61:498–503.'},{id:"B23",body:'Guastella AJ, Einfeld EL, Gray K, Rinehart N, Tonge B, Lambert TJ, Hichie IB, Intra-nasal oxytocin improves emotion recognition for youth with autism spectrum disorder, Biological Psychiatry, 2009;67:692–704.'},{id:"B24",body:'Green LA, Fein D, Modahl C, Waterhouse C, Morris M, Oxytocin and autistic disorders; alteration in peptide forms, Biological Psychiatry, 2001;50:609–613.'},{id:"B25",body:'Jacob S, Brune CW, Carter CS, et al., Association of oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism, Neuroscience Letters, 2007;417:69.'},{id:"B26",body:'Shafai T, Mustafa M, Hild T, Promotion of exclusive breastfeeding in low-income families by improving the WIC food package for breastfeeding mothers, Breastfeeding Medicine, 2014;9:375–376.'},{id:"B27",body:'Glaser B, Hessl D, Dyer-Feldman J, et al., Biological and environmental contributions to adaptive behaviour in Fragile X syndrome, American Journal of Medical Genetics, 2003;117A:21–29.'},{id:"B28",body:'Tanoue Y, Oda S, Weaning time of children with infantile autism. 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'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Touraj Shafai",address:"shafaidocs@yahoo.com",affiliation:'
Department of Paediatrics, School of Medicine, University of California, Riverside, California
Department of Mathematics, Riverside City College, Riverside, California
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1. Introduction
Ketamine, since its difficult introduction into clinical practice nearly half a millennium ago, has now become widely utilized as an anesthetic agent, especially in adults. Its efficacy in procedural anesthesia and pain management, along with its safety, has been proven in several clinical studies. This book chapter reviews the clinical utility of ketamine when used in young individuals as a premedicant.
Surgical interventions are not merely physically stressful but are an emotionally distressful process for both children and their parents. In a scheduled surgical operation, the preoperative period is a traumatic and challenging experience for younger patients; which is often taken casually. This usually leads to preoperative anxiety, postoperative distress, prolonged child illness, and hospitalization. Excessive preoperative anxiety has been reported to result in more pain, negative postoperative outcomes as fear of anesthesia, and long-term behavioral problems [1].
Approximately 70% of the children exhibit significant stress and anxiety before surgery [2]. Preanesthetic medications are highly required in pediatric surgical patients for the management of preoperative anxiety, to help in iv cannulation, mask acceptance, and prevent long-term psychological/behavioral disturbances.
Approximately 84–100% of anesthesiologists now use the premedicants [3]. As part of the anesthetic technique, these premedicant drugs are given before the administration of an anesthetic agent, to make anesthesia safer and more agreeable to the patient. To alleviate anxiety and fear of surgery and anesthesia a premedicant is usually required before anesthesia.
2. Criteria for selection of premedication
Various factors have to be considered while selecting the premedication. The premedicant must be able:
To provide sedation and hypnosis have an amnesiac effect
To allay anxiety and apprehension
Have an anticholinergic effect
Have anti-emetic effect
Have an additive or synergistic effect on induction, for instance, ensuring a smoother and more rapid induction of anesthesia
To inhibit the parasympathetic nervous system
Reducing the dosage of anesthetic agents
Counteract certain adverse effects of the anesthetic drug
To relieve pain
2.1 Choice of premedicant
It is found that if preoperative apprehension of the child is not relieved, leads to psychic trauma, struggling, prolonged stormy induction, sometimes hypoxemia, or even anoxia owing to inadequate induction and relaxation finally airway obstruction, thereby anesthetic risk is increased or multiply. It is an unforgettable situation for children and even adults and permanent psychological trauma. The choice of premedicant is usually individualized, chosen for a particular patient and technique of anesthesia. They should relieve anxiety and central nervous system (CNS) depressants are necessary for psychic sedation.
3. Commonly used premedicant and their comparison with ketamine
They are fentanyl, midazolam, promethazine pheniramine maleate and dexmedetomidine have their own merits and demerits. Narcotics and benzodiazepines may produce respiratory depression and require close monitoring. Barbiturate, a hypnotic, is also used as a premedicant when basal narcotic doses are required. Such doses produce unconsciousness with respiratory and circulatory depression. Antisecretory agents, the anticholinergics are commonly used with premedicant drugs in children, considered mandatory in new-born and infants due to the following reasons: they suppress secretions or dry up secretion, prevent bradycardia, prevent laryngospasm (may produce due to excessive secretion), produce bronchodilatation and have an antiemetic effect. The most common method of administration of anticholinergic drugs in the past was the intramuscular route now they are used intravenously [4].
