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Major Review

Atropine in the treatment of childhood myopia

ABSTRACT
The practice of using topical atropine to prevent the progression of myopia in children has been going on for decades in some Asian populations.
The encouraging results obtained from Atropine for the treatment of childhood myopia (ATOM) studies and animal studies have created much
interest among the practitioners regarding the use of atropine in preventing myopic progression. This review aims to summarize the major
research works done on the subject and its implications in clinical practice.

Keywords: Atropine, childhood myopia, myopia, progression of myopia, treatment of myopia

INTRODUCTION the progression of childhood myopia. The use of atropine

Myopia is the most common cause of correctable visual
impairment among adults as well as children in the developed
countries.[1‑5] It is an important cause of preventable blindness
in developing countries.[6] It is estimated that one in six of
the world’s population has myopic refractive error.[7] The
prevalence of myopia varies across different geographical
regions and ethnicities. The prevalence of myopia in the
United States rose from 25% to 42%, between 1971 and
1999.[8] In Asian countries, there is a rapid increase in the
prevalence of childhood myopia, and about 80%–90% of
school leavers are affected by this condition in East Asia.[9]
A study from Delhi conducted in 2015 reported prevalence of
myopia as 13.1% among schoolgoing children,[10] which was
much higher than the previous reports.[11,12] This indicates
that myopia is a growing public health problem among Indian
children also, with huge social, educational, and economic
implications.
Myopia has been known for more than 2000 years, and it
was first described by the Greeks.[13] However, the optical
correction for myopia could be instituted only in the
16th century, following the invention of concave lenses.[14]
In addition to the optical correction, pharmacological
agents such as pirenzepine, tropicamide, and atropine
have been investigated regarding their potential to halt
in preventing the progression of childhood myopia has
generated much interest in the recent years. This review
discusses the use of atropine in childhood myopia, in the
light of current evidence.
ATROPINE FOR MYOPIA
Atropine is an alkaloid extracted from the plant “deadly
nightshade” (Atropa belladonna) and is a nonselective
muscarinic antagonist. The first report of the use of atropine
for myopia was by Wells in the 19th century.[15] In 1979,
Bedrossian[16] conducted a nonrandomized trial evaluating
the effect of 1% atropine ointment instilled once at night
in one eye for 1 year with the fellow eye as control. The
control eyes showed a significant increase in the rates of
myopia. After 1 year, treatment was switched to the fellow
eye. Although the control eyes showed significant increases
in myopia compared to the treated eyes, the possibility of
residual effects of atropine in the fellow eye could not be
eliminated from this study design.
Sanitha Sathyan1,2
1
Department of Ophthalmology, Little Flower Hospital, Angamaly,
2
Vettam Eye Clinic, Mulanthuruthy, Ernakulam, Kerala, India
Address for correspondence: Dr. Sanitha Sathyan,
Vettam Eye Clinic, Perumpilly, Mulanthuruthy,
Ernakulam ‑ 682 314, Kerala, India.
E‑mail: dr.sanitha@gmail.com

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DOI:
10.4103/kjo.kjo_6_19 How to cite this article: Sathyan S. Atropine in the treatment of childhood
myopia. Kerala J Ophthalmol 2019;31:4-10.

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Sathyan: Atropine in myopia
There are many other studies which attempted to evaluate
the effect of topical atropine on myopia progression.[17‑26] Yen
et al.[27] compared the effect of cyclopentolate 1% and atropine
1% against placebo drops in 96 myopic children, who were
randomized to three groups. Group 1 received atropine 1%
eye drops every other night; Group 2 received cyclopentolate
1% eye drops every night; and Group 3 received normal saline
eye drops every night. The patients were rechecked every
3 months and the results were analyzed at the end of 1 year.
Analysis showed that atropine and cyclopentolate were
effective in slowing the progression of myopia and that the
effect of atropine was better than that of cyclopentolate.
Shih et al.[28] evaluated the effects of different concentrations
of atropine in controlling myopia in 186 myopic children,
between 6 and 13 years of age. The individuals were treated
each night with different topical concentrations (0.5%, 0.25%,
and 0.1%) of atropine groups. According to their results, all
three concentrations of atropine had significant effects in
controlling myopia at two years; however, treatment with
0.5% atropine was the most effective.
