Effect of physical exercise on postoperative shoulder mobility and upper limb function in patients with breast cancer: a systematic review and meta-analysis

Introduction

Breast cancer, a common condition among women, is the primary cause of cancer deaths in this demographic (1). According to the World Health Organization (WHO), breast cancer is the most common cancer among women worldwide, representing about 12% of all new cancer cases each year (2). The risk of breast cancer increases with age. Although breast cancer can occur at any age, it is most commonly diagnosed in women aged 50 years and older. The year 2020 saw approximately 685,000 women succumbing to breast cancer globally (3). Each year, the global incidence of breast cancer surpasses one million cases (4), underscoring its status as a formidable health challenge worldwide. Research findings suggest that as many as 67% of breast cancer survivors suffer from diminished shoulder mobility and impaired upper limb function (5-7). Shoulder pain and reduced range of motion are common in the immediate postoperative period and can persist long-term. Up to 30% of patients may experience significant shoulder impairment 2 years after surgery. A review indicated that impairments in shoulder movement and muscle strength can be present even beyond the 2-year mark, with varying degrees of severity depending on individual circumstances and treatment received (8). Such persistent impairments can escalate into chronic pain, diminished muscle strength, lymphedema, and compromised cardiorespiratory health (9,10), potentially culminating in permanent disability. The long-term morbidity associated with breast cancer treatments can significantly impact the quality of life (11).

The 2019 edition of the Guidelines and Norms for Diagnosis and Treatment of Breast Cancer, issued by the Chinese Anti-Cancer Association, advocates for targeted physical exercise in breast cancer patients post-surgery (12). Evidence suggests that participation in physical activity is essential for functional limb rehabilitation after breast cancer surgery, common procedures include axillary lymph node dissection and mastectomy (13). A positive relationship has been observed between the extent of postoperative rehabilitation and the level of physical activity among breast cancer patients (14). Given the common issue of upper limb dysfunction following surgery, physical exercise plays a critical role by strengthening muscles, preventing wound adhesions, and activating the deep shoulder and latissimus dorsi muscles to gradually replace the axillary tissue, thus improving shoulder mobility and upper limb function in these patients. Both aerobic and resistance exercises have been shown to enhance upper limb function post-surgery (15). Regular exercise helps reduce lymphedema by promoting protein reabsorption and enhancing the flexibility of soft tissues (16), which is believed to contribute to improved upper limb function. Additionally, exercise has been found to regulate estrogen levels and boost patients’ immune responses, thereby aiding in the functional recovery of patients after breast cancer surgery (17).

Systematic reviews conducted in the past suggest that while aerobic exercise enhances shoulder mobility among breast cancer survivors, its impact on upper limb strength is inconclusive (18). There is a need to incorporate more recent studies for a comprehensive analysis. Experimental studies have highlighted the benefits of resistance training (19) and mind-body exercises (20) in improving upper limb function post-surgery in breast cancer patients. However, a systematic evaluation and comparison of these interventions are lacking. Additionally, the specific influences of various exercise parameters—including type, intensity, duration, intervention cycle, and frequency—remain unclear. This study, therefore, seeks to systematically analyze randomized controlled trials (RCTs) that investigate the effects of physical exercise on postoperative shoulder mobility and upper limb function in breast cancer patients, using an evidence-based approach. The goal is to provide a foundation for developing effective exercise protocols tailored to post-surgical breast cancer patients. We present this article in accordance with the PRISMA reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-24-255/rc) (21).

Methods

Study framework

This study is registered on the International Platform of Registered Systematic Review and Meta-Analysis Protocols (registration number INPLASY202460058). The detailed structure of the research is outlined in Table 1.

Search strategy

Two researchers independently searched seven databases—Web of Science, PubMed, The Cochrane Library, Embase, China National Knowledge Internet (CNKI), WanFang Data, and VIP—from their inception until April 16, 2024. The search strategy combined subject headings with free-text terms, finalized after several preliminary searches, and was enhanced by manual checks, including tracing back to references of included studies when necessary.

