Diagnostic efficacy of the contrast-enhanced ultrasound thyroid imaging reporting and data system classification for benign and malignant thyroid nodules

Introduction

Thyroid nodules are distinct lesions inside the thyroid gland that differ radiologically from the surrounding thyroid parenchyma. Their etiology ranges from common inflammatory responses and hyperplasia to substantial changes in the tumor. In recent decades, nodule detection has significantly improved, driven by the development and widespread availability of high-resolution ultrasound (US) technology. Thyroid nodules are prevalent, occurring in an estimated 60% of adults (1). Although only approximately 5% of nodules are ultimately found to be malignant (2), the possibility of malignancy is a major concern and timely screening of thyroid nodules is increasingly important to clinicians and patients. Accurate detection of benign and malignant thyroid nodules is a critical element of preoperative US, which can effectively reduce the risk of puncture.

Several US risk stratification systems for thyroid nodules, including the thyroid imaging reporting and data system (TI-RADS) have been introduced by many international organizations, among them the major associations in Chile and Korea, the European Thyroid Association, the American College of Radiology (ACR), and the Chinese Medical Association (CMA) (3-7). Nonetheless, these systems are based on a two-dimensional US assessment of thyroid nodules, which lacks information on blood flow microcirculation and thus make the precise assessment of the nodules difficult. Unlike conventional US, the contrasted-enhanced ultrasound (CEUS) can provide real-time insights into the vascular perfusion and hemodynamics of thyroid nodules, allowing dynamic assessment of microvascularization patterns (8), which is considered a valuable novel approach for identifying benign and malignant nodules (9,10). In recent years, several researchers in China and internationally have examined and characterized the contrast patterns of malignant nodules, such as inhomogeneous enhancement, centripetal or centrifugal enhancement, hypoenhancement, and irregular ring enhancement, of which hypoenhancement is considered to be the main CEUS pattern feature of malignant thyroid nodules (11,12). In addition, CEUS has nonnegligible clinical value for the prediction of cervical lymph node metastasis of thyroid malignant nodules. For cervical lymph node metastases, Liu et al. (13) found that the larger diameter of the thyroid tumor, the closer the thyroid tumor is to the thyroid capsule, or the greater the number of neovascularizations, the higher the probability of cervical lymph node metastasis is. All these factors represent channels for the invasion and metastasis of cervical lymph nodes. Additionally, it has been reported that the CEUS features of metastatic lymph nodes in the neck typically show centripetal enhancement, heterogeneous enhancement, and perfusion defects (14). Through univariate and multivariate logistic regression analyses, Ruan et al. (15) discovered that nodule composition, echogenicity, shape, margins, echogenic foci, and extrathyroidal extension on US, as well as the direction of enhancement, peak intensity, and circumferential enhancement on CEUS, are important predictors of thyroid carcinoma. However, previous research has also found that the size of thyroid nodules influences vascular development and visualization and the biological behavior and prognosis of thyroid nodules (16-19), resulting in variability in clinical decisions. In this study, we investigated the diagnostic value of CEUS TI-RADS in nodules of different sizes by using a maximum diameter of nodule of 1 cm and a boundary of 4 cm for more discerning reference information in clinical decision-making.

This study sought to confirm the diagnostic efficacy of CEUS TI-RADS in thyroid nodules and further assess the diagnostic performance of CEUS TI-RADS for thyroid nodules of various sizes. Moreover, the use of CEUS TI-RADS between sonographers of different seniorities was assessed according to the interobserver concordance of CEUS TI-RADS scores. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-457/rc).

Methods

Ethics statement

This retrospective study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the medical ethics committee of the Affiliated Hospital of Guangdong Medical University (No. PJKT2024-028). Each patient signed the informed consent papers for the CEUS, fine-needle aspiration (FNA), and surgery tests/procedures.

