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Abstract
Purpose To assess the effect of weekly 1% atropine use on children’s myopia progression and whether the effect is sustainable.
Methods Medical records of myopic children aged 3–15 years receiving weekly 1% atropine for more than 1 year were retrospectively reviewed. Axial length (AL) and spherical equivalent refraction (SER) at every visit were collected. The changes in AL or SER over time were analysed using generalised estimating equation. The related factors of myopic progression were performed by multiple linear regression. The performance of short-term AL change to predict atropine-poor responders (AL change >0.2 mm/year) was assessed using receiver operating characteristic analysis.
Results A total of 694 participants with a mean age of 8.83 years were included. The participants with follow-up time reached 1, 2, 3 and 4 years were 256 (36.9%), 250 (36.0%), 143 (20.6%) and 45 (6.5%) separately. The cumulative change in AL was 0.05 mm, 0.24 mm, 0.47 mm, 0.56 mm separately for 1-year, 2-year, 3-year and 4- year treatment. Approximate 0.20 mm elongation per year was observed since the second-year of the treatment. Older age and lower initial myopic refraction were independently associated with less myopic progression. A decrease in AL of more than 0.04 mm during the initial 2 months could serve as an indicator for identifying fast progressors (AL change >0.2 mm/year) over a 2-year period, with sensitivity and specificity rates of 0.78 and 0.73, respectively.
Conclusion Weekly 1% atropine may be a potentially effective treatment with longer lasting effects for children with myopia control especially in those with older age and lower myopia.
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Data availability statement
Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author, MZ, on reasonable request.
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
The daily use of 1% atropine has been shown to significantly slow down the progression of myopia and ocular axial elongation within 2 years. Weekly application of 1% atropine is clinically employed to alleviate atropine-related side effects. However, there is still a lack of long-term studies to elucidate the effectiveness of this method for myopia control and its sustainability.
WHAT THIS STUDY ADDS
Compared with daily use of 1% atropine, weekly use could achieve approximately the same level of myopia control with tolerable side effects, maintaining effectiveness over a period of 4 years.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Weekly application of 1% atropine represents an effective and stable strategy to aid children with myopia. Specifically, those with low myopia, particularly spherical equivalent refraction within −1.00D, may benefit more from the weekly atropine regimen.
Introduction
The past decades have witnessed a dramatic increase in the prevalence of juvenile myopia, becoming an acknowledged global public health problem. East Asian countries have the highest myopia prevalence, with a steady increase from 25.7% (before 2001), to about 39% (2001–2010) and then to 46.1% (2011–2015) in Chinese children and adolescents.1 Myopia affects juveniles’ academic performance and psychosocial well-being, quality of life and future career choice, moreover, aggravating the burden of lost productivity.2 The results of a 12-year Chinese cohort suggest the risk of high myopia in adulthood is highly correlated with the age of myopia onset during school years, calling for myopia interventions to be applied at early age.3 The comparison of 16 interventions of myopia control indicated pharmacologic therapy, that is, muscarinic antagonists such as atropine was the most effective in retardation of either refraction or axial elongation.4
Atropine was supposed to regulate muscarinic receptors; therefore, directly or indirectly stretching of the sclera, contributing to the suppression of myopia development.5 Previous randomised placebo-controlled trial6 and ATOM (Atropine for the treatment of Childhood Myopia) study7 demonstrated myopic refraction progression was significantly restrained by the 1% atropine compared with placebo treatment as well as axial elongation, with an approximate 77% reduction over the treatment period. However, photophobia and blurred near vision during treatment and marked rebound effect after cessation of 1% atropine6 8 made it difficult to translate large-scale into clinical practice. To balance the antimyopic effects and the relative rate of side effects, researchers turned attention to lower concentrations of eye-drops, such as 0.5%, 0.1% and 0.01% and conducted a series of clinical trials to assess their efficacy in myopia prevention. ATOM-2 in 2012 revealed the 0.01% atropine group had the smallest total progression of myopia taking 2-year treatment and third-year wash-out period together,9 contributing to the popularity of 0.01% atropine eye-drops as a medical prevention of juvenile myopia.10
Although low-concentration atropine has a significantly superior effect on controlling myopia, with limited rebound effects and tolerable side effects, neither 0.01% nor 0.05% atropine is officially available in China. Thus, patients face difficulties in accessing low-concentration atropine. The daily use of 1% atropine sulfate eye gel, as recommended by the ATOM study, leads to evident photophobia and blurred near vision, significantly impacting patients’ learning and daily activities and causing many to discontinue atropine treatment. Therefore, optimising the frequency of high-concentration atropine use is crucial to strike a balance between myopia control effectiveness and associated adverse effects. A recent study11 suggested that reducing the frequency of 1% atropine could result in a lower side effect profile compared with daily doses, making it a potential alternative to balance the occurrence of secondary unwanted effects and myopia retardation. However, the efficacy of reducing the frequency of high-concentration atropine (1%) to part-time use remains unclear. Hence, this study retrospectively reviewed medical records to investigate the short-term and long-term effects of low-frequency 1% atropine use in Chinese myopic children and determine whether the effect is sustainable over time.
