Selection criteria for patients with severe disabilities who are candidates for orthodontic treatment (modified from [9]).
\r\n\t
",isbn:"978-1-80356-777-8",printIsbn:"978-1-80356-776-1",pdfIsbn:"978-1-80356-778-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"84908e027f884ec3fcbaea42eb69b698",bookSignature:"Dr. Hayri Baytan Ozmen",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11524.jpg",keywords:"Computational Intelligence, Fuzzy Clustering, Fuzzy Sets Theory, Genetic Algorithm, Neural Network, Artificial Intelligence, Decision Making, Control Theory, Computer-Aided Diagnosis, Fuzzy Optimization, Pattern Recognition, Feature Extraction",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 1st 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:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Researcher with more than sixty-five research papers published in international journals and has been involved in more than ten national and international research projects. 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We should therefore ask ourselves the following question: Are these patients susceptible to orthodontic treatment? The main indication for orthodontic treatment is dental malocclusion. In 1956, Lyons [2] had already suggested that CP had effects on dentofacial development and, in particular, on tooth occlusion (to facilitate comprehension, a glossary of orthodontic terms has been included at the end of the chapter [Box 1]). The most common malocclusions described in CP patients are overjet and overbite, which have significantly higher prevalences in these patients than in healthy controls matched for sex and race [3]. Overjet ≥ 4 mm has been reported in around 70% of spastic CP children and anterior open bite ≥ 2 mm in up to 90% of cases [4]. Compared with other physical disabilities, there is a particularly high prevalence of open bite in CP; it is estimated that children diagnosed with CP have a threefold greater chance of having open bite than children with other special needs [5]. Paradoxically, when anteroposterior malocclusion is analysed, the prevalence of Angle Class I (normo-occlusion) in patients with CP is higher than in the general population [3]. However, malocclusion in the vertical plane provokes marked functional alterations that, in some cases, could justify performing orthopaedic-orthodontic treatment (Figure 1).
Severe open bite and oral functional impairment in a spastic cerebral palsy patient.
A study carried out in Minas Gerais in Brazil, with the participation of 60 spastic CP children and 60 age-matched controls, showed that some orofacial alterations with functional repercussions were more common in CP children than in the controls: severe lip incompetence was 2.8 times more common, mouth breathing 4.8 times more common and long facies 5.4 times more common [4]. Unfortunately, oral functionality is often left as a secondary issue when discussing the need for orthodontic treatment and many dental practitioners focus treatment on cosmetic objectives. The index most widely used for this purpose is the Dental Aesthetic Index (DAI), published 30 years ago by investigators in the University of Iowa. That index gives us the following classification for malocclusion: mild or absent (DAI score <25), defined (DAI = 26–30), severe (DAI = 31–35) and very severe or debilitating (DAI > 35) [6]. ‘Severe’ and ‘very severe’ malocclusions (DAI ≥ 31) are usually considered susceptible to orthodontic correction from a cosmetic point of view [6]. In a study of 44 CP patients of 12–59 years of age performed in Spain, significant differences were observed in the DAI scores for lip incompetence and mouth breathing compared with healthy controls [7]. In that series, resting head position also affected the DAI score; the highest scores were observed in patients with absent resting heading position control, followed by those who held their head permanently in flexion, those who held their head in hyperextension and, finally, those with a resting head position in a vertical axis [7].
\nA relevant issue is whether CP patients with associated mental disability have a less favourable facial phenotype than those with an intellectual coefficient in the normal range (Figure 2). On this subject, a study performed in Leeds, in the United Kingdom, found significantly greater overjet in CP with mental disability (mean of 8.3 versus 5.5 mm) as well as a higher frequency of Angle Class II division 1 (Class II-1) malocclusion (75% versus 36%) [3].
Cerebral palsy is a physical disability and many patients have a normal intelligence.
No large series of CP patients undergoing orthodontic treatment has been published in the literature, with the exception of a group of 62 adult CP individuals living in Bad Oeynhausen in Bielefeld, Germany; 32% of the patients aged between 18 and 36 years had worn orthodontic appliances, whereas none of the 31 patients aged over 36 years had received treatment. A possible interpretation of such a difference is that it could have been due to the individual initiative of a single dental practitioner or group of practitioners, and the results should therefore be extrapolated with a degree of caution [8]. It has been suggested that the aims of orthodontic treatment in patients with disabilities should focus on optimal aesthetic improvement and enhanced social acceptance, taking into account that an ‘ideal’ treatment may not be possible [9]. In a review of the literature, we found no studies or case reports that explored the benefits and effects of functional or fixed orthodontic appliance therapy in children with CP [10].
\nThe following basic requirements need to be satisfied when considering orthodontic treatment in children with disabilities: the commitment of the patient and of the parents/carers, adequate oral hygiene, the degree of patient collaboration (behaviour management) and manual dexterity [11]. The criteria for patient selection are detailed in Table 1.
