Sex differences in pain presentation and its association with distal extent in acute type A aortic dissection: a retrospective cohort study

Introduction

Background

Acute type A aortic dissection (ATAAD) is a detrimental diagnosis that without swift intervention is associated with high mortality (1,2). ATAAD is characterized by an intimal tear in the ascending aorta (Asc), causing blood flow into the medial layer leading to dissection of the aortic wall with a false lumen. Significant improvements in patient care over the past decades have decreased mortality rates. However, even with surgical intervention, the early mortality rate remains high at 15–18% (3).

Symptomatology in ATAAD is a guide for diagnosis. However, definitive diagnosis is made by imaging techniques, such as computed tomography (CT) or magnetic resonance angiography scans, as also recommended by the current guidelines (4). Following imaging-aided diagnosis, ATAAD requires acute surgical intervention with resection of the proximal pathology and primary entry tear. Timing and extent of intervention also depend on co-morbidities, such as cerebral malperfusion, cardiac tamponade, aortic regurgitation, hemorrhagic stroke, or paraplegia.

ATAAD patients typically present with acute onset of chest pain with prominent chest pain, pain between the shoulder blades and/or abdominal pain. The pain is usually described as tearing or stabbing (4,5). Patients presenting with any of these pains and with predisposing factors (e.g., connective tissue disease, family history, and hypertension) and/or high-risk clinical examination features (e.g., perfusion deficits, and aortic insufficiency murmur) are considered high risk. Specifically, acute chest pain is considered a strong diagnostic indicator for aortic dissection, yet it has a low positive predictive value of only 11%, meaning chest pain alone is not specific for diagnosis of aortic dissection (6).

Rationale and knowledge gap

There are key sex differences in epidemiology and etiology of ATAAD. Women less frequently develop ATAAD compared to men, however, early mortality in women is considered higher (7,8). Strikingly, this was attributable to delayed diagnosis time in women (approximately 4–5 hours) and fewer women are diagnosed within 4–24 hours compared to men (9). This is relevant, as time to surgical intervention is a crucial predictor of mortality, as mentioned before (10). These data show that the reported increased mortality in women is related to challenges in timely diagnosis, possibly due to ATAAD symptomatology being less “typical” in women. Improving our understanding of sex-specific pain manifestation is therefore critical for narrowing this gap.

Objective

Previous research suggests that women more often present with atypical symptoms (4,11,12). Despite chest pain still being a major hallmark of cardiothoracic disturbances in women, non-specific and less acute symptoms are also significantly more present in women. A more thorough insight of pain manifestation of ATAAD in men and women, holds significant potential to ultimately decrease diagnosis time and thereby improve survival risk in patients, especially for women. The aim of this study is to compare sex differences in pain manifestation of ATAAD, using a single center retrospective cohort of 460 ATAAD patients. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1011/rc).

Methods

Study population

The cohort comprised all adult ATAAD patients in the Leiden University Medical Center who underwent surgical treatment between January 1992 and April 2025. Patients were followed from initial diagnosis and surgical procedure until the end of the study period or death. A total of 460 adult patients were enrolled in the cohort throughout the study period. Exclusion criteria included a documented history of pre-existing diabetes mellitus (DM) and missing documentation on symptom information. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Given the retrospective nature of this study, the Medical Ethics Committee Leiden-Den Haag-Delft waived the need for ethical approval and informed consent with a declaration of no objection (protocol No. G19.113, nWMODIV2_20240016; 20-03-2024).

Data collection

Patient characteristics, such as age, sex, co-morbidities, (pain) symptoms, clinical presentation, and history were derived from medical records and operative reports, all documented in EPD Vision (in-house software) and ChipSoft HiX Software (Gouda, The Netherlands). Prospective follow-up was derived from medical records up until the end of the study period or loss to follow-up. For deceased patients, the date and cause of death were retrieved from in-hospital databases, which is directly linked to the Dutch National Health Register (the date and cause of death of all Dutch inhabitants are required to be reported by law).

