Contrast-enhanced ultrasound for differentiating benign from malignant Breast Imaging Reporting and Data System 4a breast lesions: a prospective diagnostic accuracy study

Introduction

Breast cancer is the most frequently diagnosed malignancy worldwide and the second leading cause of cancer-related mortality among women in developed regions, following lung cancer (1,2). According to the GLOBOCAN 2022 estimates, there were approximately 2.3 million new cases and 666,000 deaths from breast cancer globally, accounting for 11.6% of all cancer incidence and 6.9% of cancer mortality (1). Early and accurate diagnosis remains paramount for improving patient outcomes.

While histopathological examination remains the standard diagnostic method, its invasive nature precludes its use as a primary screening tool. Ultrasonography (US) has become a cornerstone of breast imaging due to its wide availability, lack of ionizing radiation, real-time capability, and cost-effectiveness (3). The American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) provides a standardized framework for lesion description, risk stratification, and management recommendations (4,5). Within this system, category 4a designates lesions with low suspicion for malignancy, with an estimated probability of 2–10% (6). Current guidelines recommend biopsy for all such lesions to exclude malignancy (7). However, this approach subjects the majority of patients with ultimately benign findings to unnecessary invasive procedures, with attendant psychological distress, physical morbidity, and economic burden (8-11). Therefore, a reliable non-invasive adjunctive tool is needed to further stratify BI-RADS 4a lesions and safely reduce avoidable biopsies.

Contrast-enhanced ultrasound (CEUS) represents an advanced functional imaging technique that enables real-time visualization of tissue microvascular perfusion following intravenous administration of a microbubble contrast agent (e.g., sulfur hexafluoride, SonoVue^®) (12,13). Malignant tumors typically exhibit distinct angiogenic features on CEUS, including heterogeneous hyper-enhancement, centripetal perfusion, internal perfusion defects, and rapid wash-in/wash-out kinetics—patterns that differ from the more homogeneous enhancement seen in benign lesions such as fibroadenomas (14,15). Meta-analyses have confirmed the diagnostic utility of CEUS for breast lesions in general populations (14,16). However, the specific performance of CEUS in the narrowly defined BI-RADS 4a subcategory—and its potential to potentially reduce unnecessary biopsies, although further large-scale validation is warranted in this population—remain inadequately quantified. Most prior studies have either pooled all BI-RADS 4 lesions together or focused on higher-risk categories where biopsy is already mandatory (14,16).

Accordingly, this prospective diagnostic study was designed to evaluate the performance of CEUS in differentiating benign from malignant pathology specifically within BI-RADS 4a breast lesions, using histopathology as the reference standard. Our primary objectives are to quantify sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), and to estimate the proportion of biopsies that could potentially be avoided using CEUS as a triage tool. We hypothesized that CEUS would demonstrate a high NPV, suggesting that it could potentially identify a substantial subset of patients with low-suspicion lesions in whom biopsy might be safely deferrable—a hypothesis that requires confirmation in future prospective, multi-center trials. We present this article in accordance with the STARD reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0315/rc).

Methods

Study design and participants

This prospective diagnostic accuracy study was conducted at Xi’an Hospital of Traditional Chinese Medicine between (Aug, 2023) and (Aug, 2025). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Review Board of Xi’an Hospital of Traditional Chinese Medicine (approval No. LLSCYJ-LW-2026002), and written informed consent was obtained from all participants prior to enrollment.

Consecutive female patients aged 18 years or older, who were scheduled for ultrasound-guided biopsy or surgical excision of a breast lesion initially classified as BI-RADS category 4a on US, were screened for eligibility. The BI-RADS 4a assessment was independently performed by two sonographers (L.F. and W.Q.) with over 5 years of experience in breast imaging, following the ACR BI-RADS Atlas (5^th edition). In cases of disagreement, a consensus was reached through discussion with a third senior breast imaging specialist (Y.K.).

Inclusion and exclusion criteria

The inclusion criteria were: (I) presence of at least one breast lesion categorized as BI-RADS 4a on conventional US; (II) scheduled for core needle biopsy or surgical excision with subsequent histopathological examination; (III) willingness to undergo a pre-procedural CEUS examination; and (IV) provision of informed consent.

