Documente Academic
Documente Profesional
Documente Cultură
Research Paper
Institute of Mental Health, Singapore, Buangkok Green Medical Park, 10 Buangkok View, Singapore
Faculty of Health and Social Care, Dearne Building, University Of Hull, UK
c
Assisi Hospice, Singapore
d
Advanced Practice Nurses, Department of Psychological Medicine, National University Hospital, Singapore
e
Alice Lee Centre for Nursing Studies, National University of Singapore, Level 2, Clinical Research Centre Block MD11, Singapore
b
a b s t r a c t
This study aimed to investigate the effect of a VR-based stress management program on people with mood disorders. A quasi-experimental study was conducted in a tertiary hospital in Singapore, and a convenience sample
of 22 was recruited. The program comprised three daily 1-hour sessions incorporating psychoeducation and VRbased relaxation practice. Participants who completed the program had signicantly lowered subjective stress
(t = 6.91, p b 0.001), depression (t = 5.62, p b 0.001), and anxiety (t = 5.54, p b 0.001); and increased skin
temperature (F = 17.71, p b 0.001), perceived relaxation (F = 26.20, p b 0.001) and knowledge (F = 13.77,
p b 0.001). Participants' feedback on the program was positive. Findings from this study contribute to improving
clinical practice and serve as preliminary data to conduct more rigorous research in the future.
2014 Elsevier Inc. All rights reserved.
Across the world, stress has been cited as the second most frequent
health problem aficting individuals' health and well-being (World
Health Organization [WHO], 2005). Stress refers to individuals' physiological responses to any demand perceived to be threatening to the physical, emotional or psychological health (Varvogli & Darviri, 2011). At low
to moderate levels, stress can be benecial to the individuals. However, at
high and persistent levels, stress becomes unhealthy, causing more harm
than benet and can contribute to poor mental health (Wilson, 2009).
Several studies show that stress can trigger mental disorders, especially
mood disorders (Danese & Pariante, 2008). In Singapore, major depressive
disorder (MDD) and bipolar disorder (BD) are commonly found with a lifetime prevalence of 5.8% and 1.2%, respectively (Chong et al., 2012). Individuals with mood disorders often experience illness-related stress, which
further aggravates their mental health problems (Wilson, 2009). As a result,
the persons may encounter relationship breakdowns, occupational disruptions and even premature deaths through suicide (Walsh, 2011).
Stress management interventions, including psychoeducation and relaxation therapy, have been developed for people with mental disorders.
Evidently, psychoeducation was efcacious in mitigating stress-related
Corresponding Author: Piyanee Klainin-Yobas, PhD, RN, Assistant Professor, Alice Lee
Centre for Nursing Studies, National University of Singapore, Level 2, Clinical Research
Centre Block MD11, 10 Medical Drive, Singapore 117597.
E-mail addresses: lubna.ishah@gmail.com (L.B.I. Shah),
samanthatorres613@gmail.com (S. Torres), prema_k@assisihospice.org.sg
(P. Kannusamy), cecilia_ml_chng@nuhs.edu.sg (C.M.L. Chng), nurhhg@nus.edu.sg
(H.-G. He), nurpk@nus.edu.sg (P. Klainin-Yobas).
http://dx.doi.org/10.1016/j.apnu.2014.09.003
0883-9417/ 2014 Elsevier Inc. All rights reserved.
perceived stress in comparison to controls (Pallavicini et al., 2013). Another study tested the ESCAPE (VR stress management program) on
university students and public ofcers (Villani & Riva, 2012). Participants had signicantly lower heart rate than those in the control
group (Villani & Riva, 2012). Little is known about the effects of VR
stress management interventions on people with mental disorders.
The VR has been used as a tool to deliver exposure therapy,
psychoeducation, and relaxation therapy in people with anxiety
disorders. A quasi-experimental study tested the virtual realityincorporated psychoeducation intervention on ten participants with
posttraumatic stress disorder (PTSD) and found that the participants
in the experimental group had signicantly lower depression (Gamito
et al., 2010). Similarly, another quasi-experimental research reported
that the virtual-reality based psychoeducation helped reduce anxiety
and depression among 14 individuals with social anxiety disorder
(Yuen et al., 2013). Furthermore, a randomized controlled trial (RCT)
was conducted to compare the VR-guided combined psychoeducation
and relaxation therapy with cognitivebehavioral therapy (CBT) in 39
patients with anxiety disorders (Banos et al., 2011). Findings showed
that participants in the VR group had signicantly lowered depression
and greater relaxation intensity than controls. However, there were
no signicant differences in anxiety between these two groups.
