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A giant bronchogenic cyst associated with partial pericardial defect and anomalous origin of the right coronary artery
Journal Pre-proof A giant bronchogenic cyst associated with partial pericardial defect and anomalous origin of the right coronary artery Xinpeng Qu, Hui Zhang PII:
S2213-5766(19)30197-6
DOI:
https://doi.org/10.1016/j.epsc.2019.101288
Reference:
EPSC 101288
To appear in:
Journal of Pediatric Surgery Case Reports
Received Date: 6 August 2019 Accepted Date: 21 August 2019
Please cite this article as: Qu X, Zhang H, A giant bronchogenic cyst associated with partial pericardial defect and anomalous origin of the right coronary artery, Journal of Pediatric Surgery Case Reports (2019), doi: https://doi.org/10.1016/j.epsc.2019.101288. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
A giant bronchogenic cyst associated with partial pericardial defect and anomalous origin of the right coronary artery
Abstract Bronchogenic cyst combined with partial defect of the pericardium is a rare congenital anomaly, seldomly diagnosed in young children. We describe the case of a 20-month-old girl with anomalous origin of the right coronary artery and a giant bronchogenic cyst protruding into the pericardium and causing partial pericardial defect. The cyst was successfully resected and postoperative recovery was uneventful.
Introduction Bronchogenic cysts are a rare congenital malformation that arise from abnormal budding of the primitive tracheobronchial tube during embryogenesis. They are mostly located in the mediastinum and are the most common type of intrathoracic foregut cysts[1]. Within the mediastinum, bronchogenic cysts are mainly found to be near large airways, cases of cysts growing in the pericardium are seldomly reported in the literature[2]. Here, we present a case in which a cysts-like structure inside the pericardial cavity was discovered incidentally in a 20-month-old patient by echocardiography. Further examination revealed a giant cyst the lower part of which protruding into the pericardium, causing a right-sided partial pericardial defect. The cyst was completely resected and histological assessment demonstrated respiratory epithelium consistent with a bronchogenic cyst.
Case Presentation A 20-month-old girl was referred to the Cardiology clinic because of hoarseness after exercise for the preceding two months. Parents denied any symptoms of respiratory infections and history of witnessed foreign body aspiration. A transthoracic echocardiography was arranged and it revealed a cysts-like mass that is 3.0cm×2.2cm inside the pericardial cavity, and showed normal cardiac structure and function. The patient was immediately admitted to our department for further treatment. Physical examination, chest radiography, ECG were found to be normal. The standard blood tests and the concentration of tumor markers were within normal reference range. The investigation was continued with a thoracic computed tomography (CT) scan and angiogram which showed a soft tissue mass which was situated superior to the right atrium, anterior to the right pulmonary artery, between the superior vena cava and the ascending aorta, with the lower part growing in the pericardial cavity. The size of this mass was 53×36×28mm, the CT value was 45Hu（as shown in Figure 1）. Meanwhile anomalous origin of the right coronary artery from the left coronary sinus without hemodynamic abnormalities was revealed. This mass was further delineated by magnetic resonance imaging (MRI) which showed a mass of high intensity in T1W and T2W, and the localization and size was identical to what CT revealed. However, definite diagnosis cannot be obtained from the data at hand. Therefore, the patient underwent thoracotomy, and the cystic mass was found to originate from 1cm above the carina, adjacent to the right pulmonary artery, and rise through the space between the superior vena cava and the ascending
aorta to the right subclavian artery. The lower part of the mass was in the pericardial cavity, causing a right-sided pericardial defect. At this moment it became clear that the cyst had an intrapericardial development(as shown in Figure 2). After removing the adhesion with the pericardium and surrounding tissue, the lesion was resected, leaving the pericardium partially opened which was then closed with continuous sutures. There were no complications after surgery, the patient being discharged on the 7th day after the surgical intervention. Histological examination identified that the cyst wall was composed of fibrous and smooth fibromuscular tissue, with some bronchial gland cells. These findings suggested the diagnosis of bronchogenic cyst.
