RESEARCH ARTICLE

Effectiveness of a primary care-based

integrated mobile health intervention for
stroke management in rural China (SINEMA):
A cluster-randomized controlled trial
Lijing L. Yan ID1,2,3,4,5☯*, Enying Gong ID1,6☯, Wanbing Gu1,7, Elizabeth L. Turner2,8, John
A. Gallis ID2,8, Yun Zhou ID9, Zixiao Li9, Kara E. McCormack ID8, Li-Qun Xu ID10, Janet
P. Bettger ID2,11, Shenglan Tang ID2, Yilong Wang9, Brian Oldenburg ID6
a1111111111
1 Global Health Research Center, Duke Kunshan University, Jiangsu, China, 2 Duke Global Health Institute,
a1111111111
Duke University, Durham, North Carolina, United States of America, 3 The George Institute for Global Health,
a1111111111 Beijing, China, 4 School of Health Sciences, Wuhan University, Wuhan, Hubei, China, 5 Peking University
a1111111111 School of Global Health and Development, Beijing, China, 6 Melbourne School of Population and Global
a1111111111 Health, The University of Melbourne, Victoria, Australia, 7 Vital Strategies, Jinan Representative Office,
Beijing, China, 8 Department of Biostatistics & Bioinformatics, Duke University, Durham North Carolina,
United States, 9 Beijing Tiantan Hospital, Capital Medical University, Beijing, China, 10 China Mobile
Industry Institute, Chengdu, China, 11 Department of Orthopedic Surgery, Duke University, Durham North
Carolina, United States of America

OPEN ACCESS ☯ These authors contributed equally to this work.

Citation: Yan LL, Gong E, Gu W, Turner EL, Gallis * [Link]@[Link]
JA, Zhou Y, et al. (2021) Effectiveness of a primary
care-based integrated mobile health intervention
for stroke management in rural China (SINEMA): A Abstract
cluster-randomized controlled trial. PLoS Med
18(4): e1003582. [Link]
pmed.1003582
Background
Academic Editor: Joshua Z. Willey, Columbia
University, UNITED STATES Managing noncommunicable diseases through primary healthcare has been identified as
Received: November 3, 2020 the key strategy to achieve universal health coverage but is challenging in most low- and
middle-income countries. Stroke is the leading cause of death and disability in rural China.
Accepted: March 11, 2021
This study aims to determine whether a primary care-based integrated mobile health inter-
Published: April 28, 2021
vention (SINEMA intervention) could improve stroke management in rural China.
Copyright: © 2021 Yan et al. This is an open access
article distributed under the terms of the Creative
Commons Attribution License, which permits Methods and findings
unrestricted use, distribution, and reproduction in
Based on extensive barrier analyses, contextual research, and feasibility studies, we con-
any medium, provided the original author and
source are credited.
ducted a community-based, two-arm cluster-randomized controlled trial with blinded out-
come assessment in Hebei Province, rural Northern China including 1,299 stroke patients
Data Availability Statement: The data in this study
cannot be shared publicly because of the
(mean age: 65.7 [SD:8.2], 42.6% females, 71.2% received education below primary school)
limitations imposed by the study’s ethics approval. recruited from 50 villages between June 23 and July 21, 2017. Villages were randomly
The de-identified database could be shared by assigned (1:1) to either the intervention or control arm (usual care). In the intervention arm,
specific enquiry to the data management
village doctors who were government-sponsored primary healthcare providers received
committee (contact via research-
support@[Link]). training, conducted monthly follow-up visits supported by an Android-based mobile applica-
tion, and received performance-based payments. Participants received monthly doctor vis-
Funding: The study is funded by the United
Kingdom Medical Research Council, Economic and its and automatically dispatched daily voice messages. The primary outcome was the 12-
Social Research Council, Department for month change in systolic blood pressure (BPAU ). Secondary
: PleasenotethatBPhasbeendefinedasbloodpressureinitsfi
outcomes were predefined,

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PLOS MEDICINE SINEMA intervention for stroke management in rural China

International Development, and Wellcome Trust including diastolic BP, health-related quality of life, physical activity level, self-reported medi-
(Grant No: MR/N015967/1). The funders had no cation adherence (antiplatelet, statin, and antihypertensive), and performance in “timed up
role in study design, data collection and analysis,
decision to publish or preparation of the
and go” test. Analyses were conducted in the intention-to-treat framework at the individual
manuscript. LLY is also supported by the National level with clusters and stratified design accounted for by following the prepublished statisti-
Science Foundation of China (Grant no: cal analysis plan. All villages completed the 12-month follow-up, and 611 (intervention) and
71774075). EG is supported by the University of
615 (control) patients were successfully followed (3.4% lost to follow-up among survivors).
Melbourne Graduate Scholarship and NHMRC
(1170937). BO is supported by NHMRC The program was implemented with high fidelity, and the annual program delivery cost per
(1170937). capita was US$24.3. There was a significant reduction in systolic BP in the intervention as
Competing interests: The authors have declared compared with the control group with an adjusted mean difference: −2.8 mm Hg (95% CI
that no competing interests exist. −4.8, −0.9; p = 0.005). The intervention was significantly associated with improvements in 6
Abbreviations: AU
BP, blood out of 7 secondary outcomes in diastolic BP reduction (p < 0.001), health-related quality of
: Anabbreviationlisthasbeencompiledforthoseusedinthetext:Pleaseverifythatallentriesarecorrect:
pressure; CI, confidence
interval; LMICs, low- and middle-income countries; life (p = 0.008), physical activity level (p < 0.001), adherence in statin (p = 0.003) and antihy-
mHealth, mobile health; NCD, noncommunicable pertensive medicines (p = 0.039), and performance in “timed up and go” test (p = 0.022).
chronic disease; pp, percentage points; RD, risk
We observed reductions in all exploratory outcomes, including stroke recurrence (4.4% ver-
difference; RR, risk ratio; SD, standard deviation;
SINEMA, system-integrated and technology- sus 9.3%; risk ratio [RR] = 0.46, 95% CI 0.32, 0.66; risk difference [RD] = 4.9 percentage
enabled model of care. points [pp]), hospitalization (4.4% versus 9.3%; RR = 0.45, 95% CI 0.32, 0.62; RD = 4.9 pp),
disability (20.9% versus 30.2%; RR = 0.65, 95% CI 0.53, 0.79; RD = 9.3 pp), and death
(1.8% versus 3.1%; RR = 0.52, 95% CI 0.28, 0.96; RD = 1.3 pp). Limitations include the rela-
tively short study duration of only 1 year and the generalizability of our findings beyond the
study setting.

