Hereditary hemorrhagic telangiectasia with pulmonary hypertension: a report of three cases

Introduction

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic condition that is distinguished by the abnormal development of multiple vascular systems. The condition manifests at a comparatively low incidence rate and is frequently misdiagnosed due to its rarity (1-3). Pulmonary hypertension (PH) constitutes a grave but uncommon complication of HHT, and the absence of clinically effective treatments exerts a direct influence on the quality of life and prognosis of those affected.

This report delineates the clinical evaluation, therapeutic interventions, and family medical histories of three patients diagnosed with HHT in conjunction with PH. The objective of this report is to furnish clinicians specializing in respiratory medicine and otorhinolaryngology with a reference point for diagnosis and treatment, with a view to reducing the rate of missed diagnoses and misdiagnoses.

All patient-specific identifiers, including name, and hospital number, have been removed in order to ensure patient confidentiality. We present these cases in accordance with the CARE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-724/rc).

Cases presentation

All procedures in this study were performed in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Case 1

A 51-year-old male patient was diagnosed with PH five years prior to attending the First Affiliated Hospital of Zhengzhou University and had experienced increased exertional dyspnea and bilateral lower limb edema for a period exceeding one year. In 2018, his chest computed tomography (CT) revealed dilated pulmonary arteries, although no further treatment was administered. Prior to this, the patient had been diagnosed with PH by right heart catheterisation (RHC) at another medical facility, and the efficacy of targeted drug therapy with macitentan and tadalafil to reduce pulmonary artery pressure had been deemed unsatisfactory. Further enquiry revealed that the patient had experienced recurrent epistaxes since early adulthood and had recently undergone rhinoplasty subsequent to a worsening of symptoms. Based on the frequency of the patient’s epistaxis, bleeding duration and other Epistaxis Severity Score (ESS) criteria (4), his ESS was 3.50. It was also established that the patient’s mother had a documented history of a pulmonary arteriovenous fistula, accompanied by recurrent episodes of hemoptysis and epistaxis. A thorough physical examination of the patient revealed the presence of telangiectasias in scattered areas of both lips, mucous membranes and fingertips on both hands (Figure 1). The results of the routine haematological tests are shown in Table 1. The subject was also subjected to a 6-minute walk test, during which a distance of 310 meters was traversed. Echocardiographic analysis yielded an ejection fraction of 69%, accompanied by dilatation of the pulmonary artery, PH, and augmentation of both the right heart and the left atrium. Cardiac magnetic resonance imaging revealed further findings, specifically including dilatation of the right ventricle and PH, in addition to severe tricuspid valve insufficiency and the presence of right ventricular wall thrombus. The presence of small microbubbles in the left heart was suggested by right ventricular angiography imaging (grade I) (Figure 2). Ultrasonography of the portal vein indicated a high probability of a hepatic artery portal vein fistula (Figure 2). Contrast-enhanced chest CT revealed signs of an enlarged heart, including a shadow, and PH with pericardial effusion. Vascular reconstruction further revealed pulmonary vascular malformation (Figure 3). A detailed analysis of the patient’s case revealed that the enhanced CT scan of the abdomen indicated the presence of cirrhosis and multiple abnormal, enhanced nodules in the liver (Figure 3).

Figure 1 Mucocutaneous telangiectasia on the lips, mucous membranes, and fingertips of Case 1 (A,B). This image is published with the patient’s consent.

Figure 2 Right ventricular angiography and portal vein ultrasound findings from Case 1. (A) Right ventricular angiography showed several bubbles in the left heart. (B) Portal vein ultrasound revealed significantly increased hepatic artery velocity.

Figure 3 Pulmonary artery CT, vascular reconstruction, and abdominal enhanced CT findings from Case 1. (A) Pulmonary artery CTA indicated that the main pulmonary artery was dilated. (B) Vascular reconstruction revealed pulmonary vascular malformations (indicated by arrows). (C) Abdominal enhanced CT showed that the liver exhibited diffuse nodular vascular malformations, consistent with hepatic vascular abnormalities. CT, computed tomography; CTA, computed tomography angiography.

