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Abstract
Background Myocarditis is a global epidemic that causes various medical conditions associated with an increased incidence and death numbers. This study aimed to investigate the trends in myocarditis-associated incidence, mortality, and disability-adjusted life-years (DALYs) with health inequalities, risk factors, and predict the disease burden, thereby mitigating the health hazards of myocarditis.
Methods This was a modelling study that used data from the Global Burden of Diseases 2021, from which myocarditis was included in the analysis. Incidence, death, DALYs, age-standardised incidence rate (ASIR), age-standardised mortality rate (ASMR), age-standardised DALYs rate (ASDR), cases change, corresponding estimated annual percentage change (EAPC), Slope Inequality of Index (SII) and Concentration Index were analysed.
Results From 1990 to 2021, incidence and death cases increased by 66.88% and 45.94%, respectively. The myocarditis-associated incidence and death cases increased in all five sociodemographic index (SDI) regions. Among the five SDI regions, the High SDI region had the highest myocarditis-associated ASIR with the least ASMR and ASDR in 2021. Regionally, Central Asia had the largest increase in EAPC of ASIR, ASMR and ASDR. Among 204 countries, Japan had the highest ASIR in 2021 and Romania had the highest ASMR and ASDR. Between 1990 and 2021, the SII and Concentration Index for DALYs have shown declining trends. The extreme temperatures were major contributors to the burden of myocarditis during 1990–2021. The projections suggested that the myocarditis-related global number of new cases and death would increase over the next 15 years. There may be upward trends in people of 15+of incidence number and 40+of death and DALYs number.
Conclusions Myocarditis is an increasing global health challenge with rising incidence and death. Management of extreme temperatures remains a major challenge. The number of incidence, death and DALYs in different age groups would continue to grow over the next 15 years. Therefore, measures should be taken to target risk factors and high-risk groups.
- Global Burden of Disease
- Epidemiology
- Myocarditis
Data availability statement
Data are available in a public, open access repository. The data that support the findings of this study are available from the Global Burden of DiseaseStudy 2021 (GBD 2021) at https://vizhub.healthdata.org/gbd-results/.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Myocarditis is a global epidemic that causes various medical conditions associated with an increased incidence and death numbers.
WHAT THIS STUDY ADDS
In this analysis in 2021, there were 1 319 703.61 incidence cases of myocarditis globally, resulting in 31 764.52 death cases and 963 138.69 disability-adjusted life-years (DALYs) cases; and since 1990, there were 66.88% and 45.94% increases in incidence and death cases, respectively.
The myocarditis-associated incidence and death cases increased in all five sociodemographic index (SDI) regions. Among the five SDI regions, the High SDI region had the highest myocarditis-associated age-standardised incidence rate with the least age-standardised mortality rate and age-standardised DALYs rate in 2021.
Between 1990 and 2021, the Slope Inequality of Index and Concentration Index for DALYs have shown declining trends.
Management of extreme temperatures is a critical challenge in reducing the burden of myocarditis.
The number of incidence, death and DALYs in different age groups would continue to grow in the next 15 years.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Myocarditis is a major health issue, and measures should be taken to target risk factors and high-risk groups. Identification of myocarditis and respective interventions should be improved across various healthcare settings.
Introduction
Myocarditis, defined as inflammatory injury of the heart muscle, can also involve the cardiac conduction system and pericardial layers.1 This condition can arise from infections, immune-mediated responses, drugs or vaccines.2 Some patients have decreased cardiac strength, heart rhythm abnormalities or acute heart failure, and even develop cardiogenic shock. Approximately 1–7% of patients die of acute myocarditis.3 Individuals in all age groups may also be affected.4 Therefore, accurately assessing the epidemiology of myocarditis is crucial for its prevention, diagnosis and treatment.
