Midterm outcomes and costs of Pipeline embolization device alone versus Atlas stent-assisted coiling for unruptured anterior circulation aneurysms: a propensity score matched comparative analysis

Introduction

Endovascular treatment has achieved great progress over the past few decades, providing multiple options for the treatment of intracranial aneurysms (IAs). In the present era of flow diverters (FDs), the optimum endovascular management for unruptured IAs amenable to both stent-assisted coiling (SAC) and FDs remains to be determined. The Pipeline embolization device (PED; Medtronic, Irvine, CA, USA) was approved by the Food and Drug Administration in 2011, and it was initially used to treat large and giant wide-necked unruptured IAs, from petrous to superior hypophyseal internal carotid artery segments (1). Since then, its clinical indications have been expanding, with increasing evidence of effectiveness in treating distal internal carotid artery aneurysms and small aneurysms (2). While many institutions have recommended the PED as the first-line option for the treatment of anterior circulation aneurysms, some researchers are still cautious of the high morbidity rate related to PED and continue to favor the traditional SAC technique (3,4).

SAC is a widely accepted endovascular therapy that prevents coil protrusion into the parent artery, achieves high-density packing within the aneurysm sac, and also provides a scaffold for endothelial attachment (5). It could improve the final occlusion rate and decrease the recurrent rate compared with coiling alone; and also it does not significantly increase the procedural complication for saccular aneurysm (6,7). The Neuroform Atlas stent (Stryker Neurovascular, Fremont, CA, USA) is a new self-expanding laser-cut nitinol stent delivered via a low-profile microcatheter (0.0165–0.017 inches) (8). It is a hybrid open/closed cell design that enhances stent conformability and coil support, as well as improves deployment accuracy (9). The PREMIER and ATLAS IDE prospective trials demonstrated the safety and efficacy of both devices (1,10). However, few studies have directly compared these two devices for the treatment of anterior circulation saccular aneurysms. Furthermore, previous studies comparing the costs of PED and conventional SAC for treating IAs have shown inconsistent results, and few studies have considered follow-up costs (11-14).

In this study, we compared the medium-term clinical outcomes, hospital costs, and follow-up costs of PED alone and Atlas SAC for the treatment of unruptured anterior circulation aneurysms, controlling for baseline information and aneurysm characteristics through propensity score matching (PSM). We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1581/rc).

Methods

Study population

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study protocol was approved by the institutional research ethics board of Beijing Tiantan Hospital (approval No. KY2024-335-02), informed consent from patients was not needed because of the retrospective nature of the study. All consecutive IA patients treated with PED alone or Atlas SAC in Beijing Tiantan Hospital between January 2018 and June 2023 were retrospectively reviewed. Inclusion criteria were age from 18 to 80 years, saccular IAs, and unruptured anterior circulation aneurysms. Exclusion criteria were previous treatment of IAs, aneurysms treated with PED plus coiling, the presence of arteriovenous malformations, moyamoya diseases or fistulas, and lack of radiological follow-up. Finally, a total of 731 patients with 739 aneurysms were enrolled in this study. The schematic representation of the study’s progression is depicted in Figure 1.

Figure 1 Flow chart of patient inclusion and exclusion. IA, intracranial aneurysm; PED, Pipeline embolization device; SAC, stent-assisted coiling; UIA, unruptured intracranial aneurysm.

Procedural details

Patients were administered an antiplatelet therapy that included a combination of aspirin (100 mg daily) and clopidogrel (75 mg daily) at least 5 days before the procedure. However, patients who were identified as clopidogrel non-responders were administered aspirin (100 mg daily) and ticagrelor (90 mg twice daily) (15). Under general anesthesia and full heparin anticoagulation, the procedures were performed through the conventional transfemoral arterial route. The PED (PED flex) was delivered and deployed through a Marksman microcatheter (Medtronic), while Atlas stents were delivered through SL-10 microcatheters (Stryker Neurovascular). In the Atlas SAC group, the jailing technique was used for adjunctive coils placement while ensuring that the coils were densely packed in the aneurysm sac to reduce the recurrence at follow-up. After the operation, patients were maintained with daily oral 75 mg doses of clopidogrel for 6 months and daily oral 100 mg doses of aspirin for the rest of their life in both groups.