Conclusions
In this study, a primary care-based mobile health intervention integrating provider-centered
and patient-facing technology was effective in reducing BP and improving stroke secondary
prevention in a resource-limited rural setting in China.

Trial registration
[Link] NCT03185858.

Author summary

Why was this study done?

• In low- and middle-income countries, there is an urgent need to develop effective and
cost-effective approaches to strengthen primary healthcare system in noncommunicable
disease management.
• Rural China suffers from an increasing burden due to stroke, with no existing effective
strategy to manage community-dwelling stroke patients.
• Results from mobile health studies, usually not integrating health solutions for both pri-
mary healthcare providers and patients, were mixed with some demonstrating effective-
ness while others had neutral findings.

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PLOS MEDICINE SINEMA intervention for stroke management in rural China

What did the researchers do and find?

• We conducted a cluster-randomized controlled trial in rural China to investigate
whether a primary care-based integrated mobile health intervention could improve
blood pressure (BP) control and secondary prevention of stroke.
• We identified individuals with stroke from 50 villages. Villages allocated in the interven-
tion arm received both provider and patient-facing interventions over 12 months.
• There was a significant net reduction in systolic BP between the intervention and con-
trol groups, and the intervention also led to significant improvement in other health
outcomes and reduction in hospitalization and mortality among stroke patients in rural
China.
• The program was well implemented with relatively high fidelity and low cost (US$24.3
per participant per year).

What do these findings mean?

• A primary care-based integrated mobile health intervention that aims to overcome both
health system and individual barriers could lead to an improvement in BP control and
secondary prevention of stroke in rural China.
• This model, with low program delivery cost, has the potential, when adapted to local
contexts appropriately, to be relevant to other chronic conditions and in other resource-
limited settings.

Introduction
Since the Declaration of Alma-Ata in 1978, primary care strengthening has been identified as
the key strategy for disease management and achieving universal health coverage [1]. Low-and
middle-income countries (LMICs) bear the double burdens of long-standing infectious dis-
eases and emerging noncommunicable chronic diseases (NCDs) [2]. However, primary care
providers in LMICs often focus on infectious diseases and maternal and child health; thus,
there is a lack of capacity to provide evidence-based essential primary care for patients with
NCDs [3]. Several dozen trials have been conducted to evaluate various human-based or tech-
nological approaches to strengthen primary care for NCD control [4–9]. According to recent
systematic reviews, these trials as a whole were effective in improving the quality of primary
and community-based care, while results from mobile health (mHealth) technological inter-
ventions, mainly message-based programs, were inconclusive [8–11].
Our previous trials in rural China and India demonstrated that primary care-based multi-
component interventions to train, equip, and incentivize primary care providers were effective
in changing providers’ behaviors and improving patient outcomes [12–14]. However, the
interventions were not embedded in the existing healthcare system. In addition, in previous
studies, the mHealth components targeted either providers [13] or patients [14] but were not
integrated with each other. Many other trials suffered from similar problems [6] or did not uti-
lize the rapidly evolving and promising mHealth technology at all [4,5].

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To address these limitations, we designed an intervention program entitled “system-inte-

grated and technology-enabled model of care (SINEMA)” [15]. This model strengthens the
existing primary care workforce through training and support embedded in the entire health-
care system and integrates both provider-side and patient-facing mHealth technology. It is
applicable to many types of NCDs, but we chose to focus on stroke management in rural
China. Stroke is the leading cause of death and disability in rural China where primary care
lacks the capacity to provide guideline-based essential care to stroke patients, and community-
based management for secondary prevention of stroke is far from adequate [16,17]. We per-
formed extensive feasibility and contextual research to adopt this model for stroke manage-
ment in the setting of resource-limited areas in rural China [15,18,19]. We hypothesized that
the SINEMA intervention would be more effective in improving blood pressure (BP) control
and other health outcomes than usual care among stroke patients. To test this hypothesis, we
conducted a cluster-randomized controlled trial in Northern China.

Methods
Trial design
The SINEMA study was an open-label, two-arm, cluster-randomized controlled trial with
blinded assessment and analysis. We chose cluster-randomized design to implement the inter-
vention at the cluster (village) level. Such a design could reduce contamination within clusters
and enhance the feasibility of implementation. Over a 1-year period in preparation for the
trial, we conducted extensive contextual field research on intervention design, technology
development, and a 3-month pilot study in 4 villages [15,18,19]. We then conducted the main
trial in 50 rural villages in rural China to evaluate the effectiveness of the intervention with
embedded process evaluation and economic evaluation. Duration of the intervention was 12
months. The trial was registered on [Link] (NCT03185858). The study is reported
according to the CONSORT guidance for reporting cluster-randomized trial (S1 Checklist)
[20]. The trial protocol, technological development, and statistical analysis plan were published
in detail [15,18,19,21]. We describe a condensed version below.

Study setting and participants

The study was conducted in a rural region of Hebei Province, Northern China, where the inci-
dence of stroke was 236.2 per 100,000 population, more than double the national average
(109.7 per 100,000 population) [16,22]. In rural China, there is a 3-tier healthcare system
including village clinics, township healthcare centers, and county hospitals [23,24]. Village
clinics and township healthcare centers form the rural primary healthcare system and provide
both general clinical care and the National Basic Public Health Services Program to residents
in the region [23,25]. VillageAUdoctors
: PleaseconfirmthattheedittothesentenceVillagedoctorswhoarenotboard
who are not board-certified physicians but government-
sponsored primary healthcare providers practice in village clinics. In general, they have high
school or equivalent education with prescription rights for medicines in provincial essential
medicine formularies. They are managed by and receive their supply from township healthcare
centers. Although substantial investment and efforts had been made in primary healthcare
strengthening since the Chinese healthcare reform in 2009, the resources remained substan-
tially constrained, the quality of care is still suboptimal, and the utilization of primary care ser-
vices has decreased [23–25].
In our study, eligible clusters were villages with a minimum population size of 1,500 and at
least 1 village doctor who was willing to participate. The research team screened the eligible
clusters among 218 villages from 8 townships in the region and selected 60 potentially eligible
villages from 5 townships (as strata) where there were at least 10 clusters for further screening

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and recruitment. The main participant inclusion criteria were adults with a history of stroke
diagnosed at the county- or higher-level hospitals and in a clinically stable condition with at least
basic communication ability. Patients who were unable to get out of bed, had severe life-threat-
ening diseases, or an expected life span shorter than 6 months were excluded. To ensure gener-
alizability, mobile phone ownership or technology literacy was not a criterion for patient
recruitment. Village doctors screened and invited potentially eligible patients in their villages to
participate in the study. The research team conducted the final recruitment and consent process.

