GRAPHICAL ABSTRACT

INTRODUCTION

Parkinson’s disease (PD) is the second most common neurodegenerative disease and the fastest-growing neurological disorder in terms of prevalence, disability, and mortality [1]. Its pathophysiology involves the degeneration of nigrostriatal dopaminergic pathways in addition to other nonmotor centers [2].

The prevalence of PD varies among different countries, with a reported high prevalence in Egypt [3].

The clinical manifestations of PD include the cardinal motor features which are tremors, rigidity, bradykinesia, and postural instability, in addition to nonmotor symptoms (NMSs) [2], which are independent predictors of patients’ quality of life (QoL) similar to motor severity [4].

Pain is one of the most common NMSs in PD and has been described by PD patients as one of their most bothersome symptoms, ranging in prevalence from 24% to 85% [4-8]. However, it remains underrecognized and undertreated. This could be explained by the absence of particular assessment instruments and the lack of consensus regarding the classification of pain and the mechanisms underlying its pathology [5].

In 2015, the King’s Parkinson’s Disease Pain Scale (KPPS) was introduced as the first disease-specific scale to assess pain in PD patients, and it has been accepted by the International Parkinson and Movement Disorders Society (MDS) [9]. Consequently, the King’s Parkinson’s Disease Pain Questionnaire (KPPQ) has been validated as a screening tool for pain in clinical practice [10].

Using the KPPS, several studies have described the prevalence, severity, and frequency of pain in PD alongside its correlates but did not represent different populations. Moreover, these studies showed variable frequencies and determinants of pain in different countries and ethnicities [5,11-14].

The aim of this study was to translate and validate the KPPS and KPPQ into Arabic versions. Additionally, this study aimed to investigate the prevalence and severity of different types of pain in Egyptian people with PD (PWP) compared to healthy controls and to identify pain determinants in those patients as well as its impact on QoL.

MATERIALS & METHODS

This national multicenter, cross-sectional case-controlled study enrolled PWP and sex- and age-matched healthy controls from seven specialized Egyptian movement disorder clinics. This study was approved by the Research Ethics Committee at the Faculty of Medicine, Ain Shams University (FMASU MS 273/2022), and informed consent was obtained from all participants.

Patients who were diagnosed with PD according to the MDS diagnostic criteria and who were older than 18 years were included from June 2022 until December 2023 [15]. Patients with atypical or acquired parkinsonism, dementia (Mini-Mental State Examination [MMSE] score ≤21), comorbidities causing pain, such as recent fractures, surgery, rheumatoid arthritis, osteoarthritis, cancer, neuropathy, or any other causes of chronic pain conditions, and those who could not complete the pain scale were excluded.

Clinical assessment of PWP

All participants were subjected to a detailed history and comprehensive neurological examination. All PWP underwent a thorough assessment using the MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), modified Hoehn and Yahr scale (H&Y) during the ON and OFF states [16], MMSE-Arabic version [17], Beck Depression Inventory-Arabic version (BDI) [18], Non-Motor Symptom Scale (NMSS) [19], Non-Motor Fluctuation Assessment (NoMoFA) Questionnaire [20], and Arabic version of Parkinson’s Disease Questionnaire for Quality of Life (PDQ-39) [4]. The levodopa equivalent daily dose (LEDD) was also calculated using the reported formula [21].

Pain assessment of PWP and controls

Pain was assessed in patients (during the ON state) and controls using the KPPS [9] and KPPQ [10] after translation to Arabic. The KPPS consists of 14 items divided into 7 domains. Each item is scored by severity (from 0 [no pain] to 3 [very severe pain]) multiplied by the frequency (from 0 [never] to 4 [all the time]), resulting in subscores that range from 0 to 12 each, the sum of which yields a total score ranging from 0 to 168. The domains and their scores ranged are as follows: 0–12 for musculoskeletal pain, 0–24 for chronic pain, 0–36 for fluctuation-related pain, 0–24 for nocturnal pain, 0–36 for orofacial pain, 0–36 for discoloration, 0–24 for edema/swelling, and 0–12 for radicular pain. The KPPQ is a valid questionnaire designed to be easily completed by patients. It consists of 14 items in the form of “Yes” or “No” questions that determine whether a specific type of pain is present, and each question of the KPPQ corresponds to one of the items of the KPPS. Additionally, controls were also evaluated using the NMSS.