The Global Burden of Disease (GBD) database provides extensive epidemiological data for analysing disease burdens of geographical distributions and trends. Based on GBD 2019 data, Wang et al5 reported that the incidence and death numbers of myocarditis increased from 1990 to 2019. Zhang et al6 used data from GBD 2019 in youth and middle-aged populations and revealed a global burden of myocarditis among the selected populations. Bao et al7 applied the age–period–cohort model to delineate the incidence and mortality trends of myocarditis in China. Besides, three studies have analysed data on myocarditis from GBD 2021.8–10 However, these three studies were lacking socioeconomic inequality analysis. Both studies failed to incorporate socioeconomic inequality metrics (eg, Slope Inequality of Index (SII) and Concentration Index) to assess disparities in disease burden across income, education or geographical subgroups, limiting insights into health equity. Furthermore, Zhang et al8 focused exclusively on children aged 0–14 years, omitting global trends and burden patterns in adults and older populations. Li et al9 did not project future trajectories of myocarditis incidence, death and disability-adjusted life-years (DALYs) in all age groups, restricting utility for long-term public health planning. In our study, we used the data from the GBD 2021 to analyse trends in the burden of myocarditis, health inequality, its associated risk factors across global, regional and national levels between 1990 and 2021, and provide a reference forecast by 2035 to guide accurate screening and prevention.
Methods
Study population and data collection
In our analysis of the GBD study 2021, which was published by the Institute for Health Metrics and Evaluation, we accessed repeated cross-sectional data from the Global Health Data Exchange (GBD 2021, https://vizhub.healthdata.org/gbd-results/).11 In the GBD 2021 study, myocarditis was identified using the International Classification of Diseases (ICD) and Injuries (ICD-9 and ICD-10). It can be caused by viral infections, autoimmune conditions and other non-ischaemic causes and can result in reduced ability of the heart to pump blood to the body. The ICD codes included for myocarditis are B33.2, I40–I41.9, I51.4 for ICD-10 and 422–422.9 for ICD-9.10 Incidence, death and DALYs for myocarditis were sourced from GBD 2021. According to the GBD world population, an age-standardised rate (ASR) analysis was recorded per 100 000 population.12 A DALY is equivalent to a one-year loss of healthy life.13 The Sociodemographic Index (SDI) is estimated to represent a comprehensive development status that exhibits a robust correlation with health outcomes. It is derived from the geometric mean of 0–1 indices of the fertility rates among females under the age of 25, average years of education for individuals aged 15 and above and lag-distributed income per capita.11 For GBD 2021, final SDI values were multiplied by 100 for reporting. Sun et al14 recently described how SDI is assembled and categorised the 204 countries into five quintiles (low, low-middle, middle, high-middle and high) based on their country-level SDI estimates for the year 2021. Two standard measures, namely SII and Concentration Index, were used to assess both absolute and relative income-related inequalities between countries. The criteria used to define ‘high’ and ‘low’ temperatures in the study were based on the theoretical minimum-risk exposure level (TMREL). For each of the 23 temperature zones (classified by annual mean temperatures), the TMREL was identified as the location-specific daily mean temperature associated with the lowest mortality risk across all included causes of death. High temperatures mean daily mean temperatures above the TMREL for a given zone. Low temperatures mean daily mean temperatures below the TMREL for a given zone.15
Statistical analysis
A descriptive analysis was performed to characterise the burden of myocarditis on a global scale. The estimated annual percentage change (EAPC) value was estimated by linear regression model. The correlation measure of relationship between the ASR and SDI was using the Pearson method. The Bayesian age–period–cohort model (BAPC) employs integrated nested Laplace approximations (INLA) to predict the myocarditis burden over the next 15 years. To ensure smoothing, BAPC models assume independent mean-zero normal distributions on the second differences of all effects.16 Specifically, the BAPC model assumes prior distribution of the age effect as follows:
(1)
Considering that we are interested in the incidence case counts for age group a, with a t period into the future, the following equation can be applied:
(2)
Here, we add an independent random effect 
to adjust for overdispersion.17 Considering the smoothing assumption, the BAPC models assume prior distribution of the period effect as follows:
(3)
The solid lines in the figures are fitted using the Locally Estimated Scatterplot Smoothing method. In our study, R software (V.4.3.2), packages involving tidyverse, dplyr, data.table, vroom, scales, sf, ggrepel, ggsci, patchwork, BAPC and INLA were employed for all statistical analyses. P values <0.05 were considered to be statistically significant. The detailed methodology employed in this study is also described in online supplemental file 1 (Methods section).