Exclusion criteria included: (I) lesions categorized as BI-RADS 2, 3, 4b, 4c, 5, or 6; (II) previous history of breast cancer or other malignancies affecting the breast; (III) pregnancy or lactation; (IV) prior intervention (surgery, radiotherapy, ablation, or biopsy) on the target lesion, as such procedures may induce inflammation, hemorrhage, or scarring that could alter vascular architecture and confound CEUS interpretation; (V) known hypersensitivity to sulfur hexafluoride or any excipient of the ultrasound contrast agent, including macrogol 4000 (polyethylene glycol), distearoylphosphatidylcholine, dipalmitoylphosphatidylglycerol sodium, and palmitic acid; (VI) severe cardiopulmonary conditions [e.g., New York Heart Association (NYHA) Class III or IV heart failure, unstable angina, recent myocardial infarction (<6 months], severe chronic obstructive pulmonary disease [Global initiative for Chronic Obstructive Lung Disease (GOLD) stage 3 or 4], or hemodynamically significant arrhythmia); (VII) known coagulopathy [international normalized ratio (INR) >1.5 or platelet count <50×10⁹/L] or ongoing anticoagulant therapy that could not be safely paused; (VIII) incomplete imaging or pathological data; and (IX) severe psychiatric or cognitive disorders.

US and CEUS examination

All conventional US and CEUS examinations were performed using a high-end ultrasound system (GE LOGIQ E9) equipped with a high-frequency linear transducer (6–15 MHz). The same machine and probe were used for both conventional US and CEUS for each patient.

First, a detailed conventional US examination was performed to confirm the BI-RADS 4a features (well-circumscribed, solid mass with no more than two suspicious features). The lesion’s location, size (in three dimensions), morphology, margins, echogenicity, and posterior features were documented.

Subsequently, CEUS was performed by an experienced sonographer (J.Z.) who was blinded to the planned biopsy site for patients with multiple lesions. The mechanical index was set to a low range (0.06–0.08) for contrast imaging. A bolus of 2.4 mL of sulfur hexafluoride microbubble contrast agent (SonoVue^®, Bracco Imaging S.p.A.) was injected intravenously through a peripheral venous cannula (18–20 gauge), followed by a 5 mL saline flush. This dose was administered as a single bolus to ensure consistent perfusion kinetics across all examinations. The timer was started at the beginning of the contrast injection. Continuous, real-time cine loops of the lesion and surrounding parenchyma were recorded for at least 120 seconds and stored digitally for offline analysis. Care was taken to maintain the transducer position steady to minimize motion artifacts. All patients were monitored for at least 30 minutes post-injection, and no adverse events were observed.

Image analysis

The CEUS cine loops were retrospectively and independently reviewed by two radiologists/sonographers (Y.K. and W.Q., with 15 and 10 years of experience in breast CEUS, respectively), who were blinded to the conventional US findings, biopsy results, and each other’s assessments. This CEUS reading session was conducted at least 4 weeks after the initial BI-RADS assignment. The reviewers were strictly blinded to the original BI-RADS category, all conventional grayscale and Doppler US features, clinical history, and pathological results. They were also blinded to each other’s assessments. Although these same individuals had participated in the original routine US classification, the CEUS review was performed in a separate session with no access to the earlier records and with explicit instruction to disregard any prior knowledge of the cases. In case of disagreement, a consensus reading was performed with a third senior reader (F.Q.).

The following qualitative CEUS characteristics were evaluated (Figure 1): (I) enhancement pattern: homogeneous or heterogeneous; (II) enhancement intensity: compared to the surrounding normal breast parenchyma, classified as hypo-enhancement, iso-enhancement, or hyper-enhancement; (III) enhancement direction: centripetal (from periphery to center), centrifugal, or diffuse; (IV) perfusion defects: presence of non-enhancing areas within the lesion; (V) margin characteristics: well-defined or ill-defined enhancing margin; (VI) wash-in/wash-out pattern: based on visual assessment of the time-intensity curve (TIC) pattern generated by manually placing a region of interest within the lesion. Patterns were categorized as: fast wash-in and fast wash-out, fast wash-in and slow wash-out, slow wash-in and slow wash-out, or slow wash-in and fast wash-out.

