An interpretative review of North American expert consensus on the clinical role of ex vivo lung perfusion (EVLP) with acellular perfusate

Introduction

Ex vivo lung perfusion (EVLP) has been utilized in lung transplantation for over a decade; however, standardized expert consensus or guidelines have long been lacking. In April 2025, a panel of 18 North American transplant specialists with extensive EVLP experience published the “North American expert consensus on the clinical role of ex vivo lung perfusion (EVLP) with acellular perfusate” in the Journal of Thoracic Disease (1). This consensus serves as an essential reference to guide clinical decision-making for optimal EVLP utilization across transplant centers, particularly in complex clinical scenarios.

Lung transplantation is the sole viable and lifesaving treatment option for patients with end-stage pulmonary disease (2). Although lung transplants continue to grow consistently every year, the supply of qualified donor lungs remains inadequate to meet clinical demand (1). EVLP is a technology which safely expands the pool of eligible donor lungs by repairing marginal lungs and extending their preservation windows (3-5). In contemporary clinical practice, the adoption of EVLP has demonstrated significant growth. Data from the United States indicate that EVLP was utilized in 3.4% of lung transplants between 2013 and 2023, a proportion that rose to 6.6% during the 2018–2024 period (6,7). This steady increase in the use of EVLP has contributed to an overall expansion in lung transplants. It is reported that EVLP typically increases lung transplant volume by approximately 20% (8). According to data from Toronto General Hospital, among 1,000 EVLP procedures performed between 2008 and 2024, approximately 65% of lungs were accepted for transplantation. These grafts accounted for 29% of all lung transplants during the study period, resulting in a remarkable 50% increase in overall transplant volume (9). However, standardized protocols for EVLP clinical decision-making remain lacking across transplant centers. There is a critical absence of evidence-based guidelines to address these practice variations in EVLP.

The consensus has established guidelines for acellular perfusate EVLP systems, addressing three critical domains: (I) general statements on EVLP; (II) decision criteria for placing donor lungs on EVLP; and (III) decision criteria for transplanting EVLP lungs. In addition, the consensus incorporates some open questions about the development of EVLP. Based on the core content of this consensus, this article conducts an in-depth analysis that transforms the expert consensus statements into a comprehensive discussion integrating background interpretation, evidence synthesis, and future directions. Serving as a crucial bridge between theoretical recommendations and clinical implementation, it aims to provide clinicians with theoretical frameworks and practical references for developing localized EVLP decision-making.

Marginal vs. standard donor lungs on EVLP

The consensus unequivocally recommends that EVLP should be applied to donor lungs with unclear or marginal quality, not for enhancing standard donor lungs. This recommendation is supported by the current lack of evidence showing improved outcomes for standard lungs undergoing EVLP (10-12). However, with optimization of EVLP strategies and gradual cost reductions, whether EVLP treatment of standard donor lungs could improve recipient survival in the future remains an intriguing question.

Decision criteria for placing donor lungs on EVLP

The consensus provides a structured framework for initiating EVLP (Figures 1,2), centered on dynamic functional parameters and morphological/structural examinations. Dynamic functional parameters encompass respiratory mechanics (compliance, deflation, peak inspiratory pressure) and gas exchange capacity [the ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO₂/FiO₂ ratio, P/F ratio)], while morphological/structural examinations include edema on imaging and bronchoscopy. The consensus emphasizes the aforementioned assessment parameters should always be considered, and that, particularly when donor lung quality remains ambiguous, decision-making must integrate a broader set of contextual factors, including edema on palpation, the type of lung injury (contusion vs. aspiration vs. other), other radiographic findings, the possibility of aspiration, donor type [donation after brain death (DBD) vs. donation after circulatory death (DCD)], the possibility of pulmonary emboli, recipient characteristics, and cold ischemia time 1 (CIT1). This framework stratifies donor lungs into three management pathways: EVLP may be unnecessary, EVLP should be considered, or reject (Figure 2). This stratified approach highlights a central challenge in modern lung transplantation: how to standardize the inherently subjective initial evaluation of marginal donor lungs using evidence-based criteria.