\n• Medical condition | \n
• Malocclusion | \n
• Aesthetic assessment | \n
• Parent/carer commitment | \n
• Child’s tolerance to treatment | \n
• Oral hygiene | \n
• Risk/benefit ratio | \n
Selection criteria for patients with severe disabilities who are candidates for orthodontic treatment (modified from [9]).
• Impressions using quick-set materials | \n
• Easy bonding of brackets | \n
• Self-etching primer | \n
• Advanced memory wires | \n
• Self-ligating brackets | \n
• Oral functionality | \n
• Advances in orthognathic surgery | \n
• Reversible mini-implant anchorage | \n
Technological innovations for dental patients with disabilities (modified with permission from Becker and Shapira [11]).
Certain technological improvements in dentistry in recent years could benefit disabled dental patients in general, including CP patients receiving orthodontic treatment [12] (Table 2). These technical innovations and the creation of multidisciplinary teams have made it possible to undertake orthodontic treatment in CP patients with extra-oral appliances (Figure 3), fixed multi-bracket appliances (Figure 4) and even complex orthodontic treatments and orthognathic surgery (Figure 5).
\nCerebral palsy patient with severe Class II-1 malocclusion. Initial phase of orthodontic treatment with a face mask.
Cerebral palsy patient with Class II-1 malocclusion treated with fixed multi-bracket appliances.
Cerebral palsy patient with open bite treated using fixed multi-bracket appliances before undergoing orthognathic surgery.
Evaluation of the results of orthodontic treatment as successful or unsuccessful requires more than simply quantifying the aesthetic improvement. Parameters such as oral functionality, quality of life and, very importantly, relapse rates must also be taken into account.
\nIn 2014, İşcan et al. [10] published a case report of a 12-year-old girl with ataxic CP who had Class II malocclusion, maxillary transverse deficiency and severe crowding. Treatment consisted of maxillary expansion with simultaneous functional therapy, fixed multi-bracket appliances and a vertical chin cup. The authors reported that acceptable occlusion, improvements in swallowing, speech and drooling, better masticatory muscle activity and a reduction in problems of impaired chewing were achieved [10]. That study demonstrated the need to develop tools able to quantify oral functional deficits—similar to the tools used to quantify cosmetic appearance, such as the Dental Aesthetic Index—to provide an objective assessment of the functional improvements accomplished by orthodontic treatment.
\nA survey of satisfaction and the appreciation of improvements answered by the parents of disabled children—including CP children—who underwent orthodontic treatment made the following findings: results exceeded expectations in 42% of cases, the reaction of friends and relatives was defined as ‘they got excited’ in 54% of cases, there was a very marked improvement in patient daily activities in 81% of cases, and the child’s social life improved significantly according to 45% of respondents [13]. An analysis of the benefits of orthodontic treatment as perceived by the parents of disabled children reported that improvement in quality of life was a response given by 83% of surveyed parents, improvement in social acceptance in 78% of cases and improvement in social integration in 71% of cases. Interestingly, when asked about their desire to enhance dental and facial appearance, only 68% of participants answered ‘a lot’ and 20% ‘a little’ [13].
\nWe have found no published studies designed specifically to address the issue of improvement in the quality of life of CP children following orthodontic treatment. In a study performed in Sao Paulo, Brazil, in which the parents of 60 CP children aged 6–14 years were interviewed, it was found that the Child Oral Health-Related Quality of Life Questionnaire (COHRQoL) score was not affected by the presence of malocclusion, dental injuries or dental fluorosis, but, in contrast, there was a significant correlation with a history of dental caries, bruxism and family income [14].
\nCerebral palsy patient with severe scoliosis that altered the resting position and affected the occlusal pattern (unilateral open bite).
Regular dental check-ups are mandatory in patients with CP because they are more prone to oral health problems related to enamel hypoplasia, pasty food intake, difficulty in maintaining good oral hygiene, drug-induced gingival hyperplasia and periodontal disease [4]. Consequently, parents and caregivers have to receive oral hygiene and diet instructions to avoid carious lesions, and patient will receive professional scaling at regular intervals before, during and after orthodontic treatment, to avoid periodontal disease [15].
\nIn an article published in 1927 by Stillwell [16], it was suggested that malocclusion and scoliosis affected posture and that this was a two-way relationship, in that alterations of posture also had repercussions on the teeth and the spine. This factor is probably often underestimated by health professionals, and it needs to be taken into account to be able to assess the risk of relapse. The relationship between malocclusion and vertebral alignment was demonstrated in an experimental model in animals (rats), in which the application of resin to induce unilateral premature tooth contact provoked iatrogenic scoliosis within a few weeks; this alteration was reversible when natural occlusal contact was restored [17]. This relationship is so strong that it has been suggested that the detection of hereditary malocclusions in young children ‘allows the identification of a group of children who have a high risk of developing scoliosis in later years’ [18]. In a systematic review published in 2011, it was concluded that there is plausible evidence for an increased prevalence of unilateral Angle Class II malocclusions associated with scoliosis and an increased risk of lateral crossbite and midline deviation in children affected by scoliosis [19] (Figure 6).