Search terms: (breast neoplasms OR breast cancer OR breast tumor OR breast carcinoma) AND (exercise OR aerobic OR resistance OR strength OR physical activity OR qigong OR tai chi OR taiji OR yoga OR baduanjin OR jogging) AND (upper limb function OR upper-extremity function OR upper limb OR limb function OR shoulder range of motion OR shoulder mobility OR range of motion OR shoulder joint OR shoulder) AND (randomized controlled trial OR randomized OR controlled OR trial OR RCT).

Criteria for inclusion and exclusion

Inclusion criteria: (I) subjects are postoperative breast cancer patients, unrestricted by race or nationality, aged 18 years or above, without mental disorders or cardiopulmonary impairments. (II) Interventions include physical exercise or enhanced physical exercise in addition to standard treatments, with at least one experimental group using physical exercise as an intervention on top of the same rehabilitation protocol as the control group; multiple comparisons within a single study are treated as separate studies. (III) The primary outcome measure is upper limb function, assessed by Constant and Murley Score (CMS)—covering pain (15 points), daily activities (20 points), joint mobility (40 points), and muscle strength (25 points), with higher scores indicating better recovery—and Disability of Arm, Shoulder and Hand (DASH), which evaluates upper limb musculoskeletal conditions and functions through 30 items, with higher scores indicating better outcomes. Secondary outcomes measure shoulder joint mobility, assessed by the maximum angles of forward flexion and abduction using an arthrometer. (IV) The control group receives either standard treatment or no additional treatment. (V) The study design must be a RCT.

Exclusion criteria: patients with recurrent or metastatic breast cancer; studies not published in Chinese or English; animal studies; studies including patients with other cancers; duplicate publications or studies with poor quality assessments.

Screening and extraction of literature

Screening process

Initially screened articles are imported into Endnote X9 for duplicate removal. The screening is independently performed by two researchers based on the inclusion and exclusion criteria. The process begins with a review of titles and abstracts for preliminary selection, followed by a full-text reading and downloading of articles that meet the criteria. After screening, results are compared, and any discrepancies are discussed with a third researcher to finalize inclusion decisions.

Data extraction

A standardized protocol is employed to extract pertinent information from the literature. This task is also independently carried out by two researchers for the included articles. For missing or unclear data, direct contact with the original authors via email is made to acquire and verify the information. In cases of conflicting information inclusion, a consensus is reached through discussion with a third researcher. The extracted data encompasses: (I) basic details (author, year, country, age, sample size, postoperative intervention time); (II) experimental specifics (type, duration, frequency) and outcome measures. The classification of exercise intervention forms in this study is shown in Table 2.

Quality assessment of literature

Using the risk of bias tool recommended by the Cochrane Handbook (22), the assessment covers seven areas: random sequence generation, allocation concealment, blinding of participants and researchers, blinding of outcome assessors, incomplete outcome data, selective reporting, and other potential biases. Each criterion is rated as “low bias risk”, “unclear bias risk”, or “high bias risk”.

Statistical analysis

The software used for data analysis was Review Manager 5.4. Heterogeneity was evaluated using the P value and I² statistic. If significant heterogeneity was detected (I²≥50%; P<0.10), a random effects model was applied; otherwise, a fixed effects model was used. The standardized mean difference (SMD) was calculated, along with a 95% confidence interval (CI). Sensitivity analysis involved sequentially excluding individual studies. If heterogeneity was substantial, a descriptive analysis was performed. The Egger’s test was used to test for publication bias.

Assessment of evidence quality

Evidence quality evaluated using GRADEPro (23). The evaluation of the quality of evidence for outcome indicators encompasses five downgrading factors: publication bias, inconsistency, imprecision, indirectness, and study limitations. The evidence is classified into four levels based on the degree of downgrading: very low, low, moderate, and high. Specifically, a three-level downgrade results in very low evidence, a two-level downgrade results in low evidence, a one-level downgrade results in moderate evidence, and no downgrade results in high evidence. The quality assessment is independently conducted by two researchers. In cases of disagreement, a third researcher is consulted to reach a consensus through discussion.

Results

Outcome of literature search

A systematic online search using computers retrieved 4,105 articles, with an additional 2 articles were found through manual search methods. After removing duplicates, 3,343 articles remained. These were initially screened by examining titles and abstracts, followed by a thorough review of the full texts to exclude those that did not fulfill the inclusion criteria. Consequently, 20 articles were selected for inclusion in the analysis, as illustrated in Figure 1.