Randomization and masking

Eligible villages were randomized in a 1:1 ratio to the intervention or the control arm with
stratification by the township. A biostatistician who was not part of the study performed the
randomization using a computer-generated random numbering system. Randomization allo-
cation was not revealed to any staff during patient recruitment and assessment. Village doctors
were informed only after patients’ baseline assessments were completed. Given the nature of
the intervention, patients and health providers were not blinded to intervention assignment.
Outcome assessors were kept unaware of the trial protocol and blinded throughout the study
period to ensure the objectivity of assessment. Statisticians who were masked to intervention
allocation conducted all statistical analyses, and allocation status was not revealed until all
results were generated.

Procedures
The SINEMA intervention package was developed with careful contextual research and pilot
study lasting for 1-year long. The contents were consistent with China’s clinical guidelines for
stroke prevention in a primary care setting [26] and tailored to the local context with special
intervention focus on medication adherence and physical activities by considering the capacity
and available resources [18,19]. In brief, the intervention included both provider-side compo-
nents and patient-facing components and were supported by a digital health system consisted
of an Android-based smart phone application—SINEMA App—for providers and linked with
a voice messages system for patients (see S1 Fig for a diagram depicting the intervention
design). The SINEMA App has been designed for multiple end-users including village doctors
and township and county physicians and included multiple modules including patients’ pro-
files, follow-up visits, training, performance indicators, and follow-up visits reminders [19].
Aided by the SINEMA App, village doctors could collect, record, and retrieve patients’ infor-
mation and follow-up history, and physicians from upper-tier hospitals could review the rec-
ords and monitoring village doctors’ performance. The digital health system was linked with a
third-party dispatching platform and a message bank containing more than 180 messages that
we codesigned with clinical experts and local healthcare providers. These messages followed
the same structure, was recorded in the local dialect, and were dispatched daily with different
contents to participants. More detailed description on the development of the intervention
package and digital health system could be found in previous publications [15,18,19].
After allocation of randomization, village doctors in the intervention arm were invited to a
1-day training session delivered by county hospital physicians who were trained by neurolo-
gists from a tertiary hospital. The training session covered the evidence-based use of essential
medicines, skills for promoting patients’ behavior changes, and the use of SINEMA App. Each
village doctor was also provided with a written intervention manual and an Android smart-
phone with the SINEMA App installed to support intervention delivery. Android instead of
iOS (iPhone) was the smartphone operating system of choice due to its lower cost and wide-
spread use among village doctors. A refresh training session was provided at the third month.

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During the 12 months of the intervention period, village doctors delivered monthly follow-
up visits to participants at the village clinics or participants’ homes, according to the standard-
ized interventional plan. The follow-up visits covered BP monitoring, stroke symptom review,
medication use assessment, and health education with a focus on medication adherence and
physical activity. These 2 aspects were emphasized because our contextual research in the
study region showed the importance of these behaviors among our study population and feasi-
bility to intervene. Consistent with stroke management guidelines, [26] emphases on medica-
tion use were placed on 3 types of medicines (antiplatelet, statin, and antihypertensive).
Village doctors were aided by the flow laid out in the SINEMA App to follow the standardized
procedures. In each monthly follow-up visit, they gave participants a standardized single-sheet
picture-rich handout listing their medications and exercise goals as a tool to illustrate the per-
sonalized recommendations. There was no cost for follow-up visits, but the cost of medications
was borne primarily by the participants with partial coverage by social insurance, in consider-
ation of the local norms and the need for sustainability and scalability.
Village doctors were provided with quarterly performance-based financial payment based
on the quantity of services and bonuses for the top 5 village doctors determined by perfor-
mance indicators that were generated from the SINEMA App and quality control measures
provided by township physicians. Village doctors were encouraged to communicate with peers
and township physicians through the App, phone calls, and the study’s virtual groups to share
experience, seek clinical support, and provide feedback.
In addition to follow-up visits, participants who had access to their own or shared cell
phones received 1 daily voice message at no cost to them over 12 months. Many patients were
illiterate or not used to receive text messages even if they could read. Our pilot study in 4 vil-
lages found that voice calls were preferred over text messages [18]. Therefore, according to an
algorithm designed based on our field research and pilot testing, [18] short voice messages—
recorded in the local dialect—were automatically dispatched every morning with particular
emphases on reminders and tips for medication adherence and physical activity.
In villages randomly assigned to the control arm, participants received usual care and vil-
lage doctors continued their existing general clinical practices and the Basic Public Health Ser-
vices. In the context of rural China, usual care involved patients seeking care in village clinics,
township healthcare centers, or county hospitals, as needed. Some participants may also
receive quarterly follow-up visits by village doctors if they had hypertension or diabetes, and
receive general health education as such health promotion activities covered by the Basic Pub-
lic Health Services were implemented widely across China [24].

Outcomes
The primary outcome for patients was the 12-month change in systolic BP, analyzed as the dif-
ference between arms in the 12-month change in systolic BP from baseline to 12-month fol-
low-up. The relatively short intervention duration and small sample size precluded the choice
of stroke as the primary outcome. Systolic BP was chosen due to its well-established and signif-
icant impact on stroke recurrence and other cardiovascular events [16]. There were 7 prespeci-
fied secondary outcomes: diastolic BP, mobility functioning measured by the “timed up and
go” test [27], physical activity based on the short-form International Physical Activity Ques-
tionnaire [28], health-related quality of life assessed by the EuroQol-5 Dimension-5L [29], and
self-reported medication adherence to antiplatelet, statin, and antihypertensive measured sep-
arately by the 4-item Morisky Green Levine Scale [30]. Four prespecified exploratory outcomes
included stroke recurrence and hospitalization, disability (modified Rankin Scale) [31], and
mortality collected from questionnaires and medical and death records.