The neurointerventionalists chose different treatment methods (PED alone or Atlas SAC) according to their experience. Two telescopic PEDs were used when a single device was not enough to cover the aneurysm neck and reconstruct blood flow. Two Atlas stents were used when the bifurcation aneurysms involve multiple branches and require Y-configuration stents to ensure branching artery patency.

Data collection and outcomes evaluation

The following information on enrolled patients was collected from the hospital’s electronic medical record system: demographics (age, gender, smoking history, and alcohol habits), comorbidities (hypertension, hyperlipidemia, diabetes, and coronary heart disease), with single/multiple aneurysms (coexisting aneurysms), regimens of dual antiplatelet therapy, aneurysm characteristics (location, maximum diameter, neck width, and parent artery diameter), procedural details (device types, device size, device number, coil number, and procedure time), hospital and follow-up costs, and clinical and radiographic outcomes. Multiple IA patients were defined as patients with two or more IAs. To minimize the impact of the number of devices on hospitalization costs, we considered patients with multiple IAs as distinct cases if they underwent only one device implantation to treat one aneurysm during each hospital stay. Patients were excluded if they received one device implantation to treat multiple adjacent IAs during a single hospital stay. Clinical and imaging evaluation was performed at 3–6, 12, and 24 months postoperatively. Patients with aneurysms completely occluded as confirmed by digital subtraction angiography (DSA) may opt for DSA, computed tomography (CT) angiography, or magnetic resonance (MR) angiography for annual follow-up evaluations. However, for patients with concomitant in-stent stenosis (ISS), DSA follow-up is still recommended as the first choice. ISS was defined as a growth process exceeding the limits of metal mesh, as evidenced by a visible gap between the contrast-filled vascular lumen and the internal contours of the PED (16). In this study, we considered ISS to be defined only if ≥50% stenosis of the parent artery was found on DSA.

The aneurysm occlusion status treated with PED was evaluated using the O’Kelly-Marotta grading scale: grade D indicates complete occlusion, while grades A, B, and C represent incomplete occlusion (17). The aneurysm occlusion status treated with Atlas SAC using the modified Raymond-Roy classification: class I for complete occlusion, while class II and III for incomplete occlusion (18). Recanalization was defined as a worsening grade on the O’Kelly-Marotta or Raymond-Roy scale for aneurysms at follow-up. During follow-up, the patients of PED group were retreated if (I) the PED may fail to fully cover the aneurysm neck, or the distal end of the PED may fall into the aneurysmal sac; (II) the aneurysm persistent filling at 2 years of follow-up. For the Atlas group, we retreated the aneurysm if (I) modified Raymond-Roy class III at follow-up; (II) modified Raymond-Roy class increased from I to II. For those aneurysms that are modified Raymond-Roy class II both immediately after Atlas SAC and on follow-up, we advocate continued conservative observation. Successful deployment after stent adjustment was defined as the successful release of the device after technical adjustment or balloon angioplasty. Successful release of the device without technical adjustment or balloon angioplasty was considered successful deployment of the device.

If the patient develops acute headache, hemiparesis, hyperalgesia, blurred vision, impaired consciousness, or other neurological deficits after the procedure, a postoperative CT or magnetic resonance imaging (MRI) would be performed immediately. Procedure-related complications were divided into hemorrhagic, ischemic, and compression symptoms. Hemorrhagic complications refer to subarachnoid hemorrhage or distal intraparenchymal hemorrhage after the procedure. Ischemic complications refer to in-stent thrombosis, transient ischemic attack (TIA), or cerebral infarction associated with the treated vascular area. Compression symptoms refer to cranial neuropathy or brainstem symptoms associated with aneurysm compression. Neurological functional status was evaluated using the modified Rankin scale (mRS) before the procedure, at discharge, and at final follow-up, and dichotomized into favorable (mRS score 0–2) or poor (mRS score 3–5).