Figure 1 Representative CEUS images of breast lesions. (A) Benign fibroadenoma showing homogeneous iso-enhancement with diffuse perfusion pattern. (B) Malignant invasive ductal carcinoma demonstrating heterogeneous hyper-enhancement with centripetal filling. (C) Malignant lesion showing internal perfusion defects (arrow) and ill-defined enhancing margin. (D) TIC analysis showing fast wash-in and fast wash-out pattern in a malignant lesion. CEUS, contrast-enhanced ultrasound; TIC, time-intensity curve.

A lesion was considered CEUS-positive for malignancy if it exhibited at least two of the following suspicious features: heterogeneous hyper-enhancement, centripetal or centrifugal enhancement, presence of perfusion defects, ill-defined enhancing margins, or a TIC pattern showing fast wash-in and fast wash-out. Lesions not meeting these criteria were classified as CEUS-negative (likely benign).

The threshold of ≥2 suspicious features was selected based on multiple considerations: (I) evidence from prior studies indicating that multi-parameter assessment improves diagnostic accuracy compared to single features (6,17,18); (II) the need to avoid false positives that might arise from relying on a single feature, as certain benign lesions (e.g., inflammatory changes, papillomas) may occasionally exhibit one malignant-like characteristic; (III) a parallel to the BI-RADS framework, which integrates multiple suspicious findings for risk stratification; and (IV) pilot data from our institution demonstrating an optimal balance between sensitivity and specificity at this threshold, which was subsequently validated by the substantial inter-observer agreement (κ=0.76) achieved in this study. This diagnostic criterion was established based on a review of prior literature and preliminary internal consensus (7,13,14,16).

Reference standard

Histopathological diagnosis from ultrasound-guided core needle biopsy (14-gauge needle, with at least 3 samples) or surgical excision served as the reference standard (15,19,20). All pathological specimens were reviewed by experienced breast pathologists and classified as benign, high-risk, or malignant [invasive carcinoma, ductal carcinoma in situ (DCIS)]. For the primary analysis, high-risk lesions [e.g., atypical ductal hyperplasia (ADH)] were grouped with malignant lesions, as they typically warrant surgical excision. A sensitivity analysis considering them as a separate category was also planned.

Statistical analysis

Statistical analysis was performed using SPSS software (version 17, IBM Corp.). Continuous variables were expressed as mean ± standard deviation or median (interquartile range) based on distribution, and compared using Student’s t-test or Mann-Whitney U test. Categorical variables were presented as frequencies (percentages) and compared using the Chi-square test or Fisher’s exact test.

The diagnostic performance of CEUS (based on the consensus reading) was assessed by calculating sensitivity, specificity, PPV, NPV, and overall accuracy, along with their 95% confidence intervals (CIs). The area under the receiver operating characteristic curve (AUC) was also calculated. Inter-observer agreement between the two initial readers for CEUS classification was evaluated using Cohen’s kappa statistic (κ): values ≤0.20 indicated slight agreement; 0.21–0.40, fair; 0.41–0.60, moderate; 0.61–0.80, substantial; and 0.81–1.00, almost perfect agreement. A two-tailed P value <0.05 was considered statistically significant.

Handling of indeterminate results: CEUS examinations with technically inadequate cine loops (n=3) were excluded from the final analysis, as pre-specified in the exclusion criteria. No indeterminate reference standard results occurred.

Sample size determination: Based on an expected sensitivity of 85% and specificity of 80% from prior meta-analyses (14), with a malignancy prevalence of approximately 10% in BI-RADS 4a lesions, a minimum of 150 lesions was required to achieve a 95% CI: half-width of 10% for sensitivity and specificity estimates.