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Outcome assessors were staff members from the Center for Disease Control and Prevention
in a nearby county who were not involved in any of the program implementation. They were
blinded on the intervention allocation and trained to follow a standard protocol to measure
outcomes in exactly the same way in all villages and for all participants at baseline and 12
months. Data on patients’ self-reported information were collected through face-to-face inter-
views and recorded in an online survey platform (Qualtrics, Provo, Utah), with built-in skip
patterns, logic checks, and quality control. BP was measured on the right upper arm with par-
ticipants seated and after 5 minutes of rest, with an electronic BP monitor (Omron HEM-
7052), validated by the European Society of Hypertension. Two measurements were taken. If
the difference between the 2 systolic BP measures was larger than 10 mm Hg, a third measure-
ment was conducted. The mean value of the only or the last 2 readings was used in all analyses.

Sample size calculation and statistical analysis

We estimated that a sample of 1,250 prevalent stroke patients in 50 villages (with 25 villages
per arm and on average 25 patients per village) would provide 83% power at a two-tailed 5%
significance level to detect a 5-mm Hg mean difference in 1-year change of systolic BP between
the intervention and control arms [32]. This estimation considered the cluster design and
assumed a loss of 2 clusters per arm and loss of 1 patient per village, a standard deviation of
change of 25 mm Hg, and an intracluster correlation coefficient of change of 0.04.
Analyses were conducted in the intention-to-treat framework, and all analyses were at an
individual level with clusters and stratified design taken into account by following the prepub-
lished statistical analysis plan [21]. The main analysis (minimally adjusted) compared the
1-year change in systolic BP between the intervention and control arms by using a mixed-
effect model with a random intercept for the cluster (village) and a fixed effect for townships to
account for the stratified design, baseline systolic BP, age, and sex. Restricted maximum likeli-
hood was used together with the between-within method to calculate degrees of freedom [33].
Outliers were removed from change in systolic BP based on an a priori decision to remove
those values which were more than 2 interquartile ranges above the third quartile or below the
first quartile of the distribution [21]. Four types of sensitivity analyses were performed through
changes to the minimally adjusted primary analysis model: (1) adjusting for baseline covariates
that were identified as being imbalanced between the 2 arms or associated with lost-to-follow-
up (fully adjusted analyses); (2) adjusting for covariates that were associated with baseline
imbalance only; (3) adjusting for covariates that were associated with lost-to-follow-up only;
and (4) with outliers included. We performed prespecified subgroup analyses (age, education,
and duration since stroke event) by adding the subgroup variable and its interaction term with
the intervention as fixed effects to the minimally adjusted model used in the main analysis.
Analysis of secondary and exploratory outcomes adopted a similar approach for the mini-
mally adjusted models, fully adjusted models, and other sensitivity analyses. For continuous
outcomes, the same mixed-effect modeling approach was used as described above. For binary
outcome variables, the generalized estimating equation approach was used to obtain popula-
tion-averaged intervention effects using a Poisson model with log-link and robust standard
errors in order to obtain risk ratios [34,35]. An independent working correlation matrix was
pre-specified because it was expected to provide greater stability when the cluster sizes were
variable. In addition to all prespecified analyses in the statistical analysis plan [21], post hoc
analysis on BP control rate (considering both systolic BP and diastolic BP) was also conducted
to further estimate the clinical importance of the intervention. Risk differences for binary out-
comes are computed directly from the outcome percentages at follow-up. All analyses were
conducted in Stata version 15.1 (StataCorp, College Station, Texas) and were replicated by an

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independent statistician blinded to the results reported from Stata, using the R software (ver-
sion 3.5.2) with the package of geeM [36] and Ime4 [37].

Ethical statement
The study was approved by the Institutional Review Boards at Duke University, USA, Beijing
Tiantan Hospital, and Duke Kunshan University, China. All participants (both providers and
patients) provided written informed consent before participation. Cluster-level consent was
provided by opinion leaders in the townships and villages.

Results
Recruitment and follow-up of study population
Among 8 townships, we invited 5 townships where there were enough potentially eligible clus-
ters to participate in the study and 60 village doctors performed eligibility screening among a
total of 2,333 stroke patients from 60 villages (Fig 1). After excluding 10 ineligible villages and
people who did not meet the inclusion criteria from the remaining villages, we recruited 50 vil-
lages with a total of 1,299 patients in the trial between June 23 and July 21, 2017. These 50 vil-
lages were randomized into the intervention arm (25 villages, 637 patients, and mean cluster
size 25.5 patients per village [standard deviation–SD 3.2] and the control arm (25 villages, 662
patients, and mean cluster size 26.5 [SD 2.7]). After excluding those who died during the fol-
low-up (n = 30, 2.3%) or lost to follow-up (n = 43, 3.3%), the final analyses included 1,226
participants.

Baseline characteristics at patient and cluster level

Baseline characteristics at the patient level are summarized in Table 1 and at the cluster and
village doctor levels in S1 Table. For each of these 3 levels, the intervention and control arms
were generally comparable. Patients in our trial were older adults (mean [SD] age 65.6 [8.2]
years) who had low educational level (71.2% with no schooling or only a primary school edu-
cation). The vast majority of participants (86.1%) had an ischemic stroke and had living with

Fig 1. Flow diagram of trial participants.

[Link]

