1Department of Head and Neck and Endocrine Surgery, Faculty of Medicine, University of Alexandria, Egypt; 2Department of Surgery, University College Hospital, London, UK
Continuous development of quick parathyroid hormone assays has resulted in a corresponding expansion of their applications in the practical landscape. In-theatre measurement of the parathyroid hormone has long been recognized as a valuable adjunct in parathyroid surgery, with other applications being incorporated in thyroid surgery and out-of-theatre uses. Such widespread utilization of these assays has also brought the concept of point-of-care testing to the endocrine surgical patient. We have herein summarized the established and potential applications of these assays, emphasizing their importance in the point-of-care setting, highlighting the proper selection of the assay type for intraoperative hormone monitoring and spotlighting those applications which should be validated for use in the clinical setting and those which need to be investigated further.
Intraoperative parathyroid monitoring, Parathyroid hormone assay, Point-of-care testing, Post-thyroidectomy hypocalcemia
Advances in clinical biochemistry have resulted in the development of improved assays for hormone measuring. Among the most prominent of these are the quick parathyroid hormone (qPTH) assays, since they have been found to help address a number of challenging issues in parathyroid, and to a lesser extent in thyroid, surgery. A multitude of platforms have therefore been developed to better address these issues. These platforms share a similar three-step analytical principle: 1) capturing the PTH molecule in a specific sample volume through recognizing a specific amino acid sequence within the PTH peptide by specific antibodies, 2) detection of the antibody-captured PTH molecule using signal-labeled specific antibodies and 3) reading the amount of signal with subsequent quantification of PTH. The antibodies used are usually polyclonal goat antibodies and the signal is of the Chemiluminescence type. Some differences, however, exist among these platforms regarding the solid phase and the incubating conditions, with consequent variations in the volume of sample required, time to result and the measurement range.1 This notable development in the laboratory landscape has been reflected in a corresponding expansion of clinical applications in the practical landscape. Quick measurement of PTH in blood samples from on-table patients has attracted much attention in the context of intraoperative parathyroid monitoring (IPM). However, qPTH assays have also been used for in-theatre measurement of PTH in suspected tissue or fluids as well as for out-of-theatre purposes. In addition, these assays have improved the quality of care by enabling the performance of the test within a short turnaround time and near to the site of patient care, two points which basically define the concept of point-of-care testing (PoCT).2 Given such rapid expansion of these assays’ applications, this is an opportune moment to review the relevant current knowledge. Like any technology, their use is not however free from drawbacks, such as measurement pitfalls and the extra cost involved, which considerations are reviewed elsewhere. Our focus in this article is to summarize the established applications and discuss the emerging ones, emphasize their role in provision of bedside patient care in endocrine surgery and highlight the proper selection of the assay type for intraoperative hormone monitoring with a view to identifying those applications which need to be investigated further and those which should be considered for validation in the clinical setting.
Our first step in accomplishing the goal we had set was to perform a structured search of Embase and Medline electronic databases using Ovid interface. Our strategy consisted in searching in all fields (af), using keywords extracted from the relevant MeSH headings, which were then combined using the Boolean operators, employing the following search terms: (intraoperative AND parathyroid), (point-of-care AND parathyroid), and (quick assay AND parathyroid). Limitations applied were: 1) English literature, 2) human studies and 3) publication year (2003 – current). Full text manuscripts of relevant records were assessed for eligibility. Eligible articles were those clearly mentioning the use of quick PTH assays for PTH measurement. A few relevant articles were also added from other sources, mainly from the selected manuscript bibliographies, so that a total of 106 publications were used to construct this narrative review.
IN-THEATRE USE OF QPTH ASSAYS IN PARATHYROID SURGERY
The utilization of qPTH assays has brought many benefits to parathyroid surgery, primarily through intraoperatively monitoring the hormone level in blood samples drawn from the patients and, to a lesser extent, through measuring the hormone level in suspected tissues.
Intraoperative parathyroid hormone measurement in blood samples
Recording the decline of intraoperative PTH (IOPTH) in serial samples taken at defined time points during surgery (i.e. IOPTH monitoring or IPM) has gained much interest, with extensive discussions and multiple protocols investigated in the literature. Some authors, however, have reported that other benefits can be derived from a single IOPTH measurement at the start of surgery and from observing IOPTH kinetics.
