Abstract
Neuronal surface antibody-mediated autoimmune encephalitis (NSAE) occurs across a wide age range. However, few studies focused on the onset age and their related characteristics. We aimed to explore the age-dependent profile of NSAE. A total of 134 patients with a definite diagnosis of NSAE were retrospectively enrolled from 3 tertiary hospitals between July 2014 and August 2020. Demographic, clinical, therapeutic, and prognostic data were collected and compared between the late- (≥45) and younger-onset (<45) groups. The results showed that 56 (41.8%) patients were classified as late-onset NSAE, and 78 (58.2%) as younger-onset NSAE. There were more males, especially in the late-onset group (P = 0.036). Prodromal symptoms were more common in the younger-onset group (P = 0.004). Among the onset symptoms, more late-onset patients presented as seizures, while more younger-onset patients presented as psychiatric symptoms. Throughout the disease course, the late-onset patients were more likely to have memory dysfunction (P < 0.001), but less likely to have central hypoventilation (P = 0.045). The late-onset patients also had a significantly lower modified Rankin Scale score on admission (P = 0.042), required intensive care unit (ICU) admission less frequently during hospitalization (P = 0.042) and had a shorter hospital stay (P = 0.014). Our study revealed that the late- and younger-onset NSAE had a distinct spectrum of demographic features, presentations, and prognoses. More attention is needed for the younger-onset patients, given a higher disease severity on admission, more frequent requirement for ICU admission and longer length of stay.
Keywords: neuronal surface antibody, autoimmune encephalitis, late-onset, younger-onset, anti-N-methyl-D-aspartate receptor encephalitis
Our study revealed several age-related features of NSAE. Generally speaking, male-dominant onset of seizures and memory dysfunctions had more diagnostic significance for the late-onset group. The prodromal symptoms, onset of psychiatric symptoms and central hypoventilation might be specific for those with younger-onset. Notably, in consideration of the higher severity and more frequent requirement for ICU admission, more attention is needed for the younger-onset patients, especially for those with anti-NMDAR encephalitis.
Graphical Abstract
Graphical Abstract.
Introduction
In the past 10 years, neuronal surface antibody-mediated autoimmune encephalitis (NSAE) has been more frequently identified [1–3]. NSAE occurs across a wide age range (from 0 to 94 years) [4–6]. Up to now only a few studies have focused on the onset age of NSAE. Titulaer et al. suggested that the late-onset patients with anti-N-methyl-d-aspartate acid receptor (NMDAR) encephalitis were less severe but were more frequently delayed in diagnosis and treatment, with a poorer outcome than young adults [7]. A study from China also indicated that a delayed admission and diagnosis were more common in older adults [8]. Another study of patients with anti-NMDAR encephalitis under the age of 45 years suggested that an increasing age was associated with a poorer prognosis in females but not in males [9]. Yet the overall profile of age-related characteristics of anti-NMDAR encephalitis and other subtypes of NSAE remained unknown.
Our study aimed to explore the demographic, clinical, therapeutic, and prognostic characteristics of NSAE between those with an onset less than and over 45 years old. We also examined age-dependent clinical profiles in different subtypes of NSAE. Our results present a comprehensive picture of NSAE in different age groups. Further, our findings shed new light on the management strategies and pathogenesis of NSAE from the perspective of age.
Methods
Patients
We retrospectively enrolled 134 patients from 3 tertiary hospitals (Second Affiliated Hospital School of Medicine Zhejiang University, Zhejiang Hospital, and Zhejiang Chinese Medicine and Western Medicine Integrated Hospital) in Zhejiang province between July 2014 and August 2020. The inclusion criteria included: (i) new-onset definite NSAE diagnosed according to the 2016 Lancet Neurology criteria [10]; (ii) age of onset ≥18 years. Patients with incomplete information, coexisting with other antibodies against neuronal and/or glial antigens, complicated by central nervous system infections, presence of other severe neurological or psychiatric complications, or lost to follow-up were excluded. The specific antibodies were detected and confirmed by fixed cell-based assay before immunotherapies, including 118 (88.1%) in cerebrospinal fluid (CSF), 40 (29.9%) in serum, and 24 (17.9%) in both samples. Based on the age cut-off proposed by Titulaer et al. [7], we classified patients into late- (≥45 years) and the younger-onset (18–44 years) subgroups. The flow chart was shown in Fig. 1. This study was approved by the local ethics committee of each participating center.