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Table 1. Baseline characteristics for the SINEMA trial at the patient level.
Intervention (n = 637) Control (n = 662) Total (n = 1,299)
Demographic characteristics and disease history
Age, mean (SD), years 66.2 (8.2) 65.2 (8.2) 65.7 (8.2)
Sex, % female 272 (42.7%) 281 (42.4%) 553 (42.6%)
Education, n (%)
No schooling 264 (41.4%) 274 (41.4%) 538 (41.4%)
Some schooling or primary school only 182 (28.6%) 205 (31.0%) 387 (29.8%)
Above primary school 191 (30.0%) 183 (27.6%) 374 (28.8%)
Marital status, n (%)
Married 526 (82.6%) 549 (82.9%) 1,075 (82.8%)
Widowed, divorced, or not married 111 (17.4%) 113 (17.1%) 224 (17.2%)
Phone ownership, n (%)
No phone (may have a shared phone) 164 (25.7%) 159 (24.0%) 323 (24.9%)
Basic phone 435 (68.3%) 440 (66.5%) 875 (67.4%)
Smartphone 38 (6.0%) 63 (9.5%) 101 (7.8%)
Had none of the listed assets, n (%)� 28 (4.4%) 50 (7.6%) 78 (6.0%)
Smoking status, n (%)
Current smoker 99 (15.5%) 122 (18.4%) 221 (17.0%)
Former smoker 130 (20.4%) 132 (19.9%) 262 (20.2%)
Never smoker 408 (64.1%) 408 (61.6%) 816 (62.8%)
†
No (%) enrolled in NCD insurance benefits package 72 (11.3%) 96 (14.5%) 168 (12.9%)
Stroke type, n (%)
Ischemic 555 (87.1%) 564 (85.2%) 1,119 (86.1%)
Hemorrhage 80 (12.6%) 96 (14.5%) 176 (13.6%)
Not specified 2 (0.3%) 2 (0.3%) 4 (0.3%)
Stroke duration, years (median, interquartile)
Since the first event 5.3 (2.4, 9.8) 5.2 (2.3, 9.8) 5.3 (2.3, 9.8)
Since the latest event 3.2 (1.2, 6.8) 3.3 (1.1, 6.8) 3.3 (1.1, 6.8)
Self-report diseases, n (%)
Hypertension 461 (72.4%) 436 (65.9%) 897 (69.1%)
Dyslipidemia 248 (38.9%) 271 (40.9%) 519 (40.0%)
Diabetes 113 (17.7%) 103 (15.6%) 216 (16.6%)
Heart Diseases 70 (11.0%) 54 (8.2%) 124 (9.5%)
Outcomes at baseline
Systolic blood pressure, mean (SD), mm Hg 146.0 (20.9) 145.7 (23.7) 145.9 (22.4)
Diastolic blood pressure, mean (SD), mm Hg 78.0 (11.6) 79.7 (11.7) 78.9 (11.7)
Health-related quality of life in utility, mean (SD)‡ 0.80 (0.2) 0.8 (0.21) 0.8 (0.2)
Timed up and go, n (%) with completion time �14 s§ 324 (51.6%) 347 (53.1%) 671 (52.4%)
Physical activity, median (Q1, Q3), MET minutes/week 1,128.8 (346.5, 2,325.0) 924.0 (240.0, 2,304.0) 974.0 (297.0, 2,310.0)
Medication use, n (%)
Antiplatelet 432 (67.8%) 420 (63.4%) 852 (65.6%)
Statin 158 (24.8%) 182 (27.5%) 340 (26.2%)
Antihypertensive medicines 522 (81.9%) 508 (76.7%) 1,030 (79.3%)
Adherence to medications, n (%)††
Antiplatelet 275 (63.7%) 262 (62.4%) 537 (63.0%)
Statin 106 (67.1%) 110 (60.4%) 216 (63.5%)
Antihypertensive medicines 329 (63.0%) 316 (62.2%) 645 (62.6%)
Moderate to severe disability, n (%)‡‡ 179 (28.1%) 173 (26.1%) 352 (27.1%)
(Continued )

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Table 1. (Continued)

Intervention (n = 637) Control (n = 662) Total (n = 1,299)

Stroke hospitalization in the past year, n (%) 124 (19.5%) 132 (19.9%) 256 (19.7%)

MET, metabolic equivalents; NCD, noncommunicable chronic disease; SD, standard deviation.
�
TV, refrigerator, air conditioner, and computer were listed as home assets in the questionnaire.
†
NCD insurance package is only available for people enrolled in the health insurance system and with severe chronic diseases, through which people could get
reimbursement of outpatient services at county hospital.
‡
Health-related quality of life was measured by using EQ5D-5L and was converted into a utility score based on the Chinese value set. The utility score ranged from −0.4
to 1.
§
Up and go test results were recorded in seconds during measurement and dichotomized into binary as �14 (indicating lower limb mobility) versus <14 s (higher limb
mobility) based on previous literature.
††
Medication adherence was only measured among participants who were taking the specific medicine based on 4-item Morisky Green Levine Scale.
‡‡
Disability was measured by the modified Rankin Scale, and people who received a score above 3 were grouped into the “moderate to severe disability” group.

[Link]

stroke for a median of 5.3 years (interquartile: 2.3 years, 9.8 years). Participants who died or
were lost to follow-up (n = 73) were more likely (p < 0.05) to be male, younger, a current or
former smoker, and in the control arm, and to have higher total family income and lower sys-
tolic BP at baseline (S2 Table).

Implementation fidelity and program delivery cost

The intervention was implemented with relatively high fidelity to the study protocol (S3
Table). All village doctors participated in the training adopted the SINEMA App for follow-up
visits and utilized the support mechanisms. About 90.5% participants received 12 follow-up
visits as planned. The daily voice messages were dispatched to 80.4% of participants in the
intervention arm with access to cell phones, and on any given day, half (49.7%) of dispatched
voice messages were successfully answered. The estimated annual cost of program delivery was
about US$24.3 per patient (S4 Table).

Effect of interventions on primary, secondary, and exploratory outcomes

We observed a modest but significant intervention effect on systolic BP with a greater reduction
in mean systolic BP among patients in the intervention arm (−7.1 mm Hg) compared with the
control arm (−4.3 mm Hg) (adjusted mean difference: −2.8 mm Hg, 95% confidence interval
[CI]: −4.8, −0.9, p = 0.005) within the primary minimally adjusted analytic model. The estimated
intracluster correlation for this model was 0.001. The fully adjusted model for the primary out-
come of change in systolic BP yielded a slightly higher adjusted mean reduction (−3.3 mm Hg,
95% CI: −5.2, −1.4) (Table 2). Results were robust and consistent within each level of the prespeci-
fic binary subgroup variables with exceptions of males (−0.3 mm Hg, 95% CI: −2.8, 2.2) and those
less than 65 years old (−2.0 mm Hg, 95% CI: −5.1, 1.0) for which the between-arm differences
were small (Fig 2). The additional analysis on BP control revealed that the intervention resulted in
a 19% (95% CI: 8%, 30%) relative increase in the proportion of patients reaching the target of BP
control (systolic BP < 140 mm Hg and diastolic BP < 90 mm Hg) (S5 Table).
We observed significant and meaningful beneficial effects of the intervention on 6 out of 7
prespecified secondary outcomes with a significantly greater reduction in diastolic BP,
improvement in health-related quality of life, performance in “timed up and go” test, physical
activity level, and medication adherence to statin and antihypertensives in the intervention
arm (Table 2). The intervention arm also brought significantly fewer number of events in
stroke recurrence (4.4% versus 9.3%; risk ratio [RR] = 0.46, 95% CI 0.32, 0.66; risk difference