Arabic translation and validation of the KPPS and KPPQ

The translation and validation processes were performed according to the World Health Organization’s guidelines on the translation and adaptation of instruments [22] after obtaining permission and written agreement from the original developer (Mapi Research Trust) in December 2021. Initially, two bilingual health professionals, native Arabic neurologists who are fluent in English, independently translated the original English versions of the KPPS and KPPQ into two Arabic versions. Afterward, both copies of the translated versions were compared, reconciled, and merged into one Arabic version by a third investigator in addition to the 2 translators to confirm acceptability and cultural relevance. Therefore, a merged Arabic version was approved by the three reviewers. Consequently, back translations of the merged Arabic versions to English were carried out by two different bilingual neurologists separately and without prior knowledge of the original scale. Subsequently, all translations, along with the original versions, were reviewed by the whole panel to discuss any disparities between the original and back-translated English editions to produce the final KPPS-Arabic and KPPQ-Arabic versions.

The final KPPS-Arabic and KPPQ-Arabic version were then tested with participants by the interviewers to detect any ambiguities and examine their understanding of all the questions (cognitive debriefing and pretesting). Cognitive interviews were performed to confirm respondent interest, attention span, discomfort, proper understanding, and comprehension prior to validation. Responses from the raters and patients were considered and integrated into the final Arabic versions. Furthermore, in those participants, the KPPS-Arabic and KPPQ-Arabic were retested by two different raters and then retested once more by one of the previous raters after two weeks to eventually check the interrater and intrarater validity and reliability of the final translated Arabic versions (Supplementary Materials 1 and 2 in the online-only Data Supplement).

Statistical analysis

All the data were analyzed using the Statistical Package for Social Science (IBM SPSS) version 25 (IBM Corp., Armonk, NY, USA). The normality of the data distribution was checked by the Shapiro–Wilk test, and accordingly, numerical data analysis was performed. Nonparametric tests were used to analyze the data in this study. The quantitative data are presented as medians, interquartile ranges (IQRs) and ranges, while the qualitative variables are presented as numbers and percentages.

Comparisons between two independent groups with quantitative data were performed using the Mann–Whitney test, and comparisons of qualitative data were performed using the chi‒square test. Spearman correlation coefficients were used to assess the correlation between two quantitative parameters. According to the rho value, the correlations were classified as strong (rho ≥0.60), moderate (rho in 0.40–0.59), or weak (rho ≤0.39). Furthermore, stepwise multivariate linear regression analysis was implemented to assess factors associated with the total KPPS-Arabic score and PDQ-39 total score.

Intrarater agreement between the first and second readings of the first rater for the KPPS-Arabic and KPPQ-Arabic was determined using the Wilcoxon rank test and McNemar test, respectively. Moreover, the interrater agreement between the first rater and second rater was determined using the intraclass correlation coefficient for the KPPS-Arabic and the kappa test for the KPPQ-Arabic. The internal consistency of the KPPS-Arabic total score, item scores, and domain scores was investigated by Cronbach’s alpha test. Additionally, the data and sampling adequacy were determined by factor analysis. In each domain, the 3 to 4 items with loadings greater than 0.4 were chosen. The confidence interval was set to 95%, and the margin of error was set to 5%. Therefore, a p value <0.05 was considered significant. Bonferroni correction for multiple correlations was calculated as p < 0.006.

RESULTS

Demographic and clinical characteristics of PWP

This study included a total of 292 participants, consisting of 192 PWP and 100 sex- and age-matched healthy controls. The median age (IQR) of the PWP (58.5 [range: 52–65.75] years) was matched to the control group (58 [range: 49–62] years) (p = 0.081). Males represented 71.4% of the PWP (137 patients) and 64% of the controls (64 subjects), with sex matching in both groups (p = 0.231). A total of 115 patients (59.9%) had mild disease (H&Y stages 1 and 2), 57 patients (29.7%) had moderate disease (H&Y stage 3), and 20 patients (10.4%) had severe disease (H&Y stages 4 and 5). According to the age of onset, 126 patients had late-onset PD (LOPD, 65.6%), and 66 had early-onset PD (34.4%). The demographic and clinical data of the patients in the PD group are summarized in Table 1.