Ascertainment of variables

Relevant history was extracted from the medical record and classified into hypertension, hyperlipidemia, chronic obstructive pulmonary disease (COPD)/chronic lung disease, vascular pathology, prior cardiac surgery, none or unknown. Extent of dissection was classified into 5 anatomical regions: Asc, arch, descending thoracic aorta (DTA), abdominal aorta (AA), and dissection up to the iliac arteries and downstream regions (Iliac & beyond) based on CT-scan reports. Extent of dissection was coded according to the most distal anatomical region involved, meaning that each patient was assigned to a single category. Malperfusion data were extracted from medical records and operative records and classified into the subcategories of the type-entry-malperfusion (TEM)-classification: M1—coronary, M2—supra-spinal, M3—spinal, visceral, iliac (13). Cerebral malperfusion was classified as M2. Symptoms were extracted from the earliest medical records of the event, including referral letters from primary care locations. Symptoms were categorized by lateralization where applicable. Collapse was defined as any sudden loss of postural tone, encompassing both syncope and non-syncopal episodes, as the distinction was rarely documented. Symptoms were split in pain (e.g., abdominal pain) and non-pain (e.g., nausea) symptoms. Typical pain was defined according to Czerny et al. [2024], which included any form of chest, back, and abdominal pain. Other pain symptoms were considered atypical.

Statistical analysis

Variables were compared using the Chi-squared or Fisher’s exact test (N<5) for categorical variables. Continuous variables were analyzed using the Wilcoxon rank-sum test. Ordinal categorical data were compared using the Cochran-Armitage trend test. Logistic regression was performed to assess the association between distal extent of dissection and sex, adjusting for age, hypertension, entry tear location, and malperfusion status. For sex-stratified analyses, the interaction term of sex and extent of dissection was included. All (pain) symptoms were consolidated to number of symptoms and compared between men and women using the Chi-squared test with ad hoc comparisons. The number of symptoms across the regions of distal extent of dissection was compared using Chi-squared tests and binomial tests to account for overrepresentation of ascending-contained aortic dissections within subgroups. A P<0.05 was considered statistically significant. Where applicable, corrections for multiple testing [false discovery rate (FDR)] were applied. Statistical analyses and visualization were performed using R 4.3.1 with RStudio (v2023.06, Posit Software) and Python 3.8.

Results

Study cohort and patient characteristics

The cohort consisted of 460 patients. A total of 91 patients (19.8%) were excluded from the analysis due to lack of information about symptoms in the records (N=82), or presence of DM (N=9) (Figure 1). The relatively large subset of patients excluded due to missing symptom documentation differed in some comorbid characteristics but showed comparable dissection characteristics and had similar demographic profiles, suggesting that major differences in disease presentation are unlikely (Table S1). DM may influence pain perception by underlying diabetic polyneuropathy or systemic inflammation status (14). There were no other patients with known pre-existing peripheral neurology. After exclusion, a total of 369 patients were included. There was missing data on the distal extent of dissection (N=19) and entry tear location (N=45). The 19 patients were excluded from related analyses only.

Figure 1 Flowchart describing cohort exclusion criteria. The initial cohort consisted of 460 patients that were admitted for operative intervention of ATAAD. Patients were excluded if there was no information provided of symptomatology or an existing diagnosis with diabetes mellitus was documented, leaving a total of 369 patients enrolled for primary analyses. Several patients had missing information (N=19) on distal extent of dissection and were excluded from related sub-analyses. ATAAD, acute type A aortic dissection.

The baseline characteristics of the included patients within the cohort are described in Table 1. Among the cohort, the ratio of men to women was 1.53:1, i.e., 60.4% vs. 39.6%, respectively. There was a significant difference in age of onset between men (58.9±12.5) and women (64.7±11.8) (P<0.001). Overall follow-up mortality did not differ significantly between men (35%) and women (40%, P=0.31). There were no major significant differences for co-morbidities at presentation, except for hypertension, which was more common in women (47%) compared to men (35%) (P=0.03).