Figure 1 Literature screening flow chart. CNKI, China National Knowledge Internet.

Basic features of included studies

This review encompasses 20 articles, which represent 25 RCTs and involve a total of 2,171 patients. The youngest patient was only 28 years old (20), the patients in this study (24) were the oldest on average (66.2±10.6 years old). The intervention group was subjected to a variety of exercise regimens, including traditional Chinese exercises (28%), resistance training (24%), combined aerobic and resistance training (12%), ball sports (8%), and integrated exercise routines (28%). In contrast, the control group received standard treatments such as health education, daily activity recommendations, exercise guidance, and conventional rehabilitation. Each study intervention was administered at least once, with durations spanning from a minimum of 6 weeks to a maximum of 52 weeks, and an average intervention period of 17 weeks. The exercise frequency varied from a minimum of once per week to a maximum of 7 times per week, with the predominant frequency being more than 3 times per week. The duration of each exercise session ranged from 40 to 80 minutes, with the most frequently observed duration being 60 minutes per session. The exercise regimen varied from 1 to 7 days per week, eight studies (11 RCTs) set the frequency of exercise to 3 or more times per week, seven studies less than 3 times per week, and five studies did not report. Notably, one study had a 1-month exercise duration, while all others extended for at least 2 months. The timing of interventions post-surgery ranged from 10 days to 6 weeks post-operation, and also included periods post-chemotherapy. The studies were sourced from various countries, with the majority from China (35%) and the United States (25%), followed by contributions from Denmark, Canada, Brazil, the Netherlands, Australia, the United Kingdom, Spain, Poland, and Türkiye, each contributing 5%. Details are shown in Table 3.

Evaluation of methodological quality in included studies

The review encompassed 20 articles, all of which were RCTs. Out of these, 17 provided details on the randomization process (11,20,24-38), while eight specified the allocation concealment method (24-28,34,36,39). Single-blinding was used in seven studies (20,25,26,29,30,34,37), and 12 studies blinded the outcome assessors (11,24,25,28,29,32,34-38,40). One study reported missing data (26), but there was no evidence of selective reporting. Figure 2 illustrates that the included studies exhibited varying degrees of bias, with seven studies deemed to have high methodological quality (11,25,28-30,34,41) and 16 studies rated as having moderate quality.

Figure 2 Risk chart of literature bias.

Results of meta-analysis

Impact of physical exercise on shoulder mobility post-surgery in breast cancer patients

Eleven studies with 741 breast cancer patients were included to compare the differences in shoulder flexion and abduction between the physical exercise group and the control group. Figure 3 illustrates that for shoulder flexion, the heterogeneity test indicated I²=65% and P=0.002, suggesting moderate heterogeneity among studies, leading to the application of a random-effects model for analysis. The meta-analysis demonstrated a pooled effect size of SMD =0.59, with a 95% CI of (0.32, 0.86) and P<0.001, suggesting that physical exercise significantly enhances shoulder flexion function post-surgery compared to the control group. Figure 4 shows that for shoulder abduction, the heterogeneity test revealed I²=90% and P<0.001, indicating high heterogeneity among studies, and thus a random-effects model was employed. The meta-analysis yielded a pooled effect size of SMD =1.01, with a 95% CI of (0.43, 1.60) and P<0.001, indicating that physical exercise significantly improves shoulder abduction function post-surgery compared to the control group.

Figure 3 Forest plot of the effect of physical exercise on postoperative shoulder flexion in breast cancer patients. SD, standard deviation; Std., standardized; CI, confidence interval.

Figure 4 Forest plot of the effect of physical exercise on shoulder abduction in breast cancer patients after surgery. SD, standard deviation; Std., standardized; CI, confidence interval.