\nCerebral palsy patient with open bite relapse after treatment with fixed multi-bracket appliances and orthognathic surgery.
Although the routine use of specific braces to stabilise the spine in CP children was initiated in the second half of the nineteenth century, certain improvements have been made to the modern versions of these braces. Probably the most popular model is the Milwaukee brace, whose effect on dentofacial growth has been described in detail, particularly with regard to abnormal proclination of the upper and lower incisor teeth [20]. Descriptions of cases of orthodontic treatment for malocclusion associated with scoliosis (mainly overjet) have also been published [21].
\nAll these contributions indirectly confirm not only the close two-way relationship between resting position and malocclusion but also introduce a new conditioning factor, neuromuscular alterations, particularly relevant when muscle hypertonicity or spasticity is present. In our experience, these three factors are the principal determinants of relapse, and orthodontic treatment in patients with CP should not be initiated without first evaluating muscle tone and resting position. To illustrate this proposal, we only have to look at the case described by İşcan et al. [10] that we commented above. Their patient presented a certain degree of unilateral posterior open bite in the follow-up photographs. Relapse, even if less severe than the initial occlusal situation, can overshadow the success of a complex treatment, such as in the patient shown in Figure 5. After prolonged orthodontic treatment with fixed multi-bracket appliances and bimaxillary orthognathic surgery, that patient developed a relapse with unilateral open bite and marked gingival retraction secondary to muscle hypertonicity (Figure 7).
\nSpasticity of masseter and temporalis muscles causes hypertonia—spastic hypertonia—that aggravates the mandibular malposition (mandible is usually located in a retrograde and posteriorly rotated position) and may promote relapses after orthodontic treatment. It has been shown that intramuscularly injected botulinum toxin type A significantly decreases muscle spasticity [22], which hypothetically may help to prevent relapse in selected cases.
\nOrthodontic treatment is feasible in CP children after careful patient selection, taking into account that success depends not only on obvious factors, such as the type and severity of malocclusion and the degree of patient collaboration, but also on resting position and neuromuscular disturbances. The objective assessment of treatment success requires the application of tools that quantitatively evaluate improvements in the domains of aesthetic appearance, oral functionality and quality of life. Unconventional treatment plans have to be chosen at times, and parents must be thoroughly informed to avoid inappropriate expectations.\n Angle’s classification system: A method used to classify different types of malocclusion, based on the mesiodistal relationship of the permanent molars on their eruption and locking. Bracket: A metal, plastic or ceramic element that is glued onto a tooth and that holds a metal wire called an arch wire; this system produces or guides orthodontic tooth movement. Class I: A malocclusion where the upper teeth line up with your bottom teeth (but the teeth are crooked, crowded or turned). Class II: A malocclusion where the upper teeth protrude beyond the lower teeth. This is also called ‘overbite’ or ‘buck teeth’. Class III: A malocclusion in which the lower teeth protrude beyond the upper teeth. Crossbite: A malocclusion in which some of the upper teeth are inside of the lower teeth when the jaws are closed. Crowding: An orthodontic problem caused by insufficient space for the teeth. Fixed appliance: An orthodontic component that is cemented or bonded to the teeth. Malocclusion: A poor alignment of the upper and lower teeth in the anteroposterior or transverse planes when the jaws are closed. Overjet: An extension of the incisal or buccal cusp ridges of the upper teeth horizontally (labially or buccally) beyond the ridges of the lower teeth when the jaws are closed normally. Overbite: An extension of the incisal ridges of the upper anterior teeth below the incisal ridges of the corresponding lower teeth when the jaws are closed normally. Open bite: A malocclusion that occurs in the vertical plane, characterized by lack of vertical overlap between the maxillary and mandibular dentition. Self-ligating brackets: Ligatureless bracket systems that have a mechanical device built into the bracket to close off the edgewise slot. Glossary of orthodontic terms
Calcium and phosphate are critical to skeletal mineralization; while ionized calcium is essential for neuromuscular function and serves as a signaling molecule to communicate and drive intracellular processes. Although, only about 1% of total body calcium and 15% of total body phosphorus is in circulation, the ionized fractions of circulating calcium and phosphate are tightly regulated by the interplay of several hormones to keep their status of homeostasis in response to environmental cues and the physiological needs [1].
PTH and 1,25-dihydroxy vitamin D are the major regulators of calcium metabolism, while PTH and EGF 23 and its cofactor, klotho, work concertedly to control renal excretion of phosphorus and maintain phosphate balance. The complex system is at play to keep these hormones in check in the healthy, while this intricate control mechanism is disrupted in diseases due to the hormone excess/deficiency or loss of the metabolite feedback control such as in patients with parathyroid gland dysfunction or chronic kidney diseases. Therefore, timely and accurately assessing, monitoring, and profiling of these hormones and the important metabolites is essential for the clinicians to understand the degree of calcium and phosphate imbalance when they evaluate the related disorders such as hypoparathyroidism, various forms of hyperparathyroidism, and chronic kidney disease-induced mineral and bone disorder (CKD-MBD) [2, 3].