Supplemental material
Results
Global trends
Incidence
From 1990 to 2021, the global age-standardised incidence rate (ASIR) slightly decreased from 16.82 (95% uncertainty interval (UI): 13.53, 20.72) per 100 000 in 1990 to 16.16 (95% UI: 13.11, 19.76) per 1000 00 in 2021. The EAPC was −0.20 (95% CI: −0.23, −0.17). The global ASIR among men is higher than that in women (table 1). From 1990 to 2021, for both men and women, the ASIR has trended downward (online supplemental eFigure 1). In 2021, the highest age group for ASIR was 95+years for both men and women (online supplemental eFigure 2A).
Incidence of myocarditis between 1990 and 2021 at the global, SDI and regional levels
Mortality
Over the past 30 years, the age-standardised mortality rate (ASMR) decreased from 0.56 (95% UI: 0.46, 0.65) per 100 000 in 1990 to 0.40 (95% UI: 0.32, 0.47) per 100 000 in 2021, and the EAPC was −1.37 (95% CI: −1.81, −0.92). The global ASMR in men is higher than in women (online supplemental eTable 1). From 1990 to 2021, the ASMR all showed a gradual increase until 2005 and reached a maximum in 2005, and then showed a gradual decrease (online supplemental eFigure 3). In 2021, the highest ASMR was observed among both men and women aged 95+years in 2021 (online supplemental eFigure 2B).
Disability-adjusted life-years
The age-standardised DALYs rate (ASDR) decreased from 19.93 (95% UI: 16.23, 24.41) per 100 000 in 1990 to 12.41 (95% UI: 10.37, 14.76) per 100 000 in 2021, and the EAPC was −1.71 (95% CI: −1.95, −1.46) (online supplemental eTable 2). The global ASDR in men is higher than in women. From 1990 to 2021, the ASDR showed a gradual increase and reached a maximum followed by a gradual decrease (online supplemental eFigure 4). For both men and women, in 2021, the highest rate of DALYs was observed among people aged 95+years (online supplemental eFigure 2C).
SDI regional trends
Incidence
The High SDI region had the most ASIR in 2021 (17.60; 95% UI: 14.60, 21.33, per 100 000) and the low SDI had the least 15.45 (95% UI: 12.47, 18.93) per 100 000. The greatest ASIR decrease of EAPC is in High SDI, −0.33 (95% CI: −0.40, −0.25) (table 1). From 1990 to 2021, for both men and women, the ASIR in High SDI, High-middle SDI and Middle SDI regions have trended downward, and in the rest regions ASIR showed a flat trend (online supplemental eFigure 1).
Mortality
The Middle SDI (0.58; 95% UI: 0.39, 0.74, per 100 000) and High-middle SDI (0.58; 95% UI: 0.48, 0.66, per 100 000) regions had the most ASMR and the High SDI had the least (0.20; 95% UI: 0.18, 0.21, per 100 000) in 2021. The high-middle SDI region had the highest EAPC decrease in the myocarditis-associated ASMR (−2.59; 95% CI: −3.36, −1.81) (online supplemental eTable 1). From 1990 to 2021, the ASMR in the five SDI regions all showed a gradual increase followed by a gradual decrease with fluctuating trends in some SDI regions (online supplemental eFigure 3).
Disability-adjusted life-years
In 2021, the High-middle SDI region had the most ASDR (15.86; 95% UI: 13.08, 18.04, per 100 000) and greatest EAPC decrease (−2.22; 95% CI: −2.66, −1.79). The High SDI had the least (9.14; 95% UI: 8.61, 9.72, per 100 000) ASDR in 2021 (online supplemental eTable 2). From 1990 to 2021, in addition to Low-middle SDI and Low SDI regions who have a decreasing trend in ASDR over time, the ASDR in the rest of the SDI regions all showed a gradual increase followed by a drop with fluctuating trends (online supplemental eFigure 4).
Geographical regional trends
Incidence
Among 21 geographical regions, the ASIR was highest in High-income Asia Pacific (19.36; 95% UI: 15.94, 23.71, per 100 000). Central Asia had the highest increase in the myocarditis-associated incidence rate (EAPC, 0.05; 95% CI: 0.04, 0.05) and High-income North America had the largest decrease in the incidence of myocarditis (EAPC, −0.68; 95% CI: −0.86, −0.50) (table 1). A positive association was observed between the SDI and ASIR (r=0.43, p˂0.001). When the SDI was greater than 0.6, the regions with high SDI had a correspondingly high ASIR (figure 1A).
