Endovascular intervention and risk factor assessment for postoperative pseudoaneurysms after pancreatic surgery: a 9-year retrospective study

Introduction

Pancreatic surgery is considered to be one of the most complex operations in abdominal surgery due to its large scope, long duration, and excessive intraoperative bleeding (1). In recent years, with the development of medical technology and the improvement of surgical level, the postoperative mortality associated with pancreatic surgery has been greatly reduced, but the incidence of postoperative complications remains high (2). Postoperative hemorrhage is one of the most critical complications of the surgery and is also a major contributor to the high mortality associated with pancreatic surgery (3). Most cases of postoperative delayed hemorrhage are primarily caused by infection or pancreatic fistula, and postoperative hemorrhage resulting in pseudoaneurysm formation is rare in the clinic; however, if rupture does occur, the mortality rate of patients is particularly high, and so early detection and timely treatment are needed.

In recent years, with the development of interventional radiology, endovascular therapy has gradually been come to be the preferred method for the treatment of postoperative pancreatic hemorrhage, with the advantages of reduced trauma, good efficacy, and high safety (4). Coil embolization can quickly stop bleeding, especially for patients with more tortuous branches of the artery. For those sites that require preservation of the main blood vessels and important branches of arterial blood supply, implantation of covered stents is a more suitable option (5-7).

Therefore, the purpose of this study was to evaluate the therapeutic effect of intravascular intervention in the treatment of patients with pseudoaneurysm after pancreatic surgery, to identify the potential risk factors for the formation of pseudoaneurysm after pancreatic surgery, and to inform clinical practices related to the effective prevention and treatment of pseudoaneurysm after pancreatic surgery. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1012/rc).

Methods

Patients

From April 2015 to April 2024, a total of 153 patients with postoperative pancreatic hemorrhage were treated in our hospital, including 76 patients with pseudoaneurysm confirmed by computed tomography angiography (CTA), while no pseudoaneurysms were found in the other 77 patients. The clinical information of patients was collected, including sex, age, underlying disease, pathological diagnosis, laboratory indicators before pancreatic surgery, clinical manifestations, intraoperative conditions of pancreatic surgery, and postoperative complications of pancreatic surgery. All patients or their families signed informed consent before surgery. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ruijin Hospital Ethics Committee, Shanghai Jiao Tong University School of Medicine (approval No. 2025-471). The requirement for informed consent was waived due to the retrospective nature of the analysis.

The inclusion criteria for patients were as follows: (I) pancreatic tumor confirmed by enhanced computed tomography (CT) or enhanced magnetic resonance imaging (MRI) and completion of pancreatic surgery; (II) pseudoaneurysm formation confirmed by CT; and (III) treatment of bleeding by endovascular intervention (coil embolization or covered stent implantation) at the joint decision of the pancreatic surgeon and interventional physician. Meanwhile, the exclusion criteria were as follows: (I) no interventional treatment after digital subtraction angiography; and (II) a follow-up time was less than 1 month.

Procedure

Endovascular therapy

After pancreatic surgery, a pseudoaneurysm in patients was confirmed by CTA. The pancreatic surgeon and interventional surgeon jointly decided to treat the hemorrhage through intravascular intervention. The type of interventional treatment (coil embolization or covered stent placement) was determined by the interventional surgeon depending on the location of the pseudoaneurysm. The clinical course is shown in Figure 1.

Figure 1 The clinical course of the study. CTA, computed tomography angiography.

For the procedure, the patient was placed in the supine position, and the right femoral artery was punctured with the modified Seldinger technique with the patient under local anesthesia. A 5F vascular sheath (Terumo Medical Corporation, Tokyo, Japan) was placed through the access site, and selective cannulation with an angiography catheter (right catheter: Terumo Medical Corporation; C2 catheter: Cordis, Miami Lakes, FL, USA) was performed. A 0.035-in guide wire (Terumo Medical Corporation) was passed to the artery. When angiography showed pseudoaneurysm formation, the interventional surgeon selected either covered stent implantation or coil embolization according to the diameter and tortuosity of the involved blood vessels and whether the blood supply was important organs.