Figure1. Angio-CT aspects of a mediastinal mass, with its lower part in the pericardial cavity
Figure 2. Intraoperative aspects of the cyst
Discussion Bronchogenic cysts (BCs) are a rare congenital malformation of the foregut that is typically found in the mediastinum [3]. Bronchogenic cyst is one of the early embryonic foregut malformations and commonly occurs in the chest cavity. Foregut cyst was derived from the residual foregut structure during embryonic development. According to the structure of the cyst wall, foregut cysts can be divided into four types: (1) bronchogenic cysts, (2) esophageal duplication cysts, (3) enteric duplication cysts, (4) mixed cysts. Bronchogenic cysts are found most frequently along the tracheobronchial tree in the mediastinum or within the lung parenchyma. Rarely, the cysts occurr in other locations, including cutaneous [4] and subcutaneous tissues [5], neck [6], pericardium [7], diaphragm [8], abdomen [9], and the intramedullary part of the spine [10]. Cases of intrapericardial and intracardiac bronchogenic cysts are very rare in the literature. Lima¨ıem et al. reported an incidence of 1 case per 42,000 patients in the North American population [11]. During the fifth week of embryotic development the bronchial buds develop at the caudal end of the laryngeotracheal tube and grow into the pericardialperitoneal canals, the future pleural cavities [12]. During this period the primitive heart and lungs share a common coelomic cavity and are closely connected [13]. Meanwhile, the pleural and pericardial membranes appear laterally as ridges of mesenchyme, and the membranes fuse in the midline at the end of 7th week, separating the pleural and pericardial cavities [12]. In the case of intrapericardial development of a bronchogenic cyst, the separation of the lung bud tissue and its inclusion in the pericardial cavity may occur synchronously [13]. Bronchogenic cysts usually do not cause symptoms and most of the patients are detected incidentally. Nonspecific symptoms such as retrosternal chest pain, dyspnea, cough, fever, and hoarseness may be present as first complaints. Clinical manifestations of a bronchogenic cyst are associated with the its localization, size and the oppression on its surrounding tissue and organs. If the cyst is small, without oppression on its surrounding organs, there may be no symptoms and
can only be observed during imaging examinations. When the cysts are large, there may be symptoms of cough, chest tightness, chest pain, difficulty in breathing or swallowing difficulties due to its oppression on trachea, bronchus, pulmonary or esophageal. Patients at younger age are more prone to have the compression symptoms as the trachea and bronchial tree are relatively soft and vulnerable to oppression. In our patient, obstructive symptoms were not present in the neonatal period, but ultimately symptom of hoarseness after exercise began to emerge. In this case, echocardiography played an important role in revealing the lesion in the pericardial cavity, which offered a hint of a giant mass growing in the mediastinum. It may be difficult to differentiate a bronchogenic cyst from other lesions before pathological examination, for the reason that there are no specific CT or MR imaging findings that allow easy differentiation. The attenuation of the cyst’s contents can vary from that of water to soft-tissue. The value of attenuation can be as high as 100 Hounsfield units if the cyst contains protein or calcium oxalate [14]. In this case the CT scan revealed a fluid level of attenuation, and the cyst was not obvious on the plain film. However, CT scan/MRI of the chest was still valuable for diagnosis, as it can help define the anatomy and rule out a list of differentials that include cystic hygroma, lymphangioma, neuroenteric cyst, esophageal duplication cyst, and thymic cyst [3,15] This is the first bronchogenic cyst diagnosed and treated in our service. The specific literature is abundant with case presentations of bronchogenic cysts, but only a few of them reported intrapericardial development [16,17]. Also in a search of the English literature, we found only one case of a mediastinal bronchogenic cyst with partial right-sided defect in the pericardium as seen in our case[18]. To our knowledge, this is the first case of a giant bronchogenic cyst originating from carina and growing into the pericardial cavity, thus causing a pericardial defect. Besides, this is the first case report that describes a giant bronchogenic cyst associated with anomalous origin of the right coronary artery. Based on our experience and after studying data from literature, we consider that bronchogenic cysts should be treated surgically and that a conservative approach is not recommended. Definitive tissue diagnosis can be obtained only after surgical excision. The removal of all bronchogenic cysts in children has been recommended because they do not spontaneously regress and can enlarge as the patient grows or can become infected, ruptured or malignant[19].