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PLOS MEDICINE SINEMA intervention for stroke management in rural China

Table 2. Minimally adjusted and fully adjusted results on primary, secondary, and exploratory outcomes.
Intervention Arms Minimally Adjusted Model� Fully Adjusted Model��
Outcomes Intervention (n = 611) Control (n = 615) Estimate (95% CI) † p-value Estimate (95% CI)† p-value
Primary Outcome
Change in systolic blood pressure, mean (SD), mm Hg −7.1 (18.5) −4.3 (18.9) −2.8 (−4.8, −0.9)‡ 0.005 −3.3 (−5.2, −1.4) 0.001
Secondary Outcomes
Change in diastolic blood pressure, mean (SD), mm Hg −3.9 (9.6) −2.3 (9.6) −2.2 (−3.2, −1.3) <0.001 −2.34 (−3.3, −1.4) <0.001
Change in health-related quality of life score, mean (SD)§ 0.01 (0.15) −0.03 (0.14) 0.04 (0.01, 0.06) 0.006 0.04 (0.01, 0.06) 0.008
Change in physical activity, mean (SD), MET min/wk 1,203.9 (2,243.7) 750.9 (2,097.2) 528.2 (286.3, 770.1) <0.001 490.2 (244.1, 736.3) <0.001
Timed up and go (time of completion �14 s)¶ 256 (43.7%) 298 (50.9%) 0.87 (0.77, 0.98) 0.023 0.87 (0.77, 0.98) 0.022
Medication adherence in Antiplatelets, n (%)†† 308 (69.7%) 244 (66.7%) 1.03 (0.93, 1.14) 0.614 1.02 (0.92, 1.14) 0.658
Medication adherence Statins, n (%)†† 133 (77.3%) 112 (62.9%) 1.21 (1.06, 1.38) 0.005 1.23 (1.07, 1.40) 0.003
Medication adherence Antihypertensives, n (%)†† 383 (73.7%) 315 (66.5%) 1.10 (1.00, 1.22) 0.051 1.11 (1.00, 1.22) 0.039
Exploratory Outcomes
Stroke Recurrence, n (%) 27 (4.4%) 57 (9.3%) 0.46 (0.32, 0.66) <0.001 0.45 (0.31, 0.66) <0.001
Stroke hospitalization in the past year, n (%) 27 (4.4%) 57 (9.3%) 0.45 (0.32, 0.64) <0.001 0.44 (0.31, 0.64) <0.001
Moderate to severe disability, n (%)‡‡ 128 (20.9%) 186 (30.2%) 0.65 (0.53, 0.79) <0.001 0.67 (0.55, 0.81) <0.001
Death, n (%)§§ 11 (1.8%) 19 (3.1%) 0.52 (0.28, 0.96) 0.036 NA§§ NA

CI, confidence interval; MET, metabolic equivalents; NAAU

, not :applicable;
PleasedefineNAinTable2abbreviationlistifthisindeedisanabbreviation:
SD, standard deviation.
�
Prespecified main analysis (minimally adjusted model): Adjusted for baseline outcome, township, sex, and age; removing outliers in the outcome variable (based on a
priori decision to remove those that are more than 2 interquartile range above the third quartile or below the first quartile).
��
Sensitivity analysis (fully adjusted model): Adjusted for baseline outcome, township, sex, age, variables noted to be differential by treatment arm at baseline (baseline
diastolic blood pressure, having hypertension, having none of the assets asked about, taking antihypertensive medications), and loss to follow-up (baseline systolic blood
pressure, annual household income, type of phone owned and smoking status); removing outliers in the outcome variable (based on a priori decision to remove those
that are more than 2 interquartile ranges above the third quartile or below the first quartile).
†
For continuous outcomes (systolic blood pressure, diastolic blood pressure, EQ5D-5L, physical activity), “estimate” refers to the differences between the arms in mean
1-year change in the outcome (control arm is the reference); for binary outcomes (timed up and go, medication adherence, stroke recurrence, stroke hospitalization,
disability, and death), “estimate” refers to the risk ratio (control arm is the reference).
‡
The intercluster coefficient is less than 0.001 for the model.
§
Health-related quality of life was measured by using EQ5D-5L and was converted into a utility score based on the Chinese value set.
¶
“Timed up and go test” results were recorded in seconds during measurement and dichotomized into binary as �14 (indicating lower limb mobility) versus <14 s
(higher limb mobility) based on previous literature.
††
Medication adherence refers to a perfect adherence with score of 0 based on the 4-item Morisky Green Levine Scale. Medication adherence was only measured among
participants who were taking medicines. Medication adherence outcomes were not adjusted for baseline outcome, since the set of participants taking a given medication
at baseline was not the same set taking the medicines at follow-up.
‡‡
Disability was measured by the modified Rankin Scale, and people who received a score above 3 were grouped into the "moderate to severe disability" group.
§§
The statistical model with death as the outcome was not adjusted for variables differential by the loss to follow-up, since those who died during the study were a subset
of the group lost to follow-up.

[Link]

[RD] = 4.9 percentage points [pp]), hospitalization (4.4% versus 9.3%; RR = 0.45, 95% CI 0.32,
0.62; RD = 4.9 pp), disability (20.9% versus 30.2%; RR = 0.65, 95% CI 0.53, 0.79; RD = 9.3 pp),
and death (1.8% versus 3.1%; RR = 0.52, 95% CI 0.28, 0.96; RD = 1.3 pp. Results were consis-
tent in 3 additional sets of sensitivity analyses (S6 Table).

