|Year : 2023 | Volume
| Issue : 1 | Page : 48-55
Do comorbidities and triggers expedite chronicity in migraine?
Emel Ur Ozcelik1, Ezgi Uludüz2, Rahşan Karacı3, Füsun Mayda Domaç3, Mustafa İskender4, Aynur Özge5, Derya Uludüz6
1 Department of Neurology, University of Health Sciences, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Türkiye
2 Koç University, School of Medicine, Medical Student, Istanbul, Türkiye
3 Department of Neurology, University of Health Sciences, Erenkoy Mental Health and Neurological Disorders Training and Research Hospital, Istanbul, Türkiye
4 Private Clinic, Neurology, Kocaeli, Türkiye
5 Department of Neurology and Algology, Mersin University, Mersin, Türkiye
6 Department of Neurology, Istanbul University, Cerrahpaşa Medical Faculty, Istanbul, Türkiye
|Date of Submission||31-Dec-2022|
|Date of Decision||21-Jan-2023|
|Date of Acceptance||23-Jan-2023|
|Date of Web Publication||29-Mar-2023|
Emel Ur Ozcelik
Department of Neurology, University of Health Sciences, Kanuni Sultan Süleyman Training and Research Hospital, Atakent Mahallesi Turgut Özal Bulvari No: 46/1 34303, Küçükçekmece, Istanbul
Source of Support: None, Conflict of Interest: None
Background and Aim: Several factors are suggested to be associated with an increased risk of transforming from episodic migraine (EM) to chronic migraine (CM). We aimed to examine whether some specific attack triggers and comorbidities were associated with CM. Methods: Patients followed up with a diagnosis of definite migraine for at least 1 year were divided into two groups, EM (<15 attacks per month) and CM (>15 attacks per month). The demographic and clinical data, attack-triggering factors, and comorbid diseases were compared between the groups. Results: A total of 403 (286 females) patients were analyzed; 227 (56.3%) of the migraineurs had EM and 176 (43.7%) had CM. The mean age was 40.9 ± 11.3 years in EM, and 42.2 ± 11.7 years in CM. Disease duration was longer in CM compared with EM (P = 0.007). Missing meals (P = 0.044), exposure to heavy scents/perfumes (P = 0.012), intense physical activity (P = 0.037), and withdrawal of caffeine (P = 0.012) were reported significantly higher in CM than in EM. Comorbid history of medication overuse (P < 0.001), hypertension (P = 0.048), hyperlipidemia (P = 0.025), depression (P = 0.021), chronic painful health problems (P = 0.003), iron deficiency anemia (P = 0.006), and history of surgery (P = 0.006) were found significantly high in CM. Conclusion: This study demonstrates that attack-triggering factors, vascular comorbidities, depression, medication overuse, and chronic painful health problems pose significant risks for CM. Vascular comorbidities are independent risk factors for chronification in migraine and might increase the patient's lifetime morbidity and mortality. Therefore, prompt diagnosis of migraine before the transformation to chronicity and effective early management have the utmost importance.
Keywords: Chronic migraine, migraine comorbidities, migraine triggers, vascular risk factors
|How to cite this article:|
Ozcelik EU, Uludüz E, Karacı R, Domaç FM, İskender M, Özge A, Uludüz D. Do comorbidities and triggers expedite chronicity in migraine?. Neurol Sci Neurophysiol 2023;40:48-55
|How to cite this URL:|
Ozcelik EU, Uludüz E, Karacı R, Domaç FM, İskender M, Özge A, Uludüz D. Do comorbidities and triggers expedite chronicity in migraine?. Neurol Sci Neurophysiol [serial online] 2023 [cited 2023 Jun 10];40:48-55. Available from: http://www.nsnjournal.org/text.asp?2023/40/1/48/372785
| Introduction|| |
Migraine is a worldwide common (~12%) neurologic problem that negatively affects the quality of life by causing loss of workforce and functionality during unpredictable, recurrent, and moderate/severe headache attacks., Cortical hyperexcitability, trigeminovascular system activation, and cortical spreading depression theories stand to explain the highly complex pathophysiology of migraine. Genetic predisposition and environmental factors also contribute to migraine development.