Study population

The inclusion criteria for this study were following: (I) completion of US and CEUS at the Affiliated Hospital of Guangdong Medical University; (II) a final postoperative pathological result or FNA result of Bethesda II, Bethesda Ⅴ, or Bethesda VI based on The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) (20); and (III) no history of previous treatment, including thyroid surgery, chemotherapy, radiotherapy, or I131 treatment. Meanwhile, the exclusion criteria were as follows: (I) nodules classified as Bethesda I, III, or IV according to TBSRTC and (II) missing final pathologic results. A total of 433 patients who fulfilled the inclusion criteria were included between January 2019 and June 2023 (Figure 1).

Figure 1 Study flowchart. Out of 433 patients, 400 patients had a single nodule, 32 patients had two thyroid nodules, and 1 patient had three nodules. Out of 262 malignant nodules, 12 patients had 2 malignant nodules. And out of 205 benign nodules, 8 patients had 2 benign nodules and 1 patient had three nodules. Besides, 12 patients had both 1 benign nodule and 1 malignant nodule. US, ultrasound; CEUS, contrast-enhanced ultrasound; FNA, fine-needle aspiration; pt, number of patients; n, number of thyroid nodules.

Conventional US and CEUS examination

A high-frequency linear probe (Acuson Sequoi, Siemens Healthineers, Erlangen, Germany; Aplio 500, Canon, Tokyo, Japan) was used for each US inspection. SonoVue (Bracco Imaging S.p.A., Milan, Italy), a sulfur-hexafluoride-filled microbubble contrast agent protected by a flexible phospholipid shell, was used as the contrast medium. To create an intravenous access, a 20-G needle was placed into the patient’s median cubital vein. The patient was instructed not to swallow after the contrast agent, and 5-mL of saline were combined and mixed until homogenous. Subsequently, 2.4 mL of the suspension was rapidly injected into the median cubital vein while the probe and body posture were kept constant. After injection, the timer on the US machine was set to start. The photographs were stored on the hard disk of the US device, which was constantly monitoring the dynamic perfusion process of the lesion in real-time.

The CEUS TI-RADS classification was assigned to each thyroid nodule based on the CEUS TI-RADS scoring criteria for US and CEUS features of the nodule. These features included size, echogenicity, shape, margin, echogenic foci, and extra-thyroidal invasion in US, as well as enhancement direction, peak intensity, ring enhancement, and composition on CEUS. The nodules were grouped based on their sizes as follows: nodule size ≤1 cm, group A; size >1 cm and size ≤4 cm, group B; and size >4 cm, group C.

To calculate the interobserver concordance of the CEUS TI-RADS scores, 150 thyroid nodule images were randomly selected for individual analysis of the US and CEUS features. Two sonographers performed the analysis. The junior sonographer had experience of 4 years in thyroid ultrasonography, while the senior sonographer had 8 years of experience. Importantly, both sonographers were blinded to the pathologic findings, and nodules were scored and categorized following the CEUS TI-RADS classification criteria. Subsequently, interobserver variability in CEUS TI-RADS scores was retrospectively evaluated. Figure 2 presents the criteria for the CEUS TI-RADS categories.

Figure 2 Chart of the CEUS TI-RADS, with correspondent malignant probabilities and indications for FNA. US, ultrasound; CEUS, contrast-enhanced ultrasound; CEUS TI-RADS, contrasted-enhanced ultrasound thyroid imaging reporting and data system; TR, TI-RADS; FNA, fine-needle aspiration.

Statistical analysis

Statistical analyses were performed on SPSS 27.0 (IBM Corp., Armonk, NY, USA; RRID:SCR_019096) and MedCalc 22.0 (MedCalc Software, Ostend, Belgium; RRID:SCR_015044). Normally distributed measurements are presented as the mean ± standard deviation. Comparisons of categorical variables were performed using the χ² test, and logistic regression was employed to identify independent risk factors predictive of malignant nodules for both US and CEUS characteristics. Receiver operating characteristic (ROC) analysis was used to establish the cutoff values, compute the area under the curve (AUC), and establish 95% confidence intervals (CIs). The sensitivity (SEN), specificity (SPE), accuracy (ACC), positive predictive value (PPV), and negative predictive value (NPV) were measured to assess the diagnostic efficiency of the CEUS TI-RADS system. The significance level was set at P<0.05. Interobserver agreement for CEUS TI-RADS scores was evaluated via the intragroup correlation coefficient (ICC). The agreement was classified as poor (ICC ≤0.50), moderate (0.50< ICC ≤0.75), good (0.75< ICC ≤0.90), or very good (ICC >0.90).

