A primer on pain in sickle cell disease: a literature review

Introduction

Sickle cell disease (SCD) affects up to 100,000 individuals in the US. It is the most common inherited blood disorder in the US, characterized by chronic hemolysis. Pain is the most common reason for people living with SCD (PLwSCD) to present to healthcare systems and it occurs in the context of progressive end-organ dysfunction and early mortality. PLwSCD receive inequitable care and have poor access to both quality primary and specialty medical services. PLwSCD receive comparatively poor care in acute care settings. When compared to other painful conditions, such as renal colic or bone fractures, PLwSCD receive less aggressive pain control and wait longer to be seen by emergency medicine providers (1,2).

The lifetime SCD-attributable medical costs are as high as 1.7 million dollars for nonelderly adults with a total economic burden of $811 million in 2016 (3). Those with frequent SCD-related pain have a significant impact on health-related quality of life as well as increased work absenteeism (4). This review will explore both acute and chronic pain in SCD. The objective of this review is to provide healthcare providers of all levels the tools to provide high-quality evidence-based pain management to PLwSCD. It will provide an overview of the pathophysiology and management of acute and chronic pain in SCD and models of care delivery, all while examining the inequities that PLwSCD face when seeking care. This article is presented in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-25-29/rc).

Methods

References included in this review were chosen from the author’s expertise in the field, previously accumulated references, and exploring emerging references in topics of interest including queries of online databases. Additional references were recommended for inclusion and identified during the peer-review process.

Etiology of pain in SCD

Background and pathophysiology

SCD is most well-known for its acute painful episodes, commonly referred to as vaso-occlusive episodes (VOE) or crises. Frequency of VOEs varies between different genotypes and phenotypes of SCD. Early data from the Cooperative Study of Sickle Cell Disease (CSSCD), prior to approval of hydroxyurea, demonstrated an average number of episodes per patient year of 0.8 in hemoglobin (Hb) SS, 1 in HbSβ⁰-thalassemia, and 0.4 pooled frequency for Hb SC and Hb Sβ⁺-thalassemia (5). Published reports of pain frequency have varied significantly (6) and likely underestimate the burden of acute pain episodes in SCD. The Pain in Sickle Cell Epidemiology Study demonstrated that adults with SCD experience VOEs, but do not seek healthcare on 12.7% of days recorded (7). Smaller studies demonstrate a similar trend of home-based pain management in children with SCD (8). Though the genotypes Hb SS and HbSβ⁰-thalassemia, collectively referred to as sickle cell anemia (SCA), have higher rates of VOEs, stroke, acute chest syndrome, nephropathy, and pain episodes compared to other compound heterozygous forms (Hb SC, HbS-beta plus thalassemia), there is nuance. There is significant diversity in phenotype within each genotypic category. Further, often it is communicated to patients that if they aren’t having pain, they are “doing well”. Caution should be taken with this approach, as each subtype of SCD is at risk for end-organ damage. For example, individuals with HbSC disease are at highest risk for retinopathy (9), and even within Hb SS disease, there are phenotypes with high hemolytic rates and resulting pulmonary hypertension, leg ulcers, nephropathy, and priapism with comparatively few VOEs (10).

The pathophysiology of vaso-occlusion is complex, as are the mechanisms of pain nociception and eventual development of nociplastic pain. Though commonly thought of as an “on/off” phenomenon by healthcare providers, hemolysis and vaso-occlusion is a continuous and dynamic processes. As has been well documented, the underlying pathophysiology of SCD stems from a single substitution within the beta-globin gene locus, substituting a valine for glutamic acid amino acid. Due to this change, Hb tetramers undergo a conformational change and polymerize when deoxygenated, resulting in misshapen cells. Though Hb polymerization is the primary pathophysiologic trigger, vaso-occlusion is not simply related to misshapen red blood cells (RBCs) that do not fit through the microvasculature. Though it is beyond the scope of this review, vaso-occlusion is a complex interplay of increased RBC adhesivity to the vascular endothelium, vascular inflammation, intravascular hemolysis, adhesion of platelets and neutrophils, vasoconstriction, and ischemic-reperfusion injury (11).