THE CURRENT STUDY
Despite the encouraging ndings, it is not known if the VR technology is benecial for individuals with mood disorders. Furthermore,
there is a dearth of studies exploring the effects of stress management
interventions on stress-related variables in individuals with mood disorders, especially in Asian populations, reecting gaps in the literature.
Guided by existing empirical evidence, we developed the three-session
VR-based stress management (VR DE-STRESS) program for people with
mood disorders. This study then aimed to test the feasibility and initial
Environment
Internal
External
Created
Person
Physiological
Psychological
Sociocultural
Developmental
Spiritual
Nursing
Tertiary prevention
intervention
Health
Health-related
variables
Subjective
Stress
Objective
Stress
Stressors
Persons with
Mood
Disorders
The VR DESTRESS
PROGRAM
Depression
Education
Relaxation
Anxiety
Perceived
Relaxation
Knowledge
Fig. 1. Research framework guided by the Neuman System Model (Neuman & Fawcett, 2002).
METHOD
Research Design and Sample
A single-group, pretestposttest, quasi-experimental research design and convenience sampling were used. This study was undertaken
at a mental health ward of a tertiary hospital in Singapore. Our target
population included inpatients diagnosed with MDD and BD (with depressive episode). Patients were invited to the study if they: a) aged between 21 to 65 years, b) were procient at understanding and
communicating in English, and c) were diagnosed with MDD or BD by
their attending psychiatrist. Patients were excluded if they: a) had
acute psychiatric symptoms (such as suicidal ideations, an episode of
psychosis, intellectual disability or cognitive impairment) diagnosed
by their psychiatrist, b) were pregnant, and c) had uncontrolled medical
conditions requiring hospitalization. These conditions were excluded
because they might confound research ndings.
Participant recruitment commenced following an approval from
hospital ethics committee and hospital administrators. One of the researchers (LS) liaised with clinical staff (such as advanced practice
nurses, registered nurses, and psychiatrist) to identify potential participants based on the inclusion/exclusion criteria. Then, the researcher
approached eligible patients, explained the purpose of the study, distributed the participation information sheet, and invited them to
partake in the study. Patients who agreed to participate were asked to
sign a consent form in the presence of clinical staff. Subsequently, the researcher scheduled the VR DE-STRESS Program at patients' convenience.
The VR DE-STRESS Program
The individual-based VR DE-STRESS Program was developed for individuals with mood disorders. The program had three daily 1-hour
sessions comprising two major components: psychoeducation and relaxation practice (via VR-based relaxation videos). The psychoeducation
covered information about stress, stress management, mood disorders,
positive thinking and relaxation techniques. Furthermore, participants
practiced three relaxation techniques: abdominal breathing, muscle relaxation and guided imagery using a beach scenario (Table 1). Content
of the psychoeducation as well as a step-by-step guide to the relaxation
exercises were consolidated in a participant education manual (PEM)
provided to the participant in the study. At the end of the program,
participants also received a relaxation audio CD for their optional
home practice.
At the beginning of each session, the researcher brought each participant to a private room within the ward. The psychoeducation component was delivered via face-to-face discussion. Then, the researcher
demonstrated how to carry out the relaxation exercise based on the instructions in the PEM. The participants practiced the technique with
guidance from the researcher. Subsequently, they practice relaxation
techniques while wearing the VR device and viewing instructional relaxation videos. When the relaxation component was completed, the
VR device was removed. Finally, the researcher provided a session summary of learned knowledge and skills. Time was allowed for discussion
and questions before the end of each session.
The intervention procedure was repeated for the following two sessions. The delivery of the VR DE-STRESS Program was standardized for
Table 1
Content Outline of the VR DE-STRESS Program.
