Expansion of the Phenotype of Lymphatic Anomalies Caused by Somatic Activating BRAF Variant

Expansion of the Phenotype of Lymphatic Anomalies Caused by Somatic Activating BRAF Variant | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Pediatric Blood & Cancer This is a preprint and has not been peer reviewed. Data may be preliminary. 22 March 2025 V1 Latest version Share on Expansion of the Phenotype of Lymphatic Anomalies Caused by Somatic Activating BRAF Variant Authors : Michael Fox 0000-0003-1297-6935 [email protected] , Sumukh Kumar 0009-0001-2277-8222 , Allison D. Britt , Abhay Srinivasan 0000-0002-0180-4719 , Lea F. Surrey , Seth E. Vatsky , Alexandra J. Borst , Hakon Hakonarson , Dong Li , Sarah E. Sheppard , Kristen Snyder , and Denise Adams Authors Info & Affiliations https://doi.org/10.22541/au.174262160.06182738/v1 Published Pediatric Blood & Cancer Version of record Peer review timeline 313 views 274 downloads Contents Abstract Introduction Methods Case Descriptions Discussion References Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Complex lymphatic anomalies are a morbid group of overlapping disorders associated with lymphatic malformations. Advancement in genetic testing has led to greater understanding of the etiologies of these diseases and other vascular malformations. The somatic activating variant in BRAF (p.V600E) was recently described as a novel cause of head and neck lymphatic malformations and attributed to more complex lymphatic anomalies. Here, we define the phenotype of complex lymphatic anomalies attributed to the somatic BRAF p.V600E variant in six individuals. These cases further highlight the phenotypic heterogeneity associated with this variant and suggest the value of molecular targeted pharmacotherapy. Introduction Complex lymphatic anomalies (CLA), which include generalized lymphatic anomaly (GLA), kaposiform lymphangiomatosis (KLA), Gorham Stout Disease (GSD), and central conducting lymphatic anomaly (CCLA), are a highly morbid group of disorders characterized by abnormal development of lymphatic vessels resulting in diffuse lymphatic malformations (LM), impaired lymphatic flow, and/or coagulopathy. Specific diagnoses are made based on clinical presentation, imaging features, and histopathology, but can be complicated by overlapping features.[1-3] Increased availability of somatic genetic testing has led to the identification of multiple pathogenic variants as causes of these disorders, though unclear genotype-phenotype correlation remains.[4-14] Identification of the genotype may help to classify these diagnoses more accurately and offer insight into optimal treatments. Therefore, further understanding of the molecular etiology of these diseases is critical. The somatic activating variant BRAF c.1799T>A p.Val600Glu (V600E) was recently described as a novel cause of macrocystic head and neck LM in 3 individuals.[15] This variant had been previously reported to cause other vascular anomalies, but this was the first association of this gene with lymphatic anomalies.[16-19] Since then, this variant was attributed to 3 cases of CCLA in publications by our institution.[13, 20] Here, we expand upon these studies to describe 6 cases of GLA, KLA, and/or CCLA associated with the BRAF variant, including the 3 individuals previously reported as well as 3 new individuals. These results expand the phenotypic description of this BRAF variant beyond isolated LMs to include CLAs. Methods We conducted a single-center retrospective chart review at the Children’s Hospital of Philadelphia (CHOP) with all data obtained as of February 2025. Inclusion criteria were patients with a confirmed BRAF V600E variant and diagnosis of CLA. We have received IRB exemption for this study. Genetic testing included the University of Pennsylvania Genetic Diagnostic Laboratory Somatic Overgrowth and Vascular Malformation (SOVM) Panel, CHOP’s Division of Genomic Diagnostics Solid Tumor Panel, and CHOP’s Center for Applied