PTH measurement has been used in the diagnosis and treatment of disorders of calcium/phosphate metabolism because of its predominant role in maintaining the circulating ionized calcium within a very tight concentration range, and in regulating the urinary excretion of phosphorus. PTH measurement is a valuable tool for diagnosing primary and secondary hyperparathyroidism (SHPT). It is also used as a surrogate biomarker to guide the management strategies for CKD patients presenting with systemic mineral and bone disorders (CKD-MBD) and monitoring its progression.
The presence of various circulating forms of PTH and its metabolites, the inter-assay variability and the presence of many variables from sample collection to the test reporting pose significant challenges for accurate PTH quantitation in clinical laboratories and the interpretation of PTH results by clinicians.
Circulating PTH is a heterogeneous population consisting of full-length PTH (84 amino acids, with a molecular of ~9500 Da) and various sizes of proteolytic C-terminal, N-terminal, and mid-molecule metabolites [4]. In healthy individuals, predominant C-terminal PTH fragments typically started at amino acid position 34, 37, 38, or 45 [5]; a subtype of C-PTH, known as non-1-84 or PTH (7-84), usually starts at amino acid position 4, 7, 8, 10, or 15 with the major fragment presumably starting at position 7 [6, 7]. Full-length PTH (1-84) and N-terminal PTH fragments have very short half-lives (2–4 min), while the C-terminal PTH fragments have a half-life of several hours and even longer in CKD patients with decreased renal clearance [8]. The half-life of PTH (7-84) fragments is longer, ranging from 8.1 to 24.0 min [9]. It was shown that PTH (7-84) fragments are released from the parathyroid gland directly in healthy individuals, but proportionally increase relative to total circulating PTH due to bioaccumulation in patients with CKD [10].
The first C-terminal PTH radioimmunoassay was described by Berson et al. [11]; this and the subsequent first-generation PTH assays employed a single polyclonal antibody against epitopes that were located within the C-terminal part of PTH and thus detected both PTH (1-84) and all C-PTH fragments. It was found that PTH (1-84) and C-terminal PTH fragments accounted for 20% and 80% of the circulating PTH respectively in healthy adults when measured by the first-generation PTH assay [12]. Meanwhile, in CKD patients, the proportion of measured C-terminal PTH fragments increased to 95% of circulating PTH [13]. The first generation PTH RIA assay is time-consuming and lacks specificity, especially in CKD patients and thus was totally replaced by more specific second-generation sandwich assays.
Nichols Diagnostics developed a two-site immunoradiometric assay (IRMA) for measuring PTH in 1987; this assay uses a capture antibody directed against the 39-84 C-terminal epitope region and a signaling antibody directed towards the 13−4 N-terminal epitope region to form antibody-PTH-antibody complex and thus greatly improved sensitivity and specificity of the PTH quantitation [14].
Subsequently, non-radioactive labeling assay formats (ELISA, chemiluminescent, and electrochemiluminescent methods) were brought forth and operated in automated immunoanalyzers in clinical laboratories of all sizes, which became and still remain to be the most widely-used PTH assays to date. These second-generation assays were collectively known as “intact” PTH assays, for it was thought that they measure only the full-length PTH (1-84). However, it was uncovered later that the “intact” PTH assays still cross-react with PTH (7-84) fragments (ranging from 50% to 100%), and thus overestimated PTH concentration in CKD patients [15].
To improve the diagnostic accuracy, the first third-generation “biointact,” (also known as “bioactive” or “whole”) PTH (1-84) assay, was advanced by Scantibodies Laboratories and became available as an exoteric testing service since 1999. It is an immunochemiluminometric assay with a signaling antibody directed against the epitope within the first 4 amino acids at the very N-terminus of full-length PTH [16]. More recently, non-radioactive automated and FDA-cleared third-generation assays were marketed by several manufacturers including DiaSorin, Tosoh, Fujirebio, Roche, and bioM´erieux [17]. Since third-generation assays have higher specificity to PTH (1-84) and won’t cross-react with C-PTH, the measuring values are approximately 50–70% of those measured by the second generation PTH assay in patients with CKD and approximately 15% lower than those in persons without CKD. Because second generations assays have been used for decades and are still widely in use, this inter-generation assay difference complicates the test interpretation and the adoption of the new assays. It was expected that the use of the third-generation assays can resolve the issue of cross-reactivity with non-functional PTH fragments (i.e., PTH 7-84). However, subsequent studies revealed the complexity of PTH physiology that was undetected by the older PTH assays. In addition to the full-length PTH (1-84), the third-generation “biointact” PTH also reacted with a new form of N-terminal PTH (N-PTH) that is not recognized by most second-generation PTH assays. Further investigation showed that posttranslational phosphorylation at serine position 17 of the PTH (1-84) molecule prevent (or reduces the binding affinity of) the signaling antibody in most second-generation assays from binding to its epitope in the phosphorylated N-PTH. N-PTH accounts for 4–8% versus 15% of circulating PTH measured by the third generation PTH assays in healthy versus in patients with CKD [16, 18].
