Physical functioning of patients undergoing neoadjuvant treatment for cancer of the oesophagus and the subsequent impact of exercise prehabilitation—results of a cohort study within the PREHIIT trial

Introduction

Background

For locally advanced oesophageal cancer, multimodality treatment (pre-operative chemoradiotherapy or perioperative chemotherapy) is recommended due to significant survival advantages over surgery alone (1). The chemoradiotherapy for oesophageal cancer followed by surgery (CROSS) regimen is standard of care for pre-operative chemoradiotherapy for locally advanced resectable oesophageal or junctional cancer and consists of 5 pre-operative cycles of carboplatin and paclitaxel with concurrent radiation (2). The fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) regimen is recognised as the standard of care for perioperative chemotherapy and consists of 4 cycles of pre-operative and 4 cycles of postoperative fluorouracil, leucovorin, oxaliplatin and docetaxel. In the case of adenocarcinoma of the oesophagus and oesophago-gastric junction, increasing data support clinical equipoise of the two regimens, with initial evidence from the Neo-Aegis trial reporting similar 3-year survival and no major differences in operative and health-related quality of life outcomes (3). Notwithstanding the positive impacts of these modalities on survival and long-term outcomes, clinical patients with oesophageal cancer may experience significant toxicities (4). Common toxicities associated with both regimens include fatigue, peripheral neuropathy, haematological issues (e.g., anaemia, neutropenia, and thrombocytopenia), oesophagitis, and sarcopenia (4-6). These issues may negatively impact physical functioning, “the ability to undertake the physical tasks of everyday living” (7), which in turn may be associated with poorer outcomes post-operatively (6,8). Of note, sarcopenia, the progressive loss of muscle mass and function, which has a prevalence rate of 46.3% [standard deviation (SD) 19.6%; range 14.4–81%] in oesophageal cancer (9), can be particularly detrimental to physical functioning (10), and is associated with poorer overall survival [hazard ratios (HR): 1.68, 95% confidence interval (CI): 1.54–1.83, P=0.004], disease-free survival (HR: 1.97; 95% CI: 1.44–2.69; P=0.007), and higher rate of postoperative complications (odds ratio 1.47; 95% CI: 1.21–1.77; P=0.09) (11).

Rationale and knowledge gap

Whilst many assessments of physical function have been validated for use in the cancer population, a measure used in isolation may not be indicative of the true physical function of an individual. To this end, many frameworks and models have been established to describe the different components or markers of physical functioning and their intertwined relationships (12,13). One such framework is the Functional Ability Framework developed by Rikli and Jones, which demonstrates the progressive relationship between physical parameters, functional performance, and activity goals (12). Consequently, in the context of cancer care if we apply the foundations of the Functional Ability Framework for comprehensiveness a physical function assessment battery should be inclusive of physical parameters (e.g., cardiorespiratory fitness and muscle strength), function (e.g., one’s ability to engage in functional activities such as walking), and ability to achieve activity goals (e.g., ability to engage in physical activity for work, leisure, household chores, and transport) (8,12). Comprehensive assessment of physical functioning during the cancer journey helps identify impairments and serves as a basis for prescription of rehabilitative measures (14). To date the impact of neoadjuvant treatment on physical functioning in the oesophageal cancer cohort has been relatively underexplored (8,15,16). There is accordingly considerable rationale to robustly explore physical functioning in this cohort and evaluate interventions that aim to mitigate any negative sequelae of neoadjuvant treatment and improve physical functioning in advance of oesophagectomy (17). Exercise prehabilitation is an intervention that specifically aims to improve physical functioning with a view to reducing post-operative morbidity and mortality (18). However, the optimum parameters for exercise prehabilitation in this cohort are yet to be established (19,20).