Nationwide migraine studies performed on the Turkish population have reported the prevalence of migraine as 16.7%, its incidence as 2.38% (2.98% for women, 1.93% for men), and the incidence of chronic migraine (CM) without medication overuse as 0.066%., These prevalence and incidence reports reveal that migraine is one of the leading disabling diseases and poses a serious burden. Therefore, it is crucial to reduce the frequency of attacks and prevent chronicity. Not every episodic migraine (EM) turns into a chronic form; the annual conversion rate is reported to be around 2.2%–3.1%. Medication overuse, insufficient prophylaxis, and various comorbid conditions have been associated with chronicity in studies conducted to date; however, the mechanism of transformation from EM to CM and all the associated factors have not been fully elucidated.,, Avoiding triggers is the first step toward reducing the number of attacks, but studies investigating and comparing the effects of both comorbid diseases and specific triggers on the frequency and severity of attacks in EM and CM are limited.,
Considering the psychosocial burden that CM brings to an individual's life, it is essential to examine the factors that trigger chronicity and minimize the possible risks because they may affect the course of migraine., This study aimed to reveal factors that could be associated with transformation to CM by comparing triggers and comorbid conditions in patients with migraine.
| Methods|| |
Study subjects and design
This retrospective study used data from two tertiary headache outpatient clinics of neurology departments. The medical charts of patients admitted with headaches were reviewed retrospectively. The patients who were followed up with a diagnosis of definite migraine for at least 1 year were divided into two groups, EM (<15 attacks per month) and CM (>15 attacks per month).
The demographic and clinical information, comorbid conditions, vascular risk factors, additional health problems, and attack-triggering factors were collected and compared between the two groups. Migraineurs younger than 18 years were excluded. Medication overuse was assessed as regular overuse of acute migraine treatment for >3 months, including acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, and acetaminophen for ≥15 days/month, and ergotamines, triptans, opioids, or combination analgesics for ≥10 days/month. The presence of medication overuse history was regularly questioned during the interviews with the patients and was noted in their files.
Patients were evaluated for depression and anxiety disorder according to self-reports and the evaluation of a psychologist based on the Beck Depression and Anxiety Inventory Scales.
Health problems observed in our patient sample were grouped as follows: (i) Cardiovascular disease: cardiac stent, myocardial infarcts, hypertension, (ii) metabolic/endocrinologic diseases: hyperlipidemia, diabetes mellitus, thyroid disease, (iii) hematologic diseases: anemia, (iv) other neurologic diseases: epilepsy, obstructive sleep apnea, stroke, restless leg syndrome, (v) psychiatric diseases: depression, anxiety disorder, and others (bipolar disorders, obsessive–compulsive disorder, panic attack), (vi) chronic painful health problems: musculoskeletal disorders (e.g. fibromyalgia, arthritis, neck pain, back pain, leg pain) and gastrointestinal problems (ulcers, gastritis, ulcerative colitis, constipation), and (vii) other various health problems: ocular problems, gynecologic problems, cancers, allergies, asthma, or bronchitis.,
Ethics Committee approval (Date: May 09, 2022, Decision no: 27) was obtained for this study.
Statistical analyses were conducted using the IBM SPSS Statistics for Windows, version 22.0 software package (IBM Corp, Armonk, New York, USA). Descriptive statistics were used to describe the study population characteristics. Quantitative variables are expressed as mean ± standard deviation, and qualitative variables are expressed as frequency and percentage values. The Shapiro–Wilk normality test was used to test the normality of the distribution of quantitative data. The independent samples t-test was used to compare normally distributed continuous variables, and the Mann–Whitney U-test was used for variables not normally distributed. Pearson's Chi-square and Fisher's exact tests were used to compare categorical variables and frequencies of occurrence. Subsequently, we ran the Mantel–Haenszel test (also known as the linear by linear association test) to examine risk factors such as comorbidities and triggers associated with chronicity in migraine. In this analysis, 95% confidence intervals (CI) were reported, and statistical significance was considered P < 0.05. Stratification analyses were performed for age (>40 years and <40 years) and sex.