Figure 1:
flow chart. Abbreviations: AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CASPR2, contactin-associated protein-like 2; DPPX, dipeptidyl-peptidase-like protein 6; GABABR, gamma-aminobutyric acid-b receptor; LGI1, leucine-rich glioma-inactivated 1; NMDAR, N-methyl-d-aspartate acid receptor; NSAE, neuronal surface antibody-mediated autoimmune encephalitis.
Data collection
We collected the following data: demographic characteristics (sex, age at onset), clinical (e.g. disease duration, prodromal symptoms [those developed before the onset of encephalitic symptoms, such as headache, fever, or other associated symptoms] [11], symptoms at onset and during disease course, intensive care unit [ICU] admission, length of stay [LOS]), and paraclinical features (types of antibodies, CSF, electroencephalogram, and brain magnetic resonance imaging findings), therapeutic information (treatment options, interval from admission to initiation of treatment), side effects, and neurological status (measured by modified Rankin Scale [mRS] at different time points).
Disease severity on admission and clinical outcome after treatment
Disease severity on admission was assessed by mRS. The clinical outcomes were defined as follows: (i) short-term outcome: ‘stabilization’, ‘remission’, and ‘exacerbation’ respectively indicated by no change of mRS score, a decrease or increase in mRS score ≥1 point within 4 weeks after immunotherapies; (ii) 1-year outcome: ‘good’ and ‘poor’ each represented the score ≤2 and >2 (including death, i.e. mRS = 6) at 1-year follow-up; (iii) long-term outcome: ‘good’ and ‘poor’ at last follow-up; (iv) relapse: reappearance of symptoms, or aggravation of original symptoms (increased mRS score of 1 point or more), after clinical symptom improvement or stabilization for ≥2 months [3].
Statistical analysis
All statistical analyses were performed using R software (Version 4.0.2). Continuous variables were reported as median and interquartile range (IQR), and inter-group differences were assessed using the Mann-Whitney U tests. Categorical variables were described as percentages, and chi-squared or Fisher’s exact tests were used for comparisons. Two-tailed P-values <0.05 were considered statistically significant.
Results
Demographic characteristics of the late- and younger-onset groups
A total of 134 NSAE patients (83 males), with a median age of onset at 40.5 (IQR = 25.0–57.0, range = 18.0–83.0) years were eligible for our study, including 81 patients with anti-NMDAR encephalitis, 29 with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, 17 with anti-gamma-aminobutyric acid B receptor (GABABR) encephalitis, 4 with anti-contactin-associated protein-like 2 encephalitis, 2 with anti-dipeptidyl-peptidase-like protein 6 encephalitis, and 1 with anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor encephalitis. As shown in Table 1, 56 (41.8%) patients were classified as late-onset NSAE (median = 58.0, IQR = 54.0–66.3 years), and 78 (58.2%) as younger-onset NSAE (median = 27.0, IQR = 23.0–33.0 years). The age of onset showed a bimodal distribution with the first peak at the age 20–29 years (41/134, 30.6%, predominantly females with anti-NMDAR encephalitis), and a second peak at the age 50–69 years (45/134, 33.6%, predominantly males with anti-LGI1 and anti-GABABR encephalitis) (Supplementary Fig. 1). The male-dominant prevalence was more pronounced in the late-onset group (P = 0.036). In detail, patients with anti-GABABR encephalitis had the highest male-to-female ratio of 13:3, followed by those with anti-NMDAR encephalitis (9:4) and anti-LGI1 encephalitis (15:8), though no significant difference was reached among these 3 subtypes (P = 0.545).