Figure 1 Priority classification of parameters for decisions about putting lungs on EVLP by expert panel members. Reproduced from Bacchetta et al. J Thorac Dis 2025 (1), which is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0) (https://creativecommons.org/licenses/by-nc-nd/4.0/). CIT1, cold ischemia time 1; DBD, donation after brain death; DCD, donation after cardiocirculatory death; EVLP, ex vivo lung perfusion; P/F ratio, the ratio of partial pressure of oxygen to fraction of inspired oxygen.

Figure 2 The structured approach for EVLP decision-making based on unanimous agreement among expert panel members. Reproduced from Bacchetta et al. J Thorac Dis 2025 (1), which is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0) (https://creativecommons.org/licenses/by-nc-nd/4.0/). CIT1, cold ischemia time 1; DBD, donation after brain death; DCD, donation after cardiocirculatory death; EVLP, ex vivo lung perfusion; P/F ratio, the ratio of partial pressure of oxygen to fraction of inspired oxygen; PIP, peak inspiratory pressure; WIT, warm ischemia time.

Decision criteria for transplanting EVLP lungs

The decision to transplant lungs after EVLP relies on a systematic assessment of graft quality. The majority of panelists agreed that the following parameters must be evaluated: respiratory mechanics [compliance, deflation, peak airway pressure (PAP)], gas exchange capacity (ΔPO₂ at the conclusion of EVLP), morphological/structural examinations (radiography and bronchoscopy), dynamic perfusion indicators (STEEN Solution™ loss), and subjective clinical assessments (overall movement and palpation). Parameters such as pulmonary vascular resistance (PVR), glucose and lactate levels, lung weight (LW) gain, and other relevant clinical variables should also be considered in specific clinical contexts. Regrettably, the expert panel failed to reach a consensus on specific thresholds for these parameters. Although this consensus suggests a set of parameters and criteria (Table 1), there remains a lack of clear, universally accepted standards for determining the suitability of EVLP-treated lungs for transplantation. Furthermore, in specific clinical scenarios, such as when marginal EVLP lungs exhibit certain borderline parameters or during bilateral evaluations where one lung demonstrates borderline values, a comprehensive analysis of the specific clinical situation is required to assess transplantation feasibility. This absence of a standardized system represents a major obstacle in the evolution of EVLP from an experience-based technique to a precision medicine tool, resulting in clinical decisions that continue to rely heavily on institutional experience rather than universally applicable, evidence-driven standards.

Key parameters and approaches for EVLP lung assessment

Compliance and deflation

Compliance and deflation serve as critical parameters guiding clinical decisions during EVLP and lung transplantation. In EVLP, lung compliance is calculated by dividing tidal volume by the difference between PAP and positive end-expiratory pressure (PEEP). The PEEP value, typically set at 5–7 cmH₂O during EVLP, is determined by ventilator settings (13). The rate and extent of donor lung deflation reflect elastic recoil, serving as indicators of donor lung compliance quality and airway integrity. Assessment of passive deflation is particularly important in EVLP systems that use more aggressive ventilatory protocols (14). Moreover, this consensus recommends that changes in donor lung compliance should remain less than 15% compared to baseline values. During EVLP, tidal volume is typically set at 5–7 mL/kg. Since this setting correlates with weight, donor body size, and ideal body weight influences lung compliance (13). Similarly, PAP represents both a driving factor for mechanical injury in donor lungs and an important parameter reflecting functional changes during EVLP (15).

PAP and PVR

This consensus recommends maintaining the PAP increase during EVLP below 15% of baseline values. Some researchers argue that focusing on the relative changes of these evaluation parameters rather than absolute values can more accurately assess donor lung quality and has better applicability (13). However, there is one criterion that considers that PAP should be below 25 cmH₂O, which is an exact cutoff value (16). PVR, as the term suggests, reflects changes in PVR. An increase in PVR during EVLP can be observed, but a persistent and significant rise in PVR over time is often secondary to worsening pulmonary edema, indicating endothelial dysfunction accompanied by inflammatory changes that reduce capillary diameter, likely due to inflammatory injury from ischemia-reperfusion (13). This consensus recommends that the increase in PVR during EVLP should remain below 15%, whereas previous guidelines typically permitted a 15–20% increase.