RHC was performed, revealing the following measurements: mean pulmonary artery pressure (mPAP), 51 mmHg; pulmonary artery wedge pressure (PAWP), 2.13 mmHg; pulmonary vascular resistance (PVR), 10.78 Wood units; cardiac index (CI), 2.94 L/min/m²; cardiac output (CO), 5.32 L/min; and right atrial pressure, 15 mmHg. The patient’s right ventricle demonstrated a systolic pressure of 85 mmHg, a diastolic pressure of 3 mmHg, and a mean pressure of 30 mmHg. Additionally, the patient exhibited a pulmonary artery oxygen saturation of 51.2% and a pulmonary circulation blood flow of 4.73 L/min. Genetic testing of the patient’s peripheral blood revealed a nonsense mutation in the ACVRL1 gene (c.1435C>T [p.R479*]). The final diagnosis of HHT in combination with precapillary PH (pPH) was assessed as World Health Organization (WHO) functional class IV. Despite the administration of targeted pharmaceuticals, including tadalafil and macitentan, resulting in a reduction in pulmonary artery pressure, the efficacy of this approach was deemed to be inadequate. The administration of diuretics and iron supplements was also employed to address heart failure symptoms; however, these interventions also proved to be ineffective.

However, the administration of 300 mg of bevacizumab (5 mg/kg, administered once every two weeks) resulted in a marked improvement in symptoms and a clinical decrease in PAP, which was evaluated using echocardiography. The patient’s WHO functional class improved from IV to II. ESS decreased from 3.50 to 0. Echocardiographic assessment showed a reduction in mPAP from 51 to 44 mmHg after the second treatment cycle (Table 1).

Case 2

The patient was a 59-year-old female who had been experiencing intermittent chest tightness and a chest pain that had been present for more than three years when she received evaluation and treatment at the First Affiliated Hospital of Zhengzhou University. Over a period of at least four months, the symptoms had worsened. Since 2020, the patient had been experiencing symptoms including chest tightness and chest pain after exertion and activity, which abated after rest. In addition, she had been suffering from intermittent nosebleeds for a period of more than two decades. It is notable that a diagnosis of HHT was made in 2015. The patient’s relatives, including her mother, brother, sister and son, had previously experienced recurrent epistaxis. A physical examination was conducted, revealing the presence of an accentuated pulmonic valve closure (P2) that exceeded the aortic valve closure (A2). The following results were derived from the patient’s routine hematological examination (Table 1).

The cardiac function exhibited by the patient was categorized as WHO Class III, indicative of severe heart failure. Echocardiography revealed moderate PH, and the 6-minute walk test revealed a distance of 530 metres. A nasal endoscopy revealed diffuse capillary dilatation of the nasal mucosa on both sides (Figure 4). Pulmonary CT angiography (CTA) indicated changes consistent with PH (Figure 5). Furthermore, enhanced abdominal CT suggested the presence of a hepatic arteriovenous fistula, characterized by multiple tortuous vascular masses within the liver (Figure 5). The results of the RHC investigation revealed the following: mPAP of 31 mmHg; PAWP of 11 mmHg; PVR of 3.27 Wood units; CI of 6.73 L/min/m²; and CO of 11.3 L/min. Subsequent genetic analysis identified a missense mutation in the ACVRL1 gene (c.916G>C [p.Ala306Pro]). The final diagnosis was HHT complicated with combined post- and precapillary PH (CPC-PH).

Figure 4 Diffuse capillary telangiectasia of the bilateral nasal mucosa.

Figure 5 Pulmonary artery CT and abdominal enhanced CT findings of Case 2. (A) Pulmonary artery CT revealed findings suggestive of pulmonary hypertension. (B) Abdominal enhanced CT indicated hepatic arteriovenous fistulae, characterized by multiple tortuous vascular clusters within the liver. CT, computed tomography.

Following a 12-month period of combination therapy with thalidomide, sildenafil and macitentan, the patient underwent a subsequent RHC, which revealed an mPAP of 20 mmHg. The patient’s WHO functional class improved and remained stable at class II. Hemoglobin (Hb) level increased to 100.8 g/L, and the ESS decreased from 3.28 to 0. No significant adverse events were observed. The patient continued to be followed up regularly until June 30, 2024.