3.1 Comparison with phenothiazines
In comparison to ketamine the phenothiazine derivatives as chlorpromazine (the prototype), prochlorperazine, trimeprazine, and promethazine (phenergan), enhance the effects of other central nervous system depressants. They are neuroleptics and dopamine antagonists having antihistaminic, antiadrenergic, anticholinergic, and antiemetic activity.
Contrary to ketamine phenothiazines are sympatholytic and ganglioplegic, can cause hypotension due to alpha-1-adrenergic blockade and peripheral vasodilation; contraindicated in shock, hypotensive, or anemic patients. Phenothiazines possess antiarrhythmic properties, and promethazine of this group has the least side effects and is often recommended. In the past, trimeprazine and promethazine were the most commonly used premedicant in children. Furthermore, they lack any generalized hypnotic effect and do not produce analgesia, instead are ant analgesia. A large dose can depress ventilation, when combined with opioids and hypnotics, due to additive effects, thus respiratory depression may occur.
Contrarily, ketamine is sympathomimetic, a potent analgesic, and has anti-inflammatory, antidepressant, and antiemetic effects through its action centrally on the chemoreceptor trigger zone as well on the vomiting center of the CNS.
Metabolism of phenothiazine is by biotransformation in the liver with glucuronic acid. If overdosed, metabolites are excreted in the urine for several days, as no specific antagonist is available. Phenothiazines can be given, orally, subcutaneously, intramuscularly, or intravenously.
3.2 Comparison with benzodiazepines
The sedative-hypnotic drugs are usually essential premedicants in children, as a struggling child is often challenging to provide anesthesia to. A drowsy or sleepy child makes the process easier. The benzodiazepines are the most common premedicant in this group used in infants and children apart from adult patients because of their good anxiolytic properties coupled with fewer side effects. It was used approximately in 83% population to get smooth induction of anesthesia along with sedation and amnesia. In the past, temazepam or diazepam have been used in children when using ether-based or chloroform-based anesthetic protocols. Temazepam is most frequently used due to its short half-life as compared to diazepam [4]. Midazolam is a benzodiazepine believed to be a good choice for premedication due to its anxiolytic, sedative, anticonvulsant, antiemetic, rapid onset, and relatively short duration of action [5], but several studies have shown that satisfactory results are seen only in 60–80% of cases [6].
However, these drugs are less frequently used by some anesthetists probably due to concern of delayed recovery from anesthesia and respiratory depression following intravenous injection, which requires close monitoring.
The antagonist agent to benzodiazepines is flumazenil which is not frequently used in most parts of the world due to the high cost involved. Flumazenil injection is indicated for a complete or partial reversal of the sedative effects of benzodiazepines in conscious sedation and general anesthesia in both adult and pediatric populations.
3.3 Comparison with alpha 2 adrenergic agonists
In uncooperative children, clonidine or dexmedetomidine can also be used as a premedicant due to its anxiolytic property. They can reduce the need for rescue analgesics, reduce emergence agitation, postoperative nausea and vomiting, and postoperative shivering [7]. Dexmedetomidine being highly selective having sympatholytic properties provides sedation, analgesia, and anxiolysis without causing respiratory depression. It can be used as an adjunct for premedication, especially for those patients who are susceptible to preoperative stress [8].
Thus, children treated with dexmedetomidine are more adequately sedated at the time of arrival in the PACU and a less volatile anesthetic is required to achieve hemodynamic endpoints. This allows rapid recovery from anesthesia with greater overall cardiovascular stability and fewer episodes of tachycardia in the perioperative period [8].
4. Use of ketamine as a premedicant
Ketamine as a premedicant in children is not a very popular practice. It is a non-barbiturate anesthetic, meeting most of the criteria of ideal premedicant produces balanced sedation with intact airway reflexes, immobility, analgesia, amnesia, and dissociation from the environment. The incidence of agitation, anxiety at parental separation, and reaction to insertion of the intravenous catheter were very low while adverse side effects were seen rarely. There is less respiratory depression and no myocardial depression. The cardiovascular changes including changes in blood pressure (BP) or heart rate (HR) are significant when used alone. However, its effects on intracranial pressure and intraocular pressure have been concerning overtime.