Results

Study population, US, and CEUS features of thyroid nodules

In total, 500 patients with 535 nodules underwent US, CEUS, and FNA/surgery between January 2019 and June 2023. A total of 8 nodules were excluded due to FNA history (n=7) or ablation (n=1). Moreover, 60 nodules, including 34 Bethesda I nodules, 20 Bethesda III nodules, and 6 Bethesda IV nodules were excluded for the lack of reference standard. Finally, 467 nodules from 433 patients were included, among whom 33 had two nodules and 1 patient had 3 nodules. The mean age of all malignant nodules was 45±13 years, and the mean age of benign nodules was 48±13 years. The mean maximum diameter of the nodules was 1.85±0.06 cm (range, 0.50–9.00 cm). Out of the 467 nodules, 262 were malignant and 205 were benign. A total of 242 malignant nodules were diagnosed with the pathologic result, including 234 papillary thyroid carcinomas (PTCs), 6 follicular thyroid carcinomas (FTCs), and 2 medullary thyroid carcinomas (MTCs). A total of 91 benign nodules were surgically confirmed, including 62 nodular goiters, 12 follicular thyroid adenomas (FTAs), 7 cases of Hashimoto thyroiditis, 3 cases of granulomatous thyroiditis, 3 Hürthle cell tumors, 1 ectopic thymus, and 3 noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs). The cytologic assessment confirmed 20 malignant and 114 benign nodules, among which 3 were Bethesda V, 17 were Bethesda VI, and 114 were Bethesda II. Table 1 shows the US and CEUS characteristics of all nodules.

Logistic regression analysis and diagnostic effect of CEUS TI-RADS

As shown by logistic regression analysis, punctate echogenic foci (P<0.001), taller-than-wide shape (P=0.015), extrathyroidal invasion (P=0.020), irregular margins/lobulation (P=0.036), hypoechoicity (P=0.038) on US, and hypoenhancement (P<0.001) on CEUS were the independent risk factors for malignant thyroid nodules (Table 2). The nodules were grouped based on their sizes. The diagnostic efficacy of the CEUS TI-RADS classification in differentiating benign and malignant thyroid nodules was examined using ROC analysis (Figure 3). The AUC of CEUS TI-RADS for all nodules was 0.898 (95% CI: 0.867–0.924, P<0.001), whereas nodules of the group B obtained excellent performance with an AUC, SEN, SPE, ACC, PPV, and NPV of 0.949 (95% CI: 0.916–0.971; P<0.001), 95.9%, 88.1%, 92.8%, 92.6%, and 93.2%, respectively. Meanwhile, the AUC, SEN, SPE, ACC, PPV, and NPV of ACR-TIRADS for diagnosing malignant thyroid nodules in group B were 0.899 (95% CI: 0.857–0.942, P<0.001), 91.8%, 88.1%, 90.3%, 92.3%, and 87.3%, respectively. Table 3 presents the AUC, SEN, SPE, ACC, PPV, and NPV of the CEUS TI-RADS for different groups.

Figure 3 ROC analyses for the diagnostic performance of the CEUS TI-RADS for predicting the malignancy of thyroid nodules in different groups. The nodules were grouped based on their sizes as follows: size ≤1 cm, group A; size >1 and ≤4 cm, group B; and size >4 cm, group C. AUC, area under the curve; ROC, receiver operating characteristic; CEUS TI-RADS, contrasted-enhanced ultrasound thyroid imaging reporting and data system.

US and CUES characterization of the three groups of thyroid nodules

In group A, echogenicity, shape, and calcification on the US, as well as the direction of enhancement (Figures 4,5), peak intensity (Figure 6), and composition (Figure 7) on CEUS, were statistically different between benign and malignant nodules (P<0.05). On the other hand, margin (P=0.050), extrathyroidal invasion (P=0.306) on US, and ring enhancement (P=0.878) on CEUS were not statistically different between benign and malignant nodules. In group C, margin, calcification, and extra-thyroidal invasion on US, as well as peak intensity, ring enhancement, and composition on CEUS, were statistically different between benign and malignant nodules (P<0.05), whereas echogenicity (P=0.171), shape (P>0.999) on US, enhancement direction (P=0.845), and composition (P>0.999) on CEUS were not statistically different. In group B, all US and CEUS characteristics were statistically different (P<0.05) (Table 4).