Case 3

The patient was a 31-year-old female who had been experiencing symptoms of chest tightness and shortness of breath for a period of two years. These symptoms had worsened during the 15 days preceding her visit to the First Affiliated Hospital of Zhengzhou University. Since 2020, the patient had been experiencing persistent symptoms of chest tightness and shortness of breath, which had been exacerbated by exertion and alleviated by rest. These symptoms were accompanied by edema of the lower extremities and face. The exacerbation of symptoms necessitated echocardiography at a different medical facility, which revealed severe PH. The patient was treated with sildenafil and ambrisentan, but this treatment was not found to be satisfactory. Physical examination revealed telangiectasias on the tongue of the patient and her father. Further investigation revealed that the patient had been experiencing intermittent epistaxis for a period of 10 years, and that both her father and brother had a history of recurrent epistaxis.

A comprehensive hematological examination yielded the following results in Table 1. The 6-minute walk test distance was 299 metres, and cardiac function was assessed as WHO class II. Echocardiography revealed severe PH, with suspected portal PH. Liver ultrasound results were consistent with changes in arteriovenous fistula (Figure 6).

Figure 6 Hepatic arterioportal fistula.

Pulmonary CTA did not demonstrate any significant indicators of embolism or thickening of the primary pulmonary artery (Figure 7). However, taking into account the patient’s PH, tortuous pulmonary veins and anomalous venous traffic were evident in the right middle lung and mediastinum, with thickening of the three hepatic veins and inferior vena cava. RHC yielded the following results: mPAP, 44 mmHg; PAWP, 14 mmHg; PVR, 3.97 Wood units; and CO, 6.9 L/min. The diagnosis of HHT combined with pPH was made based on the Curaçao criteria. The prescription of sildenafil and ambrisentan was made with the objective of lowering PAP. However, the patient’s mPAP increased from 44 to 58 mmHg after administration of these medications, indicating that the treatment was ineffective.

Figure 7 Pulmonary artery CTA of Case 3. Curved pulmonary veins with an anomalous connection to the azygos vein and thickening of the three hepatic veins and dilation of the inferior vena cava. CTA, computed tomography angiography.

Despite the treatment, the patient’s condition deteriorated due to progressive PH, leading to respiratory failure, and she passed away at home in December 2022. The genetic results for both the patient and their family members were not obtained.

All patients’ treatment adherence was determined by evaluating the patients’ compliance with scheduled follow-up visits. Treatment tolerability was evaluated through a process of continuous monitoring, incorporating the following elements: the presence of adverse events (AEs), clinical symptoms, and changes in laboratory test results.

Genetic characteristics

A family tree was constructed on the basis of a survey of family members and the Curaçao diagnostic criteria (Figure 8). Confirmed or suspected cases of HHT were identified in all three families, suggesting an autosomal dominant inheritance pattern. Among the subjects under scrutiny, genetic testing was conducted on patients described in Cases 1 and 2, revealing nonsense mutations in the ACVRL1 gene in Case 1 and his offspring.

Figure 8 Family pedigree of the three cases. HHT-PH, hereditary hemorrhagic telangiectasia with pulmonary hypertension.