The role of hormone monitoring in assuring the adequacy of parathyroid surgery
Physiological and pathobiological basis
Achieving a satisfactory post-excision reduction of IOPTH at a defined time point, in comparison to a baseline level, is a reliable criterion that the hyperfunctioning parathyroid tissue has been adequately removed and surgery can be safely concluded, thereby predicting subsequent surgical success.3-5 Three physiological facts have formed the scientific background to such a concept: 1) the PTH molecule is solely released from the secretory granules of the chief cells within the parathyroid glands,6 2) normally functioning parathyroid glands are suppressed by excess PTH released by the hyperfunctioning gland(s)1 and 3) the half-life of PTH has been calculated by various assays to be less than 5 minutes.7 While this concept has been approved and used by many surgeons to assure the adequacy of surgery in primary hyperparathyroidism (PHPT), its use has nevertheless not found a similar place in renal HPT.
Several protocols have been proposed for deciding the adequacy of surgery in HPT, e.g. Miami, Halle, Vienna and Rome.8 Variable performance has been achieved by these protocols owing to their controversial parameters, e.g. required PTH drop, baseline PTH level and timing of decision.9 Despite the debated parameters, IPM’s ability to achieve early prediction of surgical adequacy has supported the implementation of minimal access surgery (MAS) in HPT surgery and has improved surgical success rates.
Implementing minimal access surgery
For PHPT patients with localizing preoperative scans, IPM has enabled surgery to be conducted through unilateral exploration,10 and even obviating the need to visualize the ipsilateral possibly normal gland.11 This subsequently has standardized the concept of MAS for the surgical management of PHPT (minimally invasive parathyroidectomy, MIP) with the multiple techniques that already exist or are evolving (focused, endoscopic, video assisted, radioguided12 or robotic-assisted13-16). Additionally, operating through MAS has allowed PHPT surgery to be occasionally carried out under local anesthesia17 and even be practiced as day-care surgery.18 In addition to gaining the expected advantages of MAS (e.g. minimal incision, minimal dissections and short hospital stays), excellent cure rates have been achieved,17 with the risk of persistent or recurrent disease comparable to traditional bilateral neck exploration (BNE).19,20 Furthermore, cases with prior contraindications to MIP, including parathyroid cancer, prior neck surgery (persistent or recurrent HPT) and high risk of multiglandular disease (MGD) (i.e. risk of parathyroid hyperplasia in patients having familial HPT or a history of prior neck radiation),21 can occasionally be concluded through various MAS techniques, aided by IPM.22-26 Likewise, approaching an ectopic mediastinal parathyroid through video-assisted thoracoscopic surgery (VATS) has also been facilitated through IPM.27,28 On the other hand, BNE should prudently be prompted if IOPTH does not show satisfactory reduction. Indeed, albeit classic BNE is still resorted to as initial surgery in selected PHP cases or as conversion after failed MIP, its appeal and indications have obviously progressively decreased in the era of IPM-guided MIP.29
Similarly to PHPT, surgery has been accepted as the standard of care for management of tertiary HPT (THPT). By contrast, however, the management of secondary HPT (SHPT) is predominantly medical, with surgery required only in severe cases as indicated by calciphylaxis or PTH level higher than 800pg/ml.30 While IPM-guided MAS has become a routine practice in managing PHPT patients, it has not yet found a similar place in SHPT and THPT, i.e. renal HPT surgery for two main reasons. Firstly, in patients with renal HPT, the four glands are almost always hyperplastic;30 this consequently emphasizes the importance of visually inspecting the four glands at surgery, necessitating therefore adequate exposure. In support of the latter, a significantly lower failure rate has been associated with adequate in comparison to inadequate surgery (defined as more vs less than 3½ gland resection).31 Secondly, some studies have demonstrated lack of correlation between percent IOPTH decline and operation outcome or postoperative PTH in renal HPT patients, findings which question the efficiency of IPM in assuring the adequacy of renal HPT surgery.32,33 However, in addressing these two issues, it has been demonstrated that both neck sides could possibly be explored through the central access provided by video-assisted neck surgery (VANS).34 In addition, IPM has been demonstrated in other studies to efficiently predict the success of parathyroidectomy for renal HPT. Hence, reasonable evidence exists to support investigating whether surgery for renal HPT could be efficiently concluded through IPM-guided MAS. Indeed, when guided by IPM, minimally invasive video-assisted parathyroidectomy (MIVAP) for SHPT has been successfully completed in 92% of cases, as reported by Alesina et al35 in their initial experience. In contrast, conversion to traditional BNE has been reported in 30% of SHPT patients initially undergoing non-IPM-guided MIVAP.36
Reduction of operative failures
The term operative failure, equivalent to persistent HPT, is defined as occurrence of a HPT biochemical profile within six months of surgery and, broadly speaking, can be attributed to technical, structural or pathobiological issues.
