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• W4200438863 abstract "HomeHypertensionVol. 79, No. 2Hypertension With Negative Metaiodobenzylguanidine Scintigraphy Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBHypertension With Negative Metaiodobenzylguanidine Scintigraphy Antoine-Guy Lopez, Anna F. Dominiczak, Rhian Touyz, Markus Schlaich, Jean-Baptiste de Freminville and Laurence Amar Antoine-Guy LopezAntoine-Guy Lopez https://orcid.org/0000-0002-3479-8693 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité Hypertension Artérielle, Paris, France (A.-G.L., J.-B.d.F., L.A.). Normandie Univ, UNIROUEN, INSERM U1239, Rouen University Hospital, Department of Endocrinology, Diabetology and Metabolic Diseases, Rouen, France (A.-G.L.). Search for more papers by this author , Anna F. DominiczakAnna F. Dominiczak https://orcid.org/0000-0003-4913-3608 Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences (A.F.D.), University of Glasgow, United Kingdom. Search for more papers by this author , Rhian TouyzRhian Touyz https://orcid.org/0000-0003-0670-0887 Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre (R.T.), University of Glasgow, United Kingdom. Search for more papers by this author , Markus SchlaichMarkus Schlaich https://orcid.org/0000-0002-1765-0195 Dobney Hypertension Centre, School of Medicine, Royal Perth Hospital Unit, Royal Perth Hospital Medical Research Foundation, The University of Western Australia, Australia (M.S.). Search for more papers by this author , Jean-Baptiste de FreminvilleJean-Baptiste de Freminville https://orcid.org/0000-0003-3829-9506 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité Hypertension Artérielle, Paris, France (A.-G.L., J.-B.d.F., L.A.). Université de Paris, PARCC, INSERM, France (J.-B.d.F., L.A.). Search for more papers by this author and Laurence AmarLaurence Amar Correspondence to: Laurence Amar, Université de Paris, AP-HP, Hôpital Européen Georges Pompidou Hypertension Unit 20 rue Leblanc Paris, N/A F-75015, France. Email E-mail Address: [email protected] https://orcid.org/0000-0003-3942-4276 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité Hypertension Artérielle, Paris, France (A.-G.L., J.-B.d.F., L.A.). Université de Paris, PARCC, INSERM, France (J.-B.d.F., L.A.). Search for more papers by this author Originally published9 Dec 2021https://doi.org/10.1161/HYPERTENSIONAHA.121.18012Hypertension. 2022;79:474–478Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: December 9, 2021: Ahead of Print Case IntroductionA 34-year-old woman was referred to our department due to severe hypertension during pregnancy. Hypertension was diagnosed incidentally in 2016 when she was 32 years old. In 2018, she was admitted twice to the cardiology department for severe hypertension.She also complained of palpitations, headaches, and dyspnea. Her blood pressure was ≈225/110 mm Hg, and her physical examination results were unremarkable. Left ventricular hypertrophy was observed on her ECG and confirmed via echocardiography. Routine blood tests showed abnormally high glycated hemoglobin at 7.8% and elevated low-density lipoprotein cholesterol at 5.18 mmol/L. She also had elevated troponin levels at 127 µg/L (normal range, <0.6) and N-terminal pro-B-type natriuretic peptide at 10 923 ng/mL (normal range, 0–155).The patient was screened for pheochromocytoma, and it was found that her urinary normetanephrine levels were elevated at twice the normal range (495 nmol/d) and her blood catecholamines were elevated to 116 301 pmol/L (normal range, 0–3000). A 123I-metaiodobenzylguanidine (MIBG) scintigraphy was performed, which failed to detect any pathological uptake. Therefore, the physicians ruled out the differential diagnoses of pheochromocytoma and paraganglioma (PPGL). The patient’s hypertension was treated with atenolol, ramipril, and furosemide, and her diabetes was treated with metformin.The first question to begin the discussion is: Do you agree with this management?Discussion: When and How to Screen for PPGL?Professor Dominiczak: I do not agree with this management, as I have seen similar cases, and pattern recognition is always helpful in medicine, as you know. I do not want to give everything away, but I think negative MIBG is not enough to rule out pheochromocytoma or other causes of catecholamine excess in a patient with such a high level of noradrenaline in the blood. I know this is subject to errors, but not to that extent. This is a hundred thousand times the upper range. Additionally, this was confirmed only via 24-hour urine collection. More importantly, if I were diagnosing young women with paroxysmal hypertension, I would have also used diagnostic imaging techniques, such as magnetic resonance imaging (MRI) and computed tomography. I would not have given up at the stage in the case report.Anonymous Question from Live Chat: Was there any history of syncope or presyncope? Did the palpitation and headache occur at same episodes or separated in time?Professor Amar: To our knowledge, this patient did not have any history of syncope or