Understanding the basic mechanisms of pain is important to the identification of new therapeutic targets. Advances have been made in our understanding of SCD pain, primarily utilizing mouse models, such as transgenic HbSS-BERK and HbSS-Townes mice. For example, findings that SS mice deficient in E- and P-selectins are protected from vaso-occlusion (12) led to the development of crizanlizumab, a humanized p-selectin monoclonal antibody, that is now Food and Drug Administration (FDA) approved for use in the US (13). More recently, oral carbon monoxide is an intriguing therapy for SCD, as it has demonstrated multiple benefits in mouse models of SCD, including reversing vaso-occlusion (14) and amelioration of endothelial inflammation (15). Evaluation of the safety, tolerability, pharmacodynamics, and pharmacokinetics of oral carbon monoxide is currently underway for adults with SCD (NCT06144749) (16).

Triggers of VOEs

Within individual patients, some may identify a specific trigger of their VOE. Broadly, there are multiple triggers that can promote a VOE. The most recognized conditions are such as infections, dehydration, sleep apnea, metabolic acidosis, and pregnancy. However, both the lived environment and psychosocial stressors also play a role in the onset of VOEs.

Weather, particularly temperature, wind, and humidity, plays a role in VOEs. Hospitalizations for VOEs and acute chest syndrome increase during colder months compared to warmer months (17) as well as with temperature drops (18). Wind is also a strongly reproducible trigger of sickle cell pain. In addition to weather, particulate matter and pollutants, as encountered when living near an interstate, have also been demonstrated to trigger VOEs (19). This is of particular importance as it may be an underrecognized social driver of health.

Lastly, mental stress and trauma are another trigger of VOEs. The mechanism of this is likely due to stress-induced vaso-constriction and resultant occlusion (20). Additionally, baseline anxiety levels have an effect on vaso-constriction in PLwSCD, something not found in healthy controls (20). Another stressor that is encountered often is the anticipation of pain itself, which may further contribute to global vasoconstriction and vaso-occlusion (21).

Acute VOEs

Persons living with SCD have inadequate pain control

Before delving into how to treat SCD VOE pain, the context and environments where SCD pain is managed should be examined. SCD care is marred by racism in medicine, unconscious biases, fears surrounding opioids, and is provided by healthcare providers who, by and large, harbor negative attitudes towards SCD and are uncomfortable providing SCD care (22). With this discomfort comes erroneous reliance on vital signs and laboratory values as surrogates for pain. PLwSCD encounter significant barriers when seeking acute care, are often labeled as “drug seekers”, and their pain is not believed.

These attitudes are born out in the experiences of patients. Compared to renal colic, PLwSCD have worse pain control and wait longer to see a physician, despite higher triage scores (2). Compared to patients with long-bone fractures, they wait 50% longer to see a physician, despite higher triage scores (1). These experiences have significant impacts on patients, with 67% of PLwSCD delaying their emergency care for fear of how they will be treated (23). When asked, emergency medicine providers and nurses have identified high patient volumes, lack of protocols, stigma, and poor communication as primary barriers to receiving care (24). These perspectives were collected in 2017, and emergency departments (EDs) have become even more congested with impacts of the coronavirus disease 2019 (COVID-19) pandemic (25).

It should be emphasized that vital signs and lab results do not predict the presence of pain. The gold-standard for diagnosing pain in SCD is self-report.

Management of acute SCD pain

Timely analgesia with frequent reassessment is the cornerstone of VOE management. Guidelines from the National Heart, Blood, and Lung Institute (NHLBI) in 2014 and American Society of Hematology (ASH) in 2020 recommend rapid initiation of analgesia within 60 minutes of arrival (26,27). Pain should be reassessed frequently, at least every 30–60 minutes to ensure adequate pain control (24). There has been longstanding expert consensus that rapid and aggressive pain management may help prevent hospital admissions (26,28). This has been demonstrated in our current environment of the electronic medical record. Interventions such as order sets and clinical practice guidelines can be disseminated throughout institutions to improve care, improving timeliness of analgesia and decreasing hospital admissions (29,30).