Another study[29] analyzed 227 school children with myopia,
between 6 and 13 years, who were stratified based on
gender, age, and the initial amount of myopia and were
randomly assigned to three treatment groups: 0.5% atropine
with multifocal glasses, multifocal glasses, and single vision
spectacles. At 18 months, they concluded that 0.5% atropine
with multifocal lenses slowed down the progression rate of
myopia while multifocal lenses alone showed no difference
in effect compared to the control group.
Many retrospective studies, Dyer,[20] Sampson,[21] Kennedy
et al.,[24] Gimbel,[26] Kelly et  al.,[30] Bedrossian,[31] Gruber[32]
etc., have demonstrated that 1% atropine tends to slow the
progression of myopia by almost 80%.
ATROPINE IN MYOPIA STUDIES
Atropine in myopia: 1 study
ATOM: 1 was a parallel‑group, placebo ‑controlled,
randomized, double‑masked study conducted at Singapore,
which evaluated the efficacy and safety of topical atropine, in
slowing the progression of myopia and ocular axial elongation
in Asian children.[33] Recruitment of participants was from the
general public, primary schools, and ophthalmology practices
through the distribution of standardized brochures and
letters describing the study as well as public talks.
The study, conducted between 1999 and 2004, enrolled
400 children between 6 and 12 years of age, with spherical
equivalent of refractive error between 1.00 and 6.00 diopters
Kerala Journal of Ophthalmology / Volume 31 / Issue 1 / January-April 2019
and astigmatism ≤1.50 diopters. Participants were assigned
with equal probability to receive either 1% atropine or
vehicle eye drops once nightly for 2 years. Only one eye of
each individual, chosen through randomization, underwent
treatment. The main efficacy outcome assessed was change in
spherical equivalent of refraction as measured by cycloplegic
autorefraction and change in ocular axial length as measured
by ultrasonography. The primary safety outcome measure
was the occurrence of adverse events.
Three hundred and forty‑six (86.5%) children completed the
2‑year study duration. In atropine‑treated eyes, the mean
myopia progression was only  −0.28  ±  0.92 D whereas
it was  −1.20  ±  0.69 D in the placebo‑treated eyes. The
axial length remained essentially unchanged from baseline
in atropine‑treated eyes  (0.02  ±  0.35  mm), compared to
the placebo  (0.38  ±  0.38  mm). The differences in myopia
progression and axial elongation between the 2 groups were
0.92 D (95% confidence interval, 1.10–0.77 D; P0.001) and
0.40 mm (95% confidence interval, 0.35–0.45 mm; P = 0.001),
respectively. No serious adverse events related to atropine.
The progression of spherical equivalent in patients on 1%
atropine versus controls.[33] The change in axial length in
patients on 1% atropine versus control.[33]
Based on the above observations, they concluded that topical
atropine was well tolerated and effective in slowing the
progression of low and moderate myopia and ocular axial
elongation in the study population.
Atropine in myopia: 2 study
Atropine in myopia: 2 study (ATOM 2), phase: 1 study
The ATOM 2 study was a single‑center, double‑masked,
randomized study, conducted in the Singapore Eye Research
Institute, Singapore, between 2006 and 2012. The aim of this
study was to compare the efficacy and visual side effects of 3
lower doses of atropine: 0.5%, 0.1%, and 0.01%. A total of 400
children between 6 and 12 years with myopia of at least −2.0
diopters and astigmatism of −1.50 D or less were randomly
assigned in a 2:2:1 ratio to 0.5% (n = 161), 0.1% (n = 155),
and 0.01% (n‑84) atropine, to be administered once nightly
to both eyes, for 2 years. Cycloplegic refraction, axial length,
accommodation amplitude, pupil diameter, and visual acuity
were noted at baseline, 2 weeks, and then every 4 months for
2 years. The main outcome measure was myopia progression
at 2 years.