| Results|| |
Demographic and clinical characteristics
Among the total 403 participants, 227 (56.3%) had EM and 176 (43.7%) had CM. The mean age was 41.2 ± 11.6 (min–max: 18–75) years and 286 of the individuals (71%) were women [Table 1]. There was no statistical significance between the EM and CM groups in terms of age, sex distribution, and headache onset age. The disease duration of migraine was longer in the CM group (P = 0.007) [Table 1].
|Table 1: The clinical and demographic data in episodic versus chronic migraine|
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History of prophylactic medication use was as follows: Antidepressants (EM: 43.4%, CM: 55.1%, P = 0.019), antiseizure medications (EM: 19.8%, CM: 29%, P = 0.032) beta-blockers (EM: 13.2%, CM: 15.3%, P = 0.544), calcium-channel blockers (EM: 6.6%, CM: 11.9%, P = 0.092) magnesium (EM: 4.4%, CM: 11.9%, P = 0.009), botulinum toxin injections (EM: 13.7%, CM: 25%, P = 0.004), other interventional therapies such as peripheral nerve blocks (EM: 17.6%, CM: 34.1%, P < 0.001), and alternative approaches (EM: 14.1%, CM: 18.2%, P = 0.266). Experience of using two or more prophylaxis agents was more common in CM than in EM (P = 0.04).
Analysis of comorbidities
Statistically significant differences (CM > EM) were found between the two groups for the following: medication overuse (P < 0.001), the existence of psychiatric disease (P = 0.028), having chronic painful health problems (P = 0.003), history of surgery (P = 0.006), and iron deficiency anemia (P = 0.006), and having vascular risk factors such as hyperlipidemia (P = 0.025), and hypertension (P = 0.048). [Figure 1] shows the distribution of comorbidities in each group. [Table 2] gives the odds ratio (OR) for the significant differences between the groups.
|Figure 1: The comorbidities in episodic versus chronic migraine. (*: P <0.05, **: P <0.01)|
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The distribution of comorbid chronic painful health problems was as follows: Musculoskeletal disorders were reported by 22.5% in the EM group and 28.4% in the CM group (P = 0.172), gastrointestinal problems including ulcers/gastritis/reflux, ulcerative colitis and constipation were reported by 13.2% the EM group and 22% in the CM group (P = 0.003). In the subgroup analysis of gastrointestinal problems, the frequency of constipation was 5.3% in EM and 10.8% in CM (P = 0.040).
The distribution of various health problems was as follows: allergic problems were reported by 8.8% in the EM group and 13.1% in the CM group (P = 0.170), asthma bronchitis was reported by 7.5% in the EM group and 8% in the CM group (P = 0.836), diabetes mellitus was reported by 7% in the EM group and 9.2% in the CM group (P = 0.432), and thyroid disease was reported by 13.7% in the EM group and by 19.5% in the CM group (P = 0.113).
The rate of surgery history on the head-ear-nose-throat region was 14.1% in EM and 21.6% in CM (P = 0.049), for thyroid diseases, it was 2.2% in EM and 3.4% in CM (P = 0.068), and for various other reasons, it was 30.8% in EM and 36.9% in CM (P = 0.199).
The distribution of psychiatric diseases was as follows: depression was reported by 22.5% in the EM group and 32.8% in the CM group (P = 0.021), anxiety disorder was reported by 11.9% in the EM group and 16.1% in the CM group (P = 0.226), other psychiatric disorders were reported by 0.9% in the EM group and 2.8% in the EM group (P = 0.135).
We found no significant difference between EM and CM in terms of comorbid other neurologic diseases (P = 0.97).
Additional statistical analyses (linear association) were performed for parameters with significant differences between the groups using the Chi-square test [Table 2].
In subgroup analyses, we found some significant differences (CM > EM) between the sexes. The odds for CM in women were higher when accompanied by gastrointestinal problems (OR = 2.2, 95% CI: [1.2–4.0]; P = 0.013), history of surgery (OR = 1.9, 95% CI: [1.6–3.1]; P = 0.010), metabolic/endocrinologic diseases (OR = 1.8, 95% CI: [1.1–3.0]; P = 0.018), hyperlipidemia (OR = 2.7, 95% CI: [1.3–5.9]; P = 0.007), psychiatric diseases (OR = 1.8, 95% CI: [1.2–2.9]; P = 0.015), depression (OR = 1.8, 95% CI: [1.1–3.0]; P = 0.02), iron deficiency anemia (OR = 2.3, 95% CI: [1.4–3.9]; P < 0.001), and chronic painful health problems (OR = 2.1, 95% CI: [1.4–3.5]; P < 0.001).