Currently, automated second-generation and third-generation PTH assays are employed in clinical laboratories for PTH measurement. Current second-generation assays provide convenient and relatively reliable methods (intra-assay imprecision <10 %) for PTH measurement [19]. However, different PTH assays from various assay manufacturers measure different types and amounts of the circulating PTH forms depending on the specificity of the antibodies used to construct the assay, which led to great inter-assay variability and inconsistent results among the PTH measurements when the now-obsolete Allegro PTH intact assay served as the reference [20, 21, 22]. In a more recent study, a performance comparison among six currently-existing second-generation assays was made. Imprecision was evaluated using three concentrations of commercial quality control materials, while inter-assay variability was assessed by paired comparisons using 203 serum and 193 EDTA plasma samples from healthy individuals. The results showed that the imprecision (i.e., total coefficients of variation) were between 1.1% and 10.9% and there was a good correlation for all methods overall but the considerable bias was observed between methods, the Bland-Altman plots revealed that the between assay differences were between +1.6% to −36.3%, influenced by both assays and sample types used [23].
The results of third-generation PTH assays are approximately 50–70% of those measured by the intact PTH assay in patients with CKD and approximately 15% lower
than those in persons without CKD [16, 18]. The automated third-generation assays are calibrated against the WHO 95/646 Standard and therefore displayed significantly improved inter-method agreements [24, 25]. However, the incompatibility in measurement to that of the widely-used second generation assays affect the interpretations of the method validation and may contribute to its slow adaptation to clinical laboratories in general.
The pathological changes in calcium and phosphate status and the progressive loss of feedback control in the calcium and phosphate regulatory system in hemodialyzed patients further exacerbate the problem of assay variability. A systematic performance evaluation of 15 commercial immunoassays with 47 serum pools from dialysis patients, reported by Souberbielle et al. [21] in 2006, showed great inter-assay variability among the tested PTH assays, moreover, the discrepancies of measured values in some assays compared to the then “gold-standard” Allegro PTH intact assay are unacceptable, and may cause patient harm when the discrepant results were used to make therapeutic decisions. This raised the alarm in the dialysis community to question the reliability of the PTH testing and resulted in many more investigations on these critical issues. A recent position paper issued by the IFCC Committee for Bone Metabolism tabulated 23 major assay comparison studies using samples from CKD or hemodialysis patients (published between 2005 and 2018) [17]. The results reaffirmed that existing between-method differences in PTH measurements did not improve much and likely have treatment implications.
As described earlier, third-generation assays cross-react with a phosphorylated form N-PTH was overproduced in some patients with parathyroid carcinoma and severe primary hyperparathyroidism (PHPT) [26, 27]. In these cases, PTH determination with the third generation assay will have a value greater than the one with the second-generation assay. The inverted third/second PTH ratio is therefore proposed as a screening or monitoring tool for parathyroid cancer [28]. However, the inter-assay variability makes it challenging to define a generally acceptable cutoff for validating the proposed clinical utility unless the problem of analytical variability is effectively addressed.
The unstable nature of PTH makes it essential to optimize pre-analytical parameters, including specimen type, sampling time, and storage conditions, which have all been thoroughly investigated. After a systematic review conducted under the auspice of IFCC PTH Working Group, the following evidence-based recommendations are made by IFCC: [29, 30].
For samples collected with EDTA tubes, the plasma must be separated from the cells within 24 hours of venipuncture. Samples should be kept at 4°C and analyzed within 72 hours of venipuncture.
For serum samples, the serum must be separated from the cells as soon as possible, and PTH is analyzed within 3-4 hours of venipuncture.
Central venous PTH concentrations were higher compared to peripheral venous PTH concentration, therefore, in patients undergoing hemodialysis or parathyroidectomy, if the blood samples were collected via central line or central vein; the collected tube, as well as the test report, should explicitly state the collection site and whether they are peripheral or central venous concentrations.
PTH follows a circadian rhythm, exhibiting a nocturnal peak, a mid-morning nadir, and a smaller afternoon peak. Therefore, it is suggested that samples for PTH measurement should be collected between 10:00 and 16:00, preferably in the morning with an overnight fast. Other known biological variations include the fact that PTH level increases with age and BMI, and is generally higher in African Americans than in Caucasians.