1. Patient consent: Consent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient. 2. Funding: No funding or grant support. 3. Authorship: All authors attest that they meet the current ICMJE criteria for Authorship. 4. Conflict of interest: The following authors have no financial disclosures: Xinpeng Qu, Hui Zhang.
References 1. Ahrens B, Wit J, Schmitt M, et al. Symptomatic bronchogenic cyst in a six-month-old infant:
2. 3. 4. 5. 6. 7. 8. 9. 10.
11.
12. 13. 14. 15. 16. 17.
18. 19.
case report and review of the literature. J Thorac Cardiovasc Surg 122:1021–1023. H. Jiang, H. Wang, H. Wu, and X. Li. Bronchogenic cyst of the interatrial septum. J Cardiothorac Surg vol. 8, article 171, 2013 M. M. Chowdhury and S. Chakraborty. Imaging of congenital lung malformations. Seminars in Pediatric Surgery vol. 24, no. 4, pp. 168–175, 2015. Tresser NJ, Dhams B, Berner JJ. Cutaneous bronchogenic cyst of the back: a case report and review of the literature. Pediatr Pathol 1994;14(2):207-12. Bagwell CE, Schiffman RJ. Subcutaneous bronchogenic cysts. J Pediatr Surg 1988;23(11):993-5. Riquet M, Choubrac P, Molinier H, Carnot F, Debesse B. Cervical tracheogenic air cyst. Apropos of 2 cases. Rev Pneumol Clin 1985;41(3):157-62. French. Gomes MN, Hufnagel CA. Intrapericardial bronchogeniccysts. Am J Cardiol 1975;36(6):817-22. Buddington TW. Intradiaphragmatic cyst; ninth reported case. N Engl J Med 1957;257(13):613-5. Coselli MP, Ipolyi P, Bloss RS, Diaz RF, Fitzgerald JB. Bronchogenic cysts above and below the diaphragm: report of eight cases. Ann Thorac Surg 1987;44(5):491-4. Duthel R, Brunon J, Michel D, Boucheron S. Intramedullary bronchogenic cyst. Apropos of 1 case. Discussion of the endoectodermal adhesion syndrome. Neurochirurgie 1983;29(2):15560. French. F. Lima¨ıem, A. Ayadi-Kaddour, H. Djilani, T. Kilani, and F.E. Mezni. Pulmonary and mediastinal bronchogenic cysts: a clinicopathologic study of 33 cases. Lung vol. 186, no. 1, pp. 55–61, 2008. Moore KL, Persaud TVN. The Developing Human6 edn, Philadelphia, Saunderspp 203–206 Hayashi AH, McLean DR, Peliowski A, Tierney AJ, Finer NN. A rare intrapericardial mass in a neonate. J Pediatr Surg 27:1361–1363. Jeung MY, Gasser B, Gangi A, Bogorin A, Charneau D, Wihlm JM, et al. Imaging of cystic masses of the mediastinum. Radiographics 2002;22 Spec No:S79-93. J.Durell and K. Lakhoo, et al. Congenital cystic lesions of the lung.EarlyHumanDevelopment vol.90,no.12,pp.935–939, 2014. L.L. Somwaru,1 F.M. Midgley,2 G.B. Di Russo. Intrapericardial Bronchogenic Cyst Overriding the Pulmonary Artery. Pediatr Cardiol 26:713–714, 2005. Murat Ugurlucan,1 Omer Ali Sayin,1 Matthias Felten, et al. Intrapericardial Bronchogenic Cyst: An Unusual Clinical Entity. Case Reports in Medicine Volume 2014, Article ID 651683, 3 pages. Victor S, D DI. Congenital partial pericardial defect on the right side associated with a bronchogenic cyst. A case report. Indian Heart J 1981;33:34-6. Ribet ME, Copin MC, Gosselin B. Bronchogenic cysts of the mediastinum. J Thorac Cardiovasc Surg 109:1003–1010.
Conflict of Interest Statement All authors of this manuscript have directly participated in planning, execution, and analysis of this study. The contents of this manuscript have not been copyrighted of published previously. The contents of this manuscript are not now under consideration for publication elsewhere. No financial support or incentive has been provided for this manuscript. I am one author signing on behalf of all co-authors of this manuscript, and attesting to the above.