Results

Patient and lesion characteristics

During the study period, 180 consecutive patients with breast lesions initially assessed as BI-RADS 4a on conventional ultrasound were screened. After applying the inclusion and exclusion criteria, 156 patients with 156 lesions were enrolled. Seven lesions were further excluded due to technically inadequate CEUS cine loops (n=3) or loss to follow-up without pathological confirmation (n=4). Finally, 149 patients with 149 BI-RADS 4a lesions were included in the final analysis. The flow of participants through the study is summarized in Figure 2.

Figure 2 Flowchart of patient and lesion selection. This diagram illustrates the enrollment process for the study. A total of 180 consecutive patients with breast lesions initially assessed as BI-RADS 4a were screened. After applying inclusion and exclusion criteria, 156 patients with 156 lesions were enrolled. Subsequent exclusions due to technically inadequate CEUS studies or lack of pathological confirmation resulted in 149 patients with 149 lesions being included in the final analysis. BI-RADS, Breast Imaging Reporting and Data System; CEUS, contrast-enhanced ultrasound; US, ultrasound.

The baseline characteristics are detailed in Table 1. The mean age of the patients was 42.7±10.3 years. The mean maximum diameter of the lesions was 12.1±4.8 mm. Histopathological results identified 129 (86.6%) benign lesions and 20 (13.4%) malignant/high-risk lesions. The malignant group included 15 invasive ductal carcinomas, 3 ductal carcinomas in situ, and 2 cases of ADH (grouped with malignant for analysis). The benign lesions consisted of fibroadenomas (n=78), adenosis (n=32), intraductal papillomas (n=12), and other benign findings (n=7). There was no significant difference in patient age between the benign and malignant groups (41.9±9.8 vs. 47.1±12.1 years, P=0.054). However, malignant lesions were significantly larger than benign lesions (14.8±5.1 vs. 11.6±4.5 mm, P=0.003).

CEUS features and diagnostic performance

The analysis of CEUS features revealed significant differences between benign and malignant lesions (Table 2). Malignant lesions more frequently exhibited heterogeneous enhancement (85.0% vs. 17.8%, P<0.001), hyper-enhancement (80.0% vs. 24.0%, P<0.001), centripetal perfusion (70.0% vs. 10.1%, P<0.001), perfusion defects (75.0% vs. 8.5%, P<0.001), ill-defined enhancing margins (65.0% vs. 9.3%, P<0.001), and a TIC pattern of fast wash-in and fast wash-out (80.0% vs. 14.0%, P<0.001).

Based on the predefined CEUS diagnostic criteria (≥2 suspicious features indicating malignancy), 113 lesions were classified as CEUS-negative (likely benign) and 36 as CEUS-positive (likely malignant). Compared to the pathological reference standard, the diagnostic performance of CEUS is presented in Table 3. The NPV of CEUS was notably high at 98.2%. Among the 113 lesions classified as CEUS-negative, 111 were confirmed as benign on pathology. The two false-negative cases were one subcentimeter invasive ductal carcinoma and one DCIS, both of which demonstrated relatively homogeneous iso-enhancement with slow wash-in and slow wash-out patterns.

Inter-observer agreement

As detailed in Table 4, the inter-observer agreement between the two independent readers for the final CEUS classification (positive vs. negative for malignancy) was substantial, with a Cohen’s kappa (κ) value of 0.76 (95% CI: 0.65–0.87). For individual CEUS features, κ values ranged from 0.68 (for TIC pattern assessment) to 0.82 (for the presence of perfusion defects).

Adverse events

No adverse events related to CEUS (e.g., contrast agent reactions) or biopsy procedures were observed during the study period.

Discussion

In this prospective study of BI-RADS 4a breast lesions, CEUS demonstrated a sensitivity of 85.0% and a specificity of 89.9% for differentiating benign from malignant pathology. The NPV was 98.2%, indicating that a CEUS-negative classification confers a low probability of malignancy. These findings provide preliminary evidence that CEUS may have clinical utility as an adjunctive triage tool for BI-RADS 4a lesions. However, the sensitivity of 85.0% underscores that CEUS cannot replace histopathological diagnosis and should be used as an adjunct to, not a substitute for, biopsy in high-risk settings. Given the preliminary nature of our single-center data, these results should be considered hypothesis-generating rather than practice-changing.