Pain characteristics of the PWP and control groups

A total of 188 PWP (97.9%) and 61 (61.0%) controls reported experiencing at least 1 type of pain (p < 0.001). The severity and prevalence of pain symptoms in all the KPPS-Arabic domains (presence of at least one symptom in the respective domain) were significantly higher among PWP compared to controls (p < 0.001).

In the PWP, fluctuation-related and musculoskeletal pains were the most common types (81.3% and 80.7%, respectively), followed by nocturnal pain (78.1%), chronic pain (76.6%), discoloration (72.4%), orofacial pain (61.5%) and radicular pain (58.9%), while musculoskeletal pain was the most common type of pain (61.0%) among the controls (Table 1). In total, 167 PWP (87%) had pain in 3 or more domains, of which 60 patients (31.25%) had pain in all 7 domains. Ten patients (5.3%) reported pain in 1 domain, and 11 patients (5.8%) reported pain in 2 domains. Regarding the KPPQ, pain around the joints (78.8%), pain while turning in bed (63.5%), “OFF” dystonia in a region (62.8%), and dyskinetic pain (59.9%) were the most prevalent types of pain, while burning mouth syndrome (35.8%) and pain when chewing (37.2%) were the least prevalent (Supplementary Table 1 in the online-only Data Supplement).

Comparing the pain characteristics between males and females (both groups were matched for age, disease duration and LEDD), females reported pain more frequently in the musculoskeletal, fluctuation-related, discoloration, edema/swelling (p = 0.023, 0.010, and 0.027, respectively) and pain around the joints (Q1, p = 0.023) domains. The severity and frequency of the different pain domains showed similar values in the early-onset PD (≤50 years) and LOPD (>50 years) groups, with no significant differences. However, LOPD patients had worse burning mouth syndrome (p = 0.013) and limb pain (p = 0.008) (items 11 and 12) (Supplementary Table 2 in the online-only Data Supplement).

Patients with moderate to severe PD (77 patients, H&Y stages 3, 4, and 5) showed significantly worse pain severity in all domains than patients with mild PD (115 patients, H&Y stages 1 and 2) (Supplementary Table 3 in the online-only Data Supplement).

Correlations of pain among PWP

In the PWP group, the total score and domain scores of the KPPS-Arabic showed weak to moderate significantly positive correlations with the MDS-UPDRS total score (OFF and ON states); scores in Parts I, II, III (OFF and ON states); scores for OFF and ON postural instability gait disorder (PIGD); OFF and ON axial scores; and OFF and ON H&Y scores, but not age or age of onset. Additionally, the pain score on the MDS-UPDRS-I showed a weak to moderate significantly direct correlation with the total score and domain scores of the KPPS-Arabic (p < 0.001 for the total score and most of the domains). The motor complications score (MDS-UPDRS IV) was positively correlated with the total score and pain domain scores, except for the scores for the discoloration and radicular pain domains. The disease duration was directly correlated to the total pain score and the domain scores except for the scores for the musculoskeletal and radicular pain domains. The LEDD was directly correlated with the KPPS-Arabic total score (rho = 0.241) and domain scores, except for the scores for the musculoskeletal and chronic pain domains. Total MMSE score was significantly correlated with the chronic (p = 0.004), discoloration (p = 0.008), and radicular pain domains (p < 0.001) (Table 2).

Additionally, the total score and domain scores of the KPPS-Arabic were significantly weakly to moderately correlated with the total NMSS (except for the orofacial pain score), the BDI (p < 0.001, except for the musculoskeletal and orofacial pain scores), the total NoMoFA (p < 0.001 for total, chronic, fluctuation-related, and nocturnal pain) and the total PDQ-39 (p < 0.001, except for the musculoskeletal and orofacial pain scores) scores. The total KPPS-Arabic score was significantly correlated with the scores for all the NMSS domains except the perceptual problems/hallucination domain (Table 2 and Supplementary Table 4 in the online-only Data Supplement). According to the regression analysis, the predictors of the total KPPS-Arabic score included the total NMSS score (p < 0.001), disease duration (p < 0.001), and total NoMoFA (p = 0.03).