At 2 years, the progression of myopia was −0.30 ± 0. 60
D, −0.38  ±  0.60, and  −0.49  ±  0.63 D in the atropine
0.5%, 0.1%, and 0.01% groups, respectively (P = 0.02
between the 0.01% and 0.5% groups; between other
concentrations P > 0.05). The mean increase in axial length
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Sathyan: Atropine in myopia
was 0.27  ±  0.25, 0.28  ±  0.28, and 0.41  ±  0.32  mm in
the 0.5%, 0.1%, and 0.01% groups, respectively (P < 0.01
between the 0.01% and 0.1% groups and between the 0.01%
and 0.5% groups). However, the differences in myopia
progression (0.19 D) and axial length change (0.14 mm)
between groups were small and clinically insignificant.
Atropine 0.01% had a negligible effect on accommodation
and pupil size and no effect on near visual acuity. Based on
the above observations, the investigators concluded that
atropine 0.01% has minimal side effects compared with
atropine at 0.1% and 0.5% and retains comparable efficacy
in controlling myopia. The mean change in spherical
equivalent for groups from baseline, 2 weeks, and 4–24
months with atropine 0.01%, 0.1%, and 0.5% from the
atropine for the treatment of childhood myopia study 2,
and placebo and atropine 1.0% from the atropine for the
treatment of childhood myopia study 1.[34]
Atropine in myopia 2 phase: 2 study
The participants from ATOM 2 treatment phase 1 study
entered the treatment phase 2 study at the third year, and
atropine was stopped for 1 year (year: 3). 21 patients in the
0.5% group, 14 in the 0.1% group, and 9 in the 0.01% group
withdrew from the study on their own accord. Therefore, after
2 years, data were analyzed with 139 individuals in the 0.5%
group, 141 individuals in the 0.1% group, and 75 individuals
in the 0.01% group. At the end of the third year, 24% of the
0.01% group, 59% of the 0.1% group, and 68% of the 0.5%
groups in the original ATOM 2 trial showed progression of
more than 0.5 D of myopia.
At the end of 1 year, there was a significant difference
in myopia progression between the 0.5% atropine group
and the 0.01% (P < 0.001) and 0.1% (P = 0.01) groups, but
there was no statistically significant difference between
the 0.01% and 0.1% groups. The final myopia progression
over  2  years was  −  0.49  ±  0.60 D, −0.38  ±  0.60 D,
and −0.30 ± 0.63 D in the atropine 0.01%, 0.1%, and 0.5%
groups, respectively (P = 0.07), with a significant difference
between the 0.01% and 0.5% groups. Fifty percent of the 0.01%
group had progressed by <0.5 D. However, 58% and 63% in the
0.1% and 0.5% groups had documented progression. On the
whole, approximately 18% showed progression by −1.0 D, in all
3 groups. Axial length change at 1 year was higher in the 0.01%
group (0.24 ± 0.19 mm) than in the 0.1% (0.13 ± 0.18 mm)
and 0.5% (0.11 ± 0.17 mm) groups (P < 0.001). There was
statistically significant change in the axial length measurements
between the 0.01% group and the other 2 groups (P < 0.001),
which persisted even at the end of the 24‑month period.
In terms of effect on other ocular parameters, accommodation
amplitude  (−10.9  vs. −2.4 D), mesopic pupil diameter
6 Kerala Journal of Ophthalmology / Volume 31 / Issue 1 / January-April 2019
(2.7 versus 3.5 mm), and photopic pupil diameter (2.2 vs. 3.1
D) were also significantly less in the 0.1% group compared
with the 0.5% group, making the overall efficacy side effect
profile of atropine 0.1% better than atropine 0.5%.
In conclusion, ATOM 2 study in the phase 2 showed a clear
rebound phenomenon in terms of myopia progression. This
rebound was dose dependent, with 0.01% atropine having
The change in spherical equivalent in the atropine forthe
treatment of childhood myopia study 1 eyes that received
1.0% atropine and placebo, and atropine for the treatment of
childhood myopia study 2 eyes that received 0.5%, 0.1%, and
0.01% atropine.[35] The proportional change in myopia (spherical
equivalent) in atropine for the treatment of childhood myopia
study 1 eyes that received 1.0% atropine and placebo, and
atropine for the treatment of childhood myopia study 2
eyes that received 0.5%, 0.1% and 0.01% atropine at 24 and
36 months.[35] The change in axial length in atropine for the
treatment of childhood myopia study 1 eyes that received
1.0% atropine and placebo, and atropine for the treatment of
childhood myopia study 2 eyes that received 0.5%, 0.1%, and
0.01% atropine.[35]
Atropine in myopia 2: phase 3
In phase 3 (re‑treatment phase), children who exhibited
myopia progression of 0.50 D or more in at least 1 eye during
the washout phase were restarted on atropine 0.01% for a
further 24 months.