Objective

The pre-operative exercise to improve fitness in patients undergoing complex surgery for cancer of the lung or oesophagus (PRE-HIIT) trial (https://clinicaltrials.gov/ct2/show/NCT03978325) is a two-armed randomised controlled trial comparing a high-intensity interval training (HIIT) exercise programme to standard prehabilitation in patients scheduled for surgery with curative intent for cancer of the lung or oesophagus (20,21). The primary aim of the trial was to examine whether the HIIT intervention leads to greater improvements in cardiorespiratory fitness than standard prehabilitation (22), and positively, the trial identified that pre-operative HIIT is effective at attaining meaningful improvements in pre-operative fitness. In addition, a secondary aim of the trial was to conduct a cohort study in which the impact of neoadjuvant treatment and subsequent effects of exercise prehabilitation on physical functioning would be explored in a subset of participants with oesophageal cancer from the point of their cancer diagnosis.

Accordingly, this study specifically aimed to describe the physical functioning of patients from the point of diagnosis of oesophageal cancer, through neoadjuvant treatment and completion of pre-operative exercise prehabilitation. We present this article in accordance with the STROBE reporting checklist (available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-35/rc).

Methods

Study design

This cohort study details a subset of PRE-HIIT trial participants who completed a battery of physical functioning measures across three time-points: diagnosis of oesophageal cancer (T0), post-neoadjuvant treatment (T1), and post-prehabilitation (T2) (Figure 1).

Figure 1 Study design. 1-RM, 1-repetition maximum; Control, standard care (referral to moderate intensity exercise prehabilitation); CPET, cardiopulmonary exercise test; HIIT, high intensity interval training prehabilitation arm; IPAQ, International Physical Activity Questionnaire; SPPB, short physical performance battery; T0, diagnosis; T1, post-neoadjuvant treatment; T2, post-prehabilitation.

Study participants

Potential participants were recruited at diagnosis by their consultant surgeon whilst attending the Upper Gastrointestinal (UGI) Cancer Surgery Clinic, at St James’s Hospital, Dublin, Ireland, a National Centre for UGI Cancers. Participant eligibility included a recent diagnosis of oesophageal cancer, scheduled for multimodal treatment involving neoadjuvant therapy (FLOT or CROSS protocol) in advance of oesophagectomy (2-stage, 3-stage, or transhiatal) (20). Participants were excluded if they had any American Thoracic Society/American College of Chest Physicians absolute contraindication to exercise testing (23).

Outcomes

All study assessments were conducted at the Wellcome Trust/Health Research Board Clinical Research Facility at St. James’ Hospital, Dublin. The physical function battery was completed at three time-points: diagnosis of oesophageal cancer (T0), post-neoadjuvant treatment (T1), and post-prehabilitation (T2).

Physical function battery

This study applied the Functional Ability Framework as described by Rikli et al. (12) to examine physical functioning through a comprehensive battery of measures and specifically assessed the physical parameters of cardiorespiratory fitness [cardiopulmonary exercise test (CPET) peak power] and muscle strength [leg press 1-reptition maximum (1-RM)], functions [short physical performance battery (SPPB)], and activity goals (self-reported physical activity levels).

Physical parameters

Cardiorespiratory fitness was determined by CPET, performed on a cycle ergometer (COSMED), following a progressive incremental protocol, with increments of work rate ranging from 10 to 25 watts per minute. The step gradient was determined using the formula reported by Agnew (24). Cardiovascular monitoring, including heart rate, heart rhythm [12-lead electrocardiogram (ECG)], non-invasive blood pressure and oxygen saturation, was completed before, during and after testing and the test was supervised by a medical physician. All participants completed the test until a steady state of oxygen consumption was achieved or until symptoms such as breathlessness or leg fatigue prevented continuation of the test. Peak power was defined as the highest level of resistance (watts) achieved during the test. For interpretation, results were compared to age and gender matched normative data from a large clinical database of healthy participants in Sweden (n=3,756) (25), and were categorised as those achieving or not achieving a peak power greater than or equal to normative data (Table S1).

Muscle strength was assessed by a leg press 1-RM test. The 1-RM was defined as the highest load in pounds (lbs) that could be lifted through a full range of movement once on the horizontal leg press machine (26). Results were used to calculate the leg press weight ratio, which is defined as the ratio of weight pushed in pounds to body weight in pounds (26). Results were then used to categorise participants into fitness categories (well above average, above average, average, below average, well below average) as described in the ACSM Guidelines 11th Edition (27).