5. Routes of administration of ketamine
The use of ketamine as a premedicant in children has not been a very popular practice historically. However, its oral preparations have been reported to be used by some authors in the past [5, 9, 10, 11].
Ketamine is rapidly absorbed after intravenous, intramuscular, or intranasal administrations. It was found that when it is given through the intranasal or intravenous routes, pharmacokinetic parameters were similar [12]. In general, drug absorption is mainly determined by its physicochemical properties. Ketamine’s formulation as the ketamine is highly lipid-soluble which is five times higher than thiopentone. It has an extensive distribution in the body and has low binding to plasma proteins, being approximately 10–30% [13, 14].
Bioavailability of ketamine depends largely on the route of administration as 20% oral; 93–90% intravenous or intramuscular; 25% rectal; 50% intranasal [15, 16].
After the intravenous route of administration, action is achieved within 1 min as it reaches the receptors very quickly with a transfer half-life of less than 1 min. On i.m. administration, the plasma peak concentration attained within 5 min. It is found that on intramuscular injection, the absorption occurs very fast in children as compared to adults. Children’s muscles are not well developed as compared to adults and the regional flow is different.
Ketamine has a lipid-soluble structure, which diffuses more rapidly than nonlipid soluble drugs across cell membranes. On oral administration, it diffuses across a cell membrane from a region of high concentration such as gastrointestinal fluids to low concentration as blood. Apart from the flow following diffusion gradient and lipid solubility, it also depends on size, degree of ionization, and absorptive surface area. After oral administration, most of the ketamine is destroyed in the acidic media of the gastrointestinal tract, degraded by its secretions and enzymes. Despite the large surface area of the stomach, not much of the drug is absorbed from the stomach due to the thick mucus layer. Furthermore, owing to its parasympatholytic effect it has a short transit time hence gets less time for absorption. Thus, a large part of the drug gets destroyed on oral administration as compared to intramuscular or intravenous [3].
The intrarectal ketamine bioavailability is 25% while intranasal has 50%. It is found that nor ketamine plasma concentration achieved higher as compared to ketamine on identical dose [3].
5.1 Common clinical practice regarding the route of administration
Despite faster absorption by intravenous and intramuscular routes, it was most commonly used by the oral route in the past. Oral transmucosal ketamine (OTK) in the form of a lollipop was also used in the past.
In our hospital, we use ketamine as premedication either intravenous or intramuscular route.
Figure 1 summarizes the decision-making behind choosing between the two routes of ketamine.
Figure 1.
Comparison of intravenous and intramuscular dosing of ketamine. Figure adapted from Emergency Medicine Cases website. Available from: https://emergencymedicinecases.com/pediatric-procedural-sedation/, Creative Commons License.
The effectiveness of ketamine as premedication may be assessed based on Epstein et al. [17] scoring system, i.e. the Five Points-Sedation Score.
Asleep,
Not readily arousable,
Asleep, but arousable,
Calm but awake,
Restless, agitated
With ketamine, we should be getting a score of either 1 or 2 indicating the adequacy of sedation.
Regarding the score for acceptance of separation from parents (scoring = 1. easy, 2. slightly resistant, 3. markedly resistant) we get the score of 1 usually, representing competence of ketamine as premedication.
For mask acceptance (1. easy, 2. slightly resistant, 3. markedly resistant) again, the score with ketamine is usually 1, signifying the capability of ketamine as premedication.
6. Standard protocol for ketamine as premedicant
Prerequisite for ketamine premedication includes the readily available all resuscitation equipment, emergency drugs anesthesia machine, or Ambu resuscitator for positive pressure ventilation and continuous oxygen source.
Preanesthetic evaluation to be done before ketamine administration. Children under 3 months of age are an absolute contraindication and age between 3 and 6 months is a relative contraindication to ketamine-based anesthesia. Pulmonary as current upper respiratory infection or neurologic disease as psychosis were not considered fit for ketamine premedication. Children with cardiovascular diseases where increased heart rate and cardiac workload is present as hypertension, ischaemic heart disease, cardiac failure are also cases where ketamine is contraindicated. Thyroid disease, and acute globe injury or glaucoma are considered as a contraindication to ketamine anesthesia.