Age-standardised incidence rates for myocarditis by SDI from 1990 to 2021. (A) 21 GBD regions. (B) 204 countries and territories. Expected values based on SDI and disease rates in all locations are shown as the black line. GBD, Global Burden of Diseases; SDI, Sociodemographic Index.
Mortality
In 2021, Central Europe had the highest myocarditis-associated ASMR (1.24; 95% UI: 0.99, 1.52, per 100 000). Central Asia had the highest increase in the ASMR (EAPC, 2.86; 95% CI: 2.10, 3.64), whereas Andean Latin America had the largest decrease (EAPC, −4.74; 95% CI: −5.02, −4.46) (online supplemental eTable 1). Between 1990 and 2021, there is a positive correlation between the SDI and the ASMR for myocarditis in different regions worldwide (r=0.21, p˂0.001) (online supplemental eFigure 5A).
Disability-adjusted life-years
In 2021, Central Europe had the highest ASDR (34.11; 95% UI: 26.56, 42.43, per 100 000); Andean Latin America had the lowest ASDR (2.12; 95% UI: 1.56, 2.71, per 100 000). From 1990 to 2021, Central Asia had the largest increase in the ASDR (EAPC, 2.61; 95% CI: 1.78, 3.44); Andean Latin America had the largest decrease (EAPC, −4.45; 95% CI: −4.73, −4.17) (online supplemental eTable 2). A positive association was observed between the SDI and ASDR as demonstrated in online supplemental eFigure 6A (r=0.20, p˂0.001).
National trends
Incidence
In 2021, Japan had the highest ASIR of myocarditis (19.84; 95% UI: 16.38, 24.21, per 100 000). United Arab Emirates (EAPC, 0.09; 95% CI: 0.06, 0.12) had the largest increases in myocarditis incidence (online supplemental eTable 3 and figure 2A). Additionally, our country-specific analysis revealed a weak positive correlation (r=0.39, p<0.001) between the ASIR of myocarditis and the SDI (figure 1B).
Map showing EAPCs of age-standardised rates of incidence (A), death (B) and DALYs (C) in 204 countries and territories among people with myocarditis from 1990 to 2021. DALYs, disability-adjusted life-years; EAPCs, estimated annual percentage changes.
Mortality
In 2021, Romania (5.12; 95% UI: 3.90, 6.59, per 100 000) had the highest ASMR. Kazakhstan (EAPC, 13.64; 95% CI: 11.37, 15.95) had the greatest increases in the ASMR; Italy (EAPC, −8.36; 95% CI: −10.10, −6.59) had the greatest decreases (online supplemental eTable 4 and figure 2B). As SDI increases, which reflects a nation’s overall socioeconomic development, the ASMR for myocarditis tends to decrease, indicating a lower disease burden (online supplemental eFigure 5B).
Disability-adjusted life-years
In 2021, Romania had the highest ASDR (141.03; 95% UI: 104.45, 182.00, per 100 000). Kazakhstan (EAPC, 12.37; 95% CI: 10.19, 14.60) had the greatest increase in ASDR; Italy (EAPC, −8.35; 95% CI: −9.97, −6.71) had the greatest decreases (online supplemental eTable 5 and figure 2C). As SDI increases, the ASDR for myocarditis tends to decrease (online supplemental eFigure 6B).
The detailed absolute measures across global, regional and national levels, such as incidence, death and DALYs numbers, are also described in online supplemental file 1 (Results section).
Cross-national myocarditis health inequality
In 1990 and 2021, the SII for DALYs were −10.06 (95% CI: −13.14, −6.98) and 0.25 (95% CI: −1.94, 2.44), respectively. Between 1990 and 2021, the Concentration Index for DALYs was −0.12 (95% CI: −0.26, 0.12) and 0.03 (95% CI: −0.19, 0.19), respectively (figure 3).