Discussion
Principal findings and interpretations
In this cluster-randomised controlled trial conducted among stroke patients in rural China,
BP control was significantly improved through the primary care-based integrated mHealth

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PLOS MEDICINE SINEMA intervention for stroke management in rural China

Fig 2. The adjusted mean difference in change in systolic blood pressure for the total population and by
prespecified subgroups.
[Link]

intervention. The intervention also improved 6 out of 7 prespecified secondary outcomes and
all exploratory outcomes on stroke recurrence, hospitalization, disability, and mortality, at an
annual cost of less than US$24 per patient.
The intervention group experienced a 7.1-mm Hg reduction in the primary outcome of sys-
tolic BP, and the control group also had a 4.3-mm Hg reduction; thus, the magnitude of the
net between-group difference was modest (−2.8 mm Hg). Plausible explanations for this find-
ing included (1) a deliberate interventional design that relied on existing resources, e.g., not
providing free medicines like previous trials [4]; (2) the lower BP level of 145.9 mm Hg and
higher treatment rate (79.3%) at baseline compared to other trials [4,6]; and (3) improved
implementation of the government-funded nationwide basic public health services [23,24]
leading to the considerable reduction in the control group. Although the observed difference
of 2.8 mm Hg was smaller than the 5-mm Hg estimate in the a priori power calculation, it was
statistically significant (p = 0.005), possibly due to the smaller than hypothesized intracluster

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PLOS MEDICINE SINEMA intervention for stroke management in rural China

correlation coefficient or smaller than hypothesized standard deviation. More importantly,

even a net reduction of only 2 mm Hg in systolic BP is clinically meaningful as ample research
has shown that it can lead to a 7% to 10% decrease in fatal and nonfatal cardiovascular risks
[38–40]. Additionally, our study was not a BP trial but a multicomponent stroke management
trial with BP instead of stroke as the primary outcome due to the relatively short intervention
duration of 1 year. Consistent results in systolic BP from sensitivity analyses and large effects
on behavioral, functioning, and hard clinical outcomes were reassuring.
Quality of care improvement at the primary care level for chronic diseases management is a
global challenge, especially for resource-limited settings. Rural China bears disproportionately
high burdens of stroke, lacks capacity in delivering stroke care among community-dwelling
patients, and encounters barriers in quality improvements at both the health system and indi-
vidual levels [16,22]. Our study findings suggested that the benefit of the primary care
mHealth-integrated intervention could be far beyond BP reduction alone, as demonstrated in
the results on physical functioning, and even reduction in hospitalization and mortality.
Although we were not able to pinpoint the mechanism of impact on these outcomes, the con-
sistently significant results in stroke events, hospitalization, and mortality were potentially due
to our practical and integrated intervention that addressed multiple domains. In line with pre-
vious literature [4,8,11], the training sessions, ongoing system-level technical support, and
mHealth technological enablement improved the capacity of primary healthcare providers and
the financial and nonfinancial incentives motivated them to provide evidence-based care. As
the goalkeepers living within the community, providing monthly follow-up visits through vil-
lage doctors was feasible and sustainable. The maintenance of the behavior changes was fur-
ther strengthened through low-cost automated daily voice messages sent directly to patients.
Such an intervention model is designed to be applicable to other NCDs and with high potential
to be adapted to other LMICs settings for strengthening the capacity of the primary healthcare
system in chronic disease management.

Comparison with other studies

Different from other recent trials in LMICs that have shown the effectiveness of multicompo-
nent interventions in hypertension and NCD control [4–6], our trial has 2 parallel features
that synergistically supported each other and ensured the scalability and sustainability of the
intervention. First, our primary care-based intervention was delivered by existing health work-
force with system-level support and performance-based incentives. Instead of introducing new
health workforces, we relied on primary care providers in the public sector who were already
part of the primary care infrastructure. The quality of care they provided to stroke patients was
improved through carefully designed evidence-based measures including training and ongo-
ing support, mHealth technology, and incentives, which addressed existing challenges [23]
and were in line with current guidelines [26].
Second, the intervention integrated provision of mHealth technology for both providers
(village doctors and township physicians) and stroke patients. Compared to other stand-alone
mHealth studies with inconsistent results [9,10], the SINEMA intervention was predominantly
a primary care-based model emphasizing provider–patient interactions that were empowered
via technologies. The Android-based App assisted village doctors by guiding follow-up visit
procedures, collecting and storing related information, and managing the follow-up schedules
and also shared the information with township physicians for quality control and monitoring.
The step-to-step guidance and patients’ BP history and other information contained in the
App may improve village doctors’ behaviors in prescribing evidence-based medicines and
their communication with patients on adherence to treatment and lifestyle modifications. The

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PLOS MEDICINE SINEMA intervention for stroke management in rural China

automated voice messaging system dispatched a sizable amount of health education messages
and reminders to patients that could not be achieved by traditional labor-intensive approaches.
These voice messages provided suggestions and reminders on medication adherence and phys-
ical activities, which were consistent with the focus of the follow-up visits provided by village
doctors and may reinforce the maintenance of behavior changes. The integrated mHealth sys-
tem not only created new channels of communication and information flow in an effective
and smart approach but also enhanced the effectiveness of human-delivered intervention com-
ponents by removing barriers and reinforcing the maintenance of behavior changes among
both providers and patients. Although we could not pinpoint the specific quantitative contri-
butions of the integrated mHealth component in our study, our qualitative research provided
evidence that the mHealth technology as an integral part of the package was well accepted and
enhanced the effectiveness of the overall intervention.
Our intervention is different from previous studies as it targeted and reached a general vil-
lage-dwelling population who had stroke for a relatively long term. Our participants had a
median of 5 years duration living with stroke, 69.1% had been aware of having hypertension at
baseline, and 37.2% self-reported that they were a current or former smoker. These character-
istics of our participants are similar to those reported in the national registration of stroke sur-
vivors in rural China [41]. Such target population also distinguished our study from some of
the existing hospital-oriented strategies of improving the care among stroke survivors who are
recently discharged from the hospitals [41,42].

Strengths and limitations

This trial has many strengths. First, it was designed on the bases of previous trials in rural
China [12,13] and extensive field research for contextualization and adaption of the SINEMA
model to local settings [15,18,19]. Second, it was rigorously implemented, including high
recruitment rate with minimal loss to follow-up; satisfactory protocol fidelity; and indepen-
dent standardized outcome assessment. Third, randomization and data analyses were per-
formed by experienced biostatisticians in the United States who were not involved in trial
implementation. Lastly, the report of study findings in this paper is in line with the prespeci-
fied and prepublished trial design [15] and statistical analysis plan [21].
Our study also has limitations. First, it was conducted in one province in Northern China,
which may limit the generalizability of the study findings. However, our study population are
similar to the national registered population, and our findings are relevant not only to rural
China but other resource-limited settings as the intervention model is potentially feasible to
scale-up to blood pressure or stroke management in other settings. Importantly, the adaptation
of these strategies to local contexts is indispensable. For example, village doctors are best suited
to deliver the intervention in rural China, while in other LMICs countries, collaborations
between general practitioners and community health workers are necessary. We have been
working with local and national governments in China to replicate the intervention with scale-
up trial and also have assessed the feasibility of the intervention approach in other LMICs to
provide more evidence on the generalizability [43–45]. Second, the trial was only 1 year long,
and it was not powered for subgroup analyses, so larger studies are needed for better under-
standing of subgroup differences and long-term impacts. Third, we could not assess the inde-
pendent contributions of each component and fully capture the mechanism of change due to
the nature of the complex intervention design. We have conducted process evaluation through
quarterly qualitative interviews among both providers and patients. Results from the process
evaluation will be presented in a separate full-length manuscript to provide a deeper overview
on the facilitators and barriers related to the intervention reach, adoption, implementation

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PLOS MEDICINE SINEMA intervention for stroke management in rural China

and effectiveness, and further explanation on the mechanism of impact. Although we have
reported the cost of the delivery, we will also report cost-effectiveness modeling in another
full-length manuscript.