Statistical analysis

Univariate analyses were performed to obtain valuable variables: normally distributed continuous variables were compared using the t-test and expressed as mean ± standard deviation (SD); skewed distributed continuous variables were compared using the Mann-Whitney U test and expressed as medians with interquartile range. Categorical variables were compared using the χ² or Fisher’s exact test and expressed as numbers with percentages. PSM was performed using the nearest neighbor matching, controlling for sex, age, hypertension, hyperlipidemia, smoking, symptomatic aneurysm, aneurysm location, maximum diameter, neck width, and follow-up time, which baseline characteristics were significantly different. The propensity score caliper width is 0.1 SD, in which each PED group patient in random order of the propensity score was sequentially matched to one Atlas SAC group patient. Univariate and stepwise multivariate logistic regression were applied to identify risk factors for ISS. P<0.05 was considered statistically significant. All statistical analyses were performed using R Version 4.3.0 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Patient demographics and aneurysm characteristics

A total of 731 patients with 739 aneurysms were qualified in this study. In the PED group, 299 patients were harboring 302 aneurysms. In the Atlas SAC group, 432 patients were harboring 437 aneurysms. The baseline information between the PED and Atlas SAC groups was significantly different. Patients in the PED group were younger (52.82±10.26 vs. 58.42±9.30 years, P<0.001) than those in the Atlas SAC group, and female patients were more common (71.9% vs. 63.2%, P=0.017). In the PED group, fewer patients had hypertension (33.8% vs. 62.9%, P<0.001), smoke history (15.6% vs. 22.4%, P=0.027), and were symptomatic (31.8% vs. 42.6%, P=0.004) compared to the Atlas SAC group. However, more patients in the PED group had hyperlipidemia (20.5% vs. 7.3%, P<0.001). Aneurysms treated with PED alone were more likely to be located at the proximal anterior circulation (91.4% vs. 66.4%, P<0.001). In addition, the maximum diameter (7.25±4.75 vs. 5.44±2.24 mm, P<0.001) and neck width (5.65±3.56 vs. 4.12±1.61 mm, P<0.001) of the aneurysms were larger in the PED group than those in the Atlas SAC group. There was no statistical significance in the other baseline information (Table 1).

Procedure details and follow-up outcomes

In the PED group, 98.7% of devices were successfully deployed on the first attempt, while four (1.3%) cases required stent adjustment. In the Atlas SAC group, 99.3% of stents were successfully deployed on the first attempt and three (0.7%) case required stent adjustment. All patients in the PED group were treated with the device alone without coils. In contrast, all patients in the Atlas SAC group were treated with stent and densely packed coils, and the median number of coils was 5 (Q1–Q3, 4–7). Eight (2.6%) patients were treated with overlapped PED devices, while 15 (3.4%) patients were treated with Y-configuration Atlas stents (Figure 2), but there was no statistically significant difference. The PED group had shorter procedure times (98.63±34.18 vs. 124.46±31.82 min, P<0.001) but higher total hospital costs ($31,315.16±3,800.81 vs. $27,042.12±6,738.57, P<0.001) than the Atlas SAC group (Table 2).

Figure 2 Images of a representative case of Y-configuration Atlas stents. (A) Three-dimensional rotational angiography shows a left anterior communicating artery aneurysm. (B) Measurement of aneurysm size and parent artery width in fluoroscopic mode. (C) The aneurysm was occluded completely after treatment. (D) The red area shows the reconstructed coils and stents, and the white arrows point to the end of the two Atlas stents in a Y-shape. (E) Follow-up angiography at 14 months shows complete occlusion of the aneurysm and patency of the parent artery. (F) Fluoroscopic images show the coils within the aneurysm sac and the radiopaque markers of the Atlas stent.

Table 3 compares the efficacy and safety of Y-stents and non-Y-stents in the Atlas SAC group. The results showed that total hospital costs were higher with the Y-stents than with the non-Y-stents ($36,242.93±7,804.76 vs. $26,722.20±6,646.62, P<0.001), while there was no statistical difference in other outcomes.