Similarly, both the NHLBI and ASH recommend that each patient’s analgesia be guided by an individualized care plan (ICP) (26). Creation of quality ICPs depends on the presence of an engaged team, ideally led by a SCD specialist, and thus may not be available in some systems. They should be created in collaboration with each patient with SCD. Further, there are often issues with provider awareness of ICPs. There is no current consensus on the essential components of an ICP.

SCD pain is undertreated and providers are uncomfortable prescribing opioids. Work by Tanabe and colleagues provides guidance for initial treatment of vaso-occlusive pain. By providing patient-specific doses, based on total opioid intake in the prior 24 hours, they demonstrated greater reduction in pain, lower hospitalization rates, and an acceptable side effect profile when compared to weight-based dosing in a pilot two-site study (31). In a larger multisite study, patients with a patient-specific protocol had a shorter ED length of stay (LOS) without significant difference in pain reductions, hospital admissions, or adverse effects (32). It should be noted that in the larger multi-site study, doses were more comparable between patient-specific and weight-based dose groups when compared to the pilot study. The development of this tool has been described in detail (33) and is available through the National Alliance of Sickle Cell Centers (NASCC) (34).

If hospitalization is required, patient-controlled analgesia is the standard at most institutions (26) and recommended as first-line treatment, if it is developmentally appropriate, by NASCC consensus recommendations on VOEs. The ASH SCD pain guideline panel chose not to offer a recommendation for or against the addition of continuous opioid infusions to patient-delivered doses (26) and there are varying practices in this regard. A single-center study that retrospectively evaluated an institutional guideline eliminating continuous opioid infusions in children demonstrated significant reductions in LOS, total opioid dose, acute chest syndrome, and hypoxia (35). NASCC recommends avoidance of basal infusions in adults, unless indicated in their ICP, and use of continuous pulse oximetry in children on continuous opioid infusions (36).

Multimodal analgesia

A multimodal approach to pain should be taken and tailored to each individual patient. Opioids are limited in the relief they may provide, particularly as patients develop overlapping complex chronic pain. A careful appraisal of a patient’s individual risk factors should be considered.

Non-steroidal anti-inflammatory drugs (NSAIDs) may be helpful in the treatment of SCD pain, though data have been conflicting. Nonetheless, the ASH guideline panel does recommend a short course of NSAIDs for the management of VOE in children and adults with SCD (26). This should be individualized, as patients with SCD may have pre-existing conditions that preclude the use of NSAIDs, such as renal disease or current therapeutic anticoagulation. There have been few studies evaluating the use of acetaminophen for the management of VOEs (37). Though a small retrospective chart review did demonstrate reductions in pain scores when intravenous acetaminophen was added to opioids (37).

There has been increasing interest in and use of ketamine to treat acute SCD pain (38). Data evaluating the addition of ketamine to opioids are limited, though retrospective studies do demonstrate benefits in opioid reduction and pain control (39). The implementation of ketamine therapy centers remains variable (40) and further research is necessary in this area. The NASCC has issued consensus recommendations on the implementation of ketamine, to consider the addition of subanesthetic ketamine to opioids in the context of difficult to manage and/or prolonged VOEs (36).

Models of acute care delivery for pain management

As previously noted, EDs face overwhelming rates of congestion and acuity. Day hospitals or infusion centers (IC) offer an attractive alternative. The Examining Sickle Cell Acute Pain in the Emergency Versus Day Hospital trial was a multi-center trial that demonstrated that PLwSCD treated ICs have faster time to first analgesic dose, greater likelihood of pain reassessment within 30 minutes of the first dose, and are four times less likely to be admitted to the hospital (41). ICs should be incorporated into health systems serving PLwSCD, as they offer greater opportunity to provide quality care to PLwSCD, adhere to national SCD pain guidelines, and ease stress on burdened EDs and hospitals. The ASH SCD pain guidelines suggest using SCD-specific acute care facilities, such as ICs, over the use of EDs (26). Further research is needed on the cost-effectiveness of such models, though preliminary models demonstrate cost savings (42).