P/F ratio

The P/F ratio has been established as a standardized clinical metric for quantifying pulmonary oxygenation capacity, which serves as a critical physiological indicator for assessing alveolar gas exchange function. The P/F ratio <300 is currently one of the standard eligibility criteria for EVLP. However, a study by Whitford and colleagues demonstrated that recipients receiving donor lungs with a P/F ratio <300 vs. ≥300 showed comparable outcomes in extubation time, grade of primary graft dysfunction (PGD), 6- and 12-month pulmonary function, and 12-month survival (17). The author proposed that the P/F ratio <300 largely results from lower lobe hypoxia induced by atelectasis, explaining why these lungs did not exhibit inferior post-transplant outcomes. These findings suggest that the conventional P/F ratio threshold of 300 for lung acceptance may be overly conservative, potentially leading to unnecessary discarding of viable lungs and excessive EVLP utilization (18). Regarding the decision criteria for transplanting EVLP lungs, there remains no definitive threshold for either the P/F ratio or the ΔP/F ratio. This is primarily due to the lack of standardized FiO₂ values, which significantly influence P/F ratio measurements (19). In this expert consensus, panelists have opted to use the ΔPaO₂ as the primary evaluation parameter. The panelists recommend that donor lungs undergoing EVLP are suitable for transplantation if they meet either of the following criteria: ΔPaO₂ >350 mmHg or PaO₂ >350 mmHg. Additionally, the panelists reached near-consensus that the ΔPaO₂ threshold could be lowered to 300 mmHg.

STEEN Solution™ uptake

During EVLP, a certain degree of STEEN Solution™ uptake by donor lungs is physiologically expected. However, the solution loss rate should progressively decrease over time, accompanied by a corresponding reduction in LW gain. Some researchers suggest that for donor lungs suitable for transplantation, the loss of STEEN Solution™ should be less than 100 mL/hour (20). Persistent solution loss may indicate irreparable breaches in the pulmonary vasculature or perfusion circuit, or severe pulmonary edema.

LW

LW change serves as a critical indicator of intra-pulmonary fluid dynamics in donor lungs. In a study involving 365 donors, the authors revealed that donor lungs in the highest weight quartile were associated with significantly lower utilization rates, higher incidence of grade 3 PGD at 72 hours, and prolonged intensive care unit/hospital stays (21). A parallel real-time LW study demonstrated a strong correlation between estimated LW gain and actual measured gain (pre-/post-EVLP donor LW differential). Moreover, the researchers further stratified donor lungs into four adjusted weight categories. The results showed that in Categories 2–4, the estimated LW gain during the initial 0–1 hour of EVLP was significantly higher in unsuitable cases compared to suitable cases, while PGD grades 0–1 exhibited significantly lower estimated LW gain at 60 minutes than grades 2–3. These results indicated that real-time LW measurements during the first hour of EVLP can effectively predict transplant suitability and post-transplant outcomes through early detection of extravascular lung fluid accumulation (22). Consequently, donor lungs exhibiting substantial weight gain post-EVLP warrant cautious evaluation for transplant suitability. Although no universally accepted threshold currently exists, this consensus proposes a recommended critical threshold of <15–20% weight increase. It is well established that a consistent increase in LW during EVLP indicates net fluid influx into the lung parenchyma. Therefore, a key direction for future EVLP protocol optimization lies in developing strategies to actively promote lung “drying”. This approach, analogous to the diuretic process in vivo, may be achieved by adjusting perfusate composition, optimizing colloid osmotic pressure, introducing novel pharmacological agents, or other methods.

Considerations on specific conditions

Aspiration

EVLP enables further evaluation and reconditioning of donor lungs with focal consolidation caused by factors such as contusion, aspiration, or infection before recipient transplantation. However, in most studies, lungs exhibiting significant consolidation due to infection, trauma, or aspiration are typically excluded from EVLP assessment (23). Most panelists agreed that the possibility of aspiration should be considered in specific situations. EVLP is an ideal platform to identify marginal donor lungs suspected of aspiration with bronchoscopic evaluation of the airways. Through EVLP, the underlying mechanisms of donor lung injury caused by aspiration require further investigation, as this may reveal therapeutic targets for salvaging this type of marginal lung and further enhance the efficacy of EVLP (24).