The primary outcome was progression of myopia, defined
as change in spherical equivalent over phase 3 and the
entire 5‑year study period of the ATOM trials. The secondary
outcome was change in AL. Other study variables include
changes in photopic pupil size, accommodation, and distance/
near visual acuity.
Of the 345 children, 192 (56%) were restarted on atropine
0.01% because they had progressed 0.5 D or more during
phase 2 washout year. This included 17 of 70 children (24%) in
the 0.01% group, 82 of 139 children (59%) in the 0.1% group,
and 93 of 136 children (68%) in the 0.5% group. A baseline
characteristic to be noted is that compared with children
who did not progress after phase 2, those were restarted on
atropine 0.01% in phase 3 were younger, had less myopia,
and had shorter axial lengths. Also to be noted that these
children had greater myopia progression and change in axial
length during the first year of the study.
At 1 year, those children retreated during phase 3 with atropine
0.01% had mean myopia progression of −0.38 to −0.52 D.
This was lower than the progression they demonstrated
during the phase 2 washout period (−0.62 to  −1.09 D)
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Sathyan: Atropine in myopia
and was true in all the three atropine groups. However,
the mean myopia progression (−0.38 to −0.52 D) seen in
the participants of the phase 3 trial were higher than those
children who did not require retreatment (−0.30 to −0.38 D).
The overall mean myopia progression in phase 3
was − 0.69 ± 0.46 D, −0.81 ± 0.57 D, and −0.84 ± 0.61 D in the
atropine 0.01%, 0.1%, and 0.5% groups, respectively (P = 0.09).
In contrast, the mean myopia progression over the entire
5 years was less in the 0.01% group (−1.30 ± 0.98 D) than in
the 0.1% (−1.83 ± 1.16 D, P = 0.003) and 0.5% (‑1.98 ± 1.10
D, P < 0.001) groups.
Among the children restarted on atropine 0.001% during
phase 3, there was a reduction in the rate of myopic
progression. The mean increase in myopia over the 4th and
5th years was − 0.86 ± 0.56 D in 0.01% group, −0.87 ± 0.59 D
in 0.1% group, and −0.90 ± 0.66 D in 0.5% group, respectively.
This was similar to the progression in children originally
assigned to the 0.01% group (−0.77 ± 0.49 D, P > 0.286).
This suggests that retreatment with atropine 0.01% was as
effective as primary treatment with atropine 0.01%.
By the end of phase 3, the mean axial length progression was
smaller in the 0.01% group (0.19 ± 0.18 mm) compared with the
0.1% (0.24 ± 0.21 mm, P = 0.042) and 0.5% (0.26 ± 0.23 mm,
P = 0.013) groups. The mean overall change in axial length
over  5  years was 0.75  ±  0.48  mm, 0.85  ±  0.53  mm, and
0.87  ±  0.49  mm in the 0.01%, 0.1%, and 0.5% groups,
respectively (P = 0.185).
In the children who were not restarted on atropine, axial
length elongation gradually slowed during phase 3 and
there was no difference in axial lengths among the groups at
5 years (P = 0.56). In children in whom atropine was restarted,
axial length elongation slowed in all groups (0.32 ± 0.22 mm
in the 0.01% group, 0.27  ±  0.25  mm in the 0.1% group,
0.29 ± 0.25 mm in the 0.5% group) over phase 3 to a rate lower
than that noted during phase 1 (0.58 ± 0.27 mm, P < 0.001).
The mean change in spherical equivalent overtime me within
different treatment groups (atropine 0.01%, 0.1%, and 0.5%).