It is important to critically appraise the precision of our sensitivity estimate. With only 20 malignant cases, the 95% CI for sensitivity is wide, ranging from 62.1% to 96.8%. The lower bound of this interval is particularly noteworthy: if the true sensitivity were as low as 62.1%, more than one-third of malignancies would be missed, which would be clinically unacceptable for any test intended to triage patients away from biopsy. This statistical uncertainty, driven by the modest number of malignant events in our single-center cohort, underscores that the observed high NPV (98.2%) should not be misinterpreted as evidence of safety for deferring biopsy in routine practice. Rather, this wide CI reinforces the preliminary, hypothesis-generating nature of our findings and highlights the critical need for larger, multi-center studies to obtain a more precise and reliable estimate of CEUS sensitivity before any clinical implementation can be considered.

The primary clinical imperative in managing BI-RADS 4a lesions is to minimize unnecessary biopsies while maintaining a near-perfect sensitivity for cancer detection. Our findings align with and extend previous studies investigating CEUS for breast lesions. Lin et al. (14), in a meta-analysis, reported a pooled sensitivity and specificity of 86% and 82%, respectively, for CEUS in differentiating benign from malignant breast lesions across all categories. Our study, focusing specifically on the 4a subcategory, yielded comparable sensitivity (85.0%) but higher specificity (89.9%). This improved specificity in a selected low-risk population underscores the potential of CEUS as a targeted problem-solving tool. The high NPV (98.2%) observed in our cohort is particularly noteworthy. Zhu et al. (17), studying BI-RADS 4a lesions <2 cm in diameter, reported an NPV of 95% for CEUS, which is consistent with our findings. Zhu et al. (17) also demonstrated an NPV of 95% in small breast lesions across BI-RADS categories 3–5. The convergence of these results across multiple studies supports the potential of CEUS as a hypothesis-generating tool for risk stratification for low-suspicion lesions.

The analysis of individual CEUS features provides pathophysiological insights. Malignant lesions in our study predominantly exhibited patterns consistent with aggressive tumor angiogenesis: heterogeneous hyper-enhancement, centripetal perfusion, internal perfusion defects, and fast wash-in/wash-out kinetics. Heterogeneous enhancement and perfusion defects likely reflect the chaotic, irregular vascular architecture and necrotic areas common within carcinomas. The centripetal filling pattern and rapid contrast kinetics are hallmarks of high vascular density and increased capillary permeability associated with malignant neovascularization. Conversely, the predominance of homogeneous, iso- or hypo-enhancement with slower kinetics in benign lesions mirrors their more organized and less proliferative vascular supply. These feature differences validate their utility as discriminators in the BI-RADS 4a context. Furthermore, the substantial inter-observer agreement (κ=0.76) for the final CEUS classification indicates that the applied diagnostic criteria are reproducible among trained readers, a prerequisite for clinical implementation.

The implications of our findings extend across multiple clinical specialties. For surgeons, the high NPV observed in our study suggests a potential opportunity to reduce unnecessary excisional biopsies in patients with low-suspicion lesions, though this should be confirmed in prospective management studies before clinical implementation, thereby optimizing operative resources and minimizing procedural morbidity. For pathologists, a CEUS-based triage strategy could reduce the volume of benign specimens requiring histopathological evaluation, enabling focused attention on higher-risk cases. For clinical oncologists, improved risk stratification of BI-RADS 4a lesions may facilitate earlier identification of patients requiring close surveillance or referral for high-risk lesion management. These multi-disciplinary considerations underscore the potential of CEUS to enhance collaborative, patient-centered care across the breast cancer diagnostic pathway.