Methods
Participants
The medical records of children who visited Shanghai Eye Diseases Prevention and Treatment Center and used 1% atropine sulfate eye gel for myopia control were retrospectively reviewed. The inclusion criteria: (1) age between 3 and 15 years; (2) without keratoconus, binocular vision problems and other ocular disease aside from refractive error; (3) intraocular pressure (IOP) less than 21 mm Hg; (4) cycloplegic spherical equivalent refraction (SER) greater than or equal to −6.0D and less than or equal to −0.5D; (5) best-corrected visual acuity equal or less than 0.00 logMAR unit in both eyes; (6) no history of contact lens and other myopia control treatment and (7) using atropine sulfate eye gel at least 1 year. Cases where atropine has been continuously discontinued for 2 months per year will be excluded.
The 1% atropine sulfate eye gel
The atropine sulfate eye gel (5 g : 50 mg, manufactured by Shenyang Xingqi Pharmaceutical) was prescribed by doctors and purchased by the children’s parents. Subjects were instructed to instil atropine gel into eyes without their eyelids or eyelashes touching the tip of the bottle, once daily at night in the first week. Then participants were requested to apply atropine gel once a week.
Measurements
All patients had received comprehensive examinations conducted by trained physicians, including cycloplegic refraction, axial length (AL) and corneal topography, at the first visit. The follow-up visits were scheduled for 7 days, 2 months, 6 months and every 6 months. The purpose of the 7-day monitoring visit was to assess any hyperopic shift and evaluate the severity of photophobia and near vision blurriness in patients, enabling doctors to provide tailored advice to ensure treatment adherence. The 2-month follow-up aims to promptly document changes in AL, facilitating an understanding of the patterns and characteristics of AL changes at the onset of treatment. The AL and SER were evaluated using an IOLMaster (Carl Zeiss Jena, Jena, Germany) and an auto-refractor (Topcon KR-8900, Japan). All measures were non-contact. AL and SER were measured three times for each eye, and if the difference between any two measurements was greater than 0.05 mm or 0.5D, the process was repeated until the difference was below this value. Additionally, the reasons for discontinuing atropine, such as fever, conjunctivitis, photophobia, travel and exams, will be queried and meticulously documented at each follow-up, including the duration and reason for discontinuation.
Statistical analyses
Only data from the atropine-treated eye were included in data analyses. All statistical analyses were performed by using software R (V.4.1.3). A p<0.05 was considered statistically significant. The normality of numeric variables was confirmed by Shapiro-Wilk test. Gender ratio was compared using χ2 test. Age, SER and AL at enrolment were compared between groups using independent group t-test or analysis of variance. Changes in AL and SER over time were compared using a generalised estimating equation (GEE) adjusted for initial age and refraction. The association between the short-term change and long-term change in AL and SER controlling for the baseline characteristics was analysed by linear regression analysis. Participants were stratified according to the mean age at enrolment (<9 years old vs ≥9 years old) and initial refractive error type (SER in (−6 to –3), (−3 to –1) vs (−1 to –0.5)) for further analysis. Subjects were also classified into different myopic progression groups. Those without myopic progression (decrease or unchanged in AL) were regarded as non-progressors, whereas those experiencing myopia progression not exceeding average growth (0.2 mm axial elongation per year) were allocated to slow progressors.12 Children showing myopia development exceeding 0.2 mm axial increase within 1 year were categorised as fast progressors. The performance of using short-time AL change to recognise poor responders among long-term atropine treatment was assessed using the receiver operating characteristic (ROC) area under the curve (AUC) and sensitivity as well as specificity.