Figure 4 Enhancement direction on CEUS. (A-C) Images showing centripetal enhancement of the same PTC nodule (red arrows) in the right lobe of thyroid gland of a 69-year-old woman. (D) Image of a case of a benign nodule (red arrows) in the left lobe of thyroid gland of a 41-year-old woman showing a feature of scattered enhancement on CEUS. The minutes and seconds after the contrast media injection are indicated by numbers in the bottom left corner of each panel. CEUS, contrast-enhanced ultrasound; PTC, papillary thyroid carcinoma.

Figure 5 Enhancement direction on CEUS. (A-C) Images of centrifugal enhancement of the same PTC nodule (red arrows) in the left lobe of the thyroid gland of a 69-year-old man. (D) A case of a benign nodule (red arrows) in the left lobe of the thyroid gland of a 65-year-old woman showing the feature of scattered enhancement on CEUS. The minutes and seconds after the contrast media injection are indicated by the numbers in the bottom left corner of each panel. CEUS, contrast-enhanced ultrasound; PTC, papillary thyroid carcinoma.

Figure 6 Images showing the feature of peak enhancement of thyroid nodules (red arrows). (A) Nonenhancement. (B) Hypoenhancement. (C) Isoenhancement. (D) Hyperenhancement. The minutes and seconds after the contrast media injection are indicated by the numbers in the bottom left corner of each panel.

Figure 7 Images showing features of ring enhancement and composition of thyroid nodules (red arrows). (A) Ring enhancement. (B) Lack of ring enhancement. (C) Solid. (D) Nonsolid. The minutes and seconds since the contrast media injection are indicated by the numbers in the bottom left corner of each panel.

Interobserver agreement

The ICC was used to analyze the concordance between the scores of senior and junior sonographers for 150 thyroid nodules. The results indicated that the ICC between senior and junior sonographers for the CEUS TI-RADS score was 0.862 (P<0.001).

Discussion

Currently, US is the preferred screening method for thyroid diseases due to its advantages of noninvasiveness, low cost, lack of radiation, simplicity, and reproducibility. In recent years, US technology in this field has made considerable progress in areas such as CEUS and US elastography. These novel technologies are essential to the differential diagnosis of thyroid nodules.

Zhang et al. (21) combined traditional US, shear wave elastography, and BRAF V600E mutation status to evaluate nodules with benign FNA results and then compared them with the final pathological results; they found that the diagnostic efficacy of the three combined methods was statistically higher than those of each used alone (P<0.05), suggesting that further clinical decision-making should be considered for any nodule with two or more signs suggestive of US malignancy and with hard US elasticity. Ruan et al. (15) pioneered the development of CEUS TI-RADS by combining conventional US with CEUS, and they used the CEUS TI-RADS in the differential diagnosis of benign and malignant thyroid nodules, achieving good results in internal cross-validation and external validation; the ROCs were 0.93 (95% CI: 0.92–0.95) for internal validation, 0.89 (95% CI: 0.84–0.92) for the first external validation set, and 0.90 (95% CI: 0.85–0.94) for the second external validation set. However, none of these validation sets were investigated in groups based on nodule size. Our study categorized the nodules into groups based on size to further investigate the diagnostic efficacy of CEUS TI-RADS. The World Health Organization (WHO) defines papillary thyroid microcarcinoma (PTMC) as a PTC with a maximum diameter of 1 cm (22). Although several major guidelines, including the ACR, recommend surveillance of subcentimeter nodules, many patients with suspicious subcentimeter nodules are subjected to FNA in China due to patient anxiety, physician preference, family history, and other factors (23). When the maximum diameter of the nodule exceeds 4 cm, the risk of capsular and vascular invasion, which converts follicular adenoma into follicular carcinoma, increases, with the trachea being more likely to compress, causing aesthetic problems (1). Therefore, in our study, the nodules were classified based on their sizes (size ≤1 cm = group A, size >1 cm and ≤4 cm = group B, and size >4 cm = group C).