The procedure should be explained to the parents including sedation and even about rare unpleasant emergence phenomena. Informed consent must be obtained before the use of ketamine premedication. Baseline vitals to be checked including BP, HR, RR, and O2 saturation. If the administration is planned apart from an oral route, then topical anesthetic cream should be applied approximately 45–60 min before the start of the intravenous line.
Anticholinergics as glycopyrrolate or atropine are necessary with ketamine premedication to prevent the excessive salivation associated with ketamine use, which may lead to blockage of the endotracheal tube due to drooling of saliva. However, in oral or intramuscular ketamine premedication, anticholinergic is usually given after sedation, following the start of the intravenous line. Intravenous ketamine premedication is started with anticholinergic as glycopyrrolate/atropine depending upon pediatric age, infants, or grown-up child. Benzodiazepines such as midazolam are usually given simultaneously in a low dose with ketamine via i.v. or i.m. route to prevent its psychomimetic effects like agitation, hypertension, hyperthermia, and seizures [18].
Anesthetic adjunctive agent as ondansetron may be considered before the start of ketamine sedation, in children over 8 years of age [19].
Standard monitoring includes pulse oximetry, non-invasive blood pressure, heart rate and respiratory rates (RR) along with close observation of the airway and chest movements are required. The intravenous line usually sets in after achieving sedation and analgesia.
The oral ketamine dose is 4–6 mg/kg, usually, 5 mg/kg is adequate. Intravenous dose is 1–2 mg/kg, usually, 1.5 mg/kg, given slowly (over 1–2 min) as rapid administration may lead to respiratory depression, clinical onset is 1–2 min. The intramuscular dose is 2–4 mg/kg, clinical onset 3–4 min, effective sedation is achieved within 5 min. Intranasal is 3–5 mg/kg onset 10–15 min and buccal/transmucosal is 5–6 mg/kg onset is also 10–15 min. Per-rectal ketamine usually 5–10 mg/kg is given. 10 mg/kg may lead to delayed emergence from anesthesia [20].
In our institution, we prefer the intramuscular route for ketamine premedication in an uncooperative or frightened child or when it is difficult to put IV line or where no intravenous access has been secured before the transfer of the child to the preoperative preparation room. If there is already an IV line then it is a reasonable approach to administer ketamine intravenously. However, rapid injection through the intravenous route has also been associated with respiratory depression [21].
7. Side effects of ketamine premedication
Ketamine does have side effects. Most commonly these are seen as vocalization, random purposeless movements, muscle twitching, and hypersalivation, and transient tachycardia and/or hypertension.
Hypersalivation needs essential anticholinergic in premedication and may require oral suctioning. Excessive salivation and bronchial secretions may sometimes lead to occasional laryngospasm (incidence of 0.3%) which needed immediate positive pressure ventilation, or rapid sequence intubation (RSI) [22]. Respiratory depression (0.4%) or even transient apnoea may occur, assisted mask ventilation may be needed. Vomiting is common in older children usually over 8 years of age. In short surgical procedures where oral ketamine is used as premedicant unpleasant emergence, phenomena may be seen beyond mid-adolescence, which resolve after some time in a calm and quiet environment with minimal or no stimulation.
Generally, the side effects are related to doses, larger doses take less onset time but longer time for metabolism and excretion, finally more chances of residual effects as hallucination, emergence, and vomiting. Orally administered ketamine of 6 mg/kg have an onset of action to produce sedation 10 min as compared to 3 mg/kg takes 20 min [23, 24].
8. Use of co-medication with ketamine
The combination of ketamine with other drugs has also been used in several studies, with the co-medication helping to overcome the side effects and increases bioavailability by affecting the drug disposition and its pharmacokinetics [12].
8.1 Combination of ketamine with midazolam
It is reported that when a combination of ketamine and midazolam administered orally produces 90% successful anxiolysis as compared to <75% when either drug is given alone. This oral mixture produces a better quality of sedation and amnesia and requires less IV propofol as compared to intramuscular meperidine, promethazine, and chlorpromazine for pediatric cardiac catheterization [25].