Function

The SPPB was applied as an assessment of function. This measure, validated for use in patients with cancer, combines the results of a gait speed, chair stand, and balance test to give an indication of overall functional status (28). Results were then compared to normative data from a large population study in Norway (n=7,474) (29) and categorised as those achieving or not achieving a score greater than or equal to the normative value for their age and gender (Table S1).

Activity goals

Activity goals were determined using self-reported physical activity levels captured via the International Physical Activity Questionnaire (IPAQ) long form, which calculates activity levels over four key domains of work, leisure, transportation and household over the previous 7 days (30). Overall activity levels were classified as low, moderate, or high as per the IPAQ scoring criteria (31).

Intervention

Following successful completion of the T1 (post-neoadjuvant treatment assessment), participants were randomised to one of two PRE-HIIT trial arms. Specific details of the interventions have been reported elsewhere (20,21). Participants randomised to the intervention group completed HIIT 5 days per week, for at least 2 weeks in advance of surgery. The HIIT intervention was performed on a cycle ergometer and consisted of 30 minutes of alternating 15-second intervals of cycling at 100% of peak power output with 15-second recovery period at 0 Watts. Exercise sessions were conducted either in person or via video call and were supervised by a registered physiotherapist. Participants on the control arm were invited to take part in standard exercise prehabilitation at the physiotherapy department at St James’s Hospital, Dublin, which involved either in-person or online exercise classes consisting of moderate intensity aerobic and resistance training.

Statistical analysis

Statistical analyses were performed using SPSS 29 (SPSS Inc., Chicago, IL, USA). Prior to analysis, variables were tested for normality of distribution using the Shapiro-Wilk test. Normally distributed data are presented as mean (SD), and non-parametric data are presented as median [interquartile range (IQR)]. A one-way repeated measures analysis of variance (ANOVA) was conducted to compare physical function measures at T0, T1, and T2 (normally distributed data) or Friedman’s test (non-parametric). Results are presented as P value and effect size [partial etta-squared (ηp2) for repeated measures ANOVA and Kendall’s W (W) for Friedman’s test]. Post-hoc tests were performed as appropriate. Missing data was deleted pair-wise.

Between-group changes (HIIT vs. control) during prehabilitation were analysed using ANCOVA or the non-parametric Quade’s ANCOVA test. For ANCOVA analysis, the independent variable was the study allocation (control or HIIT), the dependent variable consisted of scores of the physical function measure (e.g., peak power) at T2 and the pre-exercise prehabilitation (T1) scores on the physical function measure were used as the covariate in the analysis. Preliminary checks were conducted to ensure there were no violations of the assumptions of normality, linearity, homogeneity of variances, homogeneity of regression slopes, and a reliable measure of the covariate. Results are presented as effect size (partial etta-squared), and a P value of 0.05 was considered significant (two-tailed). Similarly, for Quade’s test, the grouping factor was the study allocation, the dependent variable consisted of T2 outcome measure scores and pre-exercise prehabilitation (T1) scores were used as the covariate in the analysis; results are presented as P value.

Ethical consideration

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Tallaght University Hospital/St James’s Hospital Joint Research Ethics Committee (REC: 2020-02 List 7) and informed consent was obtained from all individual participants.

Results

From June 2021 to September 2023, 42 eligible patients were approached to take part in the PRE-HIIT trial at the point of their oesophageal cancer diagnosis (Figure 2). A total of 14 patients were recruited, representing a recruitment rate of 33.33%. Reasons for non-participation were travel burden (n=9), not interested (n=6), unable to contact (n=4), too overwhelmed (n=3), expressed interested post-chemotherapy (n=3), felt too unwell to participate (n=1), already doing enough exercise (n=1), and work commitments (n=1). Participant characteristics are presented in Table 1. At enrolment, participants were 63.29 (7.28) years [mean (SD)], mostly male (n=9), nine were scheduled for CROSS and five were scheduled for FLOT. Four participants did not proceed to the T1 assessment (deceased n=2, medically unfit n=2). Of the 10 participants who completed the T1 assessment, one did not complete the final T2 assessment due to an exacerbation of an existing neuromusculoskeletal condition, and another participant was called for surgery prior to completion of their T2 assessment.