Covered stent implantation

For vessels larger than 4 mm in diameter that had inconspicuous tortuosity and supplied vital organs, covered stents were placed. The lesion artery diameter and length were first measured to determine the stent size. If the patient had arterial spasm, preoperative CT was performed to assess the stent size to avoid intimal leakage in type I vessels. The stent covered the proximal and distal ends of the vessel rupture by 1 cm, and other arteries and branches were kept as patent as possible. The diameter of the covered stent was generally 1–2 mm larger than that of the artery. A Mach1 8F guiding catheter (Boston Scientific, Marlborough, MA, USA)—used for a covered stent with a diameter of 5–6 mm—or a Check-Flo 7F long sheath (Cook Medical, Bloomington, IN, USA)—used for a covered stent with a diameter of 7–8 mm—was advanced through the guidewire and pushed to the proximal end of the affected artery. Angiography was performed to confirm the position and ensure no branch occlusion. A 0.018-in guidewire (V-18; Boston Scientific) was used to pass distally to the target artery, and the Viabahn covered stent system (W. L. Gore & Associates, Newark, DE, USA) was placed via a 0.018-in guidewire exchange. Covered stents were 25 or 50 mm in length and ranged from 5 to 8 mm in diameter. Repeat angiography was performed to confirm the exclusion of a pseudoaneurysm (Figure 2). After stent implantation, low-molecular-weight heparin anticoagulant therapy (0.4 mL/4,100 IU; S.C. Q12H) was generally started when the patient’s blood pressure and hemoglobin level became stable. Long-term oral aspirin [100 mg per os (PO) daily] and clopidogrel (75 mg PO daily) antiplatelet therapy was implemented in all surviving patients.

Figure 2 The process of implanting a covered stent in the superior mesenteric artery. (A) A 66-year-old female, 23 days after undergoing pancreaticoduodenectomy, was found to have a pseudoaneurysm of the branch of superior mesenteric artery on CTA examination. (B) After disinfection and dressing, 2% lidocaine was used for local anesthesia to facilitate a routine puncture and catheterization of the right femoral artery. Selective catheterization was performed to the superior mesenteric artery for angiography, which showed that the contrast agent overflowed at the beginning of the branches of the superior mesenteric artery, forming a pseudoaneurysm. (C) The catheter was selectively inserted into the distal end of the branch of the superior mesenteric artery. Through the exchange of guidewire and catheter, an 8 mm ×

25 mm covered stent was implanted at the lesion site. (D) The contrast catheter was withdrawn to the starting point of the superior mesenteric artery. Re-contrast imaging showed that the stent was unobstructed, and no contrast agent overflow was observed. A follow-up CT scan showed that the covered stent was in place, and there was no narrowing 1 month (E) or 6 months (F) after the implantation of the covered stent. The red arrows respectively represent the positions of pseudoaneurysm and covered stent. CT, computed tomography; CTA, computed tomography angiography.

Coil embolization

Embolization was applied to treat vessels with a small diameter (typically <4 mm), those with a course too tortuous or angular, and those not supplying blood to vital organs. Furthermore, for the bleeding in small arterial branches or vascular stumps that could be treated with covered stents, coil embolization was applied. A microcatheter (STC18; Boston Scientific) was placed in the lumen of the pseudoaneurysm, and contrast agent extravasation was observed on angiography. Microcoils (IDC; Boston Scientific) were used to embolize the inflow and outflow paths of the parent artery. Repeat angiography after embolization showed no extravasation of contrast medium (Figure 3).

Figure 3 The process of performing coil embolization in the splenic artery. (A,B) A 70-year-old female, 1 month after undergoing pancreaticoduodenectomy, was found to have a pseudoaneurysm of the splenic artery during a CTA examination. (C) After disinfection and draping, 2% lidocaine was used for local anesthesia at the puncture site of the right femoral artery. A selective catheter was inserted into the abdominal aorta for angiography, revealing the formation of a pseudoaneurysm at the residual end of the splenic artery. (D) Through use of a microcatheter, microcoils were filled into the residual segment of the splenic artery, which was the proximal end of the pseudoaneurysm. (E) One month after the coil embolization, a re-examination of the abdominal CTA showed that the microcoils were in place. The red arrows respectively represent the positions of pseudoaneurysm and coils. CTA, computed tomography angiography.