Subgroup analyses were performed based on intervention types, frequencies, and durations, as detailed in Table 4. For the flexion subgroup, resistance exercise (SMD =0.54; 95% CI: 0.07, 1.02; P=0.02), aerobic + resistance exercise (SMD =0.49; 95% CI: 0.11, 0.87; P=0.01), and comprehensive exercise (SMD =0.88; 95% CI: 0.24, 1.52; P=0.007) showed significant improvements. Frequency subgroup analysis indicated improvements for ≤3 times/week (SMD =0.68; 95% CI: 0.33, 1.03; P<0.001) and >3 times/week (SMD =0.49; 95% CI: 0.11, 0.87; P=0.01). Duration subgroup analysis showed improvements for <8 weeks (SMD =0.66; 95% CI: 0.24, 1.09; P=0.002) and 8–12 weeks (SMD =0.83; 95% CI: 0.45, 1.22; P<0.001), but no significant improvement for >12 weeks (P=0.20). For the abduction subgroup, resistance exercise (SMD =0.93; 95% CI: 0.08, 1.77; P=0.03) and comprehensive exercise (SMD =1.74; 95% CI: 1.10, 2.38; P<0.001) demonstrated significant improvements, whereas aerobic + resistance exercise did not (P=0.20). Frequency subgroup analysis showed improvement for ≤3 times/week (SMD =0.87; 95% CI: 0.18, 1.57; P=0.01), but no significant improvement for >3 times/week (P=0.20). Duration subgroup analysis showed improvements for <8 weeks (SMD =1.78; 95% CI: 1.30, 2.25; P<0.001) and 8–12 weeks (SMD =1.3; 95% CI: 0.50, 2.09; P=0.001), but no significant improvement for >12 weeks (P=0.56).

Impact of physical exercise on upper limb motor function

Twenty-one studies with 1,868 breast cancer patients were included to compare the effects on upper limb motor function between the physical exercise group and the control group, as depicted in Figure 5. The heterogeneity test revealed I²=93% and P<0.001, indicating high heterogeneity among studies, leading to the use of a random-effects model for analysis. The meta-analysis demonstrated a pooled effect size of SMD =0.87, with a 95% CI of (0.48, 1.26) and P<0.001, suggesting that physical exercise significantly enhances upper limb motor function post-surgery compared to the control group. Subgroup analyses were performed based on intervention types, frequencies, durations, and the timing of postoperative intervention, as detailed in Table 4.

Figure 5 Effect of physical exercise on upper limb motor function. SD, standard deviation; Std., standardized; CI, confidence interval.

Subgroup analysis demonstrated that among the intervention forms, Chinese traditional exercise (SMD =0.68; 95% CI: 0.52, 0.85; P<0.001) and resistance exercise (SMD =1.43; 95% CI: 0.88, 1.98; P<0.001) significantly improved upper limb motor function. In contrast, aerobic + resistance exercise (P=0.19), ball exercise (P=0.85), and comprehensive exercise (P=0.26) did not exhibit significant improvement effects. Frequency subgroup analysis indicated improvements for ≤3 times/week (SMD =1.21; 95% CI: 0.20, 2.21; P=0.02) and >3 times/week (SMD =0.58; 95% CI: 0.22, 0.95; P=0.002). Duration subgroup analysis showed improvements for 8–12 weeks (SMD =0.98; 95% CI: 0.43, 1.54; P<0.001) and >12 weeks (SMD =0.75; 95% CI: 0.14, 1.35; P=0.02). However, interventions starting less than 2 weeks post-surgery showed some improvement (SMD =0.42; 95% CI: 0.01, 0.83; P=0.04), while those starting ≥2 weeks post-surgery did not show significant improvement (P=0.17).

Sensitivity analysis

This study aimed to investigate whether the observed heterogeneity among studies was due to a single study by performing a sensitivity analysis on the studies with high heterogeneity concerning the impact of physical exercise on shoulder abduction and upper limb motor function post-surgery in breast cancer patients. This was achieved by sequentially excluding each study and reanalyzing the pooled effects, as detailed in Table 5. For shoulder abduction, the pooled effect size was SMD =1.01, with a 95% CI of (0.43, 1.60), P<0.001, and I²=90%. After excluding each study, the range of the pooled effect size varied from 0.86 to 1.20, with all P values ≤0.05, and the range of I² was 86–91%. For upper limb motor function, the SMD was 0.87, with a 95% CI of (0.48, 1.26), P<0.001, and I²=93%. After excluding each study, the range of the pooled effect size was 0.71–0.94, with all P values <0.05, and the range of I² was 90–94%.