presyncope, although she has a complicated personal history. In fact, she had many complaints, but she would not go to outpatient clinics and visited the hospital only when there was an emergency. Her palpitations and headaches occurred both at the same time and separately.MIBG scintigraphy was found to be very sensitive and specific in the diagnosis of pheochromocytomas, which are adrenal tumors.1,2 However, it definitely does not rule out the diagnosis of functional paraganglioma. Therefore, they should not have ruled out the diagnosis based only on MIBG scintigraphy. In the first place, they should have screened for secondary hypertension in this young patient with very severe hypertension.3,4Dr Schlaich: How often does MIBG imaging fail to detect paraganglioma?Professor Amar: We performed a study ≈8 to 10 years ago in France, wherein we compared MIBG to octreotide scintigraphy and conventional imaging. We showed that for paraganglioma, regardless of the localization, the sensitivity of MIBG was ≈40%, although it was ≈85% for all other imaging modalities.1 As we mentioned earlier, the diagnostic performance is high for pheochromocytoma, but we do not really have any diagnostic issue because conventional imaging will confirm the diagnosis. Nowadays, MIBG scintigraphy has basically been rendered useless, especially because we now have access to 18F-fluoro-dihydroxyphenylalanine (18F-DOPA) and 68Ga-1,4,7,10-tetraazacyclododecane1,4,7,10-tetraacetic acid positron emission tomography (68Ga-DOTATOC PET) scans, which have much higher sensitivities. This patient was a 32-year-old woman with a body mass index of 21 kg/m2, hypertension, and diabetes. These factors, without any other symptoms, are collectively an indication to screen for pheochromocytoma or functional paraganglioma. Indeed, everyone should keep in mind that a patient with normal body mass index, diabetes, and hypertension before 50 years of age has an elevated risk of paraganglioma or functional pheochromocytoma.5Professor Dominiczak: You are absolutely right. What we have always been saying when following-up with these patients in our center has been that unless you consider a disease or condition, you are not going to diagnose the said disease or condition. You have to think about it, which is precisely what Professor Amar just said. You have to keep in mind the suspicion of all possible conditions; otherwise, an accurate diagnosis cannot be made.Dr Sandeep Riar: Is it common to check plasma catecholamines in blood in most parts of the world? In the United States, we check metanephrines in blood and catecholamines in 24-hour urine.Dr de Freminville: It is now recommended to check metanephrines in blood or in 24-hour urine as the first-line check because they are the most accurate measurements that can confirm or rule out PPGL (negative predictive value >99% and specificity of around 94%). Diagnostic accuracy is slightly better for blood metanephrines, thus we tend to use it more frequently in France. In clinical routines, we should not use catecholamines anymore either in plasma or in urine.3,6 Indeed, as we already pointed out several times, this patient was definitely not well-managed in the first place.Professor Dominiczak: You did not comment on the very high troponin levels, which indicated that something was happening to the heart muscle, that is, to the cardiomyocytes. I would also worry about atenolol because β-blockers used without alpha blockers are dangerous in a patient suspected to have PPGL.Discussion: Antihypertensive TreatmentDr Khawaja Adnan Younis: Why start with atenolol? Also, loop diuretics are not the first-line management of hypertension; what was the role of furosemide in this case?Dr de Freminville: Atenolol might have been introduced both for hypertension and as a symptomatic treatment for palpitations. Left ventricular hypertrophy could also have been an indication for beta blockers, but the echocardiography did not find obstructive left ventricular hypertrophy. The level of proof for β-blockers as a treatment of undocumented palpitations is low, and the atenolol does not have a better half-life and bioavailability. Therefore, we also think that beta blockers were not an appropriate treatment.Regarding furosemide, it is not recommended as a first-line treatment as its antihypertensive efficacy is mostly linked to volume depletion in patients with kidney disease or heart failure, which was not the case here. Thiazide would have been a better choice.Finally, while both beta blockers and diuretics are very bad choices in cases of secreting PPGL, at that time, the physicians in charge of the patient ruled out PPGL.Dr Metaxia Driva: Why choose ramipril, which has a very small duration of action?Dr de Freminville: Among renin-angiotensin system blockers, ACE (angiotensin-converting enzyme) inhibitors, and angiotensin 2 receptor blockers have similar efficacies, provided that they have a sufficient bioavailability and duration of action. Among ACE inhibitor, perindopril is considered to have the best properties, while ramipril has