[36]
The mean change in axial length over time within different
treatment groups (atropine 0.01%, 0.1%, and 0.5%).[36]
ATOM 1 established the clinical safety and efficacy of
atropine 1% at least in the short term.[33] Phase 1 of ATOM
2 established that atropine 0.01% was almost as effective
in reducing myopia progression as higher concentrations
but with minimal pupil dilation accommodation and near
vision loss.[34] In phase 2, ATOM 2 further established that
children receiving lower doses had less myopic progression
Kerala Journal of Ophthalmology / Volume 31 / Issue 1 / January-April 2019
after atropine was stopped, resulting in 0.01% being more
effective in reducing myopia progression at 3 years.[35] ATOM
2 phase 3 proved that retreatment with atropine 0.01% could
be as effective as primary treatment with atropine 0.01%.
This indicates that the clinicians may be able to titrate the
treatment by stopping and restarting treatment according to
individual progression rates.[36]
LOW ‑ C O N C E N T R AT I O N AT RO P I N E FO R M YO P I A
PROGRESSION STUDY
Low concentration atropine for myopia progression study
was a randomized, placebo-controlled, double-masked trial,
conducted at Hong Kong,[37] which evaluated the efficacy and
safety of low‑concentration atropine eye drops at 0.05%,
0.025%, and 0.01% compared with placebo over 1‑year
period. A total of 438 children aged 4–12 years with myopia
of at least −1.0 diopter and astigmatism of −2.5 D or less
were randomly assigned in a 1:1:1:1 ratio to receive 0.05%,
0.025%, and 0.01% atropine eye drops, or placebo eye drop,
respectively, once nightly to both eyes for 1 year. Cycloplegic
refraction, axial length, accommodation amplitude, pupil
diameter, and best‑corrected visual acuity were measured
at baseline, 2 weeks, 4 months, 8 months, and 12 months.
Visual Function Questionnaire was administered at the
1‑year visit.
After 1 year, the mean change in spherical equivalent of
refraction was −0.27 ± 0.61 D, −0.46 ± 0.45 D, −0.59 ± 0.61
D, and −0.81 ± 0.53 D in the 0.05%, 0.025%, and 0.01% atropine
groups, and placebo groups, respectively (P < 0.001). The mean
increase in axial length was 0.20 ± 0.25 mm, 0.29 ± 0.20 mm,
0.36  ±  0.29  mm, and 0.41  ±  0.22  mm  (P < 0.001),
respectively. The accommodation amplitude was reduced by
1.98 ± 2.82 D, 1.61 ± 2.61 D, 0.26 ± 3.04 D, and 0.32 ± 2.91
D, respectively (P < 0.001). The pupil sizes under photopic
and mesopic conditions were increased, respectively, by
1.03 ± 1.02 mm and 0.58 ± 0.63 mm in the 0.05% atropine
group, 0.76 ± 0.90 mm and 0.43 ± 0.61 mm in the 0.025%
atropine group, 0.49 ± 0.80 mm and 0.23 ± 0.46 mm in the
0.01% atropine group, and 0.13 ± 1.07 mm and 0.02 ± 0.55 mm
in the placebo group (P < 0.001). Visual acuity and vision‑related
quality of life were not affected in each group.
Based on the above observations, the study concluded that
0.05%, 0.025%, and 0.01% atropine eye drops reduced myopia
progression along a concentration‑dependent response. All
concentrations were well tolerated without any adverse effect
on vision‑related quality of life. Of the 3 concentrations used,
0.05% atropine was most effective in controlling spherical
equivalent progression and axial length elongation over a
period of 1 year.
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Sathyan: Atropine in myopia
HOW DOES ATROPINE PREVENT PROGRESSION OF
MYOPIA?
Initially, it was thought that atropine prevents progression
of myopia through its cycloplegic action exerted on ciliary
muscles and thereby causing changes in accommodation.
Wallman documented that atropine blocks accommodation
and reduces the putative effects of excessive accommodation
on the progression of myopia.[38]
Atropine is a muscarinic antagonist and acts through M1
to M5 receptors. However, experiments in chicks, which
possesses striated ciliary muscles, innervated by nicotinic
receptors rather than muscarinic receptors, also documented
reduction in the progression of myopia following the use of
topical atropine.[39] This animal model demonstrates that
atropine prevents myopia through a nonaccommodative
mechanism and is the reason why optical approaches to
reduce accommodation (e.g., bifocals and progressive
addition lenses) failed to have any effect on retarding the
progression of myopia.[40] These evidences have prompted
research on the posterior structures of the eye rather than
the accommodative mechanism as the likely sites of action
of antimyopia effect of atropine.