Firstly, from the technical point of view, surgeon experience has, on the one hand, been recognized as being pivotal in parathyroid surgery; hence, an inexperienced surgeon would be expected to have a higher failure rate. In their retrospective study, Nawrot et al37 reported having missed hyperfunctioning parathyroid tissue in 55.5% of patients undergoing reoperative surgery which, having been detected in a eutopic position, was likely due to lack of adequate surgical expertise. Monitoring PTH intraoperatively would provide a simple biochemistry based tool to assess the adequacy of resection, either assuring the surgeon that surgery can be concluded or prompting him to take further action, e.g. convert to BNE (if initially performing MIP), or to carry out further exploration (if already performing BNE) or to seek the assistance of a senior surgeon. On the other hand, surgical decision-making, being influenced by non-100% accurate preoperative scans, could occasionally be incorrect. Such a decision could be changed intraoperatively according to whether IOPTH achieved satisfactory reduction.38
Structural variations of the parathyroids, on a second perspective, are not uncommon, with ectopic glands being reported in 16% of HPT cases.39 Supernumerary parathyroids are also reported to exist in up to 13% of individuals.40 Such aberrant glands could be missed and, if pathological, persistent PHPT would result.41,42 In addition, a missed aberrant gland in renal patients may undergo hyperplasia as a result of uremic stimulation, thereby putting the patient at risk of recurrent SHPT and ultimately necessitating reoperation.43 Indeed, missed ectopic adenomas have been reported in 53% of PHPT patients undergoing reoperation.44 In their study of PHPT patients who underwent reoperative surgery, Mariette et al45 have reported supernumerary glands in 15 out of 38 cases. In their retrospective analysis of 165 reoperated SHPT patients, Okada et al43 have reported “supernumerary” glands in 68% of patients, whereas 48% of glands excised in reoperative surgery were found in ectopic locations. Employing IPM has been reported to be useful in predicting complete removal of the hyperfunctioning parathyroid tissue, including suspected aberrant tissue.46,47
Thirdly, pathobiologically speaking, MGD, including hyperplasia and double adenomas, and parathyroid cancer (PC) account for 15% and 1% of PHPT, respectively; nevertheless, they have been reported in 28.4% to 60% and 2% to 3.4%, respectively, of reoperative PHPT patients.45 Persistence/recurrence rates of PHPT have been reported to be incrementally higher following surgery for single adenoma, hyperplasia and double adenoma.48 The latter issue would also be addressed through IPM because of its ability to predict MGD not only through showing “failure to decline” but also through demonstrating a “slow rate of decline”.49 In a study by Sugg et al50 combining ultrasound and MIBI, scans predicted MGD in only 30% of cases, while IOPTH alone was reported to predict it in 83% of cases. In their study of 260 PHPT patients, Barczynski et al8 attributed a significant value of 3.1% in their overall success rate (99.6%) to correctly identifying eight patients with MGD through IPM, despite being incorrectly stratified as solitary adenoma through concordant preoperative scans. In an analysis of PC case series, Soloranzo et al51 reported 87% PPV of IPM in eight cases who underwent initial surgery; the test was, however, less predictive in reoperative cases. A cure rate of 100% has subsequently been reported following IPM-guided en-bloc resection in four PC cases, thus supporting its use in such instances.52
In terms of addressing such potential causes of parathyroid surgery failures, IPM has been found in many studies to improve the cure rates of PHPT (Table 1).
Similarly, the role of IPM in improving surgical outcomes of renal HPT has been clearly demonstrated by Gasparri et al60 in a retrospective data analysis which captured a reduction of persistence and recurrence rates from 6.2% and 11% to 4.9% and 4.9%, respectively, for SHPT and from 4.7% and 2.3% to 2.1 and 0, respectively, for THPT cases on employing IPM.