Age stratification analyses revealed some significant differences (CM > EM) between patients aged over and under 40 years. The odds for CM were higher for hyperlipidemia (OR = 3.3, 95% CI: [1.5–7.2]: P =0.002), hypertension (OR = 3.9, 95% CI: [1.6–9.4]; P = 0.003), and chronic painful health problems (OR = 1.9, 95% CI: [1.1–3.2]; P = 0.02) in patients aged >40 years. Only the odds ratio for iron deficiency anemia (OR = 2.2, 95% CI: [1.1–4.3]; P = 0.03) was higher among patients aged under 40 years.
Analysis of triggers
The mean number of reported attack triggers was 7.7 ± 3.9 (0–18) in EM, whereas it was 8.5 ± 3.9 (0–19) in CM (P = 0.083).
Missing meals (P = 0.044), exposure to heavy scents/perfumes (P = 0.012), caffeine withdrawal (P = 0.012), and intense physical activities (P = 0.037) were reported to be more common triggers among those with CM compared with EM. Additional statistical analyses (linear association) for the parameters with significant differences between the groups using the Chi-square test are given in [Table 3].
In subgroup analyses, we found some significant differences (CM > EM) between the sexes. The risk of having CM in female patients was increased when accompanied by intense physical activity (OR = 1.9, 95% CI: [1.5–3.1]; P = 0.02) and caffeine withdrawal (OR = 2.2, 95% CI: [1.9–4.1]; P = 0.02). In contrast, male CM patients had higher odds when accompanied by missing meals (OR = 4.2, 95% CI: [1.9–9.2], P < 0.001) and hunger (OR = 2.5, 95% CI: [1.2–5.6]; P = 0.02).
Triggering factors such as stress (EM: 79.3%, CM: 85.7%, P = 0.96), lack of sleep (EM: 67%, CM: 73.1%, P = 0.181), fasting/hunger (EM: 68.7%, CM: 77.1%, P = 0.061), and climate changes (EM: 53.3%, CM: 52%, P = 0.795) were the most reported triggers in both groups. [Figure 2] shows the distribution of reported triggers in EM and CM.
|Figure 2: The triggers in episodic versus chronic migraine. (*: P <0.05)|
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| Discussion|| |
In this study, vascular comorbidities such as hypertension and hyperlipidemia, chronic painful health problems, iron deficiency anemia, history of surgery, depression, and medication overuse were associated with CM. Furthermore, attack triggers such as missing meals, withdrawal of caffeine, heavy scents/perfumes, and intense physical activities were reported significantly frequently among the patients with CM.
Comorbidities in episodic versus chronic migraine
Some studies have found an association between migraine and high blood pressure, and some noted an inverse relationship between migraine and high blood pressure., In a recent meta-analysis, data on the possible relationship between migraine and high blood pressure were heterogeneous and no definitive conclusion was possible. Methodologic, etiologic, and demographic differences in the studies may have played a role in this heterogeneity. On the other hand, it has been reported that hypertension accompanies more frequently in patients with CM compared with those with EM, and the presence of hypertension is associated with chronicity. Similarly, we found that hypertension was more common in our patients with CM than in those with EM, and in subgroup analysis, having hypertension was found to be associated with CM in migraineurs aged over 40 years.
Comorbidity of migraine and hypertension can be explained by underlying similar pathophysiologic mechanisms, such as endothelial dysfunction, autonomic cardiovascular regulation impairment, deterioration in nitric oxide release, and involvement of the renin-angiotensin system. The use of antihypertensives in migraine prophylaxis also strengthens these hypotheses.
The relationship between hyperlipidemia, the other well-known vascular risk factor, and migraine has also been the subject of various studies. Some researchers have pointed out that hyperlipidemia and other cardiovascular risk factors are more frequent, especially in migraineurs with aura, whereas others stated that there was no significant difference between migraine with and without aura, but having migraine increased the risk. Furthermore, hyperlipidemia was reported to be associated with CM more than with other migraine subgroups in some studies., Supporting these former studies, in our study, the frequency of hyperlipidemia was also higher in patients with CM than in those with EM. In addition, the risk of having CM was found to be increased among women and patients over 40 years with hyperlipidemia, which is in line with the normal population.