Fifteen (5.0%) patients in the PED group experienced procedure-related complications: 7 were ischemic (4 TIA and 3 cerebral infarction), 6 were hemorrhagic (4 delayed aneurysm rupture and 2 distal intraparenchymal hemorrhage), and 2 were emerging compression symptoms. While 28 (6.4%) patients in the Atlas SAC group developed procedure-related complications: 18 were ischemic (11 TIA and 7 cerebral infarction), 8 were hemorrhagic (7 intraoperative aneurysm rupture and 1 postoperative hemorrhagic transformation), and 2 were emerging compression symptoms. Finally, 2 patients in the PED group and 2 patients in the Atlas SAC group were discharged with poor neurological status (mRS score of 3–5). In addition, 1one patient in each group died due to rupture of the target aneurysm.

The angiographic follow-up time was longer (15.01±5.50 vs. 14.01±3.90 months, P=0.004) in the PED group than the Atlas SAC group, but there was no significant difference in follow-up costs. The final follow-up results showed that the ISS rate was higher in the PED group than in the Atlas group (4.0% vs. 0.9%, P=0.011). However, the retreatment rate was higher in the Atlas group than in the PED group (3.0% vs. 0.3%, P=0.021).

Comparison of outcomes between the PED and Atlas SAC group after PSM

After adjusting for differences in sex, age, hypertension, hyperlipidemia, smoking, symptomatic aneurysm, aneurysm location, maximum diameter, neck width, and follow-up time, matching was successful for 192 aneurysms pairs treated with PED and Atlas SAC (Figure 3). Notably, the PED group still had a shorter procedure time (97.65±33.53 vs. 125.17±30.71 min, P<0.001) and higher total hospital costs ($31,322.84±3,567.04 vs. $27,595.79±6,825.05, P<0.001) than the Atlas SAC group, while there was no significant difference in follow-up costs. The use of Atlas SAC reduced hospital costs by 13.5% compared to PED alone. Still, patients in the PED group were more likely to develop ISS (4.2% vs. 0.5%, P=0.043) compared with those in the Atlas SAC group. The retreatment rate was higher in the Atlas group than in the PED group (4.7% vs. 0%, P=0.007). No significant differences were found between the two groups in terms of complete aneurysm occlusion rates, total complications, and neurological status (Table 3).

Figure 3 Love plot showing covariate balance of the unmatched and matched cohort after propensity score matching; the degree of covariate balance between the PED and Atlas SAC groups is measured by absolute standardized mean differences. PED, Pipeline embolization device; SAC, stent-assisted coiling.

Discussion

The rapid development of endovascular devices has allowed FDs to treat unruptured anterior circulation aneurysms, which have traditionally been treated with SAC. To the best of our knowledge, this is the first study to compare the medium-term outcomes, hospital costs, and follow-up costs of PED alone and Atlas SAC for the treatment of unruptured anterior circulation aneurysms. In previous studies of cost-effectiveness analyses, researchers have included aneurysms treated with PED plus coiling, but coils as an important driver may confound cost comparisons (11,19). Therefore, we excluded the PED adjunctive coiling data to minimize the impact. Both endovascular treatments were safety and effective for unruptured anterior circulation aneurysms, with comparable rates of complete aneurysm occlusion, recanalization, and favorable clinical outcomes during medium-term follow-up.

Previous studies have compared the costs of PED and SAC, but the outcomes are not consistent. Colby et al. (11) compared the hospital costs in 30 consecutive patients treated with PED versus SAC for anterior circulation aneurysms and concluded that the total procedure cost was lower in the PED group ($16,445 vs. $22,145 per case, P=0.02). Malhotra et al. (12) also reached a similar conclusion by conducting a decision-analytical study using Markov modeling for the simulation of 5 and 7 mm unruptured aneurysms undergoing PED or SAC. Their findings suggest that PED is more cost-effective than SAC in the treatment of small unruptured IAs (<10 mm).

However, these results were different from the findings of Salem et al. (20), who used PSM to study the cost analysis of 23 pairs of unruptured small (≤10 mm) saccular anterior circulation aneurysms. They found that the total cost of the procedure was comparable between the PED and Neuroform SAC cohorts ($17,484.3 vs. $18,341.5 per case, P=0.42). Similarly, in another PSM study of the anterior circulation aneurysms, researchers also found that PED and SAC have equivalent cost-effectiveness (19).