a half-life of about 13 to 17 hours and a good bioavailability, making it appropriate for a once-daily medication and a good choice among ACE.7Dr Patricia Van der Niepen: Was there any indication of medication or drug abuse?Dr de Freminville: No, but no toxicological screening was performed at that time.Discussion: Managing Hypertension During PregnancyAfter this hospitalization, the patient was lost to follow-up. In 2019, she became pregnant. At 7 weeks of gestation, she was admitted to the diabetology department for uncontrolled diabetes, and insulin was administered. She was then transferred to our hypertension excellence center at the Hospital Georges Pompidou in Paris because of uncontrolled hypertension in early pregnancy. Ambulatory blood pressure was found to be elevated at 147/97 mm Hg (heart rate =103 bpm), with strong blood pressure variability and uncontrolled hypertension, despite treatment with methyldopa and nicardipine. There was also no significant decrease overnight (Figure 1). The management and investigation of hypertension were more complicated because of blood pressure variability and early pregnancy. Hormonal assessments showed an elevated level of plasma normetanephrine to 39 nmol/L (normal range, 0.0–1.1), with normal levels of plasma metanephrine. Indeed, metanephrine can be assessed during pregnancy.8 The patient had a high level of aldosterone at 1393 pmol/L (normal range, 70–360) and renin at 106 mUI/L (normal range, 11–33). Her 24-hour urinary free cortisol was normal at 187 mmol/24 h (normal range, 14–250).Download figureDownload PowerPointFigure 1. Ambulatory blood pressure monitoring.MRI without contrast was performed because of the hormonal results and clinical symptoms, even if MRI is contraindicated in early pregnancy.9 MRI revealed a 66×43 mm abdominal mass with hypervascular and heterogeneous characteristics (Figure 2).Download figureDownload PowerPointFigure 2. Magnetic resonance imaging (MRI) shows an abdominal mass with hypervascular and heterogeneous characteristics.We would now like to ask the readers a rhetorical question: What was the risk of the secreting paraganglioma during pregnancy?Discussion: Pregnancy and ParagangliomaDr Schlaich: Were there any symptoms triggered by positional changes or abdominal pressure, such as defecation, bending over, etc?No, the patient did not complain of any symptom linked to her position.Professor Dominiczak: That is really important, of course, because this pregnancy will progress. Excessive circulating catecholamines in pregnancy are not favorable. The tumor will then interact with the growing pregnancy, and there may be real paroxysms that can even progress to malignant hypertension. It is bad for the mother and for the baby. It is a really serious potential complication of this pregnancy.Dr Anna Szyndler: The patient had a very high level of aldosterone and renin according to your slides. Could you comment on that?Professor Amar: Regarding the levels of aldosterone and renin, there are several explanations. First of all, when you have a diagnosis of pheochromocytoma, hypovolemia is usually present at the time of diagnosis. Thus, it is pretty common to have secondary hyperaldosteronism. Some other studies have also shown that you can have vasoconstriction of the renal artery, and you can even have a real artery stenosis with a presentation of fibromuscular dysplasia or type 1 neurofibromatosis. For this patient, we also wondered if it was connected to the fact that the paraganglioma was very close to the kidney, as we have shown on the MRI scan, with a risk of compression of the renal artery. However, the most probable explanation is that it was just due to the fact that she was dehydrated when she first visited our department. She received saline infusion for a few days, but we did not check her aldosterone and renin levels afterward.Surgery and Follow-UpTo Conclude the Clinical CaseThe patient was operated upon in April 2019 at 12 weeks of gestation after preparation with α-blockers. Treatment with α-blockers was provided before surgery to ensure blood pressure control during surgery. Pathological examination confirmed the presence of a 6-cm paraganglioma. After surgery, diabetes and hypertension completely resolved, and the patient was off medication until the end of the pregnancy. Her son was born at 39 weeks gestation with a weight of 2.750 kg and without any medical complications. The genetic testing was negative in germline DNA, but an EPAS1 somatic mutation was identified in DNA extracted from the paraganglioma.Professor Dominiczak: Great. Thank you very, very much. We are coming to the end of the session. I would like to stress what you just said, Professor Amar. With these rare cases, which frequently happen in young people, an early diagnosis is important. It would have been wonderful if the primary centers these patients present to considered unusual diagnoses and had a low threshold of referrals to a specialist. A real specialist center has significant experience in diagnosing and managing secondary hypertension, such