TEM-classifications revealed no differences between men and women in dissection characteristics. It was most common for the entry tear to be present in the root/ascending region of the aorta for both men (76%) and women (70%), of which an entry tear in ascending region was most prominent with 53% and 44%, respectively. There were no significant differences between the location of the entry site between sexes (P=0.60). Yet, the extent of dissection was significantly different between men and women (P<0.001), where more than half of men tended to present with a dissection extending till the iliac arteries and beyond (52%). Logistic regression showed that male sex was significantly associated with a more distal extent of dissection (P<0.001), and this remained significant after adjusting for age, hypertension, and entry tear location [odds ratio (OR): 1.25, 95% confidence interval (CI): 1.09–1.43, P=0.006]. These results suggest that men more often present with distal extent of dissection compared to women, regardless of their entry tear location and other related factors.

Comparison of pain manifestation of ATAAD between men and women

Current guidelines describe pain characteristics as an important hallmark of ATAAD and drove us to compare pain manifestations at initial presentation between sexes (Table 2). Any form of chest pain did not show sex differences. There was a tendency for a difference in the occurrence of non-specified back pain between men and women, however statistical significance was not reached (P=0.053). Women experienced more jaw pain compared to men (P=0.02), yet this was consistently reported in combination with another symptom, mostly chest pain, and had a low overall incidence (N=20). The other pain manifestations did not reveal any significant differences.

Furthermore, we compared the occurrence of typical and atypical pain manifestation, as defined by the guidelines (chest, back, and abdominal pain), for both sexes. Patients presenting with a combination of typical and additionally atypical pain symptoms were more common in women (29% vs. 45%, P=0.002), suggesting that women more frequently present with a broader and more heterogeneous symptom profile that may complicate early clinical recognition of ATAAD. For typical pain symptoms, 67% of men presented with typical pain symptoms, whereas only 51% of the women presented with typical pain symptoms (P=0.002) (Table 2). Suggesting men more often present with typical symptoms at admission compared to women. The number of patients presenting with solely atypic pain symptoms was low and revealed no sex differences (men: 4.5%, women: 4.1%, P>0.99).

The number of pain symptoms were compared between men and women (Table 2). A significant difference was found in women, which show more variety in the number of symptoms compared to men (P=0.006). Underlying results revealed that more than half of male patients (53%) showed a single prominent pain symptom. In contrast, only a third of women (34%) presented with a single pain symptom (P=0.003). In men, the most prominent pain symptom was any form of chest pain, accounting for 65.1% of the patients experiencing a singular pain symptom. 17% presented with any form of back pain, of which half was typical pain between the shoulder blades, followed by abdominal pain (8.5%). Women presenting with a single pain symptom, had similar ratios of pain localizations as these in men.

For non-pain symptoms, most symptoms occurred equally in men and women, albeit most of them were relatively rare (<10%) (Table 3). Dyspnea was more common in women (P=0.003). Men were more likely to present with paraplegia compared to women (P=0.04), potentially correlated with the more distal extent of dissection in male patients. Interestingly, women presented with collapse more often than men (P=0.04), with a significant portion of female patients presenting with this phenomenon (23%), whereas 15% presented with isolated collapse. These findings indicate that men are more likely to present with a single typical pain symptom, whereas women may present with none to multiple pain symptoms, which can include both typical and atypical manifestations.

Asymptomatic ATAAD is seen more often in dissection contained within the Asc

The relationship between the distal extent of dissection and the number of symptoms associated with each level of distal involvement (Table 4). Both pain and non-pain symptoms were included, as several non-pain manifestations may result from vasovagal reflexes triggered by dissection. Intriguingly, while only 5% of the cohort were asymptomatic, they account for 17% of all ascending-contained dissections (P=0.001) (Table 4). Moreover, dissection contained within the Asc was significantly more frequent in asymptomatic patients (P=0.005). In contrast, among patients with more than one symptom, half showed distal extent of dissection to the iliac arteries or beyond. Despite the limited sample size, these findings suggest that proximal dissections seem to be related with fewer symptoms, potentially referring to anatomical differences in aortic (sensory) innervation.