PTH has longer stability in EDTA tube at room temperature than in serum tube, thus delayed centrifugation to allow blood clotting is not needed; however, it is important in clinical practice that PTH measurement be accompanied by a concomitant calcium value. Since calcium (and bone-alkaline phosphatase) cannot be measured in EDTA plasma, PTH and calcium are to be measured in the same serum tube and therefore may be a preferred option for practical reasons. In two recent reports, PTH values obtained from the rapid serum tubes were found to be decreased compared to those from the serum separator tubes (SSTs) [31, 32].
So far, there is no reported data on the comparison of relative PTH stability using second-generation versus third-generation assays. Such study is valuable in providing further insight into the
All immunometric assays are inherently prone to interference from heterophilic antibodies (i.e., human idiotypic antibodies that interact with assay antibodies raised from animals). Such interference can lead to diagnostic errors and may cause harm to patients as consequence. Assay manufacturers have introduced effective blockers to the assay reagent as a preventive measure against heterophilic antibody interference; however, increasing use of modified monoclonal mouse antibodies as therapeutics in recent years makes heterophilic antibodies interference a special concern in the patients who receive such treatment. Clinicians and laboratorians should keep open communication when the testing results did not match the clinical picture of the patients. Laboratorians should offer adequate confirmatory measures and be able to interpret the investigative results timely and correctly to avoid the spurious results being used to make important clinical decisions for patient management [33].
Since a great inter-assay variability is still present among current commercial PTH assays, there also exists a significant difference for the reference ranges provided by the manufacturers. This makes validation of the PTH assay in use an indispensable but tedious and challenging job. The first and foremost is the selection of the reference population; The eGFR, serum calcium, and 25[OH]D values of the candidate samples should be determined to only include those within reference ranges, especially the 25[OH]D level should be >30 ng/mL [34, 35]. The reference ranges should be established for each sample locally used. If types of collection tubes differ among the collection sites, it is advisable to perform a comparison study to determine if the reference range should be revised to accommodate the difference. In high latitude areas, the effect of seasonal variation in 25[OH]D levels may need to be taken into consideration in designing the validation study for establishing the local reference range for PTH assay.
Loss of biological activity of oxidized PTH
There is plenty of experimental evidence to support the increase of oxidative stress in patients with CKD due both to the depletion of anti-oxidants and increase of reactive oxidative species (ROS) production; increasing oxidative stress is also shown to be associated with complications such as hypertension, atherosclerosis, and anemia and therefore may contribute to the accelerated disease progression and mortality in CKD [38]. However, none of the current second-and third-generation assays can discern oxidized from non-oxidized PTH until recently due to the lack of appropriate analytical tools for investigation.
Hocher et al. developed a two-step method to measure the non-oxidized PTH; the oxidized PTH molecules were first removed by an immunoaffinity column with monoclonal antibodies specifically against the oxidized human PTH (1-34) fragment, the remaining non-oxidized PTH was then measured by Roche second-generation PTH assay. The method was applied to analyze 17 hemodialyzed samples and revealed a substantial but variable portion (70−90%) of the total PTH was in oxidized form for all samples tested [39]. These tools enable the researchers to assess iPTH, non-oxidized PTH and oxidized PTH simultaneously using the same parameters in clinical research settings to address the clinical association of oxidized PTH with the progression of CKD [40, 41]. However, the results from these studies are not conclusive.
The inherent problems of the analytical procedure are a concern. First, the
Lack of a common PTH reference range not merely cause inconvenience, but it also affects results interpretation, and possibly clinical management, especially for monitoring long-term changes of PTH level if patients are not able to use the same health care facilities. More importantly, intraindividual biological variability of PTH is known to increase in hemodialysis patients. The negative impact of PTH assay variability on the management of patients with CKD and hyperparathyroidism is especially troublesome.
In 2003, National Kidney Foundation—Kidney Disease Outcomes Quality Initiative (KDOQI) published a guideline that recommended maintaining a target range of 150–300 pg/mL for intact PTH concentrations in stage 5 CKD patients to reduce the mortality related to CKD-MBD. However, the recommendation was based on the comparison of PTH measurements using Allegro iPTH (now obsolete) with the gold standard–bone biopsy, before the problem of inter-assay variability being revealed. A later study showed that iPTH (measured by Immulite DCP assay) levels less than 150 pg/ml for identifying low turnover and greater than 300 pg/ml for high turnover presented a positive predictive value of 83% and 62%, respectively, moreover, in patients achieving the target iPTH levels, 88% had low turnover diseases [42]. The great inter-assay variability is a likely contributing factor to the poor results and indicated the misclassifications may cause harmful clinical outcomes [21].
In one study conducted by the United Kingdom National External Quality Assessment Service (UK-NEQAS), a 4.2-fold difference between highest and lowest measured PTH concentrations were observed using five commonly-used second-generation assays when testing EDTA plasma from 21 hemodialysis patients. In a subsequent study, 98 patient samples were tested by the same iPTH assays to derive assay-specific target values based on Passing and Bablok regression against Roche Elecsys E170 assay which gave the closest results to target values recommended by clinical guidelines. By applying the corrected assay-specific target values, the misclassifications of bone turnover reduced from 53% to 12% [43].