as your center and many other centers around the world. This would be preferable instead of struggling and allowing these young people to develop end-organ damage, left ventricular hypertrophy, and other such conditions. In the case of your patient, her condition could have been diagnosed before pregnancy. It would have been much less stressful for everybody concerned. Interestingly, in many cases, there are also social issues that complicate things. I think it is also extremely important for young doctors to take note of the history to understand what kept their patient from getting the best possible health care available in a given country.SummaryThis clinical case illustrates the necessity of early detection of secondary hypertension. The patient had main signs attributable to the hypersecretion of catecholamines, including the triad signs, a severe and paroxysmal hypertension, and secondary diabetes. Moreover, urinary normetanephrines were significantly elevated. Severe hypertension associated with suggestive signs of catecholamine excesses and acute cardiological complications should lead to the screening of PPGL.3 The diagnosis is based on the determination of plasma-free metanephrines or fractionated urinary metanephrines (sensitivity and specificity higher than 90%).6 In case of confirmed hypersecretion, imaging is essential to locate the tumor. The first-line examination should be a thoraco-abdominopelvic computed tomography. Functional imaging, such as PET-18FDG (18F-fluorodeoxyglucose), PET-18F-DOPA, or 68Gallium-labeled somatostatin analogue PET, must be combined to confirm the diagnosis and look for other locations or metastases.2123I-MIBG scintigraphy is not sensitive enough for paragangliomas developing alongside sympathetic and parasympathetic ganglia. In this clinical case, PPGL diagnosis should not have been ruled out by the negative results of MIBG.10123I-MIBG scintigraphy scintigraphy should not be used as a first-line diagnostic technique when PPGL is suspected. This delayed management increased the risk of the patient and her baby to severe complications or death via multivisceral failure due to catecholamine hypersecretion.11 Multidisciplinary meetings in reference centers are recommended.Article InformationAcknowledgmentsWe are grateful to the following session audience members for contributing to the discussion: Metaxia Driva, Patricia Van der Niepen, Anna Szyndler, Sandeep Riar, Zviad Kereselidze, and Khawaja Adnan Younis.Sources of FundingNone.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.The following case was presented on April 13, 2021, as part of the Clinical-Pathological conference chaired by Anna F. Dominiczak and Rhian Touyz at the virtual joint meeting of the European Society of Hypertension and the International Society of Hypertension. Antoine-Guy Lopez and Laurence Amar presented the case and led the discussion.For Sources of Funding and Disclosures, see page 477.Correspondence to: Laurence Amar, Université de Paris, AP-HP, Hôpital Européen Georges Pompidou Hypertension Unit 20 rue Leblanc Paris, N/A F-75015, France. Email laurence.[email protected]frReferences1. Gimenez-Roqueplo AP, Caumont-Prim A, Houzard C, Hignette C, Hernigou A, Halimi P, Niccoli P, Leboulleux S, Amar L, Borson-Chazot F, et al.. Imaging work-up for screening of paraganglioma and pheochromocytoma in SDHx mutation carriers: a multicenter prospective study from the PGL.EVA Investigators.J Clin Endocrinol Metab. 2013; 98:E162–E173. doi: 10.1210/jc.2012-2975CrossrefMedlineGoogle Scholar2. Taïeb D, Hicks RJ, Hindié E, Guillet BA, Avram A, Ghedini P, Timmers HJ, Scott AT, Elojeimy S, Rubello D, et al.. 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Not all angiotensin-converting enzyme inhibitors are equal: focus on ramipril and perindopril.Postgrad Med. 2013; 125:154–168. doi: 10.3810/pgm.2013.07.2687CrossrefMedlineGoogle Scholar8. Prete A, Paragliola RM, Salvatori R, Corsello SM. Management of catecholamine-secreting tumors in pregnancy: a review.Endocr Pract. 2016; 22:357–370. doi: 10.4158/EP151009.RACrossrefMedlineGoogle Scholar9. Chen MM, Coakley FV, Kaimal A, Laros RKGuidelines for computed tomography and magnetic resonance imaging use during pregnancy and lactation.Obstet Gynecol. 2008; 112(2 pt 1):333–340. doi: 10.1097/AOG.0b013e318180a505CrossrefMedlineGoogle Scholar10. Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young WFIncreased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents.J Clin Endocrinol Metab. 2004; 89:1045–1050. doi: 10.1210/jc.2003-031337CrossrefMedlineGoogle Scholar11. Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF; Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.J Clin Endocrinol Metab. 2014; 99:1915–1942. doi: 10.1210/jc.2014-1498CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails February 2022Vol 79, Issue 2 Advertisement Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.121.18012PMID: 34879700 Originally publishedDecember 9, 2021 PDF download Advertisement" @default.
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