Pulmonary embolism

Previous studies have demonstrated the utility of EVLP as a tool for detecting and clearing pulmonary emboli. Beyond conventional approaches utilizing thrombolytic agents, such as urokinase and alteplase, or vascular angioextraction, recent investigations have reported the feasibility of ex vivo pulmonary artery angioscopy during EVLP (25-28). However, the clinical efficacy of these techniques and their decision-making criteria require further validation and standardization through clinical cohorts. Notably, the vast majority of panelists rejected the use of lungs with large areas of infarction.

DCD vs. DBD donors

Current EVLP strategies are not clearly different either for DBD donors or DCD donors. A study comparing clinical outcomes between recipients of DCD-EVLP and DBD-EVLP lungs found that DCD-EVLP lungs did not affect recipient mortality (29). And another analysis reported similar results: DCD-EVLP lungs did not affect the 3-year survival rate of recipients (30). However, based on the data of the United Network for Organ Sharing national registry, a study yielded divergent results. Multivariate analysis adjusting for baseline differences in donor and recipient characteristics demonstrated that recipients of DCD-EVLP lungs had a 28% shorter survival time compared to those receiving non-EVLP DBD donor lungs (31).

DCD lungs and EVLP are two strategies employed to expand the donor lung pool, but their interaction remains controversial. Selena and colleagues revealed that EVLP emerged as an independent risk factor for graft failure, specifically in the DCD lung subgroup, whereas this association was not observed in the DBD subgroup. Adjusted survival analysis demonstrated that DCD-EVLP lung transplants in the modern era [2019–2023] exhibited inferior overall survival rates (32). The author hypothesized that these findings may be attributable to unavoidable ischemia-reperfusion injury (IRI) following warm ischemia during DCD lung transplantation. The author argued that DCD lungs exposed to prolonged warm ischemia time (WIT) represent a potential resource for donation if properly preserved and evaluated.

Although inferior survival outcomes have been observed in DCD-EVLP lung transplants compared to DBD-EVLP in certain study cohorts, Selena and colleagues emphasized that this should not preclude the use of EVLP for DCD lungs, but rather warrants exploration of distinct perfusion strategies tailored for DCD lungs. In clinical practice, EVLP is more frequently applied to DCD donor lungs. Li and colleagues found that DCD lungs demonstrate greater sensitivity to flow rates and volumetric parameters during perfusion, with conventional perfusion protocols potentially exacerbating pulmonary edema risk (32,33). Emerging evidence from EVLP studies based on animal models suggests that modifying perfusion temperature, ventilation parameters, or utilizing pre-DCD exosome treatment and other adjunct approaches can mitigate IRI and improve DCD lung outcomes, indicating that DCD lungs may require different perfusion protocols compared to DBD lungs (34-37). The development of DCD-EVLP lungs’ specific perfusion protocols, along with investigation of potential reparative therapies, will be crucial for guiding future clinical decision-making regarding EVLP application.

Prone positioning

Given the association between PGD and increased interstitial fluid retention, gravitational effects should be carefully considered in clinical management. Prone positioning has demonstrated therapeutic efficacy in managing acute respiratory distress syndrome and acute lung injury, with proven mortality reduction and oxygenation improvement (38). In conventional EVLP protocols, donor lungs are typically maintained in the supine position, which may precipitate ventilation-perfusion mismatches and subsequent pulmonary edema (39). Previous studies have found that placing the donor lung in the prone position during EVLP can reduce reperfusion injury and protect lung function (40-42). However, the implementation of the prone position during EVLP may face significant technical challenges in routine clinical practice (43), such as risks of endotracheal tube kinking or dislodgement, along with safety concerns, rendering the procedure far more challenging in practice than in theory. Some studies have reported other body positions, such as placing the donor lung in a pronated or orthostatic position for EVLP (39,43). This consensus highlights that prone positioning should not be routinely employed in EVLP protocols, except in specialized circumstances, such as the donor lungs involving lower lobe pulmonary edema. Current evidence remains insufficient to establish definitive recommendations regarding positional management during EVLP, and further investigation and clinical exploration are needed.