Follow-up

All patients were administered symptomatic treatment after the operation. Blood pressure, heart rate, blood routine, liver and kidney function, and other indicators were monitored within 1 hour after the surgery. Abdominal CTA was performed 1 month after the intervention to evaluate the efficacy of the interventional therapy. Follow-up was recorded in the inpatient electronic medical record and the outpatient medical record. All patients were followed up for at least 1 month.

Definitions

The definitions for some words or phrases in this article are described below.

Delayed hemorrhage was considered to be bleeding lasting more than 24 hours that began days or weeks after pancreatic surgery. It can manifest as sudden or intermittent intra-abdominal or gastrointestinal bleeding, and without timely and effective treatment, the mortality rate is high (8).

Pancreatic fistula was considered present if the level of amylase in abdominal drainage fluid was more than 3 times higher than normal serum amylase, the volume of drainage fluid was more than 50 mL per day for more than 3 consecutive days, or the diagnosis was confirmed by radiological methods. Pancreatic fistula was graded according to the standards of the International Study Group of Pancreatic Surgery (ISGPS) (9).

Biliary fistula was considered present if bile-like fluid was flowing out of the abdominal drainage tube after the operation, the color content did not become light with the decrease of blood bilirubin, or T-tube angiography confirmed it.

Abdominal infection was considered present if patients met one of the following criteria: (I) postoperative body temperature >38 ℃, blood white blood cell count >10×10⁹/L, abdominal pain, abdominal distension and obvious signs of peritonitis; (II) purulent abdominal drainage and positive bacteriological culture; and (III) imaging examination or reoperation confirming the presence of infection lesions, such as suppurative exudation and abscess, in the abdominal cavity.

Abdominal hemorrhage was defined as blood loss through an abdominal drainage tube, a decrease in hemoglobin concentration of more than 20 g/L within 24 hours or less than 80 g/L, and the requirement of at least 400 mL of blood supplement.

Technical success was considered to be the absence of angiographic signs of bleeding after interventional treatment. For patients with covered stent implantation, the blood flow of the diseased artery and distal branches was unobstructed. In patients with coil embolization, the inflow and outflow tracts of the parent artery were completely occluded.

Clinical success was considered to be hemodynamic stability and no requirement for reintervention of the primary site after interventional treatment.

The follow-up time was considered to be the last record in the medical history to the point when the patient returned to the outpatient clinic for a follow-up visit.

Statistical analysis

Statistical analyses included univariate and multivariate analyses and were conducted via SPSS 27.0 software (IBM Corp., Armonk, NY, USA). The chi-squared test was used for univariate analysis, while multivariate logistic regression was used for multivariate analysis. P<0.05 was considered statistically significant.

Results

Patient characteristics

From April 2015 to April 2024, a total of 153 patients with hemorrhage after pancreatic surgery performed at Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were enrolled, including 76 cases of pseudoaneurysm formation (49.7%). The mean follow-up time was 8.84±13.65 months. Among the patients with pseudoaneurysm, the most common pathological type was pancreatic ductal adenocarcinoma (n=47, 61.8%); the majority of patients underwent pancreaticoduodenectomy (n=39, 51.3%), and the most common initial clinical presentation was bleeding through the surgical drainage tube (n=36,47.4%). The vessels involved mainly included the superior mesenteric artery (n=14, 18.4%), hepatic artery (n=13, 17.1%), gastroduodenal artery (n=11, 14.5%), and splenic artery (n=11, 14.5%). Moreover, 13 patients underwent biliary drainage because of high bilirubin (>171.1 µmol/L) before operation [10 patients underwent percutaneous transhepatic cholangiography and drainage (PTCD), and 3 patients underwent endoscopic retrograde cholangiopancreatography (ERCP)]. The details of the 76 patients with pseudoaneurysm are shown in Table 1.