Publication bias assessment

The Egger’s test conducted for the DASH outcome yielded a z-value of 1.35 (continuity corrected) with a corresponding probability Pr > |z| =0.179 (continuity corrected), which is greater than 0.05. This indicates that there is no statistically significant evidence of publication bias. The overall assessment suggests that the study results are free from publication bias and are therefore reliable. See Figure 6 for details.

Figure 6 Present a bias graph. CI, confidence interval.

Assessment of evidence quality

The GRADEPro software assessment revealed no deductions for publication bias, imprecision, indirectness, or risk of bias. Inconsistency, however, led to a deduction in the evidence quality score. The evidence quality for upper limb motor function is classified as moderate, while the evidence for shoulder flexion is rated as high quality, and for shoulder abduction, it is moderate quality, as depicted in Table 6. The potential reasons for these ratings include the absence of allocation concealment in some studies and incomplete blinding, indicating that the research may have certain limitations.

Incidence of adverse events

There were no reported adverse events within the studies that were included in the analysis.

Discussion

Our study utilized a meta-analysis approach to assess the effects of physical exercise on postoperative shoulder abduction, flexion, and upper limb function in breast cancer patients. Subgroup analyses were conducted based on intervention types, duration, frequency, and timing of postoperative initiation. The results demonstrate that physical exercise can enhance postoperative shoulder abduction, flexion, and upper limb function in breast cancer patients, consistent with nearly all prior research findings. Yang et al. on the other hand, found that aerobic exercise only improves shoulder joint mobility but does not enhance upper limb strength (18). This discrepancy may arise because our study included various types of exercise, such as aerobic, resistance, and combined exercises, whereas Yang et al. focused exclusively on aerobic exercise. Similar findings have been reported in other studies as well. A systematic review by Lin indicates that aerobic exercise is effective in improving shoulder abduction, flexion, and upper limb function in postoperative breast cancer patients, whereas resistance exercise is only effective in improving upper limb function (15). Postoperative complications in breast cancer patients, such as damage to the pectoralis major and minor muscles, their blood supply, and nerves like the medial and dorsal pectoral nerves, along with incision scars, tissue adhesions, and disrupted blood and lymph circulation, can impair upper limb function (42). Physical exercise aids in improving shoulder joint mobility, potentially by facilitating increased blood flow in the surgical area, preventing the accumulation of fluids and blood beneath the skin, and reducing the risk of joint stiffness and muscle atrophy (43). Additionally, research has shown that aerobic exercise can modulate estrogen levels and boost the patient’s immune response, contributing to improved functional recovery in breast cancer patients post-surgery (17).

The study encompassed 20 articles, all of which were classified as grade B or higher, with no instances of low-quality literature, reflecting a high overall quality of the included studies. The GRADEPro assessment of the evidence level in this review identified that some studies failed to fully disclose their blinding methods or allocation concealment, potentially influencing the post-test outcomes. A test for publication bias regarding upper limb motor function did not reveal significant bias. No clear reasons for downgrading the evidence quality due to indirectness or imprecision were identified. The meta-analysis indicated an I² of 65% for flexion, with heterogeneity attributed to the type, frequency, and duration of interventions, and thus the evidence level remained unchanged; for abduction, an I² of 90% was observed, with heterogeneity stemming from the intervention type and duration, leading to a one-level downgrade in evidence quality; for upper limb function, an I² of 93% was noted, with heterogeneity due to the intervention type, resulting in a one-level downgrade. Consequently, the evidence quality for the effects of physical exercise on upper limb motor function and shoulder abduction mobility in postoperative breast cancer patients is rated as moderate, while the evidence quality for shoulder flexion mobility is rated as high. Further investigation into the intensity of physical exercise is warranted, and given the substantial heterogeneity among studies, the reliability of the conclusions may be compromised, necessitating careful interpretation.