Cold ischemia time (CIT)

In this consensus, a majority of panelists endorse 8–9 hours for CIT1 and CIT2 as acceptable, and at 10 ℃ preservation, CIT1 and CIT2 could be extended to more than 12 hours. CIT1 is defined as "time from cross-clamping to reperfusion by EVLP. It is worth noting that the panelists disagreed on the definition of CIT2. They agree that the starting point of CIT2 was the time point when the lung was removed from EVLP, but there were three different views on the end point: placement of the lung in the recipient’s chest cavity, placement of the first stitch of the anastomosis, and reperfusion of the first lung. The consensus emphasizes that standardized CIT2 definitions are very important for multiple studies on the duration of CIT, which would affect the comparability between studies.

Normothermic regional perfusion (NRP)

Unlike DBD organs, the injury profile of DCD organs is primarily driven by warm ischemic injury following cardiac arrest (44). For DCD organs, NRP has emerged as a novel procurement strategy. This technique is based on extracorporeal membrane oxygenation (ECMO) to deliver oxygenated blood to donor organs in situ under normothermic conditions before transplantation. Currently, NRP is primarily employed for abdominal organs and heart procurement (45). Although some research on NRP in lung transplantation reported encouraging outcomes (46), the consensus expert panel did not reach agreement regarding the role of EVLP for NRP DCD lungs, as the existing evidence and experience in this domain remain insufficient to formulate reliable recommendations. It is noteworthy that combining EVLP with other organ perfusion technologies represents a promising avenue for optimizing the lung transplantation workflow (47). For instance, the Dutch “HOPE After EVLP” protocol, which entails hypothermic oxygenated machine perfusion following a period of normothermic EVLP, has been reported to safely and effectively prolong ex vivo lung preservation (48). Building upon this concept, we hypothesize that continuing EVLP on the second lung during implantation of the first may likewise represent a viable strategy worthy of further exploration.

Current challenges and future perspectives

Critical gaps in current EVLP practice

Beyond establishing criteria for EVLP placement and transplantation, the consensus identifies critical gaps: evidence-based EVLP placement criteria, improved lung selection/assessment strategies and tools, biomarker roles, enhanced techniques/perfusion solutions. Addressing these gaps requires a dual focus on innovative fundamental research and large-scale, standardized multicenter prospective cohort studies. Fundamental research plays a critical role in elucidating the intrinsic mechanisms of lung injury and repair during EVLP. Such investigations not only provide theoretical foundations for discovering novel biomarkers and developing targeted perfusate, but also advance the refinement of other EVLP optimization strategies. For instance, previous studies have demonstrated that incorporating cytokine filters into the EVLP circuit to reduce levels of inflammatory mediators released from donor lungs into the perfusate can effectively mitigate inflammatory responses both during EVLP and after lung transplantation, while concurrently improving graft function (49). Meanwhile, multicenter prospective studies are critical to validate promising assessment tools and techniques, generate high-quality evidence for refining EVLP criteria, and ensure that findings are generalizable across diverse clinical settings. Only through such integrated efforts can the current limitations of EVLP be systematically overcome, paving the way for more reliable, efficient, and widely applicable practices in lung transplantation.

For China, which is in the early stage of EVLP, conducting multicenter prospective clinical research presents multiple challenges. Even though our team has already had some high-quality studies accepted internationally, the sample size is still relatively small (2,50). To facilitate the application and development of EVLP in China, the primary research focus may prioritize preclinical investigations. We recommend prioritizing foundational experimental research. Compared to human EVLP studies, experimental models utilizing small and large animals are better suited to China’s current exploratory phase. Through fundamental research to optimize the existing EVLP protocols, it can establish a robust preclinical foundation to enhance EVLP technical efficacy, improve donor lung quality, enhance recipient outcomes, optimize the operation process, and reduce application costs (51). These efforts will provide critical theoretical frameworks and practical references for advancing EVLP technology.