Interventional therapy

In this study, there were 76 patients with pancreatic postoperative pseudoaneurysm, 30 of whom underwent covered stent implantation and 46 patients underwent coil embolization; the technical success rate and clinical success rate of both treatment methods were 100% (Table 2).

Single-factor analysis

Age, gender, underlying diseases, and preoperative/postoperative indicators were selected as single factors to identify the risk factors associated with pancreatic pseudoaneurysm formation after pancreatic surgery. The results indicated that preoperative total bilirubin >17.1 µmol/L, preoperative and postoperative albumin <30 g/L, postoperative hemoglobin <90 g/L, operation time >6 hours, pancreatic fistula, and abdominal infection were risk factors for pseudoaneurysm formation (P<0.05; Table 3).

Multiple-factor analysis

The variables demonstrating statistical significance in the univariate analysis were subjected to stepwise logistic regression. The findings revealed that postoperative albumin <30 g/L, pancreatic fistula, and abdominal infection were independent risk factors for the development of pancreatic pseudoaneurysm after pancreatic surgery (P<0.05; Table 4).

Survival

The survival rate of the 76 patients with pseudoaneurysm during hospitalization was 90.8% (n=69). Among the patients, 7 died during hospitalization: 2 died of abdominal infection, 4 died of cachexia and multiple organ dysfunction syndrome, and 1 patient died of multiple vascular bleeding. The mean follow-up time was 8.84±13.65 months, and all patients were followed up for at least 1 month. During this period, none of the survivors experienced recurrence of bleeding at the treatment site or treatment-related complications. During the follow-up, after the implantation of the covered stent, 2 (2/30) patients developed local thrombosis within the stent: one developed a local thrombus in the superior mesenteric artery 2 years after the covered stent implantation, and the other experienced local thrombosis in the common hepatic artery 2 months after implantation of the covered stent. However, neither of these patients had any clinical symptoms related to thrombosis. Therefore, we administered anticoagulant therapy. No patients experienced ischemic-related complications after coil embolization during the follow-up.

Discussion

Traditionally, the perioperative mortality associated with pancreatic surgery has been particularly high. Although the perioperative mortality of pancreatic surgery has been reduced to 5% with the development of medical technology, the postoperative complications remain at 30–50%, while the postoperative bleeding rate is 2–8% (2). In recent years, it has been found that about 30–40% of delayed hemorrhage after pancreatic surgery is due to pseudoaneurysm rupture, and the common sites are the gastroduodenal artery, hepatic artery, and splenic artery (10). This is similar to the proportions of arteries involved in pseudoaneurysms in our study (common hepatic artery and branches: 32.9%; superior mesenteric artery and branches: 28.9%; gastroduodenal artery and branches: 15.8%; splenic artery: 14.5%).

Although pseudoaneurysm formation after pancreatic surgery is rare in clinical practice, the mortality rate is extremely high once it ruptures. The specific mechanism of pseudoaneurysm formation remains unclear. It is largely believed that the formation of pseudoaneurysm is related to the thinning of arterial wall caused by skeletonized lymph node dissection during operation, with other reasons including vascular corrosion caused by pancreatic fistula, biliary fistula, and abdominal abscess (11-13). When blood pressure increases, pseudoaneurysm will gradually increase under the impact of blood flow, compressing the surrounding tissues and causing abdominal pain and eventually leading to rupture and bleeding.

Abdominal pain, abdominal distension, abdominal bleeding, hematemesis, and hematochezia are the common clinical symptoms of pancreatic postoperative hemorrhage with pseudoaneurysm formation. In this study, the first clinical presentation of 47.4% patients was bleeding through the surgical drainage tube, and the second was abdominal pain. Sentinel hemorrhage is an asymptomatic interval of minor bleeding through surgical drainage or the gastrointestinal tract until hemorrhagic shock occurs, which is generally regarded as a precursor to major bleeding (14,15). It is a risk factor for secondary bleeding and may be associated with local sepsis and anastomotic rupture, indicating continuous destructive arterial bleeding caused by pseudoaneurysm (16). Studies have found that sentinel hemorrhage can be observed in 89% of patients with massive bleeding (17). Therefore, the early detection and timely intervention of sentinel hemorrhage hold considerable clinical importance. Contrast-enhanced CT examination is an effective method for the early detection and diagnosis of pseudoaneurysm, and arterial angiography is the gold standard for the diagnosis of pseudoaneurysm in clinical practice. When the pseudoaneurysm has not yet ruptured or if there is a small rupture, angiography of celiac trunk and superior mesenteric artery shows circular or similar circular distribution of contrast agent leakage in the main artery area or the adjacent area within the operation area.