Our study found that the total hospital costs of using Atlas SAC were significantly lower than those of PED, with an 13.5% cost reduction. This indicated that using PED to treat unruptured saccular anterior circulation aneurysms in our institution was much more expensive than the studies of Colby et al. and Salem et al. (11,20). We hypothesize that the following factors might account for this discrepancy. First, the cost of PEDs and their adjunctive delivery systems (such as Marksman or Phenom-27 microcatheters) at our institution was much higher than that of Atlas stents and their adjunctive delivery systems (such as SL-10). Second, PED relies heavily on flow diversion and parent artery reconstruction for aneurysm thrombosis, so the cost of PED has little correlation with aneurysm size. However, the cost of SAC was highly determined by the aneurysm size and the number of coils used. In our study, the mean aneurysm diameter in the Atlas SAC group was only 5.99 mm, with few coils, so the Atlas SAC group had lower hospital costs.

The patients received the same DSA image follow-up in the PED and SAC group, so the difference in follow-up costs between the two modalities in this study was not significant. Previous studies have shown that the rate of aneurysm complete occlusion treated with PED increases over time, and may not require further intervention in the future (21,22). Undoubtedly, this will slightly contribute to long-term cost savings for patients treated with PEDs.

In our study, the procedure time was significantly shorter in the PED group than in the Atlas SAC group. This result can be explained by the following reasons. First, the PED delivery system was relatively simple, we only needed to place the PED into the parent artery, without operating in the aneurysm sac. However, during the procedure using the Atlas SAC, in addition to placing the Atlas stent, the coil needed to be placed into the aneurysm sac, which greatly added procedure time. Also, when placing the PED, we simply needed to ensure that the PED had well wall apposition, whereas, for the Atlas SAC, we also needed to spend considerable time under fluoroscopic guidance to make sure that the coils were packed tightly within the entire aneurysm sac. The results of this study regarding the procedure time were consistent with previous literature. Chalouhi et al. (23) compared PED and traditional SAC in terms of fluoroscopy and procedure time in a retrospective study, concluding that PED treatment requires significantly shorter fluoroscopy and procedure times compared to SAC. Miller et al. (24) analyzed the procedure time of 20 patients treated with PED and 20 patients treated with SAC, and also found that the PED group showed a strong trend towards a shorter total procedure time compared to the SAC group.

The PED group had a significantly higher rate of ISS before and after PSM than the Atlas SAC group in this study (4.0% vs. 0.9%, P=0.011; 4.2% vs. 0.5%, P=0.043; respectively). This is lower than the incidence of ISS after PED treatment shown in previous studies (7.1–39%) (16,25,26). This may be related to the fact that different studies define ISS differently. According to stenosis rate (SR), ISS was generally defined as mild (SR: <25%), moderate (SR: 25–50%), or severe (SR: >50%). Several studies defined ISS as a parent artery stenosis of ≥25%, while in the present study, we defined ISS as a parent artery stenosis of ≥50%. This definition might be too conservative and result in an underestimation of the SR. However, we chose this definition due to the mild intimal hyperplasia after PED placing necessary to achieve aneurysm occlusion (16). Therefore, only more severe reactive stenoses were regarded as ISS, and such stenoses may be detrimental due to hemodynamically significant flow limitations (27). Notably, all patients with ISS in this study were clinically asymptomatic (Figure 4). We believe that the possible reason for this is that ISS progresses slowly and the cerebral circulation has enough time to form abundant collateral circulation so that patients with ISS do not develop severe symptoms. Several studies have found that ISS has improved or resolved at the last angiographic follow-up, especially in patients with asymptomatic and mild ISS (27-29). Thus, patients with asymptomatic and mild ISS during short-term DSA follow-up can prolong the follow-up time to dynamically observe their stenosis.