Figure 2 Participant flow through the study. HIIT, high-intensity interval training; n, number of participants/potential participants; RIP, rest in peace; T0, diagnosis; T1, post-neoadjuvant treatment; T2, post-prehabilitation.

Physical function results

Physical function results are detailed in Table 2, and categorical scores are presented in Figure 3.

Figure 3 Physical function battery—categorical scores for participants. 1-RM, 1-repetition maximum; IPAQ, International Physical Activity Questionnaire; No. participants, number of participants; SPPB, short physical performance battery; T0, diagnosis; T1, post-neoadjuvant treatment; T2, post-prehabilitation.

Physical parameters

At diagnosis (T0), only 1 participant (7.14%) achieved a peak power greater than or equal to the normative value for age and gender (24). Following completion of neoadjuvant treatment (T1), no participants had a peak power greater than or equal to the normative value for age and gender. However, post completion of exercise prehabilitation (T2), two participants (n=2/8, 25%) had a peak power greater than or equal to the normative values. In terms of peripheral muscle strength (leg press 1-RM) at all timepoints, greater than 40% of participants had a leg press weight ratio which was considered below average fitness (27). For peak power, the repeated measures ANOVA with sphericity assumed showed a significant difference in the measure over time with F (2,14) =8.465, P=0.004; partial eta squared (ηp2) =0.547. Mean (SD) peak power reduced from 153.57 (44.35) watts at T0 to 127 (31.9) at T1 and increased to 145.62 (46.09) at T2, but no statistically significant difference was observed in post-hoc testing (T0–T1, P=0.055; T1–T2, P=0.053). No significant changes were observed in 1-RM test scores over the three timepoints (P=0.40, ηp2=0.143).

Functions

Compared to normative data for age and gender, 71.43% (n=10) of participants had total SPPB scores greater than or equal to age and gender norms at T0, 80% (n=8/10) at T1, and 87.5% (n=7/8) at T2 (29). Friedman’s test detected no significant changes in SPPB total score over the three time-points (P=0.27, W=0.163).

Activity goals

High physical activity levels were reported by all participants (n=14) at T0, 60% of participants (n=6/10) at T1, and 75% of participants (n=6/8) at T2 (30). Friedman’s test showed significant differences in self-reported total leisure activity (P=0.045, W=0.388), total vigorous physical activity (P=0.001, W=0.851) and total physical activity (P=0.04, W=0.391) across the 3 time points. Post-hoc testing was not significant for total leisure activity between T0 and T1 (P=0.31), but was significant between T1 and T2 (P=0.03, effect size 0.52). However, for both total vigorous physical activity [median (IQR) T0 =5,566.00 (5,444.13) and T1=0.00 (520.00), P=0.001, effect size=1.28] and total physical activity [median (IQR) T0 =12,007.5 (9,491.22) and T1 =3,402.00 (3,752.00), P=0.04, effect size=0.89], a significant difference was observed between T0 and T1.

Comparison of exercise prehabilitation interventions

Table 3 presents the physical function results at T1 and T2 per study group (HIIT and control arm). After adjusting for T1 scores, no significant differences between the HIIT and control groups on T2 physical function measures were observed.

Discussion

This study describes the physical functioning of patients with oesophageal cancer from the point of diagnosis (T0), through completion of neoadjuvant treatment (CROSS/FLOT) (T1), and subsequent exercise prehabilitation in advance of oesophagectomy (T2). Cardiorespiratory fitness and physical activity engagement both changed significantly from T0 to T2. This was not reflected in the function (SPPB), which remained stable and consistent with normal values across the study. Cardiorespiratory fitness was below population norms in the majority of participants at all study time points and there was a significant decline in physical activity levels post completion of neo-adjuvant treatment, highlighting the need for exercise prehabilitation to maintain and improve physical function in those undergoing multimodality treatment for cancer of the oesophagus.

