HEALTHCARE EPIDEMIOLOGY
INVITED ARTICLE
Robert A. Weinstein, Section Editor
The Global Spread of Healthcare-Associated
Multidrug-Resistant Bacteria: A Perspective
From Asia
James S. Molton,1,2 Paul A. Tambyah,1,2 Brenda S. P. Ang,3 Moi Lin Ling,4 and Dale A. Fisher1,2
1
Division of Infectious Diseases, National University Health System; 2Department of Medicine, Yong Loo Lin School of Medicine, National University
of Singapore; 3Department of Infectious Diseases, Tan Tock Seng Hospital; and 4Department of Infectious Diseases, Singapore General Hospital,
Singapore
Since antibiotics were first used, each new introduced class has been followed by a global wave of emergent
resistance, largely originating in Europe and North America where they were first used. Methicillin-resistant
Staphylococcus aureus spread from the United Kingdom and North America across Europe and then Asia
over more than a decade. Vancomycin-resistant enterococci and Klebsiella pneumoniae carbapenemase–
producing K. pneumoniae followed a similar path some 20 years later. Recently however, metallo-β-lactamases
have originated in Asia. New Delhi metallo-β-lactamase–1 was found in almost every continent within a year
of its emergence in India. Metallo-β-lactamase enzymes are encoded on highly transmissible plasmids that
spread rapidly between bacteria, rather than relying on clonal proliferation. Global air travel may have helped
facilitate rapid dissemination. As the antibiotic pipeline offers little in the short term, our most important
tools against the spread of antibiotic resistant organisms are intensified infection control, surveillance, and
antimicrobial stewardship.
Keywords. bacterial drug resistance; methicillin-resistant Staphylococcus aureus; vancomycin-resistant Enterococcus; extended-spectrum beta-lactamase; carbapenem-resistant Enterobacteriaceae.
In addition to being detected in wild animals and
remote human communities with little or no antibiotic exposure, antimicrobial resistance genes have been
identified in bacterial DNA frozen in Arctic permafrost for 30 000 years, and in bacteria in a subterranean cave isolated from the surface for >4 million
years [1]. But whereas antimicrobial resistance clearly
predates modern antibiotics, the advent and mass production of antibiotics since the 1940s resulted in unprecedented selection pressure. Alexander Fleming
was aware of the potential consequences as early as
Received 5 October 2012; accepted 9 January 2013; electronically published 18
January 2013.
Correspondence: Dale Fisher, FRACP, National University Health System, Level
10, Department of Medicine, 1E Kent Ridge Road, Singapore 119228 (mdcfda@
nus.edu.sg).
Clinical Infectious Diseases 2013;56(9):1310–8
© The Author 2013. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
DOI: 10.1093/cid/cit020
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1945, warning of the risk of emergent resistance in his
Nobel prize lecture [2]. Just 3 years after Fleming’s
speech, one London hospital reported Staphylococcus
aureus penicillin resistance rates of 38% [3]. Each successive antibiotic introduction has been followed by
global emergence of resistance, frequently starting in
hospital settings (Figure 1). Asia faces a greater
burden of gram-negative resistance compared to the
West [4]. The potential for global spread is illustrated
by the dissemination of New Delhi metallo-β-lactamase 1 (NDM-1) rapidly from India to the West, and
the slower spread of Klebsiella pneumoniae carbapenemase (KPC) from West to East.
This review describes the global epidemiology of the
major antibiotic-resistant bacteria over the past few
decades, focusing on Singapore’s epidemiology and response. In much of Asia, surveillance of antimicrobial
resistance is hampered by political and financial constraints. Singapore has a developed economy with a
large migrant population and significant health
Figure 1. Antibiotic timeline. This timeline indicates the approximate dates that the major antibiotic classes or important antibiotics of each class were
introduced into clinical use. The dates that resistant organisms were identified are shown in the centre of the timeline. Abbreviations: AmpC,
AmpC–producing Enterobacteriaceae; ESBL, extended-spectrum β-lactamase–producing Enterobacteriaceae; KPC, Klebsiella pneumoniae carbapenemase–
producing Enterobacteriaceae; MRSA, methicillin-resistant Staphylococcus aureus; NDM-1, New Delhi metallo-β-lactamase-1–producing Enterobacteriaceae; PRSA, penicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant Enterococcus; VRSA, vancomycin-resistant Staphylococcus aureus.
tourism. Its strategic international location allows it to serve as
a sentinel site for monitoring the emergence and spread of
resistant organisms.