Session
1 (1 hour)
2 (1 hour)
3 (1 hour)
Program
Psychoeducation: Stress, its causes, symptoms and effective management techniques
VR-guided relaxation practice: Abdominal breathing, muscle relaxation, and guided imagery (using a beach scenario)
Psychoeducation: Mood disorders & their relationship with stress
VR-guided relaxation practice: Abdominal breathing, muscle relaxation, and guided imagery (using a beach scenario)
Psychoeducation: Positive thinking & other relaxation techniques
VR-guided relaxation practice: Abdominal breathing, muscle relaxation, and guided imagery (using a beach scenario)
researcher waited for 1 minute to ensure that device fully captured the
nger temperature. The stress thermometer reads temperatures between
58 F and 158 F with higher scores indicating lower levels of objective
stress. The accuracy of the stress thermometer was +/0.1 F (Stress
Market, 2011). Concurrent validity of the stress thermometer was supported by its signicant correlation with the Numeric Stress Rating scale
on a Singaporean sample (Lim, Klainin-Yobas, & Chen, 2014).
To minimize possible confounding factors, all physiological instruments were assessed under controlled conditions. Firstly, the same participant was measured twice before and immediately after the
intervention, only 1 hour apart. This might help control individual factors (such as psychiatric diagnoses and treatments). Therefore, it
might be logical to conclude that any physiological changes result
from the intervention. Secondly, the same researcher (LS) collected
data across all participants across the two time points. Finally, all pretest
and posttest measurements were assessed under the same physical environment (such as venue and room temperature).
Depression, anxiety and subjective stress were measured with the
21-item Depression Anxiety Stress Scale (DASS-21) (Lovibond &
Lovibond, 1995). Participants rated on a four-point scale ranging from
0 (did not apply to me at all) to 3 (applied to me most of the time).
The DASS-21 has three subscales: depression (7 items), anxiety
(7 items), and stress (7 items). Each subscale has possible scores ranging from zero to 21, with higher scores indicating higher symptoms.
Alpha coefcients of 0.880.90 were reported for the depression,
0.820.84 for anxiety, and 0.860.90 for stress (Crawford et al., 2009;
Henry & Crawford, 2005; Mahmoud, Hall, & Staten, 2010). Furthermore,
alpha coefcients of the DASS-21 on Singaporean participants was 0.94,
suggesting excellent internal consistency reliability (Ang, 2012).
Relaxation levels were measured by the Perceived Relaxation Scale
(PRS), a single-item visual analogue scale (Lee, 2011). The PRS is a
numeric-visual analogue scale comprising a ten centimeter line with
calibration at every one centimeter. Participants were asked to rate
their perceived levels of relaxation from a scale of zero (very tensed)
to 10 (very relaxed). The Content Validity Index (CVI) of the PRS on cardiovascular patients in Singapore was 1.00 (Lee, 2011).
Participant knowledge was assessed by the Knowledge on Stress and
Stress Management Questionnaire (KSSMQ), which was developed by
the researchers for this study. The KSSMQ is a 15-item questionnaire
whereby every ve items were administered before and after each intervention session. The content of the KSSMQ was based on information
in the PEM. The questionnaire included 15 statements which can be
assessed as true, false or not sure. For every correct statement, a point
was given, making possible in the range of zero to 15 with higher scores
indicating more knowledge. Content validity of the KSSMQ was examined by two mental health nurses and one psychologist; and the CVI
of 0.98 was obtained.
Additionally, the program feedback form was administered at the
end of the third session to explore the participants' perception of the
overall VR DE-STRESS Program. Participants were asked to comment
on strengths and weaknesses; and to provide any other additional comments through three open-ended statements.
Ethical Consideration
Approval to conduct this study was received from the hospital ethics
committee. We explained the purpose of study to eligible patients, distributed patient information sheet (PIS), answered questions they
might have and seek their participation. All participants signed a written informed consent prior to participating in the study. They were
also informed that their information would be strictly condential and
that participation in this study was voluntary. The researchers also emphasized that their decision to participation or not to participate in this
study would not affect healthcare services they received from the
hospital.
Data Analyses
Data obtained in this study were entered into IBM SPSS (Version
20.0). Univariate analyses were used to describe participants' characteristics and study variables. Paired t-tests and repeated measures analysis
of variance (RMANOVA) were performed to test the effects of the intervention on outcome variables. Content analyses were used to analyze
open-ended questions.