8.2 Combination of ketamine with dexmedetomidine
The combination of dexmedetomidine with ketamine reduces its cardiovascular effects and slower the elimination, as dexmedetomidine is a strong inhibitor of the N-demethylation of ketamine to norketamine.
9. Conclusions
As a potent analgesic, ketamine has a complex mechanism of action, producing a state of sedation, immobility, analgesia, amnesia, and dissociation from the environment. Ketamine as a premedicant especially in subanaesthetic doses and in combination with midazolam produces prompt sedation. Some institutions are using ketamine in infants over 7 months and toddlers as part of premedication protocols for preoperative sedation, prevention of response to separation and intravenous access, and postoperative pain control in infants. This helps in smooth separation from parents and the child accepts the face mask easily, is immobile, is dissociated from the environment. There is little incidence of emergence phenomenon on recovery. The patient is somewhat sedated without any respiratory depression or suppression of protective reflexes or any other untoward side effects with good postoperative analgesia. Intramuscular ketamine as a premedicant in subanaesthetic doses has a special role in the management of uncooperative children.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"ketamine, procedural sedation, analgesia, dissociative anesthesia, preanesthetic drug, premedication",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/79471.pdf",chapterXML:"https://mts.intechopen.com/source/xml/79471.xml",downloadPdfUrl:"/chapter/pdf-download/79471",previewPdfUrl:"/chapter/pdf-preview/79471",totalDownloads:73,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 3rd 2021",dateReviewed:"October 22nd 2021",datePrePublished:"November 26th 2021",datePublished:null,dateFinished:"November 26th 2021",readingETA:"0",abstract:"Ketamine, since its difficult introduction into clinical practice nearly half a millennium ago, has now become widely utilized as an anesthetic agent, especially in adults. Its efficacy in procedural anesthesia and pain management, along with its safety, has been proven in several clinical studies. This book chapter reviews the clinical utility of ketamine when used in young individuals. Premedication is an essential component of anesthetic protocol for parents and children to overcome emotional or psychological distress. Preoperative anxiety, being associated with greater pain during postoperative recovery in children, calls for the effective use of premedicants. This chapter describes how the cognizance of perioperative pain and the use of ketamine in children has become especially popular over the past few decades. It also discusses how intramuscular ketamine as a premedicant in subanaesthetic doses has a special role in the management of highly uncooperative children. As a potent analgesic, ketamine has a complex mechanism of action, producing a state of sedation, immobility, analgesia, amnesia, and dissociation from the environment. Some institutions are using ketamine in infants over 7 months and toddlers as part of premedication protocols for preoperative sedation, prevention of response to separation and intravenous access, and postoperative pain control in infants. This chapter also discusses the pearls and pitfalls in using ketamine in these challenging populations.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/79471",risUrl:"/chapter/ris/79471",signatures:"Shahla Haleem",book:{id:"11036",type:"book",title:"Ketamine Revisited - New Insights into NMDA Inhibitors",subtitle:null,fullTitle:"Ketamine Revisited - New Insights into NMDA Inhibitors",slug:null,publishedDate:null,bookSignature:"Dr. Nieves Saiz-Sapena and Dr. Manuel Granell Gil",coverURL:"https://cdn.intechopen.com/books/images_new/11036.