Distal extent of dissection can be linked to specific pain manifestations for both sexes

Logistic regression was performed to identify symptom manifestations (symptoms in at least 10% of cohort) related to a likelihood of having a further distal extent of dissection, initially without stratification for sex. Regression was adjusted for age, hypertension, and any malperfusion. Patients manifesting with paraplegia, abdominal pain, or non-specified back pain are more likely to have a further distal extent of dissection (P<0.001, P=0.004, P=0.007, respectively) (Figure 2). Additionally, malperfusion was also positively associated with paraplegia (P<0.001), a symptom known to be caused by spinal malperfusion. Oppositely, collapse was significantly associated with a more proximal extent of dissection (P=0.006). Malperfusion was associated with collapse (P=0.03), likely due to collapse being an umbrella term that includes syncope. Chest pain, as well as dyspnea, was negatively associated with any malperfusion (P<0.001 and P=0.02). Interestingly, the data did not reveal that chest pain and back pain between shoulder blades were indicative of a farther or more proximal extent of dissection. Age and hypertension did not have any significant effects on the interactions.

Figure 2 Heatmap depicting the association of symptom manifestation with distal extent of dissection. Each row represents all symptom manifestations in at least 10% of the cohort. The columns show the distal extent of dissection and the values represent the percentage of patients of given manifestations, having their extent of dissection till the given region. The last column is the FDR-corrected P values of logistic regressions adjusted for age and hypertension. AA, abdominal aorta; Asc, ascending aorta; DTA, descending thoracic aorta; FDR, false discovery rate.

Subsequently, we stratified for sex (Figure 3). We did not find any significant differences in the predictive traits of symptoms between sexes. Adjustment for malperfusion revealed that malperfusion itself was significantly associated with selected symptom manifestations, indicating that certain symptoms are independently related to the presence or absence of malperfusion. Yet correcting for malperfusion did not influence the associations between symptom manifestations and distal extent of dissection.

Figure 3 Forest plot depicting sex-stratified logistic regression for symptom manifestations and distal extent of dissection. Each row represents all symptom manifestations in at least 10% of the cohort. Logistic regression results are expressed in OR and 95% CI per sex. The P values are FDR-corrected P values for either male or female regressions, adjusted for age and hypertension. The last column depicts the FDR-corrected interaction P value between the sexes. CI, confidence interval; FDR, false discovery rate; OR, odds ratio.

Back pain between shoulder blades was potentially more indicative for distal extent of dissection in men compared to women. However, this was not significant after multiple testing correction (P=0.28). Similarly, collapse seems to be more informative of a more proximal extent of dissection in men compared to women, however not statistically significant (P=0.70). Additionally, chest pain showed a negative effect on malperfusion in both sexes (men: P=0.02, women: P=0.045) and paraplegia was positively associated with malperfusion in both sexes (men: P=0.02, women: P<0.001), confirming the unstratified findings. No sex differences were identified herein. Contrary, collapse was associated with malperfusion only in men (P=0.02) but not in women (P=0.69). However, no statistical difference was reached between sexes (interaction P=0.74). Furthermore, no significant interaction between sex and malperfusion was observed, suggesting that malperfusion-related symptom patterns do not differ between men and women.

Overall, sample size was likely too limited to identify significant differences in the relation of symptom manifestation and distal extent of dissection for men and women separately. The data indicated that distal extent of dissection and malperfusion can be associated with specific symptoms and sex has little effect.

Discussion

Key findings

This retrospective observational cohort study revealed notable sex differences in the pain manifestation of ATAAD. Furthermore, our study suggests that specific pains may be related to distal extent of dissection. Key findings in this study are: (I) in patients with ATAAD, women are older and present with more co-morbidities such as hypertension, while men have a farther distal extent of dissection; (II) women are less likely to present with a single, dominant symptom, in contrast to men, but are more likely to report either no or a combination of typical and atypical symptoms; (III) proximal dissections were associated with a more asymptomatic profile, whereas symptoms like paraplegia and abdominal pain are indicative of a more distal extent of dissection.

More than half of men with ATAAD presented with a single pain symptom, which was usually a typical symptom presentation. Women, in contrast, exhibited a more heterogeneous symptom profile, more frequently presenting with combinations of typical and atypical symptoms. This broader symptom presentation may complicate early clinical recognition of ATAAD in women, particularly when atypical symptoms accompany, rather than replace, classical chest or back pain. The absence of a clearly distinguishable female-specific symptom pattern further emphasizes the diagnostic challenge in women.