Results
General characteristics
A total of 694 participants aged 3–15 years with follow-up duration of 1–4 years were included in the data analysis, among whom 47.6% (330) were boys. As table 1 shows, patients were stratified according to follow-up time. The participants with follow-up time reached 1, 2, 3 and 4 years were 256 (36.9%), 250 (36.0%), 143 (20.6%) and 45 (6.5%) separately. According to one group’s mean sample size estimation formula, having 265 participants in the first year, with an average increase in AL of 0.046±0.178, could achieve a statistical power of 0.98. Baseline characteristics, such as age (8.80±1.82 vs 8.89±1.83 vs 8.83±1.84 vs 8.67±1.94), gender (girls 51.2% vs 54.0% vs 53.8% vs 46.7%) or SER (−1.87±1.09 vs −1.76±0.91 vs −1.69±0.91 vs −1.73±1.09) did not differ significantly between the 4 follow-up groups (all p>0.05).
Characteristics of participants in different groups*
Cumulative myopia control effect of atropine
As table 2 shows, over the study period, the mean AL decreased in the first half year, with the change of −0.03 mm, −0.07 mm and −0.03 mm, respectively, after 7 days, 2 months and 6 months atropine treatment. Besides, the cumulative axial elongation was 0.05 mm, 0.24 mm, 0.47 mm, 0.56 mm separately for 1-year, 2-year, 3-years and 4-year intervention, indicating approximant 0.14 mm annual axial elongation. As for the refractive error, the period of SER increase was longer than the duration of AL decrease, which lasted 1 years with the change of 0.21D. The cumulative change in SER was −0.21D, −0.65D and −0.74D in 2-year, 3-year and 4-year atropine treatment, indicating 0.19D SER decrease every year.
Change in axial length (mm) and spherical equivalent refraction (D) at different times*
Stabilised myopia control effect of atropine
Table 2 also compared the change in AL and SER over different yearly periods. The increment in SER and nearly unchanged AL was found in first atropine treated year. Besides, other yearly periods had observed average 0.2 mm axial elongation and approximate 0.4–0.5 D myopic progression, which demonstrated that the effect of atropine on myopia control remains stable after the first year.
The effect of initial age and refraction on atropine-treated myopic progression
Figure 1 demonstrates that children with different ages and refractive errors presented slight difference in the AL change time trend. Children with larger ages at baseline and lower initial myopic participants presented a slower rate of myopia increase. Figure 2 also shows the proportion of different progressors among age or refraction group during yearly treatment period. Children under 8 years old are more likely to experience fast myopic progression (more than 0.20 mm yearly axial elongation) while children older than 9 years old are more likely to remain unchanged AL (p<0.001). Children with low myopia especially whose SER are between −0.5D and −1.0D are more inclined to show good response to atropine treatment (less than and equal to 0.20 mm axial elongation) compared with moderate myopic children in the first 2 yearly treatments. Online supplemental table 3 also displays the lower baseline age and higher initial myopic refraction were risk factors for poor axial elongation controlling effect (AL change >0.20 mm/year).
Supplemental material
Time course of changes in axial length (AL) at different times stratified by different age (A) and refractive error group (B). Error bars represent the SE.
Proportion of different progressors in age (A) and refractive error group (B) among 1-year treatment.
Association between short-term variation and long-term change in AL
A positive association was observed between the short-term AL change and eye growth over a long period. The more pronounced the short-term reduction in AL, the less the long-term increase in AL. As table 3 shows, for using 7 days, 2 months and 6 months change to predict long time effect, the ability of explanatory decreased as the long-term period expanded (R2=0.533, 0.440 and 0.422 for 1 year, 2 years and 3 years change). The 6 months change showed the best performance for predicting long-term myopia control effect (R2=0.195, 0.440 and 0.644 for 7 days, 2 months and 6 months prediction).
Regression analysis of baseline characters and short-term AL change associated with the elongation of AL*
Considering early detection of poor responders to atropine treatment, short-term (ie, 7 days, 2 months and 6 months) change of AL was applied as a predictor for long-term poor efficacy. Area under ROC curve decreased as long-term period extended while increased as short-term period extended with AUC for 2/6 months prediction more than 0.75 (figure 3). Table 4 compares the accuracy of different cut-off point in detecting long-term fast progression. The amount of reversal in AL during the initial treatment could help detect long-term fast progressors. A −0.04 mm change in 2 months expressed good performance (Youden=0.508) for recognition of 2 years poor responders based on sensitivity (0.778) and specificity (0.730) simultaneously.