The common interventional treatment methods for pseudoaneurysm after pancreatic surgery include coil embolization and covered stent implantation. Studies report a coil embolization success rate of 83% to 100%, but there are certain risks, including ischemic injury to tissue and irreversible functional failure (18). Therefore, before embolization of important vessels, a comprehensive evaluation of the vasculature should be conducted to avoid organ infarction. N-Butyl cyanoacrylate (NBCA) is a synthetic biodegradable cyanoacrylate-based adhesive. In recent years, it has been widely used in various clinical situations. For severe arterial bleeding, this adhesive glue has a high success rate in stopping the bleeding, and it can achieve this effect within a short period of time (19-21). It is found that the addition of microcoils and NBCA to gelatin sponge enhances both the efficacy and durability of embolic interventions (22). In our study, the bleeding volume in all patients was insignificant. Moreover, the microcoils we used during the operation had cilia, which made it easier to promote blood clotting and achieve hemostasis. Therefore, adhesive was not used in our study.

Meanwhile, covered stent implantation can immediately control bleeding, further maintain blood flow to terminal organs, and thus reduce the risk of ischemic reinjury. In our study, we decided upon covered stent implantation as opposed to coil embolization if the diameter of the affected vessel was greater than 4 mm and was not very tortuous. In this study, 46 patients (60.5%) received coil embolization treatment, with an average of 3.83±2.14 microcoils implanted; 30 patients (39.4%) received covered stents, with an average diameter and length of 6.28±0.99 mm and 3.75±1.27 cm, respectively, and an average of 1.17±0.46 stents implanted. After stent implantation, low-molecular-weight heparin anticoagulant therapy was generally initiated when the patient’s blood pressure and hemoglobin level became stable. Long-term oral aspirin and clopidogrel antiplatelet therapy was implemented in all surviving patients. In this study, 2 (2/30) patients developed local thrombosis within the stent after cover stent implantation. Thrombi occurred in the superior mesenteric artery and the common hepatic artery separately. You et al. (5) found that after the treatment with covered stents for pseudoaneurysms, the incidence of local thrombosis within the stent was 18.5%, which was higher than the incidence of 6.67% (2/30) in our study. The risk factors for thrombosis after covered stent implantation for pseudoaneurysms mainly include an overly long stent, a small vessel diameter, poor outflow tract, and insufficient antiplatelet therapy. It is recommended that high-risk patients receive dual-antiplatelet therapy for at least 3 months.

Severe obstructive jaundice may lead to coagulopathy or multisystem organ damage; however, the reduction of preoperative jaundice remains a controversial issue among clinical surgeons. In this study, 38 (50%) patients with pseudoaneurysm had a preoperative total bilirubin >17.1 µmol/L, while among those without pseudoaneurysm, the proportion was only 22.1%, representing a statistically significant difference (P<0.05). In the pseudoaneurysm group, 11 patients had severe obstructive jaundice, all of whom received preoperative biliary drainage (6 underwent PTCD, and 5 underwent ERCP). However, since liver mitochondria require 6 weeks of decompression to restore normal function, a short period of preoperative biliary drainage does not affect the incidence of postoperative hemorrhage or mortality in patients with jaundice. However, abdominal catheterization may increase the incidence of infection and postoperative complications (23). In this study, preoperative total bilirubin >17.1 µmol/L was not included in the logistic model; therefore, we do not consider preoperative total bilirubin >17.1 µmol/L to be an independent risk factor for pseudoaneurysm.