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-83962-793-4",printIsbn:"978-1-83962-792-7",pdfIsbn:"978-1-83962-831-3",isAvailableForWebshopOrdering:!0,editors:[{id:"204651",title:"Dr.",name:"Nieves",middleName:null,surname:"Saiz-Sapena",slug:"nieves-saiz-sapena",fullName:"Nieves Saiz-Sapena"}],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. Criteria for selection of premedication",level:"1"},{id:"sec_2_2",title:"2.1 Choice of premedicant",level:"2"},{id:"sec_4",title:"3. Commonly used premedicant and their comparison with ketamine",level:"1"},{id:"sec_4_2",title:"3.1 Comparison with phenothiazines",level:"2"},{id:"sec_5_2",title:"3.2 Comparison with benzodiazepines",level:"2"},{id:"sec_6_2",title:"3.3 Comparison with alpha 2 adrenergic agonists",level:"2"},{id:"sec_8",title:"4. Use of ketamine as a premedicant",level:"1"},{id:"sec_9",title:"5. Routes of administration of ketamine",level:"1"},{id:"sec_9_2",title:"5.1 Common clinical practice regarding the route of administration",level:"2"},{id:"sec_11",title:"6. Standard protocol for ketamine as premedicant",level:"1"},{id:"sec_12",title:"7. Side effects of ketamine premedication",level:"1"},{id:"sec_13",title:"8. Use of co-medication with ketamine",level:"1"},{id:"sec_13_2",title:"8.1 Combination of ketamine with midazolam",level:"2"},{id:"sec_14_2",title:"8.2 Combination of ketamine with dexmedetomidine",level:"2"},{id:"sec_16",title:"9. Conclusions",level:"1"},{id:"sec_20",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Deshmukh PV, Kulkarni SS, Parchandekar MK, Sikchi SP. Comparison of preanesthetic sedation in pediatric patients with oral and intranasal midazolam. Journal of Anaesthesiology Clinical Pharmacology. 2016;32(3):353-358'},{id:"B2",body:'Kain ZN, Mayes LC, O’Connor TZ, Cicchetti DV. Preoperative anxiety in children. Predictors and outcomes. Archives of Pediatrics and Adolescent Medicine. 1996;150:1238-1245'},{id:"B3",body:'Mion G, Villevieille T. Ketamine pharmacology: An update (pharmacodynamics and molecular aspects, recent findings). CNS Neuroscience & Therapeutics. 2013;19:370-380'},{id:"B4",body:'Mirakhur RK. Preanaesthetic medication: A survey of current usage. Journal of the Royal Society of Medicine. 1991;84:481'},{id:"B5",body:'Funk W, Jakob W, Riedl T, et al. Oral preanaesthetic medication for children: Double-blind randomized study of a combination of midazolam and ketamine vs midazolam or ketamine alone. British Journal of Anaesthesia. 2000;84:335-340'},{id:"B6",body:'Kogan A, Katz J, Efrat R, Eidelman LA. Premedication with midazolam in young children: A comparison of four routes of administration. Pediatric Anaesthesia. 2002;12:685-689'},{id:"B7",body:'Nishina K, Mikawa K. Clonidine in paediatric anaesthesia. Current Opinion in Anaesthesiology. 2002;15:309-316'},{id:"B8",body:'Bhana N, Goa KL, McClellan KJ. Dexmedetomidine. Drugs. 2000;59(2):263-268'},{id:"B9",body:'Gutstein HB, Johnson KL, Heard HB, Gregory GA. Oral ketamine preanesthetic medication in children. Anesthesiology. 1992;76:28-33'},{id:"B10",body:'Gingrich BK. Difficulties encountered in a comparative study of orally administered midazolam and ketamine. Anesthesiology. 1994;80:1414-1415'},{id:"B11",body:'Ashwani K, Anuradha AS, Rakesh G, Mridu PN. Comparative evaluation of ketamine, midazolam and combination of both as oral premedicants in children. Journal of Anaesthesiology Clinical Pharmacology. 2009;25:449-453'},{id:"B12",body:'Vlerick L, Devreese M, Peremans K, Dockx R, Croubels S, Duchateau L, et al. Pharmacokinetics, absolute bioavailability and tolerability of ketamine after intranasal administration to dexmedetomidine sedated dogs. PLoS One. 2020;15(1):e0227762. DOI: 10.1371/journal.pone.0227762'},{id:"B13",body:'Drug Absorption—Clinical Pharmacology—MSD Manuals. Available from: https://www.msdmanuals.com'},{id:"B14",body:'Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. Journal of Pharmaceutical Sciences. 1982;71(5):539-542. DOI: 10.1002/jps.2600710516'},{id:"B15",body:'Fanta S, Kinnunen M, Backman JT, Kalso E. Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing. European Journal of Clinical Pharmacology. 2015;71:441-447'},{id:"B16",body:'Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. British Journal of Anaesthesia. 1996;77:203-207'},{id:"B17",body:'Epstein RH, Mendel HG, Witkowski TA, Waters R, Guarniari KM, Marr AT, et al. The safety and efficacy of oral transmucosal fentanyl citrate for preoperative sedation in young children. Anesthesia and Analgesia. 1996;83:1200-1205'},{id:"B18",body:'Rabie ME. Combination of oral ketamine and midazolam versus midazolam alone as a premedication in children undergoing tonsillectomy. Alexandria Journal of Anaesthesia and Intensive Care. 2005;8(3):58-64'},{id:"B19",body:'Langston WT, Wathen JE, Roback MG, Bajaj L. Effect of ondansetron on the incidence of vomiting associated with ketamine sedation in children: A double-blind, randomized, placebo-controlled trial. Annals of Emergency Medicine. 