ROC curve of using short-term AL change to recognise poor responders among long-term atropine treatment (AL elongation>0.2 mm/year). AL, axial length; AUC, area under the curve; ROC, receiver operating characteristic.
Using short-term AL change to recognise poor responders among long-term atropine treatment (AL elongation>0.2 mm/year)
Side effects
Nearly all participants reported experiencing photophobia and near-blurred vision. Photochromic glasses and presbyopic glasses could alleviate these discomforts and aid participants in adjusting to their daily study and life routines. There were no observed changes or losses in distance or near visual acuity. Allergic conjunctivitis occurred in three participants (mainly presenting with eye redness, which typically subsided within 1–3 days after applying atropine). Nosebleeds were reported by two participants, and allergic purpura occurred in one participant.
Discussion
In our long-term retrospective research, myopia progression and axial elongation were distinctly suppressed by weekly use of 1% atropine with 0.19D/year SER reduction and 0.14 mm/year AL increase. The yearly change of AL and SER also demonstrated the suppressive effect of weekly use of high-concentration atropine was sustainable over the 4 years study period. Meanwhile, our results also revealed the short-term change characteristics of AL after atropine use are associated with the long-term effect of myopic management, which could help clinicians to early estimate the poor response population to atropine treatment and select more feasible myopia control interventions.
Although daily high-dose atropine use showed excellent efficacy in retarding myopia progression,7 adverse effects associated with higher concentration atropine, such as photophobia and near-vision problem, cause myopic children unable to adhere to this pharmacological management for a long time. An ideal myopia control approach must balance efficacy and safety. Foo et al showed a lower frequency use of higher dosage of atropine (once, twice and thrice per week) could achieve less side effects profile,11 suggesting decreasing frequency of 1% atropine as an alternative regimen of treating myopia. As low-dose atropine is not readily available in Shanghai, in the current study, high-concentration atropine was weekly used to control myopia in order to reduce adverse reactions. As table 5 displays, the axial elongation was suppressed to 0.24 mm over 2 years (0.12 mm/year), which equals to approximately 67%–71% reduction compared with 0.72 mm/2 years, 0.41 mm/1 year and 0.41 mm/1 year separately of placebo group in our previous study,13 LAMP study14 and research by Wei et al.15 As for refraction, this study also reported an approximate 85% more myopic retardation effect (current: −0.21D/2 years vs previous: −1.36D/2 years,13 LAMP: −0.81D/1 year14 and Wei: −0.76D/1 year15). In addition, compared with daily use of atropine, weekly use could also achieve the same myopia control effect (current AL increase: 0.24 mm/2 years vs Zhu et al16: 0.12 mm/year and Han17: 0.16 mm/year). The result of this study indicated part-time 1% atropine usage could be an efficacious regime of myopia control. In our study, the periodic use of atropine is accompanied by gradually reduced photophobia and near-vision symptoms in the next few days of each cycle. And myopic children solved the side effects by wearing photochromic and progressive multifocal glasses. Hence, part-time treatment strategy could also be relatively well tolerated for a prolonged time.
Characteristics of studies evaluating the efficacy of atropine in myopia control
Recently, a reduced additive effect was observed in AOK (0.01% atropine with orthokeratology) study while no attenuated effect was observed in monotherapy with ortho-k.18 19 The possible explanation is that the eyes adapted to 0.01% atropine, resulting in the additive effect wearing off with time. Therefore, will long-term use of atropine lead to the attenuation of its myopia control effect? Most studies reported atropine treatment period of only 1–2 years. According to the 3-year findings of the LAMP study, continued atropine treatment showed persistent and stable dioptre and axial growth with three low concentrations (0.05%, 0.025% and 0.01%) atropine daily use.20 Our 4-year clinical outcomes have similar findings, except in the first year with a 0.05 mm decrease in AL and 0.21D hyperopic shift, an approximate 0.20 mm axial elongation (table 2) and 0.45D myopic progression (table 2) per year was observed for the next follow years, supporting the continuation of weekly 1% atropine treatment offered ideal and non-declining myopia control effect. Since the optimal length of atropine treatment is currently not established, the potentially magnitude of rebound effect and the characteristics of childhood myopia progression rate should be co-considered during determining the timing of atropine cessation. The LAMP study found treatment cessation resulted in a concentration dependence rebound effect in SER and AL and the older the subject’s age, the smaller the rebound effect.20 Although 1% atropine once daily treatment showed a prominent rebound effect,8 whether the once weekly frequency of atropine use is accompanied by an equivalent degree of rebound effect or follows a frequency-dependent order has not been observed. Polling et al detected no AL rebound among myopic children after initial treatment with 0.5% atropine for 1 year, followed by tapering to 0.25%, and further to 0.1% and 0.01% every 6 months.21 The ACAMP study also shows that consecutive use of 1% and 0.01% atropine experience better efficacy than 0.01% atropine alone in 1-year follow-up.22 Thus, we recommend a stepwise strategy (stepwise reduction in frequency or concentration of atropine) at an older age, when the myopia progression gradually slows down, to strive for the maximum control efficacy and minimum rebound effect.