The total KPPQ-Arabic score was significantly correlated with the duration of illness and LEDD (p < 0.001). There was a significant weak negative correlation of the total KPPQ-Arabic score with years of education (rho = -0.235, p = 0.002). Moreover, the total KPPQ-Arabic score was significantly correlated with the MDS-UPDRS total score OFF and its three parts, the PIGD OFF, as well as H&Y OFF (p < 0.001). Interestingly, it was also correlated with the total NoMoFA score and pain question in MDS UPDRS. The KPPQ-Arabic total score also showed a significant correlation with the cardiovascular domain of the NMSS and the mobility and activities of daily living scores of the PDQ-39 (p = 0.005, 0.001 and <0.001, respectively) (Table 2 and Supplementary Table 4 in the online-only Data Supplement).

Predictors of pain among PWP

Regression analysis for all patients, including the disease duration, MMSE, BDI, NMSS, MDS-UPDRS (total, part III-OFF and part IV), and H&Y OFF, was performed. The predictors of the total KPPS-Arabic score included the total MDS-UPDRS score (p < 0.001), part III-OFF score (p = 0.04), disease duration (p = 0.03), and total NMSS score (p < 0.001) (Table 3). The addition of the total NoMoFA score (80 patients) significantly predicted KPPS severity (p = 0.03). Regression analysis of the PDQ-39 revealed that depression, total NMSS score and MDS-UPDRS-III (motor) score, but not the total KPPS-Arabic score, were predictors of QoL (p < 0.001).

Validation of the Arabic versions of the KPPS and KPPQ

Cognitive interviewing revealed proper understanding and comprehension of all items by all patients for the KPPS-Arabic and KPPQ-Arabic. There was no statistically significant difference between the first and second readings of the same rater (rater A) regarding the total score or domain scores of the KPPS-Arabic (46 patients) and KPPQ-Arabic (31 patients), which indicates the reliability of both tests (Table 4 and Supplementary Table 5 in the online-only Data Supplement).

The interclass correlation coefficient of the translated KPPS-Arabic was 0.957–0.997, showing that there was no statistically significant difference between the total score and domain scores of the KPPS-Arabic for the first and second raters (raters A and B) (Table 4). Similarly, the kappa test was used to investigate the Arabic version of the KPPQ and showed high agreement between the two raters’ results (Supplementary Table 6 in the online-only Data Supplement). The internal consistency of the KPPS-Arabic for the items and domains was tested by Cronbach’s alpha, which was 0.739 for the items and 0.759 for the domains, indicating a strong relationship between the included variables.

No missing data were found in the KPPS-Arabic or KPPQ-Arabic in the total sample. The convergent validity of the KPPS-Arabic and KPPQ-Arabic was determined by the low to moderate correlations of their total scores and KPPS-Arabic domains with the total score, scores of the different parts and pain item of the MDS-UPDRS, the total NMSS and its miscellaneous domains (for the KPPS-Arabic and its domains), the H&Y and the PDQ-39 total and bodily discomfort scores (KPPS-Arabic) (Table 2 and Supplementary Table 4 in the online-only Data Supplement). Additionally, the total KPPQ-Arabic score was strongly correlated with the KPPS-Arabic score (rho = 0.614) and its domains (rho = 0.280–0.460) (p < 0.001).

The KPPS-Arabic domain scores and total scores showed negligible floor or ceiling effects (2.08% and 0.52%, respectively), as they were both <15%. On the other hand, the highest percentage of patients (4.69%, 9 patients) achieved a total score of 17.26%. The total KPPQ-Arabic assessment showed negligible floor or ceiling effects (2.08% and 4.69%, respectively), as they were both <15%. On the other hand, the highest percentage of cases was 12.50% (24 cases), achieving a total assessment of 57.14% and 50.00%.

The construct validity was explored by factor analysis. The Kaiser–Meyer–Olkin test revealed sufficient sampling adequacy (0.791), and Bartlett’s test of sphericity was highly significant (p < 0.001). Factor 1 included RLS-associated pain, lower abdominal pain, pain related to internal organs, and pain deep within the body (internal pains); Factor 2 included shooting pain/pins and needles, burning pain in the limbs, dyskinetic pain, and burning mouth syndrome; Factor 3 included “off” dystonia in a region and generalized “off” period pain; and Factor 4 included orofacial pains (Supplementary Table 7 in the online-only Data Supplement).