Clinic and population-based studies reported various comorbid conditions, including noncephalic chronic pain conditions, gastrointestinal problems, thyroid diseases, allergies, diabetes, respiratory diseases, and head-and-neck trauma history in migraine, particularly in CM. We grouped gastrointestinal problems and musculoskeletal disorders as chronic painful health problems because both conditions lead to pain.,
The high comorbidity rate of having gastrointestinal problems in CM is most probably due to the frequent use of analgesics and polypharmacy. In addition, increased stress levels in patients with CM may cause cortisol release by activating the hypothalamic–pituitary (HPA) axis, and subsequently, prolonged release of cortisol may lead to pain and inflammation, which may explain gastrointestinal symptoms. In subgroup analyses for gastrointestinal problems, constipation was found more commonly in our patients with CM; this may be related to the frequent use of antidepressants, which was also significantly greater in patients with CM than in those with EM. Moreover, the shared triggering factors such as stress, dehydration, bad eating habits, and shared pathophysiologic mechanisms such as fluctuations in serotonin (5-hydroxytryptamine) levels may cause both chronic constipation and CM.
In several studies, chronic pain disorders due to musculoskeletal problems, including fibromyalgia, back pain, and neck pain, were reported to be more common in CM. Scher et al. noted that the presence of noncephalic pain was associated with CM onset and also with the persistence of CM.
The frequent coexistence of migraine and chronic pain conditions may be due to pathophysiologic mechanisms such as abnormal facilitation of trigeminal and extratrigeminal pain pathways, abnormalities in the levels of neurotransmitters such as serotonin and dopamine, microstructural abnormalities in periaqueductal gray matter, and various brain structures related to the pain matrix.
Surgical history is not well-documented among the risk factors of CM. However, we found that having a history of surgery for miscellaneous reasons was more frequent in CM, especially surgeries for areas of the head, including the ear, nose, and throat. Head-and-neck trauma history has been reported as a risk factor for chronification. Having a surgical history may be considered a stressor or a traumatic cause for CM.
Iron deficiency anemia was more common in our patients with CM, especially among women. The relation between migraine and iron deficiency anemia was shown in a few studies, particularly in menstruation-related migraine. Iron deficiency affects various cellular functions at enzymatic steps. As a result, the disruptions of serotonin synthesis and oxygen transmission may be the main pathophysiologic mechanisms for triggering migraine attacks. Treating anemia and other comorbidities can help in controlling migraine attacks; hence, it seems that questioning systemic diseases in detail is of particular importance to prevent chronicity.
Having a psychiatric disease, including depression and anxiety, was more common in our patients with CM compared with those with EM, but in subgroup analysis, only depression was significantly high among patients with CM and female patients with CM. Female sex dominancy for depression was not a surprising finding; depression among women is a well-known entity; a complex relationship between sex hormones and neurotransmitters is purported to be responsible. The common comorbidity of migraine and psychiatric diseases has been demonstrated in several studies. It is hypothesized that there is a bidirectional relationship between these chronic disorders, and the presence of one increases the risk of the development of another. Some research showed that depression emerged before the development of CM and was more common in those who converted from EM to CM, and the risk of developing CM increased as the severity of the depression increased., Studies conducted on the Turkish population have also revealed the relationship between the presence of depression and migraine. The findings of the current study are consistent with previous research; depression was seen as twice as frequently in patients with CM than in those with EM.