Key findings

Suboptimal cardiorespiratory fitness (peak power) in this cohort is a key finding. CPET is the gold standard for assessment of cardiorespiratory fitness (27), and is an established predictor of post-operative outcome due to its ability to simulate the stress major surgery places on the cardiorespiratory unit (17). Specifically in the context of oesophageal cancer, lower cardiorespiratory fitness levels at diagnosis have been associated with poorer outcomes (8,32). In a cohort of 39 participants who completed neoadjuvant chemotherapy pre-oesophagectomy, lower VO₂ at anaerobic threshold (HR =0.84, 95% CI: 0.73–0.97, P=0.01) and at peak (HR =0.90, 95% CI: 0.83–0.99, P=0.03) measured at diagnosis were associated with a greater 1-year mortality rate (32). In addition, this study highlighted a trend towards lower treatment tolerance for those with lower cardiorespiratory fitness at diagnosis (32). Despite the low levels of cardiorespiratory fitness recorded by our cohort, the majority were functioning well as measured by SPPB. This result was unsurprising as a prior systematic review by this group highlighted that function is not always synonymous with cardiorespiratory fitness, and that functional measures may lack the sensitivity to detect the underlying anatomical and physiological changes that are accruing as a result of oesophageal cancer and its treatments (8,33). Prior to commencement of neoadjuvant treatment, all of our participants reported high levels of physical activity. Higher pre-operative physical activity levels are associated with lower post-operative morbidity and mortality (17), and specifically in the context of oesophageal cancer, evidence suggests that higher pre-operative physical activity engagement reduces the risk of post-operative pulmonary complications post-oesophagectomy (34). Vigorous and total physical activity levels declined significantly in our cohort following completion of neoadjuvant treatment, and did not recover significantly post-exercise prehabilitation. This is a worrying finding given that physical activity participation is strongly linked to risk of sarcopenia, which as aforementioned, is associated with poorer outcomes in oesophageal cancer (11). In a cohort study of 62 participants pre-operative step count <7,800 steps/day (OR =5.17, 95% CI: 1.38–19.33, P=0.02), and postoperative step count <2,400 steps/day (OR =3.55, 95% CI: 1.01–12.45, P=0.048) were associated with a greater risk of sarcopenia (35). Considering these findings, there is a strong rationale to implement interventions that aim to prevent decline, maintain, and improve physical functioning in advance of oesophagectomy.

Exercise prehabilitation in the context of oesophageal cancer is relatively underexplored, and many questions persist regarding its efficacy. In this cohort study, whilst values for peak power, vigorous, and total physical activity levels showed evidence of recovery post completion of exercise prehabilitation, our sample size was too small to detect significant changes in these measures. In contrast, the larger PRE-HIIT randomized control trial (RCT), which was adequately powered, within which this cohort study was based, demonstrated significant improvements in physical functioning for patients scheduled for either oesophageal or lung resection following completion of HIIT (22). Whilst this study focused on the impact of prehabilitation on physical functioning, for those engaged in oesophageal cancer care, the key efficacy question is: does exercise prehabilitation improve surgical outcomes? A recent systematic review by An et al. (36) involving 1,803 patients, including 584 in RCTs and 1,219 in observational studies, demonstrated a reduction in post-operative pneumonia and pulmonary complications in observational studies of exercise prehabilitation pre-oesophagectomy. However, no difference in post-surgical outcomes was observed in the RCTs included in the review. Their findings highlight the paucity of evidence in the area and vindicate the need for high-quality RCTs exploring exercise prehabilitation pre-oesophagectomy. With an increase in those undergoing multimodality treatment for cancer of the oesophagus, the ideal timing of exercise prehabilitation also requires investigation. Whilst the PRE-HIIT trial delivered exercise prehabilitation post completion of neoadjuvant treatment, there are increasingly calls to commence exercise prehabilitation during neoadjuvant treatment to preserve and improve physical function (37). A systematic review and meta-analysis involving 3 RCTs and 9 non-RCTs found prehabilitation during neoadjuvant treatment to be safe, to have preventative effects on physical function, improved treatment tolerance, and reduced risk of post-operative complications (37). However, given the low number of RCTs in the field, additional high-quality trials are required to confirm the efficacy of exercise prehabilitation during neoadjuvant treatment. Moreover, exercise prehabilitation trials, which aim to improve physical function, also need to carefully design their intervention to ensure maximum benefits. A RCT examining the impact of a community-based exercise programme on physical function during neoadjuvant treatment for oesophagogastric cancer demonstrated significant improvements in 6-minute walking test distance, whilst no changes in habitual activity were observed, highlighting the need for strategies to enhance physical activity participation in addition to exercise prescription in prehabilitation (38).