RESULTS
A total of 26 patients were approached during the data collection period. However, four patients declined to participate in the study due to
disinterest or low mood. Hence, a total of 22 participants agreed to engage in the study, representing a response rate of 84.62%. Three had
early discharge before completing the intervention. These missing
data were handled by using intention-to-treat (ITT) analysis to minimize type I error. Participants in this study (Table 2) were diagnosed
with MDD (45.45%; n = 12) or BD with depressive episode (54.55%;
n = 10) with age ranging from 21 to 60. Most participants were Chinese
(63.64%; n = 14), female (72.73%; n = 16), and married (54.55%; n =
12) without children (50.00%; n = 11). All patients received standard
care (such as medications) prescribed by their physicians.
Table 2
Demographic Data of Study Participants (n = 22).
Characteristics
Clinical diagnosis
Bipolar Disorder
Major Depressive Disorder
Length of time since rst diagnosed
b 1 year
110 years
N10 years
Age (years)
2130
3140
4150
5160
Gender
Male
Female
Marital status
Single
Married
Widowed
Nationality
Singaporean
Singaporean-PR
Ethnicity
Chinese
Malay
Indian
Highest education level
Secondary
Certicate
Diploma
University
Post-graduate
Currently employed
Yes
No
Income level ($SGD)
b$1000
$1000$3000
$3001$6000
$6001$9000
N$12000
Undisclosed
Frequency (n)
Percentage (%)
12
10
54.54
45.46
6
14
2
27.27
63.64
9.09
5
6
7
4
22.73
27.27
31.82
18.18
6
16
27.27
72.73
9
12
1
40.90
54.55
4.55
20
2
90.91
9.09
14
5
3
63.63
22.73
13.64
12
2
4
3
1
54.54
9.09
18.18
13.64
4.55
12
10
54.55
45.45
5
12
2
1
1
1
22.73
54.54
9.09
4.55
4.55
4.55
10
Objective Stress
Objective stress was measured before and immediately after each
intervention session across 3 days to capture immediate physiological
changes, making up six measurements. RMANOVA was used to compare mean differences across the six measurement points, and results
indicated signicant differences in skin temperature (F = 17.17,
p b 0.001) (Table 3). Post-hoc pair-wise comparisons suggested that
posttest scores of all sessions were signicantly higher than their respective pretest scores. Posttest scores S1, S2 and S3 were also signicantly higher than the baseline (pretest S1). Note that higher scores of
skin temperature signify lower levels of objective stress.
Unfortunately, there were no signicant differences in systolic blood
pressure (F = 2.12, p = 0.10), diastolic blood pressure (F = 0.22, p =
0.97) and heart rate (F = 1.91, p = 0.14) across six measurement points.
However, pair-wise comparison tests revealed that heart rate at posttest
session 3 was signicantly lower than its respective pretest (X difference = 4.16, Se = 1.00, p = 0.007).
Subjective stress, anxiety, and depression
These three variables were measured two times; at baseline and
the completion of the 3-day program. T-tests were used to compare
means of pretest and posttest scores of stress, anxiety, and depression (Table 4). Following the 3-day intervention, the participants
had signicantly lowered subjective stress (X difference = 7.62,
SD = 5.17, t = 6.91, p b 0.001), depression (X difference = 8.09,
SD = 6.75, t = 5.62, p b 0.001), and anxiety (X difference = 5.64,
SD = 4.77, t = 5.54, p b 0.001).
Perceived Relaxation and Participant Knowledge
These two variables were measured before and immediately after
each the intervention session across 3 days (six measurement points).
There was a signicant difference in perceived relaxation across the
six time points (F = 26.20, p b 0.001) (Table 5). Posttest scores of perceived relaxation of all sessions were signicantly higher than their respective pretest scores. Furthermore, posttest S1, S2, and S3 were
signicantly higher than the baseline. Similarly, there was a signicant
difference in participants knowledge across the three time points
(F = 13.77, p b 0.001) (Table 6). Posttest scores S3 and S1 were significantly higher than their respective pretest scores. However, no signicant difference score was observed in session 2.
Feedback on the VR DE-STRESS Program
Participants provided useful feedback on the program concerning its
strengths and weaknesses. Regarding the strengths, the participants
Table 3
Scores of Skin Temperature in Fahrenheit Across Six Measurement Points (n = 22).