2008;52(1):30-34'},{id:"B20",body:'Tanaka M, Sato M, Saito A, Nishikawa T. Reevaluation of rectal ketamine premedication in children: Comparison with rectal midazolam. Anesthesiology. 2000;93(5):1217-1224. DOI: 10.1097/00000542-200011000-00014'},{id:"B21",body:'Deasy C, Babl EF. Intravenous vs intramuscular ketamine for pediatric procedural sedation by emergency medicine specialists: A review. Pediatric Anesthesia. 2010;20:787-796'},{id:"B22",body:'Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, review and implications. Annals of Emergency Medicine. 1990;19:1033-1046'},{id:"B23",body:'Filatov SM, Baer GA, Rorarius MG, Oikkonen M. Efficacy and safety of premedication with oral ketamine for day-case adenoidectomy compared with rectal diazepam/diclofenac and EMLA. Acta Anaesthesiologica Scandinavica. 2000;44:118-124'},{id:"B24",body:'Sekerci CM, Donmez A, Ates Y, Okten F. Oral ketamine premedication in children (placebo controlled double blind study). European Journal of Anaesthesiology. 1996;13:606-611'},{id:"B25",body:'Auden SM, Sobczyk WL, Solinger RE, Goldsmith LJ. Oral ketamine/midazolam is superior to intramuscular meperidine, promethazine, and chlorpromazine for pediatric cardiac catheterization. Anesthesia and Analgesia. 2000;90:299-305'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Shahla Haleem",address:"shahlahaleem@yahoo.co.in",affiliation:'
Faculty of Medicine, Department of Anaesthesiology and Critical Care, J.N. Medical College, AMU, Aligarh, India
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\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
\r\n
\r\n\t
\r\n
\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
\r\n
\r\n\t
\r\n
\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
\r\n
\r\n\t
\r\n
\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
\r\n
\r\n\t
\r\n
\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
\r\n
\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
\r\n
\r\n\t
\r\n
\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
\r\n
\r\n\t
\r\n
\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"June 28th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. 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Currently, he is a professor of Orthodontics. He holds a Certificate of Advanced Study type A in Technology of Biomaterials used in Dentistry (1995); Certificate of Advanced Study type B in Dento-Facial Orthopaedics (1997) from the Faculty of Dental Surgery, University Denis Diderot-Paris VII, France; Diploma of Advanced Study (DESA) in Biocompatibility of Biomaterials from the Faculty of Medicine and Pharmacy of Casablanca (2002); Certificate of Clinical Occlusodontics from the Faculty of Dentistry of Casablanca (2004); University Diploma of Biostatistics and Perceptual Health Measurement from the Faculty of Medicine and Pharmacy of Casablanca (2011); and a University Diploma of Pedagogy of Odontological Sciences from the Faculty of Dentistry of Casablanca (2013). 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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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. 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\r\n\tThis series will provide a comprehensive overview of recent research trends in business and management, economics, and marketing. Topics will include asset liability management, financial consequences of the financial crisis and covid-19, financial accounting, mergers and acquisitions, management accounting, SMEs, financial markets, corporate finance and governance, managerial technology and innovation, resource management and sustainable development, social entrepreneurship, corporate responsibility, ethics and accountability, microeconomics, labour economics, macroeconomics, public economics, financial economics, econometrics, direct marketing, creative marketing, internet marketing, market planning and forecasting, brand management, market segmentation and targeting and other topics under business and management. This book series will focus on various aspects of business and management whose in-depth understanding is critical for business and company management to function effectively during this uncertain time of financial crisis, Covid-19 pandemic, and military activity in Europe.