S2213-5766(19)30197-6
DOI:
https://doi.org/10.1016/j.epsc.2019.101288
Reference:
EPSC 101288
To appear in:
Journal of Pediatric Surgery Case Reports
Received Date: 6 August 2019 Accepted Date: 21 August 2019
Please cite this article as: Qu X, Zhang H, A giant bronchogenic cyst associated with partial pericardial defect and anomalous origin of the right coronary artery, Journal of Pediatric Surgery Case Reports (2019), doi: https://doi.org/10.1016/j.epsc.2019.101288. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
A giant bronchogenic cyst associated with partial pericardial defect and anomalous origin of the right coronary artery
Abstract Bronchogenic cyst combined with partial defect of the pericardium is a rare congenital anomaly, seldomly diagnosed in young children. We describe the case of a 20-month-old girl with anomalous origin of the right coronary artery and a giant bronchogenic cyst protruding into the pericardium and causing partial pericardial defect. The cyst was successfully resected and postoperative recovery was uneventful.
Introduction Bronchogenic cysts are a rare congenital malformation that arise from abnormal budding of the primitive tracheobronchial tube during embryogenesis. They are mostly located in the mediastinum and are the most common type of intrathoracic foregut cysts[1]. Within the mediastinum, bronchogenic cysts are mainly found to be near large airways, cases of cysts growing in the pericardium are seldomly reported in the literature[2]. Here, we present a case in which a cysts-like structure inside the pericardial cavity was discovered incidentally in a 20-month-old patient by echocardiography. Further examination revealed a giant cyst the lower part of which protruding into the pericardium, causing a right-sided partial pericardial defect. The cyst was completely resected and histological assessment demonstrated respiratory epithelium consistent with a bronchogenic cyst.
Case Presentation A 20-month-old girl was referred to the Cardiology clinic because of hoarseness after exercise for the preceding two months. Parents denied any symptoms of respiratory infections and history of witnessed foreign body aspiration. A transthoracic echocardiography was arranged and it revealed a cysts-like mass that is 3.0cm×2.2cm inside the pericardial cavity, and showed normal cardiac structure and function. The patient was immediately admitted to our department for further treatment. Physical examination, chest radiography, ECG were found to be normal. The standard blood tests and the concentration of tumor markers were within normal reference range. The investigation was continued with a thoracic computed tomography (CT) scan and angiogram which showed a soft tissue mass which was situated superior to the right atrium, anterior to the right pulmonary artery, between the superior vena cava and the ascending aorta, with the lower part growing in the pericardial cavity. The size of this mass was 53×36×28mm, the CT value was 45Hu（as shown in Figure 1）. Meanwhile anomalous origin of the right coronary artery from the left coronary sinus without hemodynamic abnormalities was revealed. This mass was further delineated by magnetic resonance imaging (MRI) which showed a mass of high intensity in T1W and T2W, and the localization and size was identical to what CT revealed. However, definite diagnosis cannot be obtained from the data at hand. Therefore, the patient underwent thoracotomy, and the cystic mass was found to originate from 1cm above the carina, adjacent to the right pulmonary artery, and rise through the space between the superior vena cava and the ascending
aorta to the right subclavian artery. The lower part of the mass was in the pericardial cavity, causing a right-sided pericardial defect. At this moment it became clear that the cyst had an intrapericardial development(as shown in Figure 2). After removing the adhesion with the pericardium and surrounding tissue, the lesion was resected, leaving the pericardium partially opened which was then closed with continuous sutures. There were no complications after surgery, the patient being discharged on the 7th day after the surgical intervention. Histological examination identified that the cyst wall was composed of fibrous and smooth fibromuscular tissue, with some bronchial gland cells. These findings suggested the diagnosis of bronchogenic cyst.