Genomics (CAG) research genetic panel. [20] Case Descriptions Patient #1 was diagnosed with a mesenteric “lymphangioma” as a neonate and underwent partial resection of the lesion (Figure 1A) (Table 1). Thirteen years later, she was incidentally found to have a left-sided chylothorax. Dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) demonstrated findings consistent with CCLA (Figs. 1B-C). She underwent thoracentesis, selective glue embolizations, and lymphovenous anastomoses. Genetic testing from biopsy of gluteal lymphatic tissue demonstrated a somatic BRAF V600E variant at 2.15-2.62% variant allele frequency (VAF). She was treated with sirolimus for three years with no clinical improvement, then transitioned to trametinib for five months until toxicities became severe with little improvement in her condition. She was then started on a BRAF inhibitor, vemurafenib, but discontinued after two months due to several toxicities including nausea, weight loss, muscle aches and hand contractures coupled with a lack of improvement. Though she continues to have chronic pain and discomfort, her pleural effusion has resolved, and she is able to participate in activities of daily living despite no medical treatment for two years. Patient #2, with a history of left inguinal hernia repair as a toddler, was incidentally diagnosed with “lymphangiomatosis” on MRI (Fig. 1D-E) at age 3 (Table 1). She was largely asymptomatic at the time and subsequently followed for 3 years before being lost to follow-up. At age 15, she presented with bacterial pneumonia complicated by bilateral bloody chylothorax. She had normal coagulation studies, but a markedly elevated angiopoietin-2 level. Magnetic resonance imaging (MRI) and DCMRL demonstrated findings consistent with KLA (Fig. 1F-H). Research genetic testing of cell free DNA (cfDNA) isolated from pleural lymphatic fluid revealed a somatic BRAF V600E variant at 0.19-2.26% VAF. [20] She was initially treated with sirolimus, changed to selumetinib once the BRAF variant was found, then transitioned to dual therapy with dabrafenib and trametinib. She has tolerated these medications well but has significant ongoing burden of disease and recently underwent lung decortication and selective glue embolization. At 16 months, Patient #3 was incidentally found to have a mass in the posterior mediastinum and numerous splenic lesions on computed tomography (CT) imaging (Fig. 1I-L) (Table 1). Biopsy of the chest mass demonstrated a combined venous and lymphatic malformation. He developed chylothorax after the biopsy. At 3 years old, he underwent DCMRL, which showed features consistent with GLA and CCLA (Fig. 1I-L), with selective glue embolization. Research genetic testing of cfDNA isolated from thoracic duct lymphatic fluid and left paraspinal mass biopsy identified a somatic BRAF V600E variant at 0.39% VAF and 1.34% VAF, respectively. He responded well to diuretics and intervention and did not require targeted pharmacotherapies. The patient has remained healthy without evidence of recurrent chylothorax or lymphatic conduction abnormality for 2 years. Patient #4 was diagnosed with “lymphangiomatosis” at age 3, at which time she underwent excision of an abdominal LM and splenectomy (Fig. 2A) (Table 1). She remained in good health until age 16, when she presented with protein-losing enteropathy (PLE) and hypothyroidism. MRI and DCMRL were consistent with GLA and CCLA (Fig. 2B-D). Genetic testing of the abdominal tissue excised 13 years prior demonstrated a somatic BRAF V600E variant at 8% VAF. She responded well to diuretics and dietary modifications and did not require targeted pharmacotherapies. Patient #5 had a prenatal ultrasound suspicious for intestinal atresia but MRI at birth demonstrated diffuse LM in the neck and abdomen (Table 1). She then presented again at 16 months with PLE and anasarca. DCMRL demonstrated findings consistent with LM and CCLA (Fig. 2E-H). Genetic testing of cfDNA from pleural lymphatic