Prevention of acute pain episodes

Disease modification is the cornerstone of preventing VOEs. When compared to other rare diseases, such as cystic fibrosis, disparities exist in research funding and development of disease modifying agents for SCD (43). Hydroxyurea has remained the cornerstone of the management of SCA (HbSS and HbSβ⁰-thalassemia), with associated reductions in VOEs, hospitalizations for VOE, acute chest syndrome, and mortality (44-46). Less evidence exists for the other compound heterozygous forms of SCD. A recent phase II trial evaluating the use of hydroxyurea in HbSC disease failed to meet its primary endpoint, as more hematologic toxicities were noted in the treatment group. However, a reduction in VOEs was noted in both children and adults with HbSC treated with hydroxyurea (47).

Hydroxyurea remained the only FDA-approved medication for almost two decades, until the approval of L-glutamine in 2017. In persons with HbSS and HbSβ⁰-thalassemia, L-glutamine demonstrated modest reductions in VOEs when compared to placebo, decreasing median annual crises (3 versus 4) and hospitalizations (2 versus 3) (48). Two additional medications have since been approved by the FDA. Voxelotor has been voluntarily withdrawn from the market and is no longer available for use. Crizanlizumab, a humanized p-selectin monoclonal antibody, showed promise in phase II trials, reducing both rates of VOE and time to first VOE (13). However, these findings were not replicated in the phase III trial (49). Though still available in the US, crizanlizumab is not available in the European Union, after its conditional marketing authorization was revoked in 2023.

When a patient is intolerant of the above disease modifiers or has continued severe disease activity despite them, chronic transfusion therapy may be considered, though the benefits need to be weighed against significant risks of alloimmunization, transfusion reactions, and iron overload. It should be emphasized that RBC transfusions are not effective therapies for acute or chronic pain. Additionally, bone marrow transplantation or gene therapy may be considered for those with severe disease, though these are outside the scope of this review.

Chronic pain in SCD

Background and pathophysiology

Chronic pain in SCD tends to emerge in late adolescence and early adulthood, with a rate of 16.7% in persons 15–19 years old increasing to 60% in adults 20–29 years old in one cohort (50). Central sensitization, which refers to increased responsiveness of nociceptive neurons, is found in up to 60% of adults with SCD (51) and has a profound impact on wellbeing and disease activity. Patients with SCD and central sensitization demonstrate higher levels of pain, increased catastrophizing, negative mood, worse sleep, and more frequent VOEs with poorer quality of life (52,53). Insight into the basic underlying mechanisms of chronic pain in SCD has been emerging through the use of functional magnetic resonance imaging (MRI), though compared to other chronic pain syndromes, there have been comparatively few studies. Functional MRI demonstrates greater connectivity between the midcingulate cortex and the default mode network in patients with frequent VOEs (54). Though subsequent results have been conflicting (55). Only one study has demonstrated that adults with chronic pain due to hip osteonecrosis demonstrated an impaired dynamic brain network with more diffuse connectivity and a shorter full synchronization time, indicating a maladaptive pattern of plasticity (56). More research is needed in this area.

Chronic pain has a profound impact on the quality of life for persons with SCD (53), including depression and more frequent VOEs (57), and contributes to the economic impact of SCD on our health system. Persons with SCD and more frequent VOEs incur higher healthcare costs—$67,282 per year with a lifetime cost of $3.8 million (58)—compared to a lifetime attributable cost of $1.7 million amongst non-elderly adults with SCD (3).

Identified risk factors for developing chronic pain in SCD are poor social support, poor socio-emotional functioning, depression and anxiety, history of interpersonal violence, low income, and higher baseline levels of reported disability (59-61). Beyond frequency of VOE, no biological correlates, such as degree of anemia, predict the development of chronic pain (60).

When approaching chronic pain in SCD, it’s helpful to reference the definitions and diagnostic modifiers set forth by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks-American Pain Society Pain Taxonomy (AAPT) (62). The AAPT recommendations provided subtypes or “diagnostic modifiers” of chronic pain in SCD, including chronic pain with or without contributing disease complications, such as avascular necrosis (AVN), as well as a mixed pain type with pain occurring both in areas with contributory disease in addition to other areas without complications (62). A major takeaway from these criteria is that chronic SCD pain may exist without objective evidence of direct tissue injury from disease, a phenomenon known as nociplastic pain. However, we will first review the impact of nociceptive pain-pain that arises out of inflammation and/or direct tissue injury, followed by nociplastic and neuropathic pain.