Table 1:
demographic, clinical, and paraclinical features of patients with late- and younger-onset NSAE
| Overall (n = 134) | Late-onset group (n = 56) | Younger-onset group (n = 78) | P | |
|---|---|---|---|---|
| Demographics | ||||
| Sex, male | 83 (61.9) | 41 (73.2) | 42 (53.8) | 0.036 |
| Age at onset, years, median (IQR) | 40.5 (25.0–57.0) | 58.0 (54.0–66.3) | 27.0 (23.0–33.0) | <0.001 |
| Disease duration, days, median (IQR) | 15.0 (7.0–30.0) | 20.0 (7.8–30.0) | 14.5 (7.0–30.0) | 0.341 |
| Clinical features | ||||
| Prodromal symptoms | 54 (40.3) | 14 (25.0) | 40 (51.3) | 0.004 |
| Onset symptoms | ||||
| Seizure | 57 (42.5) | 28 (50.0) | 29 (37.2) | 0.019 |
| Memory dysfunction | 17 (12.7) | 11 (19.6) | 6 (7.7) | |
| Psychiatric symptoms | 49 (36.6) | 15 (26.8) | 34 (43.6) | |
| Others | 11 (8.2) | 2 (3.6) | 9 (11.5) | |
| Associated tumors | 8 (6.0) | 5 (8.9) | 3 (3.8) | 0.393 |
| Requiring ICU admission | 14 (10.4) | 2 (3.6) | 12 (15.4) | 0.042 |
| Paraclinical features | ||||
| Antibody types | ||||
| NMDAR | 81 (60.4) | 13 (23.2) | 68 (87.2) | <0.001 |
| LGI1 | 29 (21.6) | 23 (41.1) | 6 (7.7) | |
| GABABR | 17 (12.7) | 16 (28.6) | 1 (1.3) | |
| DPPX | 2 (1.5) | 0 (0.0) | 2 (2.6) | |
| CASPR2 | 4 (3.0) | 3 (5.4) | 1 (1.3) | |
| AMPAR | 1 (0.7) | 1 (1.8) | 0 (0.0) | |
| CSF pleocytosis (>5 cells/μL)† | 60 (44.8) | 21 (37.5) | 39 (50.0) | 0.232 |
| Abnormal MRI (T2 hyperintensity) | 65 (48.5) | 30 (53.6) | 35 (44.9) | 0.413 |
| Abnormal EEG (epileptic or slow-wave activity)‡ | 88 (65.7) | 34 (60.7) | 54 (69.2) | 0.586 |
| Disease severity on admission (assessed by mRS), median (IQR) | 2.0 (1.0–3.0) | 2.0 (1.0–2.3) | 2.0 (1.0–3.0) | 0.042 |
All data are described as numbers (%) unless otherwise stated.
†Four (3.0%) patients did not perform lumbar puncture or undertake CSF analysis.
‡Thirty-eight (28.4%) patients did not complete examination.
Abbreviations: AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CASPR2, contactin-associated protein-like 2; CSF, cerebrospinal fluid; DPPX, dipeptidyl-peptidase-like protein 6; EEG, electroencephalogram; GABABR, gamma-aminobutyric acid-b receptor; ICU, intensive care unit; IQR, interquartile range; LGI1, leucine-rich glioma-inactivated 1; MRI, magnetic resonance imaging; NMDAR, N-methyl-d-aspartate acid receptor; NSAE, neuronal surface antibody-mediated autoimmune encephalitis.
Clinical and paraclinical characteristics of the late- and younger-onset groups
Prodromal symptoms were more common in the younger-onset group (P = 0.004). The onset symptoms were significantly distinct between the 2 groups (P = 0.019). The late-onset group presented most frequently with seizures, while the younger-onset with psychiatric symptoms. Throughout the disease course, symptoms including seizures, memory dysfunction, psychiatric symptoms were also more frequent in the late-onset group (Fig. 2, Supplementary Table 1). By contrast, the younger-onset group had less frequent memory dysfunction (P < 0.001), but more central hypoventilation that merely found in anti-NMDAR encephalitis (P = 0.045). Eight patients had tumors (all undertook surgery and/or chemotherapy and/or radiotherapy), including 3 with ovarian teratoma in the younger-onset group, 4 with small cell lung cancer, and 1 with thymoma in the late-onset group. Additionally, the younger-onset patients had a significant higher mRS score on admission (P = 0.042), and required ICU admission more frequently during hospitalization (P = 0.042) (Table 1).