Figure1. Angio-CT aspects of a mediastinal mass, with its lower part in the pericardial cavity
Figure 2. Intraoperative aspects of the cyst
Discussion Bronchogenic cysts (BCs) are a rare congenital malformation of the foregut that is typically found in the mediastinum [3]. Bronchogenic cyst is one of the early embryonic foregut malformations and commonly occurs in the chest cavity. Foregut cyst was derived from the residual foregut structure during embryonic development. According to the structure of the cyst wall, foregut cysts can be divided into four types: (1) bronchogenic cysts, (2) esophageal duplication cysts, (3) enteric duplication cysts, (4) mixed cysts. Bronchogenic cysts are found most frequently along the tracheobronchial tree in the mediastinum or within the lung parenchyma. Rarely, the cysts occurr in other locations, including cutaneous [4] and subcutaneous tissues [5], neck [6], pericardium [7], diaphragm [8], abdomen [9], and the intramedullary part of the spine [10]. Cases of intrapericardial and intracardiac bronchogenic cysts are very rare in the literature. Lima¨ıem et al. reported an incidence of 1 case per 42,000 patients in the North American population [11]. During the fifth week of embryotic development the bronchial buds develop at the caudal end of the laryngeotracheal tube and grow into the pericardialperitoneal canals, the future pleural cavities [12]. During this period the primitive heart and lungs share a common coelomic cavity and are closely connected [13]. Meanwhile, the pleural and pericardial membranes appear laterally as ridges of mesenchyme, and the membranes fuse in the midline at the end of 7th week, separating the pleural and pericardial cavities [12]. In the case of intrapericardial development of a bronchogenic cyst, the separation of the lung bud tissue and its inclusion in the pericardial cavity may occur synchronously [13]. Bronchogenic cysts usually do not cause symptoms and most of the patients are detected incidentally. Nonspecific symptoms such as retrosternal chest pain, dyspnea, cough, fever, and hoarseness may be present as first complaints. Clinical manifestations of a bronchogenic cyst are associated with the its localization, size and the oppression on its surrounding tissue and organs. If the cyst is small, without oppression on its surrounding organs, there may be no symptoms and
can only be observed during imaging examinations. When the cysts are large, there may be symptoms of cough, chest tightness, chest pain, difficulty in breathing or swallowing difficulties due to its oppression on trachea, bronchus, pulmonary or esophageal. Patients at younger age are more prone to have the compression symptoms as the trachea and bronchial tree are relatively soft and vulnerable to oppression. In our patient, obstructive symptoms were not present in the neonatal period, but ultimately symptom of hoarseness after exercise began to emerge. In this case, echocardiography played an important role in revealing the lesion in the pericardial cavity, which offered a hint of a giant mass growing in the mediastinum. It may be difficult to differentiate a bronchogenic cyst from other lesions before pathological examination, for the reason that there are no specific CT or MR imaging findings that allow easy differentiation. The attenuation of the cyst’s contents can vary from that of water to soft-tissue. The value of attenuation can be as high as 100 Hounsfield units if the cyst contains protein or calcium oxalate [14]. In this case the CT scan revealed a fluid level of attenuation, and the cyst was not obvious on the plain film. However, CT scan/MRI of the chest was still valuable for diagnosis, as it can help define the anatomy and rule out a list of differentials that include cystic hygroma, lymphangioma, neuroenteric cyst, esophageal duplication cyst, and thymic cyst [3,15] This is the first bronchogenic cyst diagnosed and treated in our service. The specific literature is abundant with case presentations of bronchogenic cysts, but only a few of them reported intrapericardial development [16,17]. Also in a search of the English literature, we found only one case of a mediastinal bronchogenic cyst with partial right-sided defect in the pericardium as seen in our case[18]. To our knowledge, this is the first case of a giant bronchogenic cyst originating from carina and growing into the pericardial cavity, thus causing a pericardial defect. Besides, this is the first case report that describes a giant bronchogenic cyst associated with anomalous origin of the right coronary artery. Based on our experience and after studying data from literature, we consider that bronchogenic cysts should be treated surgically and that a conservative approach is not recommended. Definitive tissue diagnosis can be obtained only after surgical excision. The removal of all bronchogenic cysts in children has been recommended because they do not spontaneously regress and can enlarge as the patient grows or can become infected, ruptured or malignant[19].