Selection of the assay type
According to the analytical characters, two main types of PTH assays have been recognized: intact and whole PTH assays. The intact PTH assay, also known as second generation assay, reacts not only with bioactive1-84 PTH fragment but also with non-active large carboxyl terminal PTH fragments, mainly 7-84 fragments. The whole PTH or third generation assay, on the other hand, exclusively reacts with the whole PTH molecule (1-84 fragment).61 In comparison to the bioactive fragments, the non-1-84 fragments were reported to have a longer half-life.62 Given the fact that the latter fragments are known to accumulate in renal failure patients,63 false results would be likely if second generation assays were used for IPM in such patients. A Bio-Intact PTH (1-84 fragments) measuring assay has, however, been reported to be more accurate in intraoperatively differentiating sufficient from insufficient parathyroidectomy and subsequently in predicting surgical outcome, compared to conventional second generation assay;64,65 it therefore should preferentially be used in PHPT patients with renal impairment and in renal HPT patients.
Other benefits of hormone measuring in primary hyperparathyroidism surgery
Prediction of recurrence
In their study of the predictors of recurrence following surgery for PHPT, Schneider and colleagues66 interestingly reported that the greater percent IOPTH decline was not only protective against, but also significantly predictive of, recurrence. In the latter study, a threshold of 63% decline was statistically generated as the best value able to predict recurrence, with a sensitivity of 72.7%. In their study of IOPTH kinetics, the same authors67 identified an unusual “rebound” pattern in 6.2% of operated PHPT cases, in which the PTH level rose by more than 5pg/ml after achieving 50% reduction in a preceding measurement. The latter pattern was reported to be significantly associated with higher recurrence rate.
Prediction of post-parathyroidectomy hypocalcemia
In a similar fashion to its ability to predict post-parathyroidectomy normocalcemia and post-thyroidectomy hypocalcemia, a few researchers have tested several endpoints derived from IPM for their potential ability to predict post-parathyroidectomy hypocalcemia. In their analysis of a prospectively recorded database of 68 PHPT patients who underwent reoperation, Elaraj et al68 found that in patients with MGD, an IOPTH drop of 84% or more was significantly correlated with occurrence of postoperative hypocalcemia. Shoman and colleagues69 have also found that the percentage of IOPTH drop between the pre-incision and the 10 min post-excision values can significantly predict whether postoperative hypocalcemia may develop. Similar correlations have not, however, been subsequently found in other authors’ reports,70 indicating that further studies, preferably on larger patient samples, are required. If post-parathyroidectomy hypocalcemia could be anticipated intraoperatively, certain management decisions would be affected: parathyroid auto-transplantation, calcium supplementation and frequency of follow-ups.
An intraoperative lateralizing aid
A 5% or higher difference in PTH levels between both internal jugular veins at the start of surgery has been reported to be a safe and efficient lateralization method, particularly useful in PHPT patients with negative preoperative localizing studies or suspected MGD disease.71,72 A similar technique has been successfully used to localize undescended parathyroid adenoma after failed BNE and intraoperative ultrasonography.73
Useful adjunct to perioperative tools
In order to optimize the outcomes of parathyroid surgery, IPM has also been employed as an adjunct to other perioperative tools. Table 2 demonstrates the usefulness of measuring IOPTH in improving the performance of other perioperative tools for PHPT patients undergoing parathyroid surgery.
Potential alternative to other intraoperative tools
In comparison to other intraoperative tools, IPM has been shown to have higher performance measures. In view of cost savings, it is possible for IPM to replace rather than to supplement other aids, namely frozen section (FS) and intraoperative gamma probe (GP).
As an intraoperative adjunct, FS has been used to confirm the identity of the excised tissue as parathyroid so as to identify it as the culprit and to exclude the possibility of tissue being hyperplastic rather than adenomatous.79 However, in terms of assuring the surgical adequacy, it is more reasonable to have some sort of functional rather than morphologic confirmation. In their PHPT case series, Tampi et al80 demonstrated the superiority of IPM to FS, since the former was able to confirm the excision of “adenoma” in all cases, while the latter demonstrated hypercellularity “adenoma vs hyperplasia” in five cases. The inconsistent diagnostic accuracy of FS in fact challenges its usefulness in surgical decision-making.81 Quick PTH assays can help confirm excision of the offending gland, not only through picking a satisfactory PTH reduction with a high accuracy but also through measuring hormone levels in suspected specimens (discussed later). Thus, IPM has been termed “biochemical FS” and has been suggested as a replacement for the traditional histopathological FS.82
Similarly, in a comprehensive prospective evaluation of intraoperative parathyroid surgery adjuncts, IPM has been reported to be a more reliable tool when compared to gamma probe in terms of sensitivity, PPV and accuracy (99%, 100% and 98% vs 93%, 89% and 83%, respectively).83 The latter findings may therefore suggest the possibility of IPM-guided MIP replacing minimally invasive radioguided parathyroidectomy (MIRP).