International Multidisciplinary Team (iMDT) discussion

HHT, also known as Osler-Weber-Rendu syndrome, is an autosomal dominant genetic disease characterized by multisystem vascular malformations, including visceral arteriovenous malformations and mucocutaneous telangiectasias. The global incidence of the condition is estimated to be between 1/6,000 and 1/5,000 (1-3). HHT is typically the result of single-allele mutations in either the ENG (encoding endothelin) or ACVRL1 (encoding receptor ALK1) genes. These mutations can lead to the manifestation of either HHT1 or HHT2, depending on the specific gene involved (5,6). The Curaçao criteria (7), a commonly utilized clinical diagnostic framework, encompass a set of criteria for the identification of HHT. These criteria include spontaneous recurrent epistaxis, the presence of multiple telangiectasia sites such as the oral cavity, lips, fingers and nose, the existence of visceral arteriovenous malformations (AVMs), and the presence of a family history of HHT within first-degree relatives. The diagnosis can be confirmed when ≥3 criteria are fulfilled; it is suspected when 2 criteria are fulfilled, and it is ruled out when <2 criteria are fulfilled. Nosebleed is the most common and earliest clinical manifestation in 96% of patients and is age-related. In 90% of cases, the onset of nosebleed occurs before the patient reaches the age of 45, with only a small percentage (3%) experiencing this complication for the first time after the age of 60 years (8). At present, PH is regarded as a rare but serious complication of HHT; however, the actual prevalence of HHT combined with PH remains unclear.

There exist two common forms of HHT-PH. The first type is postcapillary PH, which is caused by high-output heart failure, and one of the most common related mechanisms is the high-output state caused by hepatic arteriovenous malformations (HAVMs) or pulmonary arteriovenous malformations (PAVMs). In this instance, there is mild to moderate elevation of the PAP, significantly elevated CO, and elevated or mildly elevated levels of PAWP and PVR. The fundamental therapeutic approach encompasses salt and water restriction, diuresis, and correction of anemia. For patients with persistent symptomatic high output, the current consensus of opinion amongst experts in the field is that intravenous bevacizumab is the recommended course of action (3). The rationale behind this proposal is that the drug has been shown to improve hyperdynamic circulation and CI in patients with HHT by targeting vascular endothelial growth factor (VEGF) and inhibiting abnormal vascular proliferation (9,10). In addition, thalidomide has been employed as a treatment for HHT (11). Nevertheless, owing to its suboptimal safety profile and the paucity of evidence from studies conducted to date, the use of thalidomide is not recommended by any guidelines. The findings from RHC in Case 2 were consistent with the hemodynamics of CPC-PH. The patient’s personal history, which included recurrent epistaxis, telangiectasia of the nasal mucosa, and liver AVMs, fulfilled the Curaçao criteria.

Genetic testing confirmed the presence of a pathogenic ACVRL1 mutation, thus enabling a final diagnosis to be made, confirming the patient’s condition to be HHT with CPC-PH. Furthermore, elevated CO was observed, and right-to-left shunting resulting from HAVMs led to the development of high-output heart failure. Following the administration of targeted drug therapy in combination with thalidomide, there was a decrease in mPAP, improvement in cardiac function, increase in Hb levels, and decrease in nosebleeds. During the follow-up period, no severe adverse reactions were observed. Pomalidomide, a derivative of thalidomide, exhibits a more robust safety profile. A randomised, double-blind trial demonstrated that pomalidomide significantly improved nasal bleeding symptoms in sufferers of HHT. However, further studies are necessary to evaluate its efficacy for patients with HHT who also have concomitant gastrointestinal bleeding, as well as AVMs in the lungs, liver or brain (12).

The second type of HHT-PH is hereditary hypertrophic vascular disease, which is characterized by pulmonary artery hypertension (PAH). The hemodynamic manifestation is pPH, and other manifestations include a significantly elevated PAP and PVR, a normal PAWP, and normal or reduced CO. It is noteworthy that the occurrence of HHT in conjunction with PAH is a relatively uncommon phenomenon, and its association with specific mutations in individuals affected by HHT has been well documented. The presence of various mutations in the ACVRL1 gene has been identified as a contributing factor to the development of PAH in patients with HHT (13). Research has implicated ACVRL1 in the BMP9-ALK1/Endoglin pathway. ACVRL1 mutations have been shown to disrupt the SMAD1/5/8 and BMP signalling pathways, leading to endothelial cell cycle dysregulation (14). As a result, the inhibition of smooth muscle cell (SMC) apoptosis induced by ACVRL1 mutations leads to SMC proliferation and vascular remodelling, ultimately triggering pPH (15-17). Patients with PAH due to ACVRL1 mutations are diagnosed at a younger age (21.8±16.7 years), and the disease progresses more rapidly (18). Targeted drug therapies such as endothelin receptor antagonists, type 5 phosphodiesterase inhibitors and prostaglandin drugs are recommended for patients with HHT-PAH. In Case 1, targeted drug therapies were ineffective, and the presence of a high-output circulatory state was investigated. After the patient received 300 mg of intravenous bevacizumab (5 mg/kg, once every 2 weeks), his symptoms improved without any serious adverse effects. Therefore, when patients with HHT-PAH have a high-output circulatory state, the treatment strategy should be optimized and the combination with antiangiogenic drugs should be investigated.