In this study, reduced axial elongation, which is consistent with ATOM study,7 occurred within 6 months after atropine application. Axial shortening effect was attributed to its choroidal thickening effect. Choroidal thickness, which undergoing significant thickening (18.48 µm for 0.05% atropine once a day at 4 months and 27 µm for 1% atropine once a week at 6 months) after the application of atropine according to the LAMP23 and ACAMP results,24 can act as a potential biomarker and predict long-term atropine treatment efficacy hopefully. These pathways, such as stimulation of dopamine release, muscarinic receptors, choroidal blood flow and synthesis and release of intraocular NO (nitric oxide), may participate in the mechanism of atropine regulate choroidal thickness.25–27 The thickening of the choroid causes the retinal pigment epithelium to move forward, leading to the shortening of AL measurement. Numerically, the shortening of AL and the thickening of choroidal can even be matched (27 µm of choroidal thickening and 0.03 mm of AL shortening at 6 months in ACAMP study).24 Besides, LAMP study also revealed a choroidal thickening effect along a concentration-dependent response throughout the treatment period.23 Based on these results, we hypothesise that short-stage AL change of atropine is also associated with myopia control effect in atropine treatment. In this study, we were excited to find that early-stage AL change, including 7 days, 2 months and 6 months AL change, were all correlated quantitatively with long-term therapeutic efficacy (1, 2, 3 years). Meanwhile, considering the rapid development of myopia in children and the side effects of atropine treatment, it is crucial to accurately detect poor responders at the early stage of treatment. From the ROC curve, we notably found that a cut-off value of 0.04 mm AL shortening 2 months after instilling 1% atropine weekly indicates less myopia progression among 2 years treatment, and the more obvious AL reversal, the greater long-term benefit. Accordingly, we suggest that children who experience no AL shortening effect or do not reach this cut-off threshold (−0.04 mm) should be considered for a higher frequency of atropine use or adjust to other more efficient myopia control means or combination therapy, to achieve better myopia control effect and less side effects. AL, which is widely used in evaluating SER progression and myopia-retarding effect, is more convenient to measure, compared with the choroidal thickness. Also, AL measurement is less affected by ciliary muscle regulation, making it more suitable for clinicians to make rapid judgments and develop correct and effective myopia control programmes. However, we need to take into account the measurement repeatability of the optical biometer and the diurnal fluctuations in AL. According to product reports, the SD of AL repeatability measurements with the IOL Master is 5 µm.28 Diurnal fluctuations in AL can reach 0.03–0.05 mm.29 30 Based on these results, the 0.04 mm change may simply be caused by the machine’s measurement error or diurnal fluctuations. Therefore, the reversal in AL during the initial treatment is an interesting preliminary finding. Whether this result could be a biological indicator still needs further validation.