Intraoperative parathyroid hormone measuring in suspected tissue
Confirming the parathyroid identity of excised tissue
Despite the fairly accurate results of IPM recorded in most of the literature, occurrence of false results, though uncommon, is still very problematic on account of its grave consequences, namely, unnecessary explorations with consequent morbidity (in the event of a false negative) or leaving behind pathologic parathyroid tissue, ultimately resulting in persistence HPT (in the event of a false positive). Hence, other techniques for confirming the parathyroid nature of the removed specimen continue to be sought. Rapid PTH measurement in needle aspirate from the excised suspected tissue has been reported to be an efficient method of confirming the parathyroid identity with 97% sensitivity and 100% specificity (PHPT).84 The accuracy of a PTH assay in distinguishing the parathyroid tissue has been reported to be affected by the number of needle passes, with 5 passes being optimal to achieve a minimum of false negatives.85 Moreover, measuring PTH level in 1 mm biopsy of the tissue in question has demonstrated an accuracy of 99% in identifying parathyroid tissue, exceeding the accuracy of PTH determination in FNA aspirates.86 Such “biochemical frozen section” may provide a time-effective and cost-effective alternative to the traditional one, particularly if quick PTH settings have already been set for IPM.87
Differentiation between normal and pathological parathyroids
In PHPT cases in which BNEs are deemed necessary, surgeon experience has been recognized to be of utmost importance in picking out the pathologic gland. Occasionally, the pathologic gland(s) may be of borderline size and be difficult to distinguish from normal glands. A useful adjunct in this case would be measuring the PTH in a needle aspirate from the suspicious glands, this measurement having been reported to make an efficient differentiation (<100 vs >1000 pg/ml).88
IN-THEATRE USE OF QPTH ASSAYS IN THYROID SURGERY
Prediction of the post-thyroidectomy calcemic state
The prediction of post-thyroidectomy hyocalcemia has been the subject of extensive research, since this would significantly impact subsequent management. An optimal predictor should be capable of early, accurate and measurable prediction. Although some demographic (e.g. age, gender and race) and pathobiologic (e.g. thyroid pathology, surgery extent) factors can significantly predict post-thyroidectomy hypocalcemia, no single factor among these has demonstrated a measurable performance.89 Nomograms integrating some of these factors can indeed quantitatively predict post-thyroidectomy hypocalcemia at a fairly early stage; however unfortunately, the overall reported accuracy was only 67.7%.90
Biochemical factors, in terms of perioperative Ca and PTH, have been extensively studied as candidate predictors. Although a postoperative 24 h percent Ca drop91 or 16 h low adjusted Ca92 could quantitatively predict post-thyroidectomy hypocalcemia with high accuracy (87 and 90%, respectively), unfortunately, by that time, a symptomatic hypocalcemic episode may already have occurred. In contrast, measuring PTH intraoperatively seems to fulfil the requirements of an ideal predictor of post-thyroidectomy hypocalcemia, with the percentage of PTH drop being reported to be more accurate than PTH absolute value (88% vs 72%).92 In their analysis of 249 patients, Noordzi et al93 demonstrated that IOPTH can predict post-thyroidectomy hypocalcemia with the sensitivity incrementing from 34% to 93.6% as the cut-off of the percentage of PTH decline decreased from 90% to 40% within 20 min after gland removal. Such early prediction can potentially guide important clinical decisions: 1) a second look at the excised thyroidectomy specimen, should a parathyroid gland be inadvertently removed, 2) determination as to whether parathyroid auto-transplantation is necessary, 3) timing of discharge and 4) early consideration of Ca supplementation in those patients identified as being at risk.