The Kidney Disease Improving Global Outcomes (KDIGO) 2009 Guidelines for the Diagnosis, Evaluation, Prevention and Treatment of CKD-MBD expanded the scope and refined the recommendations to assist clinicians in treating patients with CKD Stages 3–5 who are on dialysis. Aware of the problem of inter-assay variability, this guideline avoids the use of absolute PTH values but suggests hemodialyzed patients maintain PTH levels between two and nine times the upper normal limit (ULN) of the assay used and emphasize on trending the changing pattern rather than the value per se. PTH values above the target suggest high bone turnover bone disease with a specificity of 86%, while PTH levels below the target value suggest low bone turnover with a sensitivity of 66%. In its recent update (July 2017), targets for CKD-MBD biomarkers, including PTH, remain unchanged [44]. As mentioned earlier, 25[OH]D status has a substantial influence on physiological PTH level, but PTH assay reference ranges offered by the vendors might be established with samples of poor 25[OH]D status. Recent studies reported that the upper reference range for PTH established with a reference population with normal GFR and calcium levels, and a 25[OH]D level >20 ng/mL is significantly lower than the reference range provided by the manufacturers [35, 45, 46]. Cavalier et al. found that applying KDIGO guideline PTH target ranges using reference ranges established in a vitamin D replete healthy control population would reduce the percentage of misclassification of bone turnover in dialyzed patients to 16% (versus 36% using vendor-established reference range) [34].
Comparison studies compared Nichols iPTH versus Bio-intact PTH assays and Scantibodies Laboratory’s Total versus Whole PTH assays showed high diagnostic sensitivity for both second-and third-generation PTH assays (89−97%), which provided evidence that both types of PTH assays are valuable tools in diagnosing PHPT and provide comparable results [47].
It is essential, as described earlier, to use a vitamin D-replete population to establish the reference range for PTH; the diagnostic accuracy (sensitivity and specificity) for PHPT was shown to be improved in a vitamin D-replete population [46, 48]. However, there is debate over using sufficiency level (30 ng/mL) or insufficiency level (20 ng/mL) as the threshold. So far, there are still no established reference intervals for second-and third-generation PTH assays using large vitamin D-replete population cohorts; subjects with hypercalcemia and a PTH persistently within the upper reference range should be considered “asymptomatic” PHPT and closely monitored [49].
Because PTH (1-84) has a very short half-life (~5 min), measuring PTH concentrations during parathyroidectomy can inform surgeons whether the pathological parathyroid tissue has been removed completely. A 50% decline of PTH compared with the preoperative level is commonly used to define treatment success. Since second-generation assays cross-react with C-terminal fragments with a longer half-life, it is reasonable to think third-generation assays will perform better for intraoperative PTH monitoring. Studies so far did not demonstrate that third-generation assays have a better performance for ioPTH in patients with PHPT. But a more rapid rate of PTH drop was observed in the third-generation assays. In surgery performed in patients with SHPT, it takes time for PTH concentrations to drop below the 50% cutoff after removal of the last hyperplastic gland using second-generation assays. More studies are needed to determine if third-generation assays offer a superior clinical utility for ioPTH monitoring, especially in patients with SHPT [50].
In addition, PTH measurement is used 20 min after thyroidectomy to determine if intensive calcium monitoring is needed (when the PTH level is >15 pg/mL using iPTH assays) and 4 hours after to predict postoperative hypocalcemia [51, 52]. There is no published study comparing the performance of different-generation PTH assays for this particular purpose, although one can argue that third-generation PTH measurement may better reflect the biological activity of parathyroid glands.
There is a desperate need to reduce the significant inter-assay variability of PTH measurement that confounds the test interpretation and may affect clinical decision-making and cause patient harm. Assay standardization is therefore urgently required to improve the long-standing troubling situation in clinical PTH testing. Hormonal immunoassay standardization is inherently challenging because of the low circulating concentration, protein instability, and the differences in antibody-antigen complex formations; the presence of various PTH fragments and their different distributions in response to calcium, 25(OH) D status, and other effectors present additional hurdles to overcome.
International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), equipped with the experience for standardizing thyroid hormone and other protein assays, is undertaking the challenge to improve the PTH measurement in clinical communities. The IFCC Committee on Bone Metabolism has laid out the roadmap in a position statement where they set three major priorities:
Calibrate all current commercial PTH assays against a recognized International Standard, proposed to be the recombinant human PTH 1-84 standard (NIBSC 95/646) prepared by World Health Organization.
Facilitate the development of reference measurement procedure (RMP) for PTH (1-84) to enable the true metrological assignment of reference value for PTH primary, secondary and working standards in a network of reference laboratories.
Design studies to establish common reference intervals for PTH assays [30].