Figure 2:
cumulative symptoms in the initial stage by the 2 age groups. *P < 0.001; **P = 0.045; ***P = 0.042. Abbreviation: ICU, intensive care unit.
Treatment and outcome of the late- and younger-onset groups
In general, all patients received immunotherapies. Up to May 2022, the follow-up duration of the late- and younger-group were 64.0 months (IQR = 40.0–81.0) and 61.2 months (IQR = 45.8–96.7), respectively (Table 2). The late-onset group had a shorter duration from onset to definite diagnosis and treatment than the younger-onset group, yet without any significant difference. The younger-onset group had a significant longer LOS (extended hospitalization >14 days) (P = 0.014). Younger-onset patients also had a significant higher mRS score at 1 month after treatment (P = 0.032), though the ultimate outcome during follow-up were no worse than that in the late-onset group. At last follow-up, 6/56 (10.7%) late-onset patients died from causes including pre-existing tumor progression (2 patients) and cardiovascular/cerebrovascular events (4 patients), and 1/78 (1.3%) younger-onset patient died from respiratory failure due to disease progression. Meanwhile, a total of 8 patients (7 in the younger-onset group) relapsed during the follow-up.
Table 2:
treatment and outcome of patients with late- and younger-onset NSAE
| Overall (n = 134) | Late-onset group (n = 56) | Younger-onset group (n = 78) | P | |
| Interval durations | ||||
| Time from onset to diagnosis, days, median (IQR) | 17.5 (9.0–31.8) | 22.0 (9.0–35.5) | 16.5 (9.0–30.8) | 0.287 |
| Time from onset to treatment, days, median (IQR) | 20.0 (10.0–31.8) | 22.0 (9.8–33.3) | 18.0 (10.0–31.0) | 0.657 |
| LOS >14 days | 73 (54.5) | 23 (41.1) | 50 (64.1) | 0.014 |
| Follow-up information | ||||
| Follow-up, months, median (IQR) | 62.5 (45.1–6.7) | 64.0 (40.0–81.0) | 61.2 (45.8–96.7) | 0.400 |
| Score of mRS, median (IQR) | ||||
| One month after treatment | 1.0 (1.0–3.0) | 1.0 (1.0–2.0) | 2.0 (1.0–3.0) | 0.032 |
| One year after treatment | 1.0 (1.0–2.0) | 1.0 (1.0–2.0) | 1.0 (1.0–2.0) | 0.917 |
| At final follow-up | 1.0 (0.0–2.0) | 1.0 (0.0–2.0) | 1.0 (0.0–2.0) | 0.910 |
| Outcomes | ||||
| Short-term outcome | ||||
| Exacerbation | 8 (6.0) | 1 (1.8) | 7 (9.0) | 0.133 |
| Remission | 38 (28.4) | 14 (25.0) | 24 (30.8) | |
| Stability | 88 (65.7) | 41 (73.2) | 47 (60.3) | |
| One-year outcome | ||||
| Good | 116 (86.6) | 49 (87.5) | 67 (85.9) | 0.789 |
| Poor | 18 (13.4) | 7 (12.5) | 11 (14.1) | |
| Mortality | 5 (3.7) | 4 (7.1) | 1 (1.3) | 0.161 |
| Long-term outcome | ||||
| Good | 119 (88.8) | 50 (89.3) | 69 (88.5) | 0.881 |
| Poor | 15 (11.2) | 6 (10.7) | 9 (11.5) | |
| Mortality | 7 (5.2) | 6 (10.7) | 1 (1.3) | 0.021 |
| Relapse | 8 (6.0) | 1 (1.8) | 7 (9.0) | 0.138 |
| Side effects | 6 (4.5) | 3 (5.4) | 3 (3.8) | 0.694 |
All data are described as numbers (%) unless otherwise stated.
Abbreviations: IQR, interquartile range; LOS, length of stay; mRS, modified Rankin Scale; NSAE, neuronal surface antibody-mediated autoimmune encephalitis.