fluid demonstrated a somatic BRAF V600E variant at 0.21% VAF. She has responded well to treatment with sirolimus and a low-fat diet. Patient #6 was prenatally diagnosed with hydrops and small bowel obstruction and born prematurely at 29 weeks gestational age (Table 1). She underwent exploratory laparotomy with repair of gastric perforation on day of life 5. MRI and DCMRL demonstrated findings consistent with GLA (Fig. 2I-M). Research genetic testing of cfDNA from plasma and thoracic duct lymphatic fluid demonstrated a somatic BRAF V600E variant at 0.51% and 2.0% VAF, respectively. She is followed at an outside institution with no further data available for review. Discussion This report describes 6 cases of CLAs associated with the pathogenic BRAF V600E variant in the absence of other known pathogenic variants. Though all 6 individuals had diffuse LMs and abnormal lymphatic conduction, the cases demonstrate the phenotypic heterogeneity associated with this variant and further illustrate the spectrum of morbidity associated with these disorders (Table 1). To our knowledge, this is the first detailed association of the BRAF V600E with CLAs and expands the phenotypic description of this variant in patients with vascular anomalies. Interestingly, 5 of the 6 individuals developed symptoms related to abnormal lymphatic conduction only after surgical intervention, raising the possibility that these interventions could have disrupted underlying lymphatic anatomy and contributed to a worsened phenotype.[15-19] CLAs are a group of diseases that can be challenging to diagnose given significant overlap in clinical presentation, imaging, and histopathology. As we develop further understanding of the molecular etiology of these disorders, it is apparent that there may be significant genetic overlap as well. This study did not evaluate the efficacy of specific medications in this patient population. Our experience suggests that elucidating the genetics of these disorders may inform a more directed approach to pharmacotherapy, though further studies are needed. Conflict of Interest Statement The authors have no conflicts of interest to declare. No specific funding was received for this case report, but Sarah E. Sheppard is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD009003-01). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Acknowledgements The authors thank the patients and families for their participation in this manuscript. Additionally, we’d like to thank the following individuals for their dedication and the exceptional care they have provided the patients: Shivangi M. Argade, CRNP; Lauren Biroc, MSN, RN, CPNP; Jefferson N. Brownell, MD; Anne-Marie Cahill, MBBch, BAO; Melissa A. Casey, MB; Yoav Dori, MD, PhD; Tamara Feygin, MD; Ganesh Krishnamurthy, MD, DNB; Pablo Laje, MD; Bede Nriagu, MD; Erin Pinto, MSN, RN, FNP BC; Janet Reid, MD, MSEd; Tamjeed Z. Sikder, MA; Christopher Smith, MD, PhD; James R. Treat, MD. Figure 1: Imaging for cases 1-3 (A-C) 18-year-old female with GLA & CCLA. (A) CT as a neonate showing multiple intraabdominal cysts compatible with lymphatic malformation (black arrows). (B) MRL demonstrates dermal backflow from the groin (white arrows) with adjacent dilated lymphatic vessels in the superficial pelvis and gluteal region (black arrows). (C) MRL after hepatic injection shows intact thoracic duct with multifocal saccular dilation of the lymphatic network in the retroperitoneum and cisterna chyli. (D-H) 16-year-old female with KLA. (D-E) MRI as a toddler demonstrates extensive soft tissue prominence of the paravertebral soft tissues (white arrows), as well as cystic lesions in the paracolic gutters and lower chest (black arrows) consistent with multicompartmental lymphatic malformation. (F) MRI showing interval progression of disease with large right pleural effusion (asterisk) and boney involvement of the thoracic vertebrae (white arrows). (G) MRL after hepatic injection demonstrates proliferation and