Serum albumin is one of the important indicators for evaluating the nutritional status of patients, and it can significantly improve the prognosis of patients after surgery. Several studies have shown that albumin <30 g/L is an independent risk factor for postoperative complications after pancreatic surgery (24). This is consistent with the finding that postoperative albumin <30 g/L was an independent risk factor for pancreatic pseudoaneurysm formation after pancreatic surgery in the multivariate logistic regression analysis of our study. Hemoglobin is also another laboratory index reflecting the nutritional status of patients. A too-low hemoglobin level is not conducive to the healing of wounds or anastomosis and will increase the risk of infection. In this study, the proportion of hemoglobin <90 g/L in the pseudoaneurysm group and the nonpseudoaneurysm group was 57.9% and 15.6%, respectively, and the difference between the two groups was statistically significant (P<0.05). Although hemoglobin <90 g/L was not significantly different in multiple-factor analysis of pseudoaneurysm formation after pancreatic surgery (P=0.163), actively providing patients with appropriate nutritional support, monitoring serum albumin and hemoglobin levels, and correcting hypoproteinemia and anemia in a timely fashion is recommended in practical clinical work.

Pancreatic fistula is one of the most common complications after pancreaticoduodenectomy, with an incidence rate of 2–30% (25). The ISGPS classifies pancreatic fistula into three grades: A, B, and C (9). The incidence of pancreatic fistula is related to the texture of the pancreas itself, with the pancreas tending to have a soft texture after surgery (26). Schäfer et al. (27) found postoperative pancreatic fistula to be the most significant independent risk factor for pseudoaneurysm formation and late visceral artery hemorrhage. This is consistent with pancreatic fistula being an independent risk factor for pseudoaneurysm formation after pancreatic surgery in the multivariate logistic regression analysis of our study. Patients with bleeding related to pancreatic fistula often require intervention or reoperation. Therefore, the early detection of pancreatic fistula is extremely important for improving the prognosis of patients.

Abdominal infection after pancreatic surgery is typically caused by pancreatic fistula, biliary fistula, and anastomotic fistula. The exudation of digestive fluid activates pancreatic enzymes, releases inflammatory factors, erodes arteries, and eventually leads to pseudoaneurysm formation (28). In this study, abdominal infection was confirmed to be an independent risk factor for pseudoaneurysm formation after pancreatic surgery by logistic regression analysis. To prevent postoperative infection, drainage tubes are usually placed near the pancreaticojejunostomy and bilioenteric anastomosis before the end of surgery. Bacterial culture of drainage fluid is helpful for the early detection of gastrointestinal fistula and the timely application of sensitive antibiotics. In this study, the incidence of postoperative pseudoaneurysm in patients with an operation time ≥6 hours were 60.3%, which was significantly higher than that in patients with an operation time <6 hours (43.2%; P<0.05). Although this factor showed no significant difference in the multiple-factor analysis of pseudoaneurysm formation after pancreatic surgery (P=0.705), it may lead to an increased risk of abdominal infection with a longer duration of surgery, thus further increasing the risk of bleeding.

The main limitations of this study include (I) the single-center, retrospective design; (II) the small sample size and potential for sampling error; (III) the prevalence of patients with pancreatic malignant tumors, short survival time, and poor prognosis.

Conclusions

This study demonstrated that endovascular intervention is a minimally invasive, safe, and effective method for the treatment of pseudoaneurysms caused by delayed hemorrhage after pancreatic surgery. Postoperative albumin <30 g/L, pancreatic fistula, and intra-abdominal infection are independent risk factors for pancreatic pseudoaneurysm formation after pancreatic surgery. Strict perioperative management, monitoring the levels of serum albumin and hemoglobin, early detection of pancreatic fistula, and intra-abdominal infection are the keys to reducing the formation of pseudoaneurysm after pancreatic surgery, reducing the risk of delayed hemorrhage, and improving prognosis.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1012/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1012/dss

Funding: This work was supported by the National Natural Science Foundation of China (Nos. 82272089, and 82472077).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1012/coif). All authors report the funding from the National Natural Science Foundation of China (Nos. 82272089, and 82472077). The authors have no other 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Ruijin Hospital Ethics Committee, Shanghai Jiaotong University School of Medicine (No. 2025-471), and individual consent for this retrospective analysis was waived.

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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