Atropine treatment depicted large individual differences in antimyopia effect. Consistent with ATOM (13.9% for 1% atropine), ATOM2 (15.8%, 16.7% for 0.5% and 0.1% atropine) and LAMP (15.2% for 0.05% atropine) study, a certain proportion of the children, 18.7% in this study, show poor response to atropine treatment, especially in younger and higher degree of myopia. Similarly, an age-dependent manner of weekly 1% atropine treatment was also observed in this study. Multivariate analysis indicated the younger the initial age before treatment, the faster progress in AL. Although the mean annual progression rate for AL in the younger group is faster, compared with the older group (2 years AL change：0.322 mm for children <9 years, 0.171 mm for children ≥9 years), this level of progression was still less than children treated with other therapy (for children aged 5–8 years, 2 years estimated mean AL change: 0.41–0.72 mm in 0.05% atropine treatment, 0.65–0.98 mm in 0.01% atropine group.31 Meanwhile, the absolute value of AL elongation does not really indicate the benefit of atropine treatment because the low age is the most active stage of myopia growth. Same as the ortho-k treatment, although more axial elongation was observed in younger subjects, the retarding effect was stronger in low-age children.13 32 In addition, in this study, approximate 75.7% of children under 9 years old were good responders to atropine. Therefore, although younger age was likely to have greater myopia progression and higher rate of rapid progressors to atropine while comparing to older children, younger myopic still could gain a considerable control effect from weekly atropine pattern. Another important finding in this study is that those with low myopia, especially SER within −1.00D, achieved mild better treatment effect than those with moderate myopia during the first 2 year, even among younger children. In low myopia with SER within −1.00D, AL elongation was 0.005 mm and 0.182 mm in the first and second year. Almost 90% of children still had ≤0.2 mm AL elongation during the first year of the study while the values were 0.132 mm and 0.229 mm, 69.6% in moderate myopia. Based on the above findings, we recommended to commence high dose weekly atropine treatment in younger and initial stage of myopia to slow myopic progression during highly active eye growth period and ultimately reduce the occurrence of high myopia.
One main limitation of this study is that the study was a retrospective design and lacked of control group, which may lead to a certain degree of selection bias and have some influence on our findings. Meanwhile, we did not record the rate of myopia progression prior to treatment, which may also impact the result. Considering that the side effects associated with atropine treatment need a certain extent of coping capacity and tolerance, it is plausible that those who progressed faster would be more likely to chose this type of treatment, the impact would be limited. Drop-out is also an inevitable limitation, which may not fully represent all characteristics of the population. Further well-designed randomised controlled clinical trials are warranted. Second, we did not include and analyse the environmental factors, such as the amount of time spent on near-working and outdoor activities, as well as genetic parameters like parental myopia, which might affect the progression of myopia. Third, the current study did not assess the safety of weekly use of 1% atropine in accommodation amplitude and pupil size. However, we did measure the indicators of binocular visual function and pupil diameter among adolescents who stop weekly 1% atropine treatment and then choose ortho-k treatment for myopia control and found that pupil size and accommodation amplitude returned after atropine cessation, indicating that the side effects of atropine are reversible. Future prospective clinical trials were warranted to comprehensively assess the safety of weekly 1% atropine use and cessation.
In conclusion, a weekly dose of 1% atropine may be a potentially effective treatment with a longer-lasting effect in myopic children over a 4-year period. Considering the excellent slow myopia growth in lower degrees of myopia and younger children, we recommended to commence weekly high-dose atropine treatment in the younger and initial stage of myopia.
Data availability statement
Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author, MZ, on reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
The study was approved by the Institutional Ethics Committee of Shanghai Eye Diseases Prevention and Treatment Center (No. EC-20221031-02) and adhered to the tenets of the Declaration of Helsinki. In this study, only the clinical data of patients were retrospectively collected, and the requirement for informed consent was therefore waived.
References
Supplementary materials
Supplementary Data
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Footnotes
Contributors LDu: data curation, formal analysis, writing–original draft; LDing: resources, writing–review annd editing; JC, JW, JY and SL: writing–review and editing; XX: supervision, funding acquisition, writing–review and editing; XH and JH: conceptualisation, investigation, resources, project administration, funding acquisition, writing–review and editing; MZ: guarantor, conceptualisation, investigation, resources, project administration, funding acquisition, writing–review and editing. XH, JH and MZ contributed equally as co-last authors.
Funding This study was supported by Shanghai Health Commission Research Project (No. 201840199, 20214Y0427), The Shanghai Science and Technology Commission Research Project (No. 18ZR1435700, 21Y11910000), Excellent Discipline Leader Cultivation Program of Shanghai (No.GWV-10.2-XD09), 3-year Action Program of Public Health (2020-2022) (No.GWV-9.1) and National Key R&D Program (No.2021YFC2702100, China).
Competing interests The authors all confirm that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Provenance and peer review Not commissioned; externally peer reviewed.
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