Economic challenges in EVLP

EVLP currently depends on specialized equipment and perfusate that often involve high production and supply chain costs. These financial burdens are not merely theoretical; they manifest concretely in regional adoption patterns and clinical decision-making. In Japan, where the usage rate of donated lungs is nearly 80%, EVLP offers limited potential to expand the donor pool; thus, the high costs associated with the technology have resulted in relatively low enthusiasm for its adoption (52). Beyond regional variations in adoption, the relatively high costs associated with lung transplantation and EVLP raise a critical question regarding financial responsibility when marginal donor lungs fail to meet transplantation criteria after EVLP treatment. This uncertainty in cost allocation involves multiple stakeholders, including patients who often cannot afford such high-risk medical expenses, transplant centers facing ethical dilemmas about cost redistribution, organ repair centers (ORCs) balancing operational sustainability as the technology providers, and the healthcare security system lacking dedicated payment mechanisms for such special circumstances. These challenges demonstrate that EVLP cost issues extend far beyond simple payment logistics, representing a systemic challenge that intersects with technical eligibility standards, ethical review frameworks, and healthcare resource allocation protocols.

Logistic challenges in EVLP

Given that clinical EVLP implementation demands highly specialized technical expertise, complete infrastructure, and substantial resource investment, this technology is currently concentrated in high-volume lung transplant centers (53). Therefore, the transplant community explored the feasibility of the centralized EVLP concept and established ORCs. Toronto General Hospital established the world’s first ORC and partnered with United Therapeutics in the United States to establish a subsidiary entity called Lung Bioengineering, constructing 2 specialized facilities, which provide comprehensive EVLP coverage across the continent (54). Centralized EVLP facilities have the potential to increase transplant volumes and utilization of extended criteria donor organs for smaller transplant programs in specified geographic regions.

The implementation of centralized ORCs, for example, in China faces unique challenges shaped by its national context. The country’s vast territory, complex geographical environment, and pronounced regional disparities in healthcare resource distribution create multifaceted problems for site selection and operational management of such centers. Based on current medical resource allocation patterns, these technical hubs would likely emerge first in economically and medically advanced regions. However, this concentration risks creating geographical imbalances between donor/recipient institutions and the ORC. Another question is whether to establish ORCs within transplant hospitals or locate them independently between donor and recipient hospitals. The establishment of ORCs within hospitals enhances treatment efficiency and facilitates multidisciplinary collaboration, though it imposes greater spatial and financial constraints. Conversely, independently constructed external centers enable large-scale operations and specialized research but introduce logistical challenges in organ transportation and systemic coordination. The optimal location should be determined through a comprehensive evaluation of critical factors, including treatment timeliness, operational costs, and resource allocation efficiency.

Conclusions

The consensus on acellular perfusate EVLP represents a significant step forward in standardizing a critical technology for expanding donor lung availability. Its recommendations offer practical guidance on key parameters of EVLP application, while also highlighting complex issues like pulmonary embolism management, NRP for DCD lungs, and optimal CIT. However, it also underscores the ongoing challenges in EVLP practice. Critical gaps remain, including the lack of universally accepted threshold values for key parameters, unresolved debates about differential strategies for DCD vs. DBD lungs, and ambiguities in defining CIT2. Additionally, questions such as the role of prone positioning during EVLP and the integration of NRP with EVLP in DCD lungs require further research. For China, unique challenges include geographical disparities in healthcare resources, difficulties in siting centralized ORCs, and cost-allocation dilemmas. Addressing these will require prioritizing foundational preclinical research to optimize protocols. While this consensus primarily addresses acellular perfusate systems, it should be noted that blood-based perfusate EVLP devices such as the Organ Care System (OCS) Lung system represent another important modality in current clinical practice, having demonstrated favorable post-transplant outcomes in clinical studies (55). To better define their clinical value and appropriate indications, additional high-quality evidence-based research remains necessary, with the ultimate goal of establishing evidence-informed clinical decision protocols and promoting the diversified development of EVLP technologies.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1599/prf

Funding: This research was supported by “Qimingxing” Research Fund for Young Talents, West China Hospital (No. HXQMX0034).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1599/coif). D.T. serves as an unpaid editorial board member of Journal of Thoracic Disease from March 2025 to February 2026. All authors report that this research was supported by “Qimingxing” Research Fund for Young Talents, West China Hospital (No. HXQMX0034). The authors have no other 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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