Implications for policy and future research

Our primary care-based integrated mHealth intervention, rigorously designed and imple-
mented, resulted in a significant decrease in systolic BP, improvement in other health out-
comes, and reduction in hospitalization and mortality among stroke patients in rural China.
Chronic disease management requires continuous reliance on primary care, especially when
the entire healthcare system is threatened by new global health crises such as the Coronavirus
Disease 2019 (COVID-19). Our trial, conducted in the pre-COVID era, may have more impor-
tant implications in the future as effort to strengthen primary care is needed to combat both
NCDs and emerging infectious diseases. In LMICs where resources are limited or in low-
resource areas in high-income countries, mHealth technology holds the potential to bring dis-
ruptive changes to health service delivery, quality improvement, and NCD control owing to its
reach, convenience, cost efficiency, and lack of other traditional resources [8,9]. Thus, our
SINEMA model, which is primary care-based, integrates provider-side and patient-side
mHealth technology, and designed with the principles of sustainability and scalability, has the
potential to be applied to other NCDs besides stroke and to other settings in China and glob-
ally. If demonstrated to be cost-effectiveness through full economic evaluation, the model may
also have great potential to be adapted and scaled up to other settings to expand the health and
economic benefits.

Conclusions
Our primary care-based integrated mHealth intervention, rigorously designed and imple-
mented, resulted in a significant decrease in systolic BP, improvement in other health out-
comes, and reduction in hospitalization and mortality among stroke patients in rural China.
Our low-cost intervention seamlessly combines service delivery by existing primary care work-
force with mobile technology that integrates provider- and patient-side measures. If scaled up,
it is expected to lead to large health and economic benefits in rural China and with adequate
adaptations, potentially also in other resource-limited settings in both LMICs and high-
income countries.

Supporting information
S1 Checklist. CONSORT checklist.
(DOCX)
S1 Fig. SINEMA intervention diagram.
(TIF)
S1 Table. Baseline characteristics for the SINEMA trial at the cluster and provider level.
(DOCX)
S2 Table. Baseline characteristics by status on loss to follow-up at the patient level.
(DOCX)
S3 Table. Fidelity to the intervention protocol in the 25 intervention villages.
(DOCX)

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PLOS MEDICINE SINEMA intervention for stroke management in rural China

S4 Table. Program delivery costs over 12 months in US dollar.

(DOCX)
S5 Table. Sensitivity analysis of systolic blood pressure and diastolic blood pressure as
hypertension control.
(DOCX)
S6 Table. Sensitivity analysis results on primary, secondary and exploratory outcomes.
(DOCX)

Acknowledgments
We would like to thank the independent International Steering Committee Chair (Yangfeng
Wu) and members (Eric Peterson and Craig Anderson) and Advisory group members (Alba
Amaya-Burns, Allan Burns, Ninghua Wang, Xie Bin, Jesse Hao, Jixiang Ma, Jixin Sun, Jianxin
Zhang, Jianmin Yao, Jinmei Liu, Qian Long, and Cheng Sun) who have provided great advice
in designing and implementing the study. We would also like to acknowledge collaborators
from China Mobile Research Institute (Na Wu, Zhuoran Zhang, Mengyao Chen, Bo Wang,
and Nan Ding) and colleagues and students (Erdan Luo, Duan Zhao, Longkai Zang, Peng Bao,
Julian Donovan, Heng Jiang, Ying Yang, and Anran Tan) who have contributed to the devel-
opment of the SINEMA mHealth system and voice messages. We also thank Dejin Dong and
his team (Xingtai City Center for Disease Prevention and Control), Zhenli Xu and his team
(Nanhe County Center for Disease Prevention and Control), Congxuan Wu and his team
(Ren County Center for Disease Prevention and Control), and all staff members from town-
ship healthcare centers and village clinics, and all patients who participated or supported the
project.

Author Contributions
Conceptualization: Lijing L. Yan, Enying Gong, Janet P. Bettger, Shenglan Tang, Brian
Oldenburg.
Data curation: Enying Gong, Elizabeth L. Turner, John A. Gallis.
Formal analysis: Enying Gong, Elizabeth L. Turner, John A. Gallis, Kara E. McCormack.
Funding acquisition: Lijing L. Yan, Elizabeth L. Turner, Li-Qun Xu, Janet P. Bettger, Shenglan
Tang, Yilong Wang.
Investigation: Lijing L. Yan, Enying Gong, Wanbing Gu, Elizabeth L. Turner, John A. Gallis,
Yun Zhou, Zixiao Li, Li-Qun Xu, Janet P. Bettger, Shenglan Tang, Brian Oldenburg.
Methodology: Lijing L. Yan, Enying Gong, Janet P. Bettger, Shenglan Tang, Brian Oldenburg.
Project administration: Lijing L. Yan, Enying Gong, Wanbing Gu.
Resources: Lijing L. Yan, Li-Qun Xu.
Software: Lijing L. Yan, Enying Gong, Li-Qun Xu.
Supervision: Yun Zhou, Zixiao Li, Li-Qun Xu, Janet P. Bettger, Shenglan Tang, Yilong Wang,
Brian Oldenburg.
Validation: Elizabeth L. Turner.
Visualization: Enying Gong, John A. Gallis.
Writing – original draft: Lijing L. Yan, Enying Gong.

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PLOS MEDICINE SINEMA intervention for stroke management in rural China

Writing – review & editing: Lijing L. Yan, Enying Gong, Wanbing Gu, Elizabeth L. Turner,
John A. Gallis, Yun Zhou, Zixiao Li, Kara E. McCormack, Li-Qun Xu, Janet P. Bettger,
Shenglan Tang, Yilong Wang, Brian Oldenburg.

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