In addition, our findings suggest that distal extent of dissection may influence symptom manifestation. Men demonstrated a more distal extent of dissection independent of entry tear location and other factors, extending previous observations from prior literature (8). Symptoms such as paraplegia, abdominal pain, and back pain were associated with a more distal extent of dissection, whereas collapse was more suggestive of proximal involvement. Interestingly, symptom manifestation appeared to correlate more strongly with extent of dissection in men than in women, although these associations did not consistently reach statistical significance. Presence of more severe symptoms in men, like paraplegia, are more likely to be correlated with a more distal extent of dissection, rather than a direct effect of sex.

Strengths and limitations

Our cohort provided an adequate sample size for the primary analyses, but the statistical power was limited for more detailed subgroup analyses, or to draw robust conclusions regarding low incidence findings. The subgroup of patients with documented pre-existing DM was too small to allow meaningful separate analyses and were therefore excluded altogether. In the cohort, undiagnosed DM could not be fully accounted for due to the retrospective study design. The long inclusion period of 33 years, during which diagnostic imaging and documentation practices evolved substantially, may have introduced temporal heterogeneity. However, as this study focused on preoperative symptom presentation, symptom-related clinical documentation remained sufficiently consistent throughout the study period. Moreover, a recent population-based study showed a higher proportion of women with ATAAD diagnosed post-mortem compared to in-hospital diagnosis (15). We hypothesize this reflects a diagnostic survival bias, where women with presence of one or more typical symptoms are diagnosed and treated, while those with no or solely atypical symptoms largely remain undiagnosed. Consequently, a cohort of hospitalized women represent a subgroup with at least partially recognizable typical symptoms, which may mask true sex differences in symptom manifestation which translates to more homogeneous findings. Importantly, no apparent sex-differences in long-term survival are observed upon receiving surgical treatment (8,15), consistent with our findings, highlighting the importance of a diagnostic bias. Furthermore, we found that men have a more distal extent of dissection, and although we corrected for important factors such as age, hypertension, and malperfusion status, other factors that contribute to aortic wall vulnerability such as false lumen status, aortic calcification, and chronic kidney disease were not assessed and may act as residual confounders (16). Comparisons of diagnostic delay between women and men could not be assessed due to the retrospective single-center nature of this cohort, as time-to-diagnosis data were not systematically documented and could not be reliably reconstructed retrospectively. In addition, distinction between truly acute symptom onset and acute exacerbation of pre-existing symptoms could not be fully established in all patients, potentially introducing slight misclassification of symptom onset and pain characteristics in a minor subset of patients. Moreover, sex-related differences in psychological and biological pain perception and tolerance have been described in literature and may influence symptom perception and healthcare-seeking behavior (17). As these factors were not assessed in the present study, their contribution to the observed sex differences in clinical presentation cannot be quantified. These factors represent an important limitation and highlight the need for prospective studies with standardized assessment of diagnostic timelines and more in-depth studies of underlying mechanisms of sex-specific pain perception.

Comparison with similar research

The findings, regarding symptom presentation and sex differences, are broadly consistent with, and expand upon, previous literature. Like previous studies, we also revealed that in our cohort, there were more male patients with ATAAD, and that women are older and have more co-morbidities, especially hypertension. We also did not observe differences in long-term survival (7,15,18,19). However, studies show a lower survival probability in women, both short term and long term, due to a more aggressive preoperative phenotype (20,21). Unlike the other studies, these studies observed comparable time intervals from symptom onset to surgery, which may suggest women develop recognizable symptoms later in the disease course, worsening their prognosis. The current results revealed similar findings in literature for sex differences in typical symptom presentation; with no differences in chest pain, back pain, and abdominal pain (7,19). Contrastingly, we showed women more often present with collapse compared to men, whereas another study did not find a similar effect for syncope, likely due to differences in symptom definition (19). In our cohort, collapse was not specifically differentiated from syncope but encompassed both, which may account for the discrepancy. Moreover, malperfusion at presentation was associated with collapse, suggesting that hemodynamic instability likely contributes to a substantial proportion of these events. However, sex-stratified analyses revealed distinct patterns. In men, collapse was associated with malperfusion and a more proximal (shorter) extent of dissection, whereas in women, although collapse occurred more frequently, it was not associated with extent of dissection nor with malperfusion, suggesting alternative mechanisms, such as reflex-mediated (vasovagal) responses, may play a larger role in women.