dilation of lymphatic channels in the chest (black arrows). (H) MRL after inguinal injection shows diffuse abnormal architecture of the thoracic lymphatics and collateral lymphatics with drainage to both the left and right venous angles (white arrows). (I-L) 4-year-old male with GLA. (I-J) CT shows paraspinal lymphatic malformation (white arrows) and lymphatic cysts in the spleen (black arrows). (K) Chest radiograph demonstrates large left pleural effusion (asterisk). (L) MRL after hepatic injection shows opacification of the paraspinal lymphatic malformation with associated intercostal perfusion (white arrows), along with visualization of right-sided thoracic duct (black arrows). Figure 2: Imaging for cases 4-6 (A-D) 21-year-old with GLA with abnormal lymphatic conduction. (A) MRI as toddler demonstrates multilocular lymphatic malformation of the abdomen (black arrows) with splenic involvement (white arrow). (B-C) MRL after liver injection shows collateral lymphatic channels along the left paravertebral network (black arrows) and intercostal perfusion (white arrow). (D) MRL after groin injection demonstrates dilated collateral lymphatic channels of the mediastinum (white arrows). (E-H) 4 year-old with GLA and CCLA. (E) MRI during infancy shows lymphatic malformation centered in the mesentery (black arrows) with a smaller lymphatic malformation in the left supraclavicular region (white arrow). (F) Fluoroscopic imaging from direct lymphangiography after antegrade trans-abdominal access of the thoracic duct showing direct connection of the thoracic duct with the supraclavicular lymphatic malformation (white arrows). (G) MRL demonstrates the abdominal lymphatic malformation (black arrows) from liver and mesenteric injection with peritoneal leak (asterisks), as well as supraclavicular lymphatic malformation (white arrow) connected to the thoracic duct (white arrowheads) on inguinal injection. (H) Follow-up MRI at age 4 years after initiation of sirolimus showing decrease in malformations (black arrow). (I-M) 14-month-old with GLA. (I-K) Axial and coronal T2-weighted images with fat suppression shows infiltrative lymphatic malformation in the mediastinum, pleura, spleen, retroperitoneum, and pelvis (white arrows) and ascites (white arrowheads). (L-M) Maximum-intensity projection of T1-weighted spoiled gradient echo images after injection of contrast into lymphatics shows retrograde flow of contrast into mesentery and retroperitoneum (dashed arrow) after liver and mesenteric injection but not into thoracic duct. After groin injection, there is similar filling of retroperitoneal lymphatics and abnormal retrograde flow (thick arrows), but thoracic duct still does not fill with contrast.  Table 1: Patient clinical features 18 years, F Mesenteric “lymphangioma” diagnosed as neonate; incidental finding of chylothorax at 13 years MRI: Lymphatic malformations in abdomen, spleen DCMRL: Disconnected inguinal and central lymphatic system, dilated thoracic duct draining to collateral lymphatic network; bilateral chylothorax; mesenteric lymphatic malformations; lymphatic drainage to the legs and labia Dilated and irregularly-shaped lymphatics in colon mesentery and gluteal skin (CD31 + , D2-40 + , PROX1 variable) LM with CCLA - Resection as a neonate - Selective glue embolization - thoracentesis - Bilateral lymphovenous anastomoses - Sirolimus, then trametinib, then vemurafenib University of Pennsylvania SOVM Panel v3 - Sample: Affected gluteal tissue - NM_006218.3 (BRAF): c.1799T>A p.V600E 2.15-2.62% VAF 16 years, F Complex cystic mass involving neck, mediastinum, and abdomen found at 3 years as part of fever workup, diagnosed with “lymphangiomatosis”; largely asymptomatic until presenting again at 15 years with bilateral bloody, chylous effusions Normal coagulation profile Angiopoietin-2 level of 11,759 pg/mL MRI: Lymphatic malformations in chest, abdomen, pelvis, spleen; perivascular thickening of central vessels; confluent marrow replacement