Our results revealed that the highest AUC of 0.949 (95% CI: 0.916–0.971, P<0.05) was obtained for nodules in group B, whereas the AUCs for nodules in groups A and group C were 0.795 (95% CI: 0.721–0.857, P<0.05) and 0.801 (95% CI: 0.644–0.910, P<0.05), respectively. This was consistent with the findings of Li et al. (24), who used CEUS to diagnose nodules smaller than 1 cm, reporting no significant benefit of CEUS in TMC diagnosis. The poor diagnostic efficacy of CEUS TI-RADS for subcentimeter nodules might be attributed to the following. First, suboptimal FNA due to issues of insufficient specimen size and false-negative results limit efficacy, with the bulk of related studies reporting false-negative rates of less than 5% and others reporting higher rates (ranging from 7.5% to 21%) (25). Second, a volume effect can arise in CEUS due to a small nodule size, which can lead to benign nodules, including mummified nodules, being easily misdiagnosed as malignant nodules. Therefore, we suggest that for subcentimeter nodules, the contrast agent dose could be appropriately reduced based on device conditions and the sonographer’s experience to significantly minimize the volume effect. Nevertheless, when the nodule is too large for the limited probe exploration range, it is difficult to precisely diagnose the nodule, whereas CEUS could provide effective guidance for puncture to improve the positive puncture rate of nodules (26).

For the small-nodule (group A), the malignant nodules were mostly PTC, whereas the benign nodules were mainly nodular goiter. Both benign and malignant nodules were largely hypoechoic, with little evident extrathyroidal invasion, and most did not have ring enhancement features on CEUS. However, not all benign nodules in the large- nodule (group C) were predominantly iso/hypoechoic, and there were quite a few with hypoechoic features. Due to the large size, most of the nodules were wider than tall on conventional US, and nearly all appeared solid on CEUS. Due to the high number of vasculatures, branches, and arteriovenous fistulae inside the larger nodules, the inside of the nodule was simultaneously perfused with the blood-rich thyroid tissue, thus yielding unsatisfactory results in the differential diagnosis of benign and malignant large and small nodules via US and CEUS.

We found that CEUS TI-RADS had a significant benefit in the differential diagnosis of thyroid mummification and PTC. Mummified thyroid nodules (MTNs) are cystic solid nodules that change after treatment via processes such as resorption or nodal ablation. These nodules show signs of malignancy on US, including hypoechoicity or high hypoechoicity and taller-than-wide shape in atrophic collapse, which may indicate TI-RADS 5 in the ACR TI-RADS classification (27). Furthermore, we discovered that CEUS could improve the classification between PTC and MTNs, as 85.5% (224/262) of PTCs exhibited centripetal or centrifugal hypoenhancement due to relatively poor vascularization (Figures 4,5A-5C). On the other hand, the majority of MTNs did not show enhancement on CEUS (Figures 6A,7D), and this observation might help improve the diagnostic efficacy of ACR TI-RADS and reduce the unnecessary FNA or surgical resections of MTNs. This result is consistent with the findings of Chen et al. (28).

Although CEUS may play a crucial role in differentiating MTNs from PTCs, this scoring system failed to categorize FTC and inflammatory nodules. In our study, there were 6 cases of FTC, among which only 2 cases were classified as category 5 and 4 as categories 3–4A; circumferential hyperenhancement was observed in the 6 cases of FTC. Therefore, distinguishing FTC from adenoma or nodular goiter with adenomatous hyperplasia was difficult because the US manifestations of FTC did not show apparent malignant signs, including extrathyroidal invasion or microcalcifications. Since tumor invasion of the margin or blood vessels is the only pathological diagnostic criterion for FTC (29), CEUS TI-RADS could not differentiate between FTC and FTA with any degree of precision. Therefore, there is a need for additional studies on CEUS SEN and SPE for FTC diagnosis.