Discussion among physicians from the First Affiliated Hospital of Zhengzhou University

Department of Respiratory and Critical Care Medicine

Diagnosis of HHT-PH

These patients exhibited the typical clinical features of HHT, including recurrent epistaxis and telangiectasia of the skin and mucous membranes, along with a positive family history. In addition, the presence of pathogenic mutations in HHT-associated genes was confirmed, which holds significant implications for disease monitoring and management. PH is a rare complication of HHT, and individuals carrying mutations in the ACVRL1 or ENG genes are at higher risk of developing PH. Most studies of HHT-PH have relied on non-invasive assessments such as transthoracic echocardiography. However, the use of RHC remains essential for distinguishing pre- from post-capillary PH and elucidating the hemodynamic mechanisms of HHT-PH.

Classification of HHT-PH

According to hemodynamic profiles, HHT-PH can be categorized into two common subtypes. The first and more prevalent form is postcapillary PH, which is caused by high-output heart failure secondary to systemic arteriovenous malformations. The second and rarer subtype is precapillary PH, characterized by PAH, which is frequently associated with pathogenic mutations in HHT-related genes. These two subtypes have distinct pathophysiological mechanisms and require different therapeutic approaches. Thus, comprehensive evaluations including RHC and genetic testing are essential to differentiate between subtypes and to guide individualized treatment strategies.

Treatment of HHT-PH

Although anti-angiogenic therapies such as bevacizumab have been successfully applied in the management of epistaxis in HHT patients, data regarding their efficacy in HHT-PH remain limited. For patients with persistent symptomatic high-output states who fail to respond to first-line management, expert consensus and existing guidelines suggest the use of intravenous bevacizumab. In HHT patients who develop PH due to high-output circulatory conditions, anti-angiogenic agents may be considered as a therapeutic option. However, the safety and efficacy of such treatments in this specific patient population require further validation through large-scale clinical trials.

Department of Interventional Radiology

HHT is often associated with multiorgan AVMs. In the absence of significant clinical manifestations such as hypoxemia or hemoptysis, the decision to perform interventional procedures should be based on the number of PAVMs and the size of the feeding vessels. In cases where diffuse PAVMs are present, the efficacy of interventional embolization is limited. For such patients, medical management including pulmonary vasodilators, cardiac function optimization, and hemostatic therapy should remain the primary treatment approach.

Several issues of these patients were further discussed as follows

This report describes three cases of HHT with PH who were treated with different therapeutic approaches and had varying prognoses. Although antiangiogenic agents, such as bevacizumab and thalidomide, have shown potential in the treatment of HHT-PH, several issues still need to be further discussed.

Question 1: Bevacizumab, thalidomide, and other antiangiogenic agents, by blocking the VEGF angiogenesis pathway, have demonstrated success in alleviating HHT symptoms in certain cases. However, these treatments are primarily effective for skin and mucosal capillary telangiectasias, with limited improvement observed in visceral organ AVMs. Is it possible to develop more specific therapeutic strategies by targeting the downstream VEGF signaling pathways?

Francesco Nappi: In recent years, the VEGF signaling pathway has emerged as a prominent therapeutic target in the treatment of glioblastoma. While the efficacy of anti-angiogenic treatment has been demonstrated, agents such as bevacizumab have ultimately failed to improve overall survival (19).

Question 2: Research has reported an association between HHT and immune dysfunction, with immune system abnormalities potentially exacerbating the progression of PH. Could immunotherapy improve treatment responses in patients with HHT with PAH?