DISCUSSION

The current multicenter study provided translated and validated Arabic versions of the KPPS and KPPQ, which are important for better assessing pain in Arabic populations. Moreover, there was a significantly greater prevalence and severity of pain within the Egyptian PWP than in healthy controls, especially musculoskeletal pain, fluctuation-related pain, nocturnal pain and orofacial pain, which were correlated with the disease duration, motor severity, and nonmotor burden and negatively impacted patients’ QoL. Furthermore, the average number of pain types per patient was also greater in the PWP group than in the healthy control group. Our findings are consistent with those of previous studies [23-25]. Pain around joints (78.8%), pain while turning in bed (63.5%), “OFF” dystonia in a region (62.8%), and dyskinetic pain (59.9%) were the most common pain types, comparable to the findings of other studies [23,24].

In this study, 97.9% of PWPs reported at least 1 type of pain. Other studies have also reported a high prevalence of pain in PD patients, but the prevalence was lower than that in our study, ranging from 70.3% to 89% [11,23,24]. A German study reported a prevalence of pain of 95.4%, which is close to our findings, but we used different tools [25]. Studies from other populations, such as Mexican (88.6%), English (85%), Bulgarian (80%), Indian (52.1%) and Chinese (44.5%) PD patients, reported a lower prevalence of pain, while musculoskeletal pain was the most common type [11,14,26,27].

The high prevalence of pain types in our study may be attributed to several factors, including the patient characteristics, lower education years, less optimized medications, and sociocultural factors. It is also worth noting that the prevalence of pain subtypes has also varied greatly among different studies, partly due to differences in patient characteristics and assessment tools, making direct comparisons of our results difficult [28]. The availability of PD therapies and experts might have an impact on the optimization of medications and, consequently, the pain burden [3,12]. Furthermore, the frequencies of all domains and items of the KPPS-Arabic and KPPQ-Arabic were greater among patients and controls, except for Item 1 “pain around the joints,” than in other studies [10,12,23,27] but comparable to findings in other populations [14]. This variability implies the role of sociocultural factors in the perception of pain among different populations.

Notably, the current study showed a greater prevalence of fluctuation-related pain (81.3%) than did previous studies (approximately 40%) [23,24,26]. However, a Chinese study reported a similarly high frequency of fluctuation-related pain (67.4%), close to that of musculoskeletal pain (68.5%) [14].

These findings could be attributed to the undermedication of our patients, as the LEDD was lower than that in other studies, implying the importance of proper optimization of oral medications [28]. Other factors might include the younger age of the recruited patients, the high prevalence of depression, stigma and cultural differences [4,29]. A previous study reported that fluctuating pain tends to occur more often in patients with early-onset disease and in those with advanced-stage disease. They found that patients with H&Y stage greater than 2.5 had a greater percentage of fluctuation-related pain [30]. Another study demonstrated a lower frequency of fluctuation-related pain with an older age of onset [23]. This could partially explain the high prevalence of fluctuation-related pain in our study since 50.5% of the patients had H&Y scores greater than 2.5 and 34.4% had early-onset PD.

Although the majority of studies mentioned musculoskeletal pain as the most common pain type, its prevalence in our cohort was similar to that in other studies [11,14,26,27]. In particular, a study by Ghosh et al. [31] reported a similar prevalence of musculoskeletal pain (80%). On the other hand, radicular pain (40%) and orofacial pain (46.67%) were the least common types of pain in the PD group, which is in agreement with the findings of other studies [23,26].

In our study, there were significant correlations between pain and the duration of illness, years of education, depression, cognition, motor severity of the disease, PIGD scores, motor complications, NMS burden, daily dopaminergic dose and QoL, similar to the findings of most previous studies [9,24,26,27]. However, pain was not detected as a predictor of patients’ QoL, in agreement with some previous studies [23] but in contrast to other studies [11,32].

There is still some controversy regarding the clinical determinants of pain in PD patients [28]. The predictors of pain in the current study were motor and disease severity, nonmotor burden, nonmotor fluctuation (NMF) and disease duration. Consistently, motor severity and NMSs have been reported in several studies [14,24,26]. However, Silverdale et al. [11] reported no correlation between pain and motor severity among patients with early/moderate PD. In contrast, other predictors, such as depression, female sex, sleep dysfunction, and autonomic symptoms, have been reported to vary [11,14,24,26,31]. Using the SF-36 Bodily Pain Scale, Beiske et al. [33] reported that female sex was the only significant predictor of pain. Moreover, dopaminergic deficiency in the caudate nucleus and striatum has been reported recently as a determinant of musculoskeletal pain [34].