Methicillin-Resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus (MRSA) was first
identified in the United Kingdom in 1961, only 2 years after
the introduction of methicillin [5]. Over the next few decades
MRSA became established in hospitals throughout North
America and Europe, and subsequently Northeast, then
Southeast, Asia (Figure 2). In North America and Europe in
the 1970s and 1980s, healthcare-associated MRSA (HAMRSA) strains traditionally carried staphylococcal cassette
chromosome (SCC) type II, for example, USA100 (ST5) and
USA200 (ST36). However, with the exception of USA100 in
Japan, these strains have never become established in Asia. In
Singaporean hospitals the SCCmec type III strain ST239 was
endemic during this period [6]. All these strains are typically
susceptible only to vancomycin, fusidic acid, and rifampicin.
The early 2000s saw the emergence of community-associated MRSA (CA-MRSA) clones, which previously had mainly
been confined to isolated primarily rural communities
(Figure 2). The nonmultiresistant USA 300, (CC8-ST8,
SCCmec IV, Panton-Valentine leukocidin positive) strain
emerged in the community in the United States, causing
severe skin and soft-tissue infections and necrotizing pneumonia. This clone is typically susceptible to non–β-lactam antibiotics. It has never become established in Asia, for reasons
that remain unclear. However, other SCCmec type IV CAMRSA clones have become prevalent in the community in
some Asian countries [7]. In many parts of Asia the major
HA-MRSA clones that were endemic in hospitals, including
ST239, have spread to the community, and CA-MRSA clones
have become established in hospitals [8]. The terms “healthcare-associated” and “community-associated” are now therefore becoming largely historical.
In the United States and some European countries, including the United Kingdom, MRSA rates are actually falling [7].
This is likely due in part to the introduction of a care-bundle
approach of improved infection control, screening, and decolonization, as well as restriction of some antibiotic classes.
Alternatively, it may reflect biological factors rather than
human effort [9]. Many Asian countries still have increasing
rates, but in Singapore stabilization over the past 5 years is
evident. Over the past decade, Singapore’s hospital-adapted
ST239 strain has to some extent been replaced by UKEMRSA-15 (ST22, SCCmec type IV) [6]. EMRSA-15 is a
healthcare-associated strain that emerged in the United
Kingdom in 1991, which, along with EMRSA-16, replaced the
majority of the United Kingdom’s HA-MRSA strains by the
late 1990s [10]. EMRSA-15 is usually resistant to erythromycin
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Figure 2. Global dissemination of methicillin-resistant Staphylococcus aureus (MRSA). This map indicates the countries in each continent providing
the earliest reports of healthcare-associated MRSA, community-associated MRSA, and vancomycin-intermediate Staphylococcus aureus. The white
arrows indicate the early movements of healthcare-associated MRSA around the world. Poor surveillance is highlighted by the lack of data for some
regions. Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus; UK, United Kingdom.
and ciprofloxacin but susceptible to other non–β-lactam antibiotics such as trimethroprim-sulfamethoxazole.
Reducing MRSA colonization and infection rates are becoming a priority for hospital administrations, given the
excess risk of death in patients with MRSA clinical infection
(odds ratio, 5.5) [11]. In Singapore hospitals, MRSA is
endemic. At the National University Hospital, approximately
25% of all inpatient beds are dedicated to cohorting patients
with MRSA infection or colonization and 8% of all inpatients
are found to test positive via active surveillance on admission.