",coverUrl:"https://cdn.intechopen.com/series/covers/22.jpg",latestPublicationDate:"June 27th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:2,numberOfPublishedChapters:19,numberOfPublishedBooks:1,editor:{id:"356540",title:"Prof.",name:"Taufiq",middleName:null,surname:"Choudhry",fullName:"Taufiq Choudhry",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000036X2hvQAC/Profile_Picture_2022-03-14T08:58:03.jpg",biography:"Prof. Choudhry holds a BSc degree in Economics from the University of Iowa, as well as a Masters and Ph.D. in Applied Economics from Clemson University, USA. In January 2006, he became a Professor of Finance at the University of Southampton Business School. He was previously a Professor of Finance at the University of Bradford Management School. He has over 80 articles published in international finance and economics journals. His research interests and specialties include financial econometrics, financial economics, international economics and finance, housing markets, financial markets, among others.",institutionString:null,institution:{name:"University of Southampton",institutionURL:null,country:{name:"United Kingdom"}}},subseries:[{id:"86",title:"Business and Management",keywords:"Demographic shifts, Innovation, Technology, Next-gen leaders, Worldwide environmental issues and clean technology, Uncertainty and political risks, Radical adjacency, Emergence of new business ecosystem type, Emergence of different leader and leader values types, Universal connector, Elastic enterprise, Business platform, Supply chain complexity",scope:"
\r\n\tThe Business and Management series topic focuses on the most pressing issues confronting organizations today and in the future. Businesses are trying to figure out how to lead in a time of global uncertainty. In emerging markets, issues such as ill-defined or unstable policies, as well as corrupt practices, can be hugely problematic. Changes in governments can result in new policy, regulations, and interest rates, all of which can be detrimental to foreign businesses and investments. A growing trend towards economic nationalism also makes the current global political landscape potentially hostile towards international businesses.
\r\n
\r\n\tThe demographic shifts are creating interesting challenges. People are living longer, resulting to an aging demographic. We have a large population of older workers and retirees who are living longer lives, combined with a declining birthrate in most parts of the world. Businesses of all types are looking at how technology is affecting their operations. Several questions arise, such as: How is technology changing what we do? How is it transforming us internally, how is it influencing our clients and our business strategy? It is about leveraging technology to improve efficiency, connect with customers more effectively, and drive innovation. The majority of innovative companies are technology-driven businesses. Realizing digital transformation is today’s top issue and will remain so for the next five years. Improving organizational agility, expanding portfolios of products and services, creating, and maintaining a culture of innovation, and developing next -generation leaders were also identified as top challenges in terms of both current and future issues.
\r\n
\r\n\tThe most sustained profitable growth occurs when a company expands its core business into an adjacent space. This has significant implications for management because innovation in business ecosystems differs from traditional, vertically integrated firms. Every organization in the ecosystem must be aware of the bigger picture. Innovation in ecosystems necessitates collaborative action to invent and appraise, efficient, cross-organizational knowledge flows, modular architectures, and good stewardship of legacy systems. It is built on multiple, interconnected platforms. Environmental factors have already had a significant impact in the West and will continue to have an impact globally. Businesses must take into account the environmental impact of their daily operations. The advantage of this market is that it is expected to grow more rapidly than the overall economy. Another significant challenge is preparing the next generation of leaders to elevate this to the number one priority within the next five years. There can be no culture of innovation unless there is diverse leadership or development of the next generation of leaders; and these diverse, next-generation leaders are the ones who will truly understand the digital strategies that will drive digital transformation.
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\r\n\tThe topic on Economics is designed to disseminate knowledge around broad global economic issues. Original submissions will be accepted in English for applied and theoretical articles, case studies and reviews about the specific challenges and opportunities faced by the economies and markets around the world. The authors are encouraged to apply rigorous economic analysis with significant policy implications for developed and developing countries. Examples of subjects of interest will include, but are not limited to globalization, economic integration, growth and development, international trade, environmental development, country specific comparative analysis, technical innovation and knowledge management, political economy analysis, and banking and financial markets.
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\r\n\tMarketing is an important aspect in the functioning of all types of organizations. The external environment is characterized by constant and dynamic changes, that pose risks to the company. It is associated with changes in macroeconomic, political, legal, and demographic, as well as new consumer trends. It is necessary to carefully plan marketing activities in order to provide the market with products that satisfy consumers' needs and desires, provide them with value, and bring satisfaction and contentment. Therefore, in this topic, we focus on overall marketing efforts, including marketing communications through traditional and social media, pricing strategies, distribution strategies, branding, innovation, and new product launches, as well as researching the current market and consumer trends. We also analyze the latest trends and tendencies in marketing, such as product placement and neuromarketing.
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