The first task for the IFCC Working Group is to assess the commutability of PTH in a defined matrix, which is to demonstrate experimentally that the standard material and fresh patient specimens exhibit the same analytical response (regression line slope close to 1.0) when measured by two different methods.
A collaborative effort is currently undertaken to develop a protocol for the formal assessment of commutability. Once the commutability of the standard material is determined and deemed acceptable, it will be possible to use RMP to determine the recovery of PTH (1-84) in the appropriate matrices and then certify the values for secondary reference materials and external controls. Once such standards are available, assay manufacturers should use them to calibrate their assays.
In the meantime, the work is also underway to acquire an appropriate panel of plasma and/or serum samples for establishing PTH reference intervals. All the pre-analytical and physiological factors that can contribute to intra- and inter-individual variations as well as to increase inter-assay variability, as discussed in the previous section of this chapter, are to be carefully considered and minimized or ruled out.
One obvious challenge for this endeavor is the lack of consensus on how to define vitamin D sufficiency, insufficiency, and optimal vitamin D levels. The most often used definition of vitamin D sufficiency is the 25[OH]D concentration above which PTH cannot be suppressed further, however, this threshold varies with diseases states and is subject to analytical variability of 25-(OH) D assays [39]. Recently, a cross-sectional analysis of 14,289 CKD patients (stages 1−5) and a randomized control trial involving 429 patients with stage 3-4 CKD, showed levels of iPTH was not suppressed until serum 25(OH) D reached 40−50 ng/ml range, therefore, the target 25-(OH) D concentration may need to be raised in CKD patients [53, 54].
The liquid chromatography-tandem mass spectrometric (LC-MS/MS) method utilizes chromatographical separation and distinct mass/charge ratio of the product ion pairs to provide rigorous physicochemical characterization of target molecules in the biological mixture and therefore is ideal for developing reference measurement procedures for PTH. The technical advances in mass spectrometric analysis in the last decade enable LC-MS/MS to quantify PTH with accuracy and precision comparable to the results obtained with immunoassays in complex matrices, while it is more robust and flexible for identifying and measuring new or modified PTH fragments (i.e., oxidized PTH). Several published LC-MS/MS methods for PTH measurement already exist and can be readily refined and modified to become candidates for RMPs [5, 55].
IFCC working group has conducted a feasibility study as the first step to assess the suitability of a selected LC-MS/MS method as RMP for PTH quantification. In this study, 48 freeze-dried proficiency testing specimens with assigned values sent from UK NEQAS were reconstituted and analyzed by a published LC-MS/MS method used at the Mayo Clinic [56]. Results obtained from LC-MS/MS analysis were in excellent agreement with the target all laboratory trimmed mean used in the UK NEQAS for PTH and thus the feasibility of using the LC-MS/MS method as a candidate reference measurement procedure.
However, the analytical sensitivity of current MS methods still could not match that provided by immunoassays for PTH quantitation; moreover, current methods require proteolytic digestion of PTH before MS analysis, which is time-consuming and can introduce significant procedural variability. Some of the MS methods also include an immunoabsorbent step to select and enrich PTH. The specificity of the antibody used will influence what types of PTH fragments later be analyzed by LC-MS/MS and thus introduce biases to the final results. Therefore, there remain many hurdles to overcome in developing an MS-based RMP for PTH measurement [30].
Moreover, the employment of state-of-art liquid chromatography-high resolution mass spectrometry (LC-HRMS) could potentially profile various PTH fragments in different stages of CKD with a sensitivity comparable to that by immunoassays and thus offer a powerful tool to correlate PTH qualitative and quantitative changes with the progression of CKD [57].
Accurate quantitation of circulating PTH is challenging due to the presence of various molecular forms of PTH and its complex physiological interactions with other hormones and its effectors—calcium, and phosphate. PTH assays have been continuously evolving and improving since their debut six decades ago; the effort will continue to refine and adapt to resolve the issues at hand and meet the evolving clinical needs.
To improve the reliability of the PTH testing for diagnosis and monitoring along the pathway of patient management, IFCC has spearheaded an ambitious plan to standardize commercial PTH assays. It will require the collaborative efforts of academics, scientific and clinical communities, assay manufacturers, and the support of other stakeholders to achieve the goals. We can be optimistically hopeful that the communicable PTH reference material, the panels of qualified samples for establishing reference ranges, and the LC-MS/MS-based RMP method(s) will be available in the foreseeable future. Together they will enable calibration of all PTH assays with a single reliable international standard and allow accuracy-based external quality assessment. The better analytical tool can also empower us to gain more insight into the dynamic changes of PTH so we can optimize the testing to be used in the management of CKD to benefit patient care.
This is a brief overview of the main steps involved in publishing with IntechOpen Compacts, Monographs and Edited Books. Once you submit your proposal you will be appointed a Author Service Manager who will be your single point of contact and lead you through all the described steps below.
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He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:null},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. 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Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. 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