Skin temperature
(Fahrenheit)
Pretest mean
(SD)
Posttest mean
(SD)
Session 1 (S1)
Session 2 (S2)
Session 3 (S3)
85.01 (3.05)
86.87 (3.82)
86.31 (3.05)
90.58 (3.52)
90.75 (3.90)
90.34 (3.03)
Post-hoc
comparisons
Pretest S1 & posttest s1
Pretest S1 & posttest s2
Pretest S1 & posttest s3
Pretest S2 & posttest s2
Pretest S3 & posttest s3
Mean difference
(SD)
5.58 (0.96)
5.74 (0.81)
5.34 (0.66)
3.88 (0.73)
4.03 (0.71)
F-Test
p value
17.17
b0.001
95% C.I.
p value
Lower
Upper
2.40
3.07
3.16
1.46
1.70
8.76
8.41
7.51
6.31
6.37
b0.001
b0.001
b0.001
b0.001
b0.001
NOTE. a) Skin temperature was measured by the stress thermometer. b) Sphericity assumed (Mauchly's W = 0.40; p = 0.239).
DISCUSSION
This study aimed to test the feasibility and initial effect of the VR DESTRESS Program on inpatients with mood disorders in a tertiary hospital
in Singapore. The program comprised two major components:
psychoeducation and relaxation practice guided by VR-based relaxation
videos. Evidently, it was feasible to deliver the three daily 1-hour VR DESTRESS sessions to patients in the hospital setting. Findings from this
study provided empirical evidence to address the two research questions. For the rst one, participants who attended the program reported
signicantly lowered objective stress (as indicated by skin temperature), subjective stress, depression, and anxiety. For the second research
question, participants also had signicantly greater perceived relaxation and knowledge. Additionally, this study produced results that supported the Neuman System Model (Neuman & Fawcett, 2002).
Particularly, a tertiary prevention intervention (which was represented
by the VR DE-STRESS Program) could help individuals with mood disorders manage stressors from environment, minimize stress-related
symptoms (such as depression and anxiety), and possibly return to
the state of equilibrium.
Under stressful circumstances, individuals' sympathetic nervous
system is activated, resulting in periphery vasoconstriction
(i.e., decreased blood ow to the surface of skin) and thus lowered
skin temperature (Chen et al., 2009). Conversely, when the body is in
a state of relaxation, it activates the parasympathetic nervous system,
resulting in periphery vasodilation and then higher skin temperature.
In this study, participants reported lower levels of objective stress (evidenced by increased skin temperature) immediately at the end of each
intervention across 3 days. Participants also reported lowered objective
stress at the end of session two and three in comparison to the baseline.
The signicant increase in skin temperature obtained is similar to the
ndings by Chen et al. (2009) who applied progressive muscle relaxation training (PMRT) on patients with schizophrenia. The positive ndings obtained from the physiological measurement complemented and
strengthened the subjective measures of stress. Notably, participants in
our study also reported reduced subjective stress levels (as measured by
the self-reported questionnaire) post-intervention.
Moreover, participants reported signicant increases in perceived relaxation levels after all three sessions of the VR DE-STRESS Program.
This is consistent with research ndings from a previous study by Banos
et al. (2011). The relaxation response reduces the activity of the sympathetic nervous symptom, thus undoing the stress response (Schaffer &
Yucha, 2004). These changes could have increased the perception of relaxation in the participants. In addition, we believe that the VR device
was a key feature in creating the overall relaxing experience during the
relaxation practice of the VR DE-STRESS Program. The VR device might
produce positive effects on auditory, visual and sensory receptors of the
person, and thus enhancing the relaxation experience (Banos et al.,
2011). The three relaxation techniques were incorporated into the VRbased relaxation videos accompanied with peaceful music, soothing
narrator's voice and attractive visual sceneries. The personalized viewing
through the VR device grounded in a calm, quiet, and distraction-free environment contributes to the creation of a relaxing environment. These
11
Table 4
Scores of Subjective Stress, Depression, and Anxiety (n = 22).
Outcome variables
Subjective stress
Pretest session 1
Posttest session 3
Depression
Pretest session 1
Posttest session 3
Anxiety
Pretest session 1
Posttest session 3
Mean (SD)
Lower
Upper
t-test
p-value
10.23 (5.43)
2.61 (2.43)
7.62 (5.17)
5.32
9.92
6.91
b0.001
9.77 (7.34)
1.68 (0.60)
8.09 (6.75)
5.10
11.08
5.62
b0.001
8.27 (5.56)
2.63 (2.49)
5.64 (4.77)
3.53
7.76
5.54
b0.001
NOTE. Subjective stress, depression, and anxiety were measured by the Depression Anxiety Stress Scale (DASS-21) (Lovibond & Lovibond, 1995).