Since the introduction of enhanced infection control measures
(described later), MRSA colonization acquisition rates as determined by a single swab on discharge have dropped from
>10% five years ago, to <2% in intensive care units and <4%
in the general wards today (D. Fisher and colleagues, unpublished data).
Vancomycin-intermediate S. aureus (VISA) was first identified in Japan in 1996 (Figure 2) [12]. Seven cases of heteroVISA were identified in Singapore in 2001 [13] and a study in
2005–2006 identified 7 cases of VISA and 3 hetero-VISA [14].
However, at 0.2%, rates of reduced susceptibility to vancomycin are still well below those seen in some North American
centers. Until recently, reports of vancomycin-resistant S.
aureus (VRSA) in Asia were limited to Japan, but in 2011 a
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number of vanA-positive and also vanA-negative VRSA isolates were identified in Hyderabad, India [15]. VRSA has
never been identified in Singapore. However in 2010, 6 cases
of daptomycin-nonsusceptible S. aureus bacteremia were reported, all in patients previously treated with vancomycin [16]. Despite the emergence of linezolid-resistant S. aureus
in Spain and Japan, no Singaporean cases have been reported
to date [17, 18].
Vancomycin-Resistant Enterococci
Vancomycin had been used since the 1950s, but the emergence of resistance in Enterococcus species was not reported
until 1988, in the United Kingdom and France [19]. Incremental vancomycin usage for MRSA infection may explain
the timing. Over the next decade, vancomycin-resistant Enterococcus (VRE) spread throughout Europe and North
America (Figure 3). Vancomycin resistance is predominantly
mediated by vanA or vanB genes, both most likely having
emerged in Europe. VanB differs phenotypically in that it
retains susceptibility to teicoplanin. Most VRE cases in
Europe, the United States, and Korea are now due to vanA,
whereas the epidemic in Singapore and Australia has predominantly been vanB, although Singapore has recently seen a
Figure 3. Global dissemination of vancomycin-resistant Enterococcus (VRE). This map indicates the countries in each continent providing the earliest
reports of VRE. While most of the world’s VRE is vanA, Southeast Asia and Australasia experience predominantly vanB. Poor surveillance is highlighted
by the lack of data for some regions. Abbreviations: VRE, vancomycin-resistant Enterococcus; UK, United Kingdom.
number of vanA cases. In the United Kingdom, vanA is now
seen in 15%–25% of Enterococcus faecium and 2%–3% of
Enterococcus faecalis, rates it reached in the early 1990s [9].
Rates of vancomycin resistance in US hospitals reached
much higher levels. By 2002, 60% of E. faecium and 2% of
E. faecalis were resistant to vancomycin [20], climbing further
to 80% in E. faecium and 7% in E. faecalis by 2007 [21]. As
with MRSA, rates have started to decline in some parts of the
West.
VRE was first reported in Singapore in 1994 [22]. Over the
next decade, while the West was seeing a steady rise, only
sporadic cases occurred in Singapore [23], until a single hospital outbreak in 2004 [24]. The following year, >5000 patients
were screened, including 84% of one hospital’s inpatients on a
single day. A total of 147 carriers and 4 clinical cases were
detected [25]. Pulsed-field typing revealed 1 major clone and
several minor clones of vanB E. faecium. All belonged to
clonal complex 17, a distinct genetic lineage of E. faecium implicated in hospital outbreaks worldwide [26]. It is likely that
these strains were imported. The first case isolated in 2004 was
in a patient from Indonesia, and the first case isolated in 2005
was in a Singaporean who had been hospitalized in India. Interestingly, a similar outbreak of vanB VRE had occurred in
Western Australia in 2001 [27]. Control measures for the next
5 years (see the section “Control of Antimicrobial Resistance”)
resulted in VRE rates that were lower than those in many
other developed nations. Outbreak strains, however, had
become established, and maintained a low level of endemicity
interspersed with occasional outbreaks [28]. Over the past 2
years, unlike in most Western countries, VRE rates in Singapore’s tertiary hospitals appear to have been trending upward,
particularly among renal and hematology patients. This
mirrors the pattern seen in countries outside Asia a decade
ago. The reasons for this delay are unclear.