The queries regarding the mechanism of action of atropine
in preventing progression of myopia can be consolidated as
the following:
1. Where is the exact locus of action of atropine in
preventing myopic progression? Is it retina, sclera, or
choroid?
2. Whether the effect of atropine involves muscarinic
receptors at all, if so, which are the receptors involved (m1,
m2, m3, m4, m5), and where are they located?
Let us attempt to answer these questions in the light of
current evidence.
Animal studies have strongly suggested that neurochemical
signaling cascade causing myopia begins at the level of retina
level. An example in support of this is the sign of defocus changes
found in the amacrine cells of the retina.[41] Interestingly, there
are other studies also which suggest that muscarinic antagonist
control of myopia is initiated at the sclera.[42]
As relatively higher dose of atropine was needed to prevent
myopia in experimental studies, previously, it was thought
that the site of action is more likely the sclera than the retina.
However, the ATOM studies have categorically established
that even low dose of atropine can exert substantial influence
on the progression of myopia.[35‑37] These developments in
research point toward retinal site of action of atropine.
8 Kerala Journal of Ophthalmology / Volume 31 / Issue 1 / January-April 2019
Experimental evidence from the mammal tree shrew has
demonstrated that the highly selective muscarinic antagonists
MT3 (M4 receptor antagonist) and MT7 (M1 receptor
antagonist) are effective in preventing experimentally induced
myopia at nanomolar concentrations.[43] Further evidence
comes from the finding that MT3 (M4 receptor antagonist)
inhibition of myopia in chicks prevents the choroidal thinning
normally associated with induced myopia.[44] As choroid,
which is located earlier in the drug pathway than sclera is
affected, this finding argues against a scleral site of action.
These animal studies emphasize the possibility of a retinal
site of action, rather than scleral/choroidal.
Further molecular receptor level studies have demonstrated
that an M1‑specific antagonist and a highly selective M4
antagonist inhibit myopia. [43‑45] This strongly indicates
that both the M1 and M4 muscarinic receptor signaling
pathways are involved in the mechanism by which atropine
prevents myopia. Atropine also found to affect dopamine
neurotransmitter release from cellular stores and thus may
influence retinal signals that control the growth of the eye.[46]
CONCLUSION
The use of atropine for preventing progression of myopia
has received a firm clinical base with the randomized control
studies, the most significant being the ATOM studies. ATOM
1 has demonstrated the clinical safety and efficacy of atropine
1%.[33] Phase 1 of ATOM 2 established that atropine 0.01%
was almost as effective in reducing myopia progression
as higher concentrations, but with minimal pupil dilation
accommodation and near vision loss.[34] The phase 2 of ATOM
2 further underlined that children receiving lower doses of
atropine had less myopic progression after atropine was
stopped. The 3‑year results showed that 0.01% atropine is
more effective in reducing myopia progression after the
washout period.[35] Phase 3 of ATOM 2 proved that retreatment
with atropine 0.01% could be as effective as primary treatment
with atropine 0.01%. This opens up the possibility of titrating
the treatment by stopping and restarting treatment according
to individual progression rates.[36]
Animal experiments and molecular studies have strongly
suggested that mechanism of action of atropine in myopia
occurs at the level of retina and that both the M1 and M4
muscarinic receptor signaling pathways are involved.
FUTURE SCOPE
Even after all this meticulous clinical and molecular level
researches, the critical data are too meager, and there are
too many unanswered questions for these interpretations
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Sathyan: Atropine in myopia
to be conclusive. Future research related to the use of
atropine with respect to the progression of myopia is
necessary to form a better understanding of the exact
mechanism of myopic progression and the underlying effect
of atropine on this pathogenesis. Importantly, studies on
non‑Asian ethnic groups are required to determine if the
effect on non‑Asians is as significant as it has been reported
to be for Asian children. The myopic rebound associated
with all doses of atropine needs to be studied further to
formulate guidelines regarding tapering of treatment or
discontinuation of therapy.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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