Cross-national myocarditis health inequality. (A) SII analysis. Absolute income-related healthy inequality in myocarditis burden, presented using regression lines, 1990 versus 2021. (B) Concentration Index analysis. Relative income-related healthy inequality in myocarditis burden, presented using concentration curves, 1990 versus 2021. SDI, Sociodemographic Index; SII, Slope Inequality of Index.
Risk factors
A detailed analysis of global data from GBD 2021 revealed the two most detailed risk factors associated with death and DALYs for myocarditis, including low temperature and high temperature. Specifically, in 2021, low temperature caused a higher proportion of death and DALYs attributable to risk factors in global and five SDI regions (figure 4A and online supplemental eFigure 7A). People aged 85–89 years had the highest proportion of death attributable to low temperature and high temperature (online supplemental eFigure 8). Children aged<5 years had the highest proportion of DALYs attributable to low temperature and high temperature (online supplemental eFigure 9). Among individuals aged 85–89, low temperatures contribute the highest proportion to mortality, while in children aged<5 years, low temperatures have the most significant impact on DALYs. Among 21 geographical regions, the highest proportion was in East Asia of death and DALYs attributable to all risk factors in 2021 (figure 4B and online supplemental eFigure 7B). The contribution of low temperatures to myocarditis mortality and DALYs is significantly higher than that of high temperatures, particularly in East Asia and among older populations.
Percentage contribution of risk factors to death from myocarditis in 2021 at the global, SDI and regional levels. (A) Global and SDI levels. (B) Regional levels. The contribution of low temperatures to myocarditis mortality is significantly higher than that of high temperatures, particularly in East Asia. SDI, Sociodemographic Index.
Prediction of the myocarditis-related disease burden
The results indicated that the number of myocarditis-related incidence and death would increase from 2021 to 2035, and DALYs would decrease during the same period (online supplemental eFigure 10). However, the ASIR, ASMR and ASDR of myocarditis will decrease from 2021 to 2035 (online supplemental eFigure 11). There may be upward trends in people of 15+of incidence number (figure 5), 40+of death and DALYs number (online supplemental eFigures 12 and 13). There may be upward trends in people of 90+of incidence, death and DALYs rate (online supplemental eFigures 14-16).
Trends in the myocarditis-related incidence number at each age group (per 5-year cohort): observed (blue lines) and predicted numbers (red lines).
Discussion
In this study, we conducted a comprehensive epidemiological analysis of global myocarditis incidence, mortality and DALYs using high-quality data from the GBD study. Over the past 30 years, while the global incidence and death cases of myocarditis have increased from 1990 to 2021 in many regions and countries, the corresponding ASIR and ASMR have shown a downward trend. This decline in ASIR and ASMR may partly reflect improvements in the diagnosis and treatment of myocarditis, as well as the effects of population growth and ageing.18 Notably, the greatest number of myocarditis-associated DALYs was observed among children younger than 5 years of age, a group that, despite having a relatively low incidence, exhibited a disproportionately high disease burden due to higher mortality rates. Implementing timely interventions in this vulnerable age group could not only improve their prognosis but also alleviate the overall disease burden on families and healthcare systems.
Sex differences in the burden of myocarditis were evident in our analysis, with ASIR, ASMR and ASDR consistently higher in men than women across all SDI regions from 1990 to 2021. This finding aligns with prior studies, which have also reported a male predominance in myocarditis cases and outcomes.2 19 Several factors may contribute to this disparity. First, there may be sex hormone-mediated differences in the immune response to cardiac inflammation, with testosterone potentially exacerbating the severity of myocarditis, while oestrogen has been shown to exert protective effects.20 21 Second, differences in vascular haemodynamics and other pathophysiological factors may contribute to the increased susceptibility and severity of myocarditis in men.22 Interestingly, the gender gap in disease burden narrowed after menopause, and among individuals aged 80–84 years and older, the disease burden was higher in women than in men, which further supports the role of sex hormones in myocarditis pathogenesis.