Remarkably, the current study showed a correlation between pain and NMF using the NoMoFA, particularly chronic pain, fluctuation-related pain and nocturnal pain. Moreover, NMF was a predictor of pain, indicating the essential role of motor and NMS fluctuations and the importance of optimizing patients’ medications.

The correlation between pain in PWP and sex remains controversial. While several studies identified female sex as a risk factor for increased pain burden in PWP [23,24,26,33], our study and others found no correlation between sex and pain incidence or intensity [14,29]. Our study revealed a high prevalence and severity of musculoskeletal pain, fluctuation-related and discoloration, edema/swelling in females, but the total KPPS-Arabic score was consistent with that reported by Chaudhuri et al. [9] Similarly, previous studies reported more frequent musculoskeletal [23], discoloration, edema/swelling pain, and higher scores for chronic pain, fluctuation-related pain and orofacial pain [35].

In the present study, we also found that pain in PWP negatively affected their QoL, as assessed by the PDQ-39, in agreement with previous studies [25]. Using the KPPS-Arabic, we were able to further identify the types of pain that especially influence QoL in those patients, which were mainly fluctuation-related pain and nocturnal pain followed by chronic and discoloration pain, but not musculoskeletal pain. A previous study described similar findings, in which the fluctuation-related domain showed a significant independent effect on the European Quality of Life 5 Dimensions 3 Level tool (EQ-5D-3L) while discoloration and nocturnal pain were significant for the Parkinson’s Disease Questionnaire-8 (PDQ-8) [23]. This finding is also supported by another study in which PD patients with fluctuating pain had lower QoL scores than PD patients without fluctuating pain [36].

Finally, the current study provided validated Arabic versions of the KPPS and KPPQ, which showed inter- and intrarater consistency, with an acceptable ceiling effect. Moreover, both instruments showed high convergent validity and comparable structural analysis to other versions [9,10,37]. This indicates the strong reliability of the translated Arabic versions of the KPPS and KPPQ, which will allow for wider use of this tool and promote further studies on pain in PWP in Arabic countries. The original English version of the KPPS was recently translated to Arabic by a team from Jordan [38], but our study also translated and validated the KPPQ along with the KPPS and comprehensively demonstrated the pain characteristics in Egyptian PWP.

One of the limitations of our study is the mismatch of education years between patients and controls. In addition, we did not obtain enough data regarding the duration of pain or the use of medications (analgesics) for alleviating pain in those patients.

This study provided translated and validated Arabic versions of the KPPS and KPPQ to better assess pain and promote wider use of this tool in Arabic countries. Egyptian PD patients showed a greater prevalence and severity of pain, which impaired their QoL and was predicted by the disease duration, motor severity, nonmotor burden and NMF. Therefore, the proper assessment and management of different types of pain are essential for improving the care and QoL of PWP.

Supplementary Materials

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author Contributions

Conceptualization: Ali Shalash, Eman Hamid. Data curation: Salma R. Mohamed, Marwa Y. Badr, Shimaa Elgamal, Shaimaa A. Elaidy, Eman A. Elhamrawy, Hayam Abdel-Tawab, Haidy Elshebawy, Heba Samir Abdelraheem. Formal analysis: Ali Shalash, Eman Hamid, Marwa Y. Badr, Hatem S. Shehata. Investigation: Ali Shalash, Tamer Roushdy, Marwa Y. Badr, Shimaa Elgamal, Shaimaa A. Elaidy, Eman A. Elhamrawy, Hayam Abdel-Tawab, Haidy Elshebawy. Methodology: Ali Shalash, Tamer Roushdy, Eman Hamid, Marwa Y. Badr. Project administration: Eman Hamid, Marwa Y. Badr. Resources: Ali Shalash. Software: Eman Hamid. Supervision: Ali Shalash , Ehab A. El-Seidy, Hatem S. Shehata, Hazem Marouf, K. Ray Chaudhuri. Validation: Ali Shalash, Eman Hamid, K. Ray Chaudhuri. Visualization: Ali Shalash, Eman Hamid. Writing—original draft: Ali Shalash, Salma R. Mohamed. Writing—review & editing: all authors.

Acknowledgments

None

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