Table 5
Scores of Perceived Relaxation Across Six Measurement Points (n = 22).
Perceived relaxation
Posttest mean
(SD)
Session 1 (S1)
Session 2 (S2)
Session 3 (S3)
4.86 (2.66)
5.50 (2.02)
5.79 (1.70)
7.64 (1.79)
7.50 (1.62)
8.32 (1.21)
Post-hoc
comparisons
Pretest S1 & posttest s1
Pretest S1 & posttest s2
Pretest S1 & posttest s3
Pretest S2 & posttest s2
Pretest S3 & posttest s3
F-test
p value
26.20
b0.001
95% C.I.
Mean difference
(SD)
Lower
Upper
p value
2.77 (0.48)
2.64 (0.52)
3.45(0.51)
2.00 (0.25)
2.53 (0.31)
1.20
0.90
1.77
1.16
1.51
4.35
4.37
5.13
2.84
3.54
b0.001
b0.001
b0.001
b0.001
b0.001
Table 6
Scores of Stress Management Knowledge Across Six Measurement Points (n = 22).
Stress management
knowledge
Pretest mean
(SD)
Posttest mean
(SD)
Session 1 (S1)
Session 2 (S2)
Session 3 (S3)
4.00 (0.82)
3.86 (0.77)
3.79 (0.66)
4.95 (0.21)
4.57 (0.58)
4.47 (0.72)
Mean difference
(SD)
0.96 (0.17)
0.71 (0.24)
0.68 (0.13)
Post-hoc
comparisons
Pretest S1 & posttest s1
Pretest S2 & posttest s2
Pretest S3 & posttest s3
F-test
p value
13.77
b0.001
Lower
Upper
p value
0.40
0.08
0.25
1.51
1.50
1.12
b0.001
b0.001
b0.001
95% C.I.
NOTE. a) Stress management knowledge was measured by the Knowledge on Stress and
Stress Management Questionnaire. b) GreenhouseGeisser Correction Model used as
sphericity violated (Mauchly's W = 0.13; p b 0.001).
12
heart rate and blood pressure. The limitations in the study could serve as
a platform for the expansion of knowledge on stress management interventions through the implementation of true experimental designs in
future studies with a larger sample size.
Implications for Clinical Practice
Despite the aforementioned limitations, our study has demonstrated
the potential effects of the VR DE-STRESS Program in reducing stress,
depression and anxiety; while increasing perceived relaxation and
stress management knowledge in people with mood disorders. Consequently, the VR DE-STRESS Program could be incorporated into standard care in mental health settings. Given the shortage of health care
providers, the use of VR technology is a promising method in valueadding therapeutic interventions. Furthermore, VR can be a new psychotherapeutic tool, which is more appealing to patients in the mental
health setting and may increase adherence to treatment (Gaudiano,
Weinstock, & Millier, 2008). It is reported that participants in VRbased studies in mental health settings expressed high levels of support
and interest in the use of VR for their care (Banos et al., 2011). In
Singapore, most people with mood disorders are in age range 3150
years. We believed that people in this age range are familiar with advanced technology, and thus they would be more open to the implementation of VR technology.
Recommendations for Future Research
More studies concerning psychoeducation and relaxation interventions should be undertaken to expand the limited literature in areas of
VR-based interventions for people with mood disorders. Virtual reality
could be used as a psychotherapeutic tool to carry out future interventions. More rigorous studies (such RCT) with a larger sample size should
be carried out to test the efcacy of the interventions. Next, since the
PEM and an audio relaxation CD was provided to the participant so they
could benet from the intervention beyond the duration of the program,
it might be worth investigating the outcome variables at follow-up assessments to determine longer-term effects of the intervention.
In summary, ndings from this study provide empirical evidence to
inform the two research questions. The VR DE-STRESS Program was feasible and had some positive effects on individuals with mood disorders.
This empirical evidence contributes to body of knowledge concerning
stress management interventions for people with mood disorders in
Singapore.
ROLE OF THE FUNDING SOURCE
This study was supported by the Start-up Grant, Yong Loo Lin School
of Medicine, National University of Singapore. Dr. Piyanee Klainin-Yobas
is a principal investigator.
CONFLICT OF INTEREST
All authors declare no conict of interest for this study. No competing nancial interests exist.
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