Differentiating parathyroid and non-parathyroid tissue
During thyroid surgery, some tissues (thyroid nodules or lymph nodes) can occasionally be confused with parathyroids, which can present a challenging situation. On the one hand, preserving these tissues may compromise the completeness of resection, while, on the other hand, excising them may expose the patient to the risk of hypoparathyroidism. Rapid intraoperative measurement of PTH in FNA aspirates of suspicious tissue has been reported to be a reliable and simple method of differentiating parathyroid and non-parathyroid tisuue.88,94,95 This could provide an alternative to FS examination, dodging the injurious effect of the bioptic process and achieving similar or even more accurate results.96 A recently reported modification of the IOPTH assay achieved 100% sensitivity and 100% specificity in distinguishing parathyroid from non-parathyroid tissues within ultra-short turnaround time (60 seconds) and could potentially replace frozen-section assessment.97
OUT-OF-THEATRE USE OF QPTH ASSAYS
In the post-anesthesia care unit (PACU)
Rapid PTH testing has also found other useful applications outside the theatre. McLeod and colleagues98 have proposed testing PTH in the PACU for post-thyroidectomy patients with a cut-off PTH value <12 pg/ml or PTH drop >75%, achieving a sensitivity and specificity of 100%, 92% and 100%, 88%, respectively, for prediction of post-thyroidectomy hypocalcemia. Subsequently, Sabour and colleagues99 recommended initiating Ca/Vit D therapy on a selective basis for those whose PACU-PTH reads less than 15 with the aim of reducing the rate of post-thyroidectomy hypocalcemia Such an approach is superior to routine supplementation on account of the achievement of a lower rate of hypercalcemia, better patient compliance and lower cost.
In the radiology suite
The rapid PTH assay for samples collected by image-guided super-selective venous sampling (SVS) can provide a near-real time PTH level in cervical veins, leading to correct lateralization of the culprit lesion in 83%-93% of cases that have a significant gradient.100-102 Alternatively, safer and less time-consuming non-SVS has also been used to detect a localizing parathyroid gradient augmented through employing a systemic hypocalcemic challenge.103 Similarly, using rapid assay for measuring PTH in US-guided fine needle aspirate from a suspicious parathyroid lesion has also been reported to be an efficient method of localization.104 These techniques have proved useful in preoperatively lateralizing the culprit lesion particularly for recurrent or persistent HPT with non-informative conventional scans, i.e. a negative or equivocal result, thus improving subsequent surgery and even allowing it to be performed through MIP.
In the endoscopy suite
Interestingly, Graff-Baker and colleagues105 have reported the use of a rapid PTH assay for measuring the PTH value in a mediastinal mass suspected to be an ectopic parathyroid gland in an old man with medical comorbidities. In this case, aspirate was obtained by endoscopic US-guided fine needle and revealed a very high PTH level, thus confirming the parathyroid nature of the lesion and justifying major surgery in such a high-risk patient.
In the outpatient setting
Rapid PTH assays in US-guided aspirates from suspected parathyroid lesions have been reported to significantly improve sensitivity of localizing the truly offending gland from 67.7% to 91.9% when compared to US-alone-based localization, subsequently impacting the management decision in the early pre-admission phase.106
CONCLUSIONS AND RECOMMENDATIONS
The role of IPM in guiding surgery for PHPT is more or less well established. However, its role in renal HPT surgery needs to be further investigated, particularly concerning whether it could efficiently guide MAS and which IOPTH endpoint would achieve the best performance. Bio-intact, rather than intact, PTH assays should preferentially be used for intraoperative hormone monitoring in renal patients. In order to validate its use as a biochemical frozen section, potentially replacing the traditional histopathological section, prospectively designed comparative studies on large patient samples are needed to provide an adequate level of evidence. For its advantageous capability of predicting a post-thyroidectomy calcemic state, quickly measuring PTH at skin closure time should be standardized and validated for relevant decision-making. The usefulness of quick PTH assays in the clinical setting emphasize the importance of multidisciplinary teamwork, including surgeons, anesthetists, physicians and biochemists, in providing optimal care for the endocrine patient. Furthermore, given the reviewed wide range of clinical applications, it is worthy for manufacturers and companies to collaborate with researchers and health institutions to develop newer PTH measuring platforms that will provide better accuracy, more time- and cost effectiveness as well as user friendly interface.
M.S.S. would like to thank the Ministry of Higher Education- Missions sector, Egypt and the British Council for their support through Newton-Musharafa programme via the Egyptian Cultural Bureau in London.
CONFLICT OF INTEREST STATEMENT
Author declares that he has no conflict of interest.
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Address for correspondence:
Michael S. Shawky E-mails: email@example.com; firstname.lastname@example.org; email@example.com
Received: 21-05-2016, Accepted: 05-07-2016