Our findings indicate that physical exercise lasting less than 8 weeks enhances shoulder abduction and flexion in breast cancer patients post-surgery, whereas exercise lasting 8–12 weeks improves shoulder abduction, flexion, and upper limb function. In contrast, exercise exceeding 12 weeks only benefits upper limb function in these patients. This contrasts with prior research. Wang et al. conducted a study where postoperative breast cancer patients were assigned to three groups receiving Yangge dance, Tai Chi, or standard interventions, with shoulder function evaluations at 10 days, 1 month, 3 months, and 6 months post-surgery. The study revealed that all groups experienced significant improvements in shoulder function as the intervention duration increased, with Tai Chi demonstrating superior outcomes over the other two interventions (33). The discrepancy in results may stem from the varying exercise intervention methods used. Our study encompassed a range of exercise modalities, whereas Wang et al. observed that Tai Chi held a distinct advantage in long-term interventions, with aerobic exercise showing limited superiority.

Our research highlights that the choice of exercise modality is pivotal for the rehabilitation of breast cancer patients, with resistance exercise offering the most holistic improvement post-surgery. By regularly engaging in resistance exercises, patients can fortify their upper limb and back muscles, using muscles like the trapezius and latissimus dorsi to compensate for the loss of axillary tissue, thus enhancing shoulder joint functionality. These exercises also facilitate protein reabsorption and enhance the flexibility of soft tissues, thereby mitigating lymphedema (16). Traditional Chinese exercises, such as Tai Chi, which are characterized by their flexibility, stability, slowness, and continuity, can improve upper limb function (33,44,45). Nonetheless, the benefits of other exercise types for breast cancer patients are selective, possibly due to variations in patient compliance. Furthermore, resistance exercise and Tai Chi are particularly effective in integrating upper limb function, thereby fostering the recovery of upper limb function. This effectiveness may also be influenced by the type of surgery the patient has undergone, as different surgical procedures can result in varying degrees of upper limb dysfunction (45). Physical exercise conducted either ≤3 or >3 times/week can enhance shoulder abduction and flexion in breast cancer patients post-surgery. Integrating physical exercise into standard rehabilitation protocols can expedite blood flow in the surgical wound, prevent the accumulation of subcutaneous fluids and blood, deter joint stiffness, muscle atrophy, and adhesion, and foster functional recovery (43).

Our findings also indicate that initiating physical exercise within the first 2 weeks post-surgery enhances the recovery of upper limb function in breast cancer patients. Early postoperative functional exercises boost both systemic and localized blood circulation, aiding in the absorption and removal of pathological byproducts, reducing pain, and facilitating limb function recovery. Conversely, delaying physical exercise may result in disuse-induced limb dysfunction (46,47). However, other research suggests that early rehabilitation exercises may impede wound healing and lead to hematoma formation. Additionally, frequent exercises early in the recovery phase can elevate lymphatic fluid production, potentially causing fluid buildup and complications like infection and pain (48). Thus, the timing of physical exercise should be tailored to the patient’s recovery status.

Our study also has several limitations. We did not explore the impact of different surgical types, such as breast-conserving surgery and modified radical mastectomy. While both procedures hold value in early breast cancer treatment, breast-conserving surgery is safer, facilitates faster postoperative recovery, and reduces the incidence of postoperative complications (49,50). Although we investigated the effects of exercise type, duration, and frequency, the number of studies included was limited, and some studies did not provide detailed intervention protocols. Therefore, our categorizations of these factors were broad rather than detailed. Furthermore, exercise prescription also includes intensity and duration, but these parameters were inconsistently reported or not specified in the included studies. We did not conduct subgroup analyses for exercise intensity and duration, which might contribute to the heterogeneity observed in our results.

Conclusions

To conclude, physical exercise improves shoulder flexion, abduction, and upper limb function in breast cancer patients post-surgery. Resistance exercise, performed for 8–12 weeks, either ≤3 or >3 times/week, offers the most comprehensive rehabilitation for upper limbs, and exercising within the first 2 weeks post-surgery yields the most significant improvements in upper limb function. Future studies should focus on conducting more high-quality RCTs to further validate the impact of physical exercise on shoulder joint mobility and upper limb function in breast cancer patients post-surgery, thereby providing robust evidence for clinical practice.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-255/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-255/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-255/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.

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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