In addition to our findings, it is also important to highlight how conducting this type of clinical research in this complex cohort can be onerous. However, there are important learnings from this cohort study to share with the research community, which may aid the development of future studies in this field. Firstly, prior experience of conducting research during neoadjuvant treatment for oesophageal cancer at this centre had indicated that an accrual target of approximately 25 patients at the diagnosis timepoint could be achieved (10). However, this was not achieved due to a myriad of factors. The trial commenced recruitment in June 2021. At this time, the coronavirus disease 2019 (COVID-19) pandemic was still ongoing, many clinic appointments were still being held virtually, and a significant fear element existed amongst high-risk cancer patients around hospital visits, which potentially may incur an exposure risk to the virus; henceforth, recruitment was very difficult for this trial. It is also well acknowledged that the point of oesophageal cancer diagnosis is a very challenging and upsetting time for patients, with high levels of fear and an intense sense of loss and upheaval reported (39). Accordingly, the additional burden of participation in research is often something patients are unwilling to consider at this difficult time point in their life. Exercise prehabilitation researchers need to be cognisant of this, and strategies to ease the burden of trial participation need to be considered at the protocol stage to optimise recruitment and retention to research studies at this phase of the cancer journey.

Strengths and limitations

This study has some strengths and limitations. A key strength of this study is the use of a comprehensive battery to assess physical functioning, including CPET, the gold standard measure of cardiorespiratory fitness. Firstly, it provides further evidence in support of prehabilitation in this cohort, which to date has been largely underexplored. The study is however, limited by its small sample size. Whilst it is comparable to other exercise oncology works in oesophageal cancer (40-43), it does not facilitate a powered analysis of outcomes, causal relationships could not be determined, and the ability of post-hoc tests to detect differences between timepoints was restricted. Accordingly, our results should be interpreted with caution. Secondly, the stringent inclusion criteria meant the study population was free from significant co-morbidity and accordingly the generalizability of the results to a wider cohort of patients with oesophageal cancer is unclear. Furthermore, differentiation between the two exercise prehabilitation regimens was not feasible in this cohort study.

Conclusions

This study provides a comprehensive description of the physical functioning of patients undergoing neoadjuvant treatment (CROSS/FLOT) followed by exercise prehabilitation in advance of oesophagectomy. Sub-optimal cardiorespiratory fitness was evident across the three time-points studied, and physical activity engagement was observed to decline significantly following neoadjuvant treatment. Notwithstanding these findings, our conclusions are limited due to the small sample size and future adequately powered studies are required to verify our findings. Our findings do however, highlight the need for effective programmes of exercise prehabilitation to maximise physical functioning and mitigate perioperative morbidity risks.

Acknowledgments

The authors would like to acknowledge the Wellcome Trust/Health Research Board Clinical Research Facility (CRF) at St. James’s Hospital, Dublin; the Upper Gastrointestinal Cancer Surgical Team for recruitment assistance; the Physiotherapy and Clinical Nutrition Departments; the cardiology team and medical doctors supervising CPET tests (particularly Dr. Conor Larney and Dr. Rachel Enright); Associate Professor Mikel Egana and his Physiology team for equipment provision; the Senior House Officers of the Clinical Research Facility; and all members of the Trial Management Group, past and present, for their invaluable contributions to this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-35/rc

Data Sharing Statement: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-35/dss

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-35/prf

Funding: This work was supported by Health Research Board Ireland and Irish Cancer Society, MRCG-HRB Joint Funding Scheme (No. MRCG-2018-17).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-35/coif). The authors have no conflicts of interest to declare.

Ethical Statement:The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Tallaght University Hospital/St James’s Hospital Joint Research Ethics Committee (REC: 2020-02 List 7) and informed consent was obtained from all individual 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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