Enterobacteriaceae
Extended-Spectrum and AmpC β-Lactamases
The extended-spectrum cephalosporins ceftriaxone and ceftazidime were introduced in the early 1980s. By 1985, reports came
out of Europe describing an extended-spectrum β-lactamase
(ESBL) in Klebsiella pneumoniae and Escherichia coli [29].
During the 1980s and 1990s, TEM- and SHV-type ESBLs carrying Klebsiella species spread, globally causing predominantly
nosocomial infections. CTX-M type ESBLs have proliferated
since 2000, initially in community E. coli and nosocomial
Klebsiella species strains [29]. In the late 1980s, the AmpC
cephalosporinase was discovered on plasmids in K. pneumoniae and E. coli [30]. Unlike ESBL, AmpC producers are
usually susceptible to cefepime. Together ESBL and AmpC
now make up the majority of the third-generation cephalosporin resistance seen worldwide. The distribution varies
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dramatically by region, however. Nosocomial rates in North
America have stabilized at around 10% for E. coli and K. pneumoniae, and a little higher in European hospitals. In contrast,
in Asia, ESBL rates are >80% in India and >60% in China [9].
In Singapore, >30% of Klebsiella species–positive blood
culture isolates were resistant to third-generation cephalosporins by 1990. Rates have not changed significantly since then,
despite rising rates of third-generation cephalosporin use [31].
In fact, there is a recent trend toward decreasing resistance in
Klebsiella species, which is unexplained [32]. The first AmpCproducing E. coli in Singapore was documented in 2003 [31].
Between 2006 and 2007, clinical samples collected across 7
hospitals in Singapore again revealed approximately 30%
third-generation cephalosporin resistance in Enterobacteriaceae, of which ESBL rates were 19.6% in E. coli and 30.3% in
K. pneumoniae, and AmpC rates were 8.5% in E. coli and
5.6% in K. pneumoniae (based on phenotypic data) [33]. One
molecular study found that of 54 ceftriaxone-resistant E. coli
isolates, 69% were positive for blaCTX-M genes (group 1 and, to
a lesser extent, group 9), and 33% screened positive for AmpC
enzymes, of which 28% carried blaCMY-like ampC genes [34].
Current inpatient bacteremia rates of ceftriaxone or ceftazidime resistance are 47% for E. coli and 67% in K. pneumoniae
in Singapore, but these aggregate both community and hospital onset. In contrast, in India, the resistance rates in community E. coli are as high as the hospital rates, possibly because
of the unregulated use of antibiotics in the community, including in agriculture, and lower sanitary standards [35].
Carbapenemases
Carbapenem-resistant Enterobacteriaceae (CRE) are a significant and growing problem in Asia. Low-level resistance can
occur when high levels of AmpC or ESBL are combined with
porin deficiencies. High-level resistance is primarily mediated
by carbapenemases. The serine carbapenemase KPC was first
identified in North Carolina in 1996, and soon afterward
caused an outbreak in New York [36]. This enzyme inactivates
all β-lactams. KPC-producing K. pneumoniae followed the
movements of colonized patients to cause outbreaks in other
countries, including Israel in 2004 and Greece in 2007
(Figure 4). Spread is predominantly via clonal dissemination.
In Asia, KPC was initially detected in China in 2004, and subsequently South Korea and Taiwan [37]. In 2012, the first 4
cases of KPC were reported in Singapore [37, 38]. These
blaKPC-2 plasmid-containing K. pneumoniae isolates were
clonal, belonging to strain type 11 (ST11), and closely related
to the Chinese strain. They were identified from epidemiologically unrelated patients from 2 different hospitals. Two of the
patients were non-Chinese, with no recent travel, suggesting
dissemination of KPC in the community.
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Metallo-β-lactamases (MBLs) are a class of carbapenemases
that remain susceptible to