1. Patient consent: Consent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient. 2. Funding: No funding or grant support. 3. Authorship: All authors attest that they meet the current ICMJE criteria for Authorship. 4. Conflict of interest: The following authors have no financial disclosures: Xinpeng Qu, Hui Zhang.
References 1. Ahrens B, Wit J, Schmitt M, et al. Symptomatic bronchogenic cyst in a six-month-old infant:
2. 3. 4. 5. 6. 7. 8. 9. 10.
11.
12. 13. 14. 15. 16. 17.
18. 19.
case report and review of the literature. J Thorac Cardiovasc Surg 122:1021–1023. H. Jiang, H. Wang, H. Wu, and X. Li. Bronchogenic cyst of the interatrial septum. J Cardiothorac Surg vol. 8, article 171, 2013 M. M. Chowdhury and S. Chakraborty. Imaging of congenital lung malformations. Seminars in Pediatric Surgery vol. 24, no. 4, pp. 168–175, 2015. Tresser NJ, Dhams B, Berner JJ. Cutaneous bronchogenic cyst of the back: a case report and review of the literature. Pediatr Pathol 1994;14(2):207-12. Bagwell CE, Schiffman RJ. Subcutaneous bronchogenic cysts. J Pediatr Surg 1988;23(11):993-5. Riquet M, Choubrac P, Molinier H, Carnot F, Debesse B. Cervical tracheogenic air cyst. Apropos of 2 cases. Rev Pneumol Clin 1985;41(3):157-62. French. Gomes MN, Hufnagel CA. Intrapericardial bronchogeniccysts. Am J Cardiol 1975;36(6):817-22. Buddington TW. Intradiaphragmatic cyst; ninth reported case. N Engl J Med 1957;257(13):613-5. Coselli MP, Ipolyi P, Bloss RS, Diaz RF, Fitzgerald JB. Bronchogenic cysts above and below the diaphragm: report of eight cases. Ann Thorac Surg 1987;44(5):491-4. Duthel R, Brunon J, Michel D, Boucheron S. Intramedullary bronchogenic cyst. Apropos of 1 case. Discussion of the endoectodermal adhesion syndrome. Neurochirurgie 1983;29(2):15560. French. F. Lima¨ıem, A. Ayadi-Kaddour, H. Djilani, T. Kilani, and F.E. Mezni. Pulmonary and mediastinal bronchogenic cysts: a clinicopathologic study of 33 cases. Lung vol. 186, no. 1, pp. 55–61, 2008. Moore KL, Persaud TVN. The Developing Human6 edn, Philadelphia, Saunderspp 203–206 Hayashi AH, McLean DR, Peliowski A, Tierney AJ, Finer NN. A rare intrapericardial mass in a neonate. J Pediatr Surg 27:1361–1363. Jeung MY, Gasser B, Gangi A, Bogorin A, Charneau D, Wihlm JM, et al. Imaging of cystic masses of the mediastinum. Radiographics 2002;22 Spec No:S79-93. J.Durell and K. Lakhoo, et al. Congenital cystic lesions of the lung.EarlyHumanDevelopment vol.90,no.12,pp.935–939, 2014. L.L. Somwaru,1 F.M. Midgley,2 G.B. Di Russo. Intrapericardial Bronchogenic Cyst Overriding the Pulmonary Artery. Pediatr Cardiol 26:713–714, 2005. Murat Ugurlucan,1 Omer Ali Sayin,1 Matthias Felten, et al. Intrapericardial Bronchogenic Cyst: An Unusual Clinical Entity. Case Reports in Medicine Volume 2014, Article ID 651683, 3 pages. Victor S, D DI. Congenital partial pericardial defect on the right side associated with a bronchogenic cyst. A case report. Indian Heart J 1981;33:34-6. Ribet ME, Copin MC, Gosselin B. Bronchogenic cysts of the mediastinum. J Thorac Cardiovasc Surg 109:1003–1010.
Conflict of Interest Statement All authors of this manuscript have directly participated in planning, execution, and analysis of this study. The contents of this manuscript have not been copyrighted of published previously. The contents of this manuscript are not now under consideration for publication elsewhere. No financial support or incentive has been provided for this manuscript. I am one author signing on behalf of all co-authors of this manuscript, and attesting to the above.