Meanwhile, 5 nodules with Hashimoto’s thyroiditis pathology and 2 nodules with granulomatous thyroiditis pathology were misdiagnosed as malignant. The misdiagnoses were attributed to the concomitant microcalcification of the nodules, an aspect ratio >1, and low enhancement of the malignant signs. Hashimoto’s thyroiditis with fibrosclerotic nodules and granulomatous thyroiditis is characterized by a primary pathological change of fibrosis and poor blood supply. These features tend to overlap on US and CEUS, hence complicating these conditions’ differentiation from malignant nodules (30). Zhang et al. (30) demonstrated that CEUS combined with time-intensity curve (TIC) parameters could provide effective quantitative information on microvascular perfusion for the differential diagnosis of inflammatory thyroid nodules and PTC, which warrants further validation.

Unlike the results of Ruan et al. (15), our study performed logistic regression analysis of the US and CEUS characteristics of 467 nodules, in which only 1 independent risk factor was correlated with CEUS, while the rest were correlated with US. This might be explained by the fact that hypoenhancement in CEUS is obvious in most nodules, while the US characteristics are needed to differentiate small-sized malignant nodules. Moreover, we found that hyperenhancement and the presence or absence of circumferential enhancement were not statistically significant in differentiating between benign and malignant nodules, which is consistent with the findings of many previous studies (9,24,31). We believe that the inconsistent conclusions might still be attributed to the tumor size and growth stage. Tumor growth is categorized into two stages: from the slow growth stage without blood vessels (prevascular stage) to the rapid growth stage with blood vessels (vascular stage). In our study, for relatively small tumors with no or few blood vessels, the enhancement observed by CEUS was primarily hypoenhancement. Upon rapid tumor growth, a diversity of neovascularization forms due to various angiogenic factors, causing the nodule hyperenhancement that is apparent on CEUS (32). Notably, the presence of a halo is often considered a benign feature (33). However, some thin halos appearing on conventional US might be unclear and difficult to detect, whereas the surrounding rings could be observed on CEUS. A greater number of peripheral halo rings can be observed on CEUS than on conventional US. Due the factors leading to formation of ring enhancement in nodules being unclear, some researchers (34,35) analyzed this feature and have proposed that irregular ring hyperenhancement is a sign of malignancy; meanwhile, a enhanced ring with regularity or irregularity should be combined with the enhancement features inside the nodules. Therefore, we speculated that categorizing ring enhancement before allocating points could be more rigorous.

In our study, a senior and a junior medical practitioner independently assessed 150 thyroid nodules, using the CEUS TI-RADS classification system for scoring purposes. The ICC was 0.86, indicating a high degree of consistency in their assessments. This outcome confirmed the use of this approach as a valuable diagnostic tool for junior medical practitioners.

This work has several noteworthy limitations. First, we employed a single-center, retrospective design, and the reading scores of the physicians were based on static charts, which did not mimic real clinical practice; thus, the findings might not be generalizable to other institutions. Second, some of our pathology outcomes were based on FNA, which could have potentially involved false positives and false negatives. Third, most of the malignant nodules were PTCs; therefore, the diagnostic value of this scoring system needs to be assessed for other malignant pathologic types.

Conclusions

The novel CEUS TI-RADS scoring system has high efficacy in the differential diagnosis of benign and malignant thyroid nodules and may potentially help reduce the number of FNA procedures or unnecessary surgical interventions for benign nodules, particularly MTNs. Moreover, its diagnostic efficacy was influenced by the nodule size, and the optimal performance was in nodules with sizes between 1 to 4 cm. These observations may provide valuable information for clinical diagnosis and treatment.

Acknowledgments

The authors would like to thank the Clinical Trials Service Center of the Affiliated Hospital of Guangdong Medical University for assistance with the statistical analyses.

Funding: This work was supported by the Innovation and Practice Training Model for Professional Degree Postgraduates and the Graduate Teaching Reform Research Project of the Affiliated Hospital of Guangdong Medical University.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-457/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-457/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. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the ethics review board of Affiliated Hospital of Guangdong Medical University (No. PJKT2024-028). Informed consent was provided by all participants.

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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