AVN, also known as osteonecrosis, is the most encountered direct tissue injury that may lead to chronic pain. AVN may have little to no symptoms early on and it commonly progresses to more severe pain, decreased mobility, and eventual joint collapse. AVN is common, with 9.8% of PLwSCD over 5 years old having AVN of one or both femoral heads, judged by radiography, upon entry into the CSSCD (63). A more recent study of administrative data from California showed higher rates of femoral head AVN, up to 22% (64). The humeral head is the second most common site, with prevalence as high as 5.6% (63). The vertebral bodies are also susceptible to AVN, with eventual collapse and chronic back pain. Initially, the management of AVN is supportive, with joint offloading and physical therapy. However, progression occurs in many patients who will ultimately require joint replacement once bony collapse occurs. There are no prospective controlled studies evaluating the use of hydroxyurea, bisphosphonates, chronic transfusions, or curative/transformational therapies on the progression of AVN. Bone infarctions can also occur in long bones, and other locations such as the face and skull, often presenting as severe acute pain that lingers for weeks with a gradual recovery.

Leg ulcers are another manifestation of direct tissue injury from SCD that often causes chronic pain. Leg ulcers are most common in persons with Hb SS disease and the prevalence varies globally (65). In the US, the prevalence is approximately 10%. Beyond wound care and analgesia, there are no reliable treatment strategies. A Cochrane Review of treatment strategies for SCD noted all low-quality evidence and uncertainty about whether any of the interventions led to reliable improvement (66). They remain extremely difficult to treat.

Finally, often chronic pain exists in PLwSCD without evidence of underlying tissue damage or extends beyond known areas of tissue damage. This underlying pain is known as nociplastic pain, which is pain due to altered nociception without underlying tissue damage or another underlying cause (67) that may present as multifocal widespread pain (68). A survey-based study of 48 PLwSCD ages 14–35 years found that nociplastic pain was positively associated with pain interference and opioid consumption (69). Though there has been extensive study of chronic pain in SCD, there are comparatively few investigations into the nociplastic pain that go beyond the characterization and identification of central sensitization in PLwSCD. Nociplastic pain is distinct from neuropathic pain. Neuropathic pain is pain that arises out of pathologies affecting the somatosensory nervous system (70). It occurs in 25–40% of adults with SCD and often presents with unique descriptions of pain such as burning, tingling, pins and needles, and electric shocks (71). The underlying pathophysiology is poorly understood, beyond the injury from repeated vaso-occlusive insults.

Management of chronic SCD pain

There are no high-quality randomized studies on the treatment of chronic pain in SCD. The most recent guidelines from ASH look to evidence in other chronic pain syndromes for guidance. Here, we will review the available recommendations and evidence for chronic pain management.

In 2020, ASH provided guidance on the management of chronic pain. Based on indirect evidence of benefit in osteoarthritis, the guideline panel suggests the use of duloxetine and other serotonin-norepinephrine inhibitors and NSAIDs to manage chronic pain due to AVN in adults with SCD, both based on very low certainty in the evidence about effects. The guideline panel did not offer recommendations for children with AVN or the management of chronic pain due to leg ulcers (26). Caution should be taken in patient selection for chronic NSAIDs given the high prevalence of renal disease in PLwSCD.

For adults with chronic pain and “no identifiable cause beyond SCD”, the ASH guideline panel suggests the use of serotonin-norepinephrine inhibitors, tricyclic antidepressants, and gabapentinoids. All recommendations were based on very low certainty in the evidence about effects and were largely based on indirect evidence in fibromyalgia. Importantly, the guideline panel also suggests use of “cognitive behavioral pain management strategies in the context of a comprehensive disease and pain management program” as well as provider-delivered integrative approaches such as massage therapy and acupuncture (26).