Francesco Nappi: Recently, Jiang et al. have explored the immune heterogeneity, population and target cells (20) in PAH, which may be valuable for the development of new and precise therapies. The authors of the study presented a comprehensive investigation into the transcriptomic characteristics of diverse cell types in patients diagnosed with PAH. An in-depth analysis of T cell subsets, myeloid cell heterogeneity, and a comprehensive analysis of SMCs and fibroblasts (FBs) subsets in PAH was presented. The results indicated that T cell heterogeneity and functional dynamics are exhibited in PAH, suggesting that a therapeutic strategy which targets cytotoxic regulation may be a viable option. The study also identified important alterations and potential functions of myeloid cell subsets in PAH patients, with a particular focus on GPNMB+ macrophages. Furthermore, analyses of cellular interaction and signaling pathways revealed alterations associated with the pathogenesis of PAH. Furthermore, the increased macrophage migration inhibitory factor (MIF) and IL-1 signaling suggests that the induced inflammatory response in PAH is strongly driven.

Question 3: The “second hits” explains the varying clinical manifestations of HHT in individuals carrying the relevant pathogenic genes. Are there specific environmental or physiological factors (such as inflammation, infection, and oxidative stress) that may exacerbate the development of PAH in the context of hereditary HHT?

Francesco Nappi: Oxidative stress has been demonstrated to be a causative agent of endothelial dysfunction, and is implicated in the pathogenesis of cardiovascular diseases. Recently, Jerkic et al. (21) posited the hypothesis that reactive oxygen species (ROS) play a crucial role in HHT disease, a vascular dysplasia affecting 1 in 5,000–8,000 people. The genetic basis of this condition is attributed to mutations in the ENG and ACVRL1 genes, which are linked to arteriovenous malformations in HHT1 and HHT2. The genes ENG and ACVRL1 have been demonstrated to interact with endothelial nitric oxide synthase (eNOS), regulating its expression. In mice that are heterozygous for these genes [Eng (+/−) and Acvrl1 (+/−)], there is a reduction in the protein levels of ENG or ACVRL1 in endothelial cells, resulting in eNOS uncoupling. This leads to the production of ROS in place of nitric oxide (NO). This in turn causes impaired NO--mediated vasodilation. It has been demonstrated that ROS production is increased in a variety of organs, such as the lungs, liver and colon, in Eng (+/−) and Acvrl1 (+/−) mice. These findings are particularly relevant in the context of HHT, a condition characterised by vascular malformations and vascular permeability. The predominant source of elevated oxidative stress in these tissues is eNOS-derived ROS, as opposed to mitochondrial or NADPH oxidase-dependent ROS. Furthermore, it has been demonstrated that both Eng (+/−) and Acvrl1 (+/−) mice exhibit signs of pulmonary arterial hypertension attributable to eNOS-derived ROS with the progression of age. This phenomenon can be prevented by means of antioxidant treatment. It is recommended that further clinical studies be conducted in order to investigate whether the administration of antioxidants would prevent, delay or attenuate the manifestations of the disease in individuals with hereditary HHT, based on the experimental data obtained from murine models.

Conclusions

HHT is a rare autosomal dominant genetic disease in which PH is a rare and severe complication. HHT with PH can be categorized into different types based on the underlying pathogenesis and the treatment strategies employed. It is imperative for healthcare professionals to suspect HHT in patients with PH and mucocutaneous telangiectasias, prompting a thorough diagnostic evaluation for HHT with PH. This will serve to reduce the occurrence of both missed diagnoses and misdiagnoses. For patients diagnosed with HHT who exhibit poor response to targeted drug therapy, screening is recommended to ascertain the presence of a hypercirculatory state. The combined use of antiangiogenic drugs, such as bevacizumab and thalidomide, has been demonstrated to be effective in certain cases. However, treatment options for HHT with PH remain limited, and patients generally have a poor prognosis. A detailed family history should be collected and genetic screening of the family should be performed for these patients. Those with HHT who carry pathogenic genes should be thoroughly evaluated for genetic risk, and appropriate prenatal interventions should be considered.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-724/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-724/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-724/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures in this study were performed in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Gray)