Regionally, we observed that the High SDI regions had the highest ASIR but the lowest ASMR and ASDR in 2021. This discrepancy may be attributed to the robust healthcare systems, greater allocation of medical resources and higher levels of education prevalent in these regions, which enable better diagnosis, treatment and prevention of complications associated with myocarditis. Conversely, Central Asia exhibited the largest increases in EAPC for ASIR, ASMR and ASDR over the study period, highlighting the need for targeted interventions in this region. Among countries, Japan had the highest ASIR of myocarditis in 2021, while Romania reported the highest ASMR and ASDR. Despite economic growth in some regions, the development of healthcare infrastructure and educational systems has not kept pace, potentially contributing to the higher disease burden. Increased investment in healthcare and public health education in these regions could help mitigate these disparities and improve prevention and treatment outcomes.
While there is evidence suggesting an increased incidence of myocarditis due to COVID-19,23 the study’s current data does not show a significant inflection point in myocarditis burden during the pandemic. This underscores the need for ongoing research and data collection to better understand the long-term impacts of COVID-19 on myocarditis epidemiology.
Our analysis also highlighted the significant impact of environmental factors on myocarditis burden. Low temperature emerged as the most influential risk factor, with older adults aged 85–89 years experiencing the highest proportion of death attributable to extreme temperatures, and children under 5 years of age having the highest proportion of DALYs attributable to these conditions. Among the 21 geographical regions, East Asia had the highest proportion of death and DALYs attributable to all risk factors in both 1990 and 2021. Burkart et al24 investigated the impact of meteorology on human mortality suggesting moderate hypothermia and extreme heat adversely affect cardiopulmonary mortality. This may be attributed to hypothermia and hyperthermia, which are linked to elevated plasma and blood viscosity, an increase in red blood cell count and heightened amounts of certain proteins, thereby constricting the cardiovascular system.25 Our findings underscore the importance of addressing modifiable risk factors, such as exposure to extreme temperatures, through cost-effective public health strategies and targeted screening programmes.
Looking ahead, our study used GBD data to project the global trends in myocarditis-related disease burden over the next 15 years. The results indicate that the number of new myocarditis cases and death is expected to increase significantly from 2021 to 2035, particularly among individuals aged 15 years and older (for incidence), 40 years and older (for death and DALYs). This projected rise in disease burden highlights the urgent need for effective public health policies aimed at strengthening the prevention and management of myocarditis risk factors. For example, mitigating the effects of environmental factors such as extreme temperatures and improving healthcare access in vulnerable populations could substantially reduce the future burden of myocarditis.
In conclusion, while progress has been made in reducing the ASR of myocarditis globally, the absolute burden of the disease continues to rise due to population growth and ageing. Effective prevention and management strategies, including the reduction of modifiable risk factors and investment in healthcare infrastructure, are critical to alleviating the global burden of myocarditis in the coming decades.
Limitations
This study has several limitations. First, the analysis heavily relied on the GBD database. The statistical errors in data seem unavoidable in the criterion of included cases due to different diagnostic conditions. Second, the diagnosis of myocarditis presents challenges as myocarditis can be regarded as an inflammation of the myocardium with different clinical symptoms. The variations in healthcare systems, healthcare policies and medical practices across countries may have an effect on disease burden.23 Third, the GBD framework does not inherently account for temperature exposure lag effects in its analytical outputs. Regarding pathogen seasonality, while the GBD database synthesises outcomes through integrated modelling approaches rather than isolating individual factors. Lastly, in EAPC calculations, we assume that changes are stable over the observation period and evaluate this assumption by testing the linearity of the trend.
Conclusions
There still existed a burden of myocarditis over the past 30 years, according to age, sex, global scale, region, country and SDI, which would continue to increase over the next 15 years. There is an urgent need for healthcare professionals to reduce the burden of myocarditis and its risk factors. To mitigate global inequalities arising from socioeconomic disparities, it is crucial to ensure a more equitable utilisation and allocation of healthcare resources.
Data availability statement
Data are available in a public, open access repository. The data that support the findings of this study are available from the Global Burden of DiseaseStudy 2021 (GBD 2021) at https://vizhub.healthdata.org/gbd-results/.
Ethics statements
Patient consent for publication
References
Footnotes
Contributors All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Guarantor: QC. Concept and design: All authors. Acquisition, analysis or interpretation of data: All authors. Drafting of the manuscript: CL and QC. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: CL and QC. Administrative, technical or material support: All authors. Supervision: All authors.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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