Serotonergic dysfunction, hyperactivity of the HPA axis, hormonal effects, neuroinflammation and sensitization of sensory and emotional neural networks, and pain-related cognition are the main hypotheses for the neurobiological mechanisms explaining the relationship between migraine and depression. In addition, sharing similar attack triggers, such as stress, supports the existence of common neuropathophysiologic mechanisms for both. Because it has been shown that depression is more common in CM compared with other migraine subtypes, several other hypotheses have been proposed, offering that depression might contribute to the onset of CM, or depression could occur secondary to frequent migraine attacks.,
In the present study, in line with previous research, the rate of medication overuse among patients with CM was also significantly higher than in those with EM., Frequent use of medications causes a vicious cycle; frequent attacks cause excessive use of analgesics and medication overuse causes CM. Some authors underlined that the frequency of headaches and drug overuse might be predictive in the chronic process of migraine. The frequency of attacks can be reduced by preventing the excessive use of these drugs. The relationship between medication overuse and chronicity is explained mainly by the facilitation of pain pathways by peripheral and central neuroimmune interactions, such as the degranulation of mast cells in the dura causing the sensitization of primary afferent neurons and activation of glial cells (central sensitization). It has also been proposed that medication overuse may reduce the triggering threshold for headaches and the transformation from EM to CM.
On top of all the possible underlying mechanisms discussed above, some other theories have been suggested to illuminate the association between comorbid conditions and CM: one disease may cause the other one, the existence of latent brain state models, and shared environmental and genetic origins.
Triggering factors in episodic versus chronic migraine
Recent studies with neurofunctional imaging methods highlighted structural and functional changes in the brains of chronic migraineurs. Based on this, we hypothesized that the headache-triggering threshold and features of triggers might have changed in CM. Supporting this, we found differences between EM and CM in terms of the reported frequency of some specific attack triggers. Another prediction was that the number of triggers would be higher in CM than in EM; however, we found no significant differences in the mean trigger numbers between the groups.
In our study, the reported rates and features of attack triggers were similar to previous studies on this topic. Consistent with former studies, stress, lack of sleep, climate changes, and skipping meals were prominent triggers in both groups., Missing meals, withdrawal of coffee/tea, heavy scents/perfumes, and intense physical activities were reported significantly more frequently in our patients with CM than in those with EM. Interestingly, excluding missing meals, the odds ratio of triggers was found to be higher in female patients with CM than in males. On the other hand, it is worth noting that the rates of other reported triggers were relatively high in CM. There are few studies investigating how migraine attack triggers change as EM evolves into CM., Ferrari et al. reported that consumption of tea/coffee and alcoholic beverages, poor sleep quality, constipation, and the use of oral contraceptives were more frequent in CM.
Higher rates of comorbid conditions and susceptibility to triggers among patients with CM may represent a separation of a more severe disease process, but overall, this does not add to evidence pointing to single or two separate disease processes of EM and CM. Furthermore, the existence of comorbid diseases in CM and the different treatment steps in CM – compared with EM – suggest that CM and EM have different pathophysiologic mechanisms. In recent years, advanced neuroimaging studies have shown that there are structural and functional differences between EM and CM in some brain areas.,,
Although it has been shown that these comorbidities are risk factors for the chronicity of migraine, it has not yet been elucidated whether CM emerges due to these comorbidities or if these comorbidities cause chronicity. This unknown relationship still needs to be clarified. Furthermore, the association of migraine with comorbidities and triggers raises another question: if migraine frequency and severity reduce, will these risk factors similarly reduce? Although the answers to these questions are not known at the moment, it seems important to control the comorbid conditions and triggers for preventing chronicity.
Our main limitation in this study is the lack of prognostic and predictive biomarkers that could provide crucial information regarding the chronicity process. There may be recall bias and additional situations that the patients did not want to report during the interviews. Despite these limitations, we have obtained results compatible with the literature. The patients were questioned in detail and meticulously in terms of the characteristics, triggers, and comorbidities of migraine attacks. Patients in the EM and CM groups formed homogeneous groups in terms of age, sex, migraine onset age, and the number of patients.
| Conclusions|| |
- Vascular risk factors, psychiatric disorders, systemic/metabolic/endocrinologic diseases, and medication overuse should be investigated among migraineurs
- Questioning the attack-triggering factors for controlling the attack frequency is of utmost importance
- There is a lack of systematic studies in which the properties of trigger factors are compared between episodic and chronic migraineurs
- Chronification is likely the result of a combination of genetic, social, behavioral, and environmental risk factors through epigenetic mechanisms
- The development of multi-risk factor scoring that predicts chronicity in migraine may help identify individuals with EM who are at high risk for progression
- There is a need for prospective, long-term, and large-scale studies in which the changes in attack triggers and comorbid conditions can be observed closely and at frequent intervals during the evolution from episodic to CM.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]