Age-related characteristics of each disease subtype
We then explored the age-related characteristics of the 3 most common subtypes of NSAE, namely anti-NMDAR, anti-LGI1, and anti-GABABR encephalitis (Supplementary Table 2). Only patients with anti-NMDAR encephalitis exhibited the distinct age-dependent features. In detail, the late-onset group presented more frequently with memory deficits (9/13 vs. 14/68, P = 0.001) in disease course, while the younger-onset group had more seizures (46/68 vs. 4/13, P = 0.028) with a significant longer LOS (P = 0.035) and higher mRS score at each follow-up period, i.e. on admission (P = 0.011), 1-month follow-up (P = 0.006), and the final follow-up (P = 0.048).
Discussion
Our study was the first to comprehensively depict the age-dependent profile in patients with NSAE. Despite previous studies showing a higher prevalence of NSAE in youngsters [2, 5], we found the late-onset patients comprising a distinct group with different clinical and prognostic features. Notably, the younger-onset group had higher severity at disease onset and required ICU admission more frequently, thereby requiring more attention. Meanwhile, those age-related features were distinct between different subtypes. By characterizing the clinical profiles of late- and younger-onset groups, our study underscored the importance of age of onset in the diagnostic and therapeutic processes of NSAE mediated by different antibodies.
We found a significant relationship between the age of onset and the specific NSAE. The late-onset group was mainly comprised of patients with anti-LGI1 and anti-GABABR encephalitis (41.1%, 28.6%, respectively), whereas the younger-onset largely had anti-NMDAR encephalitis. The distribution of different NSAE subtypes in late- vs. younger-onset group may account for the demographic features in our cohort. There were more younger-onset patients than late-onset NSAE. This was very likely associated with the large number of anti-NMDAR encephalitis patients in our cohort, which had an early disease onset [4]. In addition, in the late-onset group, we found a marked male predominance (41/56, 73.2%). It may be attributed to the male predominance in patients with late-onset anti-LGI1 and anti-GABABR encephalitis (65.2% [15/23] and 81.3% [13/16], respectively).
Our cohort indicated that the late-onset group more commonly started with seizures, and presented more frequently with memory dysfunctions at the initial stage. By contrast, the younger-onset group typically had psychiatric symptoms as the onset presentation, developed central hypoventilation, and had prodromal symptoms more often. However, previous studies revealed some opposite views, i.e. psychiatric symptoms presented most frequently in both groups [7, 8], and seizure was a significant differential onset symptom for younger-onset ones [7]. This might also be related to the predominance of anti-NMDAR encephalitis in the younger-onset group, which mainly presented with psychiatric symptoms. The anti-LGI1 and anti-GABABR encephalitis, the major component of the late-onset group, more commonly presented with seizures. It is reasonable to speculate that the most common presentation in either age group may change if the proportion of neuronal antibodies changes. Notably, central hypoventilation, which was frequent in anti-NMDAR encephalitis, suggested a higher risk of mechanical ventilation and poor prognosis [12]. It was also a specific characteristic for younger-onset patients in our study. Moreover, the incidence of associated tumors showed no difference between age groups. For the small overall number of patients with associated tumors, further clarification is needed. The distinct clinical pictures between the 2 age groups, both at disease onset and later in the disease course, highlighted the importance of clinical history taking and consideration of the age of onset when diagnosing NSAE patients.
Interestingly, the late-onset group had lower mRS scores on admission and showed less frequent ICU admissions and had shorter LOS during hospitalization in our cohort. Similar results have been reported in anti-NMDAR encephalitis [7], the exact mechanism is still unclear. Age-related alterations in the immune system (e.g. changed thymic T-regulatory cells) and lower autoantibodies affinity in older individuals, resulting in weaker autoimmune responses, might explain this phenomenon [7, 13]. However, we did not find a tendency of delayed diagnosis and treatment in the late-onset group, which was different from previous studies [7, 8]. This might be associated with the different medical referral systems between different regions [14, 15]. Meanwhile, patients’ willingness to seek medical care in different cultures might also play a role. However, with a longer follow-up, our study did not find any significant difference on prognosis at different stage of follow-up (1-month, 1-year, and longer-term after immunotherapies) for these 2 age groups, which was similar with the results of another Chinese study [8]. On the contrary, the study with merely younger-onset patients suggested that the increasing age had a negative impact on the mRS score at discharge in females [9]. Moreover, Titulaer et al. indicated that more late-onset patients with anti-NMDAR encephalitis suffered poor outcomes at 24 months follow-up than the younger-onset group (40% vs. 20%) [7]. These differences in outcomes could be explained by a generally milder severity in our cohort both at baseline and follow-up. Meanwhile, the younger-onset group had higher severity on admission, but the prognosis was similar to those of the late-onset group, possibly attributed to the timely diagnosis and prompt treatment, as well as the better recovering capability in younger patients.