Explanations of findings

These differences raise the question whether there are sex specific properties that influence the proneness of dissection progression in the aorta. Few studies have explored the morphological sex-differences in the human tunica media. Adult women have more smooth muscle cells in the thoracic aorta, likely contributing to increased tensile strength among the elastic laminae, which in turn hampers progression of dissection (22). This is supported by a study in ATAAD patients, that found milder loss of smooth muscle cell nuclei in women compared to men. However, this difference did not reach statistical significance (23). Besides, proximal dissections, especially ascendens-contained, exhibited a more asymptomatic phenotype compared to more distal dissections. It could suggest that the Asc has lower sensitivity to structural damage compared to the other aortic zones, likely due to lower innervation density. A study using a rabbit model demonstrated that sympathetic innervation in the Asc is relatively sparse, although direct translation of these findings to human symptom manifestation remains uncertain and understudied (24). However, the current findings do raise the hypothesis that potential regional differences in aortic innervation may contribute to differences in symptom manifestation.

Delayed diagnosis in women with ATAAD remain a clinical concern, as longer intervals between onset and intervention have been linked to higher short-term mortality (4,7). The underlying reason for delayed diagnosis in women was hypothesized to be related to a higher prevalence of atypical symptoms. Our findings do not support this, as isolated atypical symptoms were uncommon and did not differ between sexes. Instead, women more frequently presented with a combination of typical and atypical symptoms, demonstrating a more heterogeneous symptom profile relative to men. This broader symptom profile may hinder rapid clinical recognition, as atypical symptoms accompanying otherwise typical presentations may obscure the classical clinical picture rather than replace it entirely, thereby potentially extending the time to diagnosis in women. Similar notions have been suggested in other cardiovascular diseases, especially cardiac disease, where women have a more complex symptomatology which may still include typical symptoms (4,11,12).

Implications and actions needed

Our findings may have several clinical implications for the evaluation and recognition of ATAAD disease progression. Paraplegia and abdominal pain were associated with a more distal extent of dissection extending beyond the iliac arteries. In cases of paraplegia, spinal cord ischemia may underlie the symptom and should be considered in the clinical assessment (4). Careful evaluation of paraplegia and abdominal pain at presentation may therefore help anticipate the anatomical extent of dissection prior to imaging confirmation, which may be more relevant in men given their higher likelihood of a further distal extent and the associated risk of intestinal ischemia. In contrast, we show women often present with a more complex symptom profile, clinicians should remain vigilant for atypical presentations to ensure timely diagnosis of ATAAD.

Conclusions

This retrospective cohort study revealed sex-differences in patients with ATAAD with regards to symptom manifestation and symptom association with distal extent of dissection. The notion that paraplegia and abdominal pain may reflect a further distal extent of dissection as well as the high incidence of asymptomatic ATAAD with ascending-contained dissections may have direct impact and can readily be implemented in the clinic aiding in early clinical risk stratification. Moreover, the significant increase of women presenting with a more heterogenous symptom profile compared to men may aid clinical decision making. Future studies are required to further elucidate sex differences in pain manifestation for ATAAD to reduce diagnostic delay and improve survival, especially in women.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1011/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1011/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1011/prf

Funding: This work was supported by the Bontius Stichting (to R.M.) and NWO-ZonMw (No. 91719347, to M.R.M.J).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1011/coif). R.M. reports funding support from Bontius Stichting. M.R.M.J. reports funding support from NWO-ZonMw (No. 91719347). The other 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 and its subsequent amendments. Given the retrospective nature of this study, the Medical Ethics Committee Leiden-Den Haag-Delft waived the need for ethical approval and informed consent with a declaration of no objection (protocol No. G19.113, nWMODIV2_20240016; 20-03-2024).

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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