Figure 4 Images of a representative case of ISS. (A) Three-dimensional rotational angiography reveals an aneurysm located in the ophthalmic segment of the left internal carotid artery. (B,C) After treatment, the parent artery is patent and the PED is well deployed (red arrows point to the ends of the PED). (D,E) Follow-up angiography at 10 months shows complete occlusion of the aneurysm but stenosis distal to the stent (red arrow points to stenosis areas). (F) Fluoroscopic images show no significant change in stent profile. Considering that the patient had no ischemic symptoms, the stenosis was not treated. ISS, in-stent stenosis; PED, Pipeline embolization device.

Although there have been many studies of PEDs and Atlas stents, there have been no studies comparing their outcomes in the treatment of unruptured anterior circulation aneurysms. The complete occlusion rate in the PED group of this study was consistent with the PREMIER trial (87.6% vs. 83.8%) (1), whereas the complete occlusion rate in the Atlas SAC group was consistent with the ATLAS IDE trial (88.2% vs. 84.7%) (10), which showed the effectiveness of both devices in the treatment of unruptured anterior circulation aneurysms. Of note, 15 patients were treated with Y-configuration stents in the Atlas SAC group, and subgroup analysis found no significant difference in morbidity or mortality between Y-stents and non-Y-stents, suggesting that the Y-configuration stent technique is a safe and effective endovascular treatment for unruptured anterior circulation aneurysms, which was also supported by the study of Rodriguez Caamaño et al. (30). Interestingly, although there was no significant difference in the recurrence rate between the two groups in this study, there was a significant difference in the retreatment rate (0% vs. 4.7%, P=0.007) between the two groups, which may be related to the treatment concept of our center. We believe that PED-induced aneurysm thrombosis was a gradually time-dependent process that relied on flow diversion and parent artery reconstruction, and therefore these aneurysms are likely to gradually occlude over time or with changes in dual antiplatelet therapy, and generally do not necessitate retreatment. In comparison, Atlas stents have less metal coverage and we tend to adopt a stent-assisted dense-filling coils strategy at the time of initial treatment, so recurrences after treatment are mostly due to blood flow impingement, causing coils compression, and blood-filled areas are still at risk of rupture, and therefore we treat these recurrent aneurysms more aggressively. Furthermore, the total complication rates in the PED and Atlas SAC groups of this study were comparable with previous literatures (PED: 5.7% vs. 8.4%; Atlas SAC: 5.7% vs. 6.2%) (31,32). Of note, although distal anterior circulation aneurysms were not the original indication for PED implantation, it has also achieved excellent results. This PSM study demonstrated that both devices achieve excellent complete occlusion rates and favorable functional outcomes with low complication rates.

Limitations

The main limitation of this study was the single-center, retrospective study design, and although PSM was performed to adjust the potential differences, other easily ignored factors may have influenced the final outcomes. Furthermore, the relatively short follow-up time of this study is another limitation. PED-induced aneurysm thrombosis was a gradually time-dependent process that relies on flow diversion and parent artery reconstruction. Early imaging evaluation may underestimate the rate of complete occlusion of aneurysms treated with PEDs. Also, the aneurysm recanalization rate treated with Atlas SAC increased over time, so early imaging evaluation may overestimate the long-term aneurysm occlusion rate treated with Atlas SAC. A longer angiographic follow-up is necessary to better evaluate the durability of treatment outcomes and detect the aneurysm occlusion. Additionally, a randomized controlled trial comparing the PED and Atlas SAC for anterior circulation aneurysms could provide more robust evidence to validate our findings and address the limitations of this study.

Conclusions

This study showed similar midterm outcome with PED alone and Atlas SAC for the treatment of unruptured anterior circulation aneurysms. Atlas SAC required a longer procedure time, and PED alone increased hospital costs, while their follow-up costs were similar. However, patients who underwent PED treatment were more likely to develop ISS during follow-up, we can prolong the follow-up time to dynamically observe their stenosis. In addition, the retreatment rate was higher in the Atlas group than in the PED group.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1581/rc

Funding: This study was supported by the National Natural Science Foundation of China (grant No. 82271319).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1581/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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study protocol was approved by the institutional research ethics board of Beijing Tiantan Hospital (approval No. KY2024-335-02), informed consent from patients was not needed because of the retrospective nature of the study.

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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