It should be noted that there is a paucity of randomized controlled trials evaluating therapies for chronic pain in SCD. A systematic scoping review in 2023 identified only seven trials, four of which showed modest improvements with varying sample sizes. Interventions included smartphone-based cognitive behavioral therapy (n=46) (72), mindfulness-based intervention (n=78) (73), a 12-week physical therapy program (n=10) (74), and five days of vaporized cannabis (n=23) (75). For cannabis in particular, it is hard to generalize this to the general population, given the relatively small study size and short course of use and risk for long-term effects. The ASH panel chose not to provide a recommendation on cannabis as it is still classified as an illegal substance under Federal law (26). More rigorous evaluation of management approaches to chronic pain in SCD is needed.

With the context of few available options to manage pain, healthcare providers have historically relied on opioids to manage chronic pain in SCD. A claims-based study in 2018 estimated that 40% of adults with SCD were on an opioid during the 12-month period of the study (76), consistent with prior estimates. It should be noted that this rate has remained relatively stable, even in the context of the opioid epidemic, as demonstrated in a claims-based study examining opioid prescriptions from 2008 to 2013 that found stable rates of opioid prescriptions to adults with SCD, while prescriptions to the general population increased substantially (77). Another recent analysis demonstrated potential harm of the 2016 Centers for Disease Control and Prevention (CDC) guidelines, with increases in healthcare utilization and decreased opioid prescriptions following their release (78). This is despite guidance from the CDC clearly stating that their recommendations do not apply to SCD-related pain (79). Considering this, the ASH guideline panel suggested against initiation of chronic opioid therapy as a first-line agent for both children and adults with SCD, unless the pain is refractory to other treatments. Recognizing that a substantial portion of PLwSCD may be on chronic opioid therapy, the guideline panel suggests shared decision-making for continuation in those who are functioning well (26). It is important to note the approach of focusing on a person’s function, rather than relying on measures such as a pain score. Care must be taken when discussing the risks and benefits of opioids, which have significant neurocognitive, psychological, gastrointestinal, and endocrine side effects. Further, in patients with chronic back, hip, or knee pain, chronic opioids were associated with worse pain intensity compared to non-opioid therapy (80).

Despite these risks, a substantial portion of PLwSCD remain on chronic opioids to manage their pain, often in the context of few other available options. A possible option for those with severe pain and who are on chronic opioid therapy is buprenorphine. There is emerging evidence that conversion to buprenorphine may be associated with improved pain control and decreased acute care utilization (81,82). Qualitative data suggests that in those in whom buprenorphine is successful, it may have positive impacts on function and relationships as well as the experience of pain (83).

Conclusions

Here, we reviewed pain in SCD through a broad lens, from episodic acute pain and its need for aggressive treatment as well as the complex nature of chronic pain in SCD and its management. This work is limited by the nature of the literature review. Given the goals of the review with breadth of material covered, a structured literature search was not feasible. Thus, it is subject to bias from the author’s personal experience and knowledge of the published literature. In conclusion, PLwSCD deserve aggressive and equitable management of their pain. A first step towards attaining this is ensuring healthcare providers have confidence and up-to-date knowledge in the management of pain.

Acknowledgments

This work was completed in part by F.C. at the University of Rochester Medical Center.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (William B. Ershler and Sheinei Alan) for the series “Adult Sickle Cell Disease” published in Annals of Blood. The article has undergone external peer review.

Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-25-29/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-25-29/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-25-29/coif). The series “Adult Sickle Cell Disease” was commissioned by the editorial office without any funding or sponsorship. F.C. reports grant funding from Mother Cabrini Health Foundation, honoraria form Virginia Commonwealth University, and support for attending meeting/travel from American Society of Hematology, National Alliance of Sickle Cell Centers and Blood Banks Across NY. F.C. also served as Co-chair of Sickle Cell Disease Health Professions Education Taskforce in American Society of Hematology, and is a formerboard member of Sickle Cell Advocates of Rochester. F.C. also serves as track co-lead for medical providers, consensus co-lead for defining an adult SCD specialist, meeting planning committee member in National Alliance of Sickle Cell Centers. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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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