This study has several limitations. First, it was conducted at a single tertiary-care center, which may limit the generalizability of our findings. The prevalence of malignancy (13.4%) in our BI-RADS 4a cohort falls within the expected range but may vary in other practice settings, which could affect the PPV and NPV. Second, while the sample size was adequate for the primary analysis, the number of malignant cases (n=20) remains modest, resulting in wide CIs (particularly for sensitivity) that limit the precision of our accuracy estimates. Larger, multicenter prospective trials with substantially more cancer cases are warranted to validate our findings and obtain narrower CIs. Third, the same two readers who assigned the initial BI-RADS 4a category also served as the primary CEUS interpreters. Although we implemented strict blinding procedures and temporal separation between the two reading sessions, we cannot exclude the possibility that prior familiarity with the case series subtly influenced their interpretation of the index test, which may have inflated the observed diagnostic performance. This overlap represents a potential source of bias and is a recognized limitation of our study. Future independent validation studies should use completely separate readers for index test and reference standard assessments to mitigate this bias. Fourth, the CEUS analysis was performed offline by expert readers aware of the study purpose, which may not fully replicate real-time clinical conditions and could introduce interpretation bias. Future studies incorporating real-time, prospective CEUS assessment into the clinical workflow are needed. Fifth, and importantly, the readers were aware that all enrolled lesions had been pre-selected as BI-RADS 4a (low suspicion for malignancy). This knowledge may have introduced spectrum bias (or review bias), potentially leading the readers to interpret CEUS features more conservatively—that is, toward a benign classification—than they would in a real-world clinical setting where lesions of varying suspicion levels are encountered without pre-sorting. Such bias could artificially elevate the specificity and NPV, and therefore the diagnostic accuracy estimates reported here may not be directly transferable to routine clinical workflows where CEUS would be applied to an unselected population. Prospective studies with real-time CEUS interpretation integrated into the clinical pathway, without the prior knowledge of pre-selected BI-RADS categories, are needed to confirm our findings in a more representative setting. Sixth, we included ADH in the malignant group for the primary analysis, as its management typically aligns with malignancy. This analytical choice is clinically justified but may slightly inflate the sensitivity. The sensitivity analysis treating ADH separately showed consistent trends.

Future research should focus on developing standardized, quantitative CEUS protocols to enhance reproducibility and facilitate broader clinical adoption. While our study establishes the diagnostic performance of CEUS as a stand-alone adjunctive tool for BI-RADS 4a lesions, we acknowledge that comparative studies incorporating other advanced ultrasound techniques, such as shear-wave elastography, strain elastography, or non-contrast microvascular imaging (e.g., SMI, Angio-PLUS), would provide valuable insights into the relative strengths and limitations of each modality. Emerging super-resolution ultrasound imaging techniques hold promise for providing finer microvascular information, as demonstrated by Arthur et al. (21), who reported that SRU achieves >91% agreement with ground truth microvascular anatomy; however, their clinical maturity and evidence base must be further accumulated before they can be recommended for routine use. Formal health economic evaluations are also warranted to quantify the cost savings associated with CEUS-guided biopsy reduction. Future research should prospectively compare CEUS with these techniques in the same patient cohort to determine the optimal diagnostic algorithm for low-suspicion breast lesions. Such studies would require larger sample sizes and multi-center collaboration to ensure adequate statistical power and generalizability.

Conclusions

In conclusion, this study provides evidence that CEUS adds significant diagnostic value in the evaluation of BI-RADS 4a breast lesions. Its high NPV provides preliminary evidence that CEUS could serve as a potential adjunctive tool for triage, suggesting that a subset of patients might be managed with imaging follow-up rather than immediate biopsy. However, given the preliminary, single-center nature of these findings, we emphasize that CEUS should not yet be used as a stand-alone test to definitively rule out malignancy or to change clinical practice, particularly given the wide CI around our sensitivity estimate. Prospective, multi-center validation studies with larger sample sizes are essential before CEUS can be recommended for routine clinical implementation. We cautiously suggest that CEUS may be considered as an adjunctive problem-solving modality in research or select clinical settings, but strongly emphasize that these findings are preliminary and require validation. Future research should focus on developing standardized, quantitative CEUS protocols and exploring its cost-effectiveness in routine clinical pathways.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0315/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0315/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0315/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0315/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 and its subsequent amendments. The study protocol was approved by the Institutional Review Board of Xi’an Hospital of Traditional Chinese Medicine (approval No. LLSCYJ-LW-2026002), and written informed consent was obtained from all participants prior to enrollment.

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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