in the vertebral bodies DCMRL: Abnormal lymphatic drainage into the mediastinum, chest, abdomen, and pelvis None obtained KLA - Diuretics - Sirolimus, then selumetinib, then dabrafenib/trametinib dual therapy CHOP CAG - Sample: cfDNA from pleural lymphatic fluid - NM_006218.3 (BRAF): c.1799T>A p.V600E 0.19-2.26% VAF 4 years, M Lymphatic malformations of posterior mediastinum and spleen incidentally found on chest CT obtained for recurrent respiratory infections at 4 years; developed chylothorax after biopsy of mediastinal mass MRI: Lymphatic malformations of the posterior mediastinum and spleen DCMRL: Hepatopulmonary perfusion leaking into the left pleural space; dilated and tortuous thoracic duct connecting to veins and mediastinal lymphatic malformation Combined lymphatic (D2-40 + , PROX1 + ) & venous (CD34 + , D2-40 - , PROX1 variable) components, focal papillary endothelial proliferation GLA with CCLA - Selective glue embolization - Diuretics CHOP CAG - Sample: cfDNA from thoracic duct lymphatic fluid and left paraspinal mass biopsy - NM_006218.3 (BRAF): c.1799T>A p.V600E 0.39% VAF from cfDNA from thoracic duct lymphatic fluid 1.34% VAF from left paraspinal mass biopsy 21 years, F Diagnosed with “lymphangiomatosis” at 3 years as part of workup for acute gastrointestinal illness, underwent excision of abdominal lymphatic malformation and splenectomy, then lost to follow up; presented again at 16 with protein-losing enteropathy (PLE) & hypothyroidism MRI: Cystic lesions in chest and retroperitoneum; pleural effusions DCMRL: Cystic abdominal collections with intercostal and duodenal lymphatic perfusion Abnormal lymphatic channels involving abdomen and extending into spleen (D2-40 + ) GLA with CCLA - Excision and splenectomy - Diuretics CHOP Solid Tumor Panel - Sample: Affected abdominal tissue - NM_004333.5 (BRAF): c.1799T>A p.V600E 8% VAF 4 years, F Diagnosed with diffuse lymphatic malformations of neck and abdomen as a neonate E.coli infection DOL 7 Developed PLE at 16 months MRI: Lymphatic malformations of neck and abdomen DCMRL: Mesenteric lymphatic malformation with bowel wall involvement; impaired communication between mesenteric and central lymphatic systems None obtained LM with CCLA - Sirolimus - Low-fat diet CHOP CAG - Sample: DNA isolated from pleural lymphatic fluid - NM_006218.3 (BRAF): c.1799T>A p.V600E 0.21% VAF 14 months, F Prenatally diagnosed with hydrops and small bowel obstruction MRI: Large volume ascites, septated cystic masses involving inguinal areas and anterior thigh DCMRL: no filling of duct with hepatic, mesenteric, or inguinal injections, indicative of primary lymphatic flow disorder None obtained GLA - None CHOP CAG - Sample: cfDNA from plasma and thoracic duct lymphatic fluid - NM_006218.3 (BRAF): c.1799T>A p.V600E 0.51% VAF from cfDNA from plasma 2% VAF from cfDNA from thoracic duct lymphatic fluid References 1. 1. Adams, D.M. and K.W. Ricci, Vascular Anomalies: Diagnosis of Complicated Anomalies and New Medical Treatment Options. Hematol Oncol Clin North Am, 2019. 33 (3): p. 455-470.2. Iacobas, I., et al., Multidisciplinary guidelines for initial evaluation of complicated lymphatic anomalies-expert opinion consensus. Pediatr Blood Cancer, 2020. 67 (1): p. e28036.3. Ricci, K.W. and I. Iacobas, How we approach the diagnosis and management of complex lymphatic anomalies. Pediatr Blood Cancer, 2022. 69 Suppl 3 : p. e28985.4. Li, D., et al., Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly. Hum Mol Genet, 2018. 27 (18): p. 3233-3245.5. Barclay, S.F., et al., A somatic activating NRAS variant associated with kaposiform lymphangiomatosis. Genet Med, 2019. 21 (7): p. 1517-1524.6. Boscolo, E., et al., Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis. Pediatr Blood Cancer, 2019. 66 (8): p. e27790.7. Li, D., et al., ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor. Nat Med, 2019. 25 (7): p. 1116-1122.8. Rodriguez-Laguna, L., et al., Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. J Exp Med, 2019. 