Our study had several limitations. First, the interpretative bias existed in our retrospective study, i.e. the onset symptoms were recorded by the caregivers’ descriptions and the clinicians’ subjective impression and expertise. Second, there was a substantial difference in sample sizes between subtypes of NSAE, which might interfere with the results of the final cohort. Considering the difference in disease nature among each subtype, prospective studies with a larger sample size, longer follow-up, and longitudinal assessments of the onset age and disease profiles are needed.
Conclusion
Our study revealed several age-related features of NSAE (Fig. 3). Generally speaking, male-dominant onset of seizures and memory dysfunctions had more diagnostic significance for the late-onset group. The prodromal symptoms, onset of psychiatric symptoms and central hypoventilation might be specific for those with younger-onset. Notably, in consideration of the higher severity on admission, more frequent requirement for ICU admission and longer LOS, more attention is needed for the younger-onset patients, especially for those with anti-NMDAR encephalitis.
Figure 3:
the different profile of NSAE with younger-onset and late-onset. *Significant characteristics for each group (P < 0.05): (1) Late-onset: males, central hypoventilation; (2) Younger-onset: prodromal symptoms, required ICU admission, LOS >14 days. Abbreviations: ICU, intensive care unit; LOS, length of stay; NSAE, neuronal surface antibody-mediated autoimmune encephalitis.
Supplementary Material
Acknowledgements
Not applicable.
Glossary
Abbreviations
- AMPAR
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
- CASPR2
: contactin-associated protein-like 2
- CSF
cerebrospinal fluid
- DPPX
dipeptidyl-peptidase-like protein 6
- EEG
electroencephalogram
- GABABR
gamma-aminobutyric acid B receptor
- ICU
intensive care unit
- IQR
interquartile range
- LGI1
: leucine-rich glioma-inactivated 1
- LOS
length of stay
- MRI
magnetic resonance imaging
- mRS
modified Rankin Scale
- NMDAR
N-methyl-d-aspartate acid receptor
- NSAE
neuronal surface antibody-mediated autoimmune encephalitis
Contributor Information
Meng-Ting Cai, Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
Yang Zheng, Department of Neurology, Zhejiang Provincial Hospital of Chinese Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China.
Qi-Lun Lai, Department of Neurology, Zhejiang Hospital, Hangzhou 310013, China.
Gao-Li Fang, Department of Neurology, Zhejiang Chinese Medicine and Western Medicine Integrated Hospital, Hangzhou 310003, China.
Chun-Hong Shen, Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
Mei-Ping Ding, Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
Yin-Xi Zhang, Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
Ethical approval and patient consent
This research was approved by the local ethics committee of each participating center (Second Affiliated Hospital School of Medicine Zhejiang University, Zhejiang Hospital, and Zhejiang Chinese Medicine and Western Medicine Integrated Hospital). The requirement to obtain patient consent was waived for this retrospective study.
Conflict of interest
The authors declare that they have no competing interests.
Funding
Not applicable.
Data availability
Anonymized data not published within this article will be made available upon reasonable request from any qualified investigator within 5 years after publication.
Author contributions
M.-T.C.: Conceptualization, data curation, formal analysis, investigation, writing-original draft, writing-review and editing. Y.Z.: Conceptualization, data curation, formal analysis, investigation, writing-original draft, writing-review and editing. Q.-L.L.: Data curation, formal analysis, investigation, writing-review and editing. G.-L.F.: Data curation, formal analysis, investigation, writing-review and editing. C.-H.S.: Data curation, formal analysis, investigation, writing-review and editing. M.-P.D.: Data curation, formal analysis, investigation, supervision, validation, writing-review and editing. Y.-X.Z.: Conceptualization, data curation, formal analysis, investigation, supervision, validation, writing-review and editing.
Permission to reproduce
Not applicable.
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