216 (2): p. 407-418.9. Foster, J.B., et al., Kaposiform lymphangiomatosis effectively treated with MEK inhibition. EMBO Mol Med, 2020. 12 (10): p. e12324.10. Li, D., et al., Expanded phenotypic spectrum of JAG1-associated diseases: Central conducting lymphatic anomaly with a pathogenic variant in JAG1. Clin Genet, 2021. 99 (5): p. 742-743.11. Allen-Rhoades, W., et al., Cellular variant of kaposiform lymphangiomatosis: a report of three cases, expanding the morphologic and molecular genetic spectrum of this rare entity. Hum Pathol, 2022. 122 : p. 72-81.12. Byrne, A.B., et al., Pathogenic variants in MDFIC cause recessive central conducting lymphatic anomaly with lymphedema. Sci Transl Med, 2022. 14 (634): p. eabm4869.13. Liu, M., et al., Genetics etiologies and genotype phenotype correlations in a cohort of individuals with central conducting lymphatic anomaly. Eur J Hum Genet, 2022. 30 (9): p. 1022-1028.14. Grenier, J.M., et al., Pathogenic variants in PIK3CA are associated with clinical phenotypes of kaposiform lymphangiomatosis, generalized lymphatic anomaly, and central conducting lymphatic anomaly. Pediatr Blood Cancer, 2023: p. e30419.15. Zenner, K., et al., Somatic activating BRAF variants cause isolated lymphatic malformations. HGG Adv, 2022. 3 (2): p. 100101.16. Al-Olabi, L., et al., Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Invest, 2018. 128 (11): p. 5185.17. Goss, J.A., et al., Somatic mutations in intracranial arteriovenous malformations. PLoS One, 2019. 14 (12): p. e0226852.18. Groesser, L., et al., BRAF and RAS Mutations in Sporadic and Secondary Pyogenic Granuloma. J Invest Dermatol, 2016. 136 (2): p. 481-6.19. Hong, T., et al., High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations. Brain, 2019. 142 (1): p. 23-34.20. Li, D., et al., Genomic profiling informs diagnoses and treatment in vascular anomalies. Nat Med, 2023. 29 (6): p. 1530-1539. Figures and Tables Google Scholar Information & Authors Information Version history V1 Version 1 22 March 2025 Peer review timeline Published Pediatric Blood & Cancer Version of Record 30 Aug 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Pediatric Blood & Cancer Keywords hematology/oncology molecular genetics vascular malformations Authors Affiliations Michael Fox 0000-0003-1297-6935 [email protected] The Children's Hospital of Philadelphia View all articles by this author Sumukh Kumar 0009-0001-2277-8222 The Children's Hospital of Philadelphia View all articles by this author Allison D. Britt The Children's Hospital of Philadelphia View all articles by this author Abhay Srinivasan 0000-0002-0180-4719 The Children's Hospital of Philadelphia View all articles by this author Lea F. Surrey The Children's Hospital of Philadelphia View all articles by this author Seth E. Vatsky The Children's Hospital of Philadelphia View all articles by this author Alexandra J. Borst The University of North Carolina at Chapel Hill View all articles by this author Hakon Hakonarson The Children's Hospital of Philadelphia View all articles by this author Dong Li The Children's Hospital of Philadelphia Center for Applied Genomics View all articles by this author Sarah E. Sheppard The Children's Hospital of Philadelphia View all articles by this author Kristen Snyder The Children's Hospital of Philadelphia View all articles by this author Denise Adams The Children's Hospital of Philadelphia View all articles by this author Metrics & Citations Metrics Article Usage 313 views 274 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Michael Fox, Sumukh Kumar, Allison D. Britt, et al. Expansion of the Phenotype of Lymphatic Anomalies Caused by Somatic Activating BRAF Variant. Authorea . 22 March 2025. DOI: https://doi.org/10.22541/au.174262160.06182738/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.174262160.06182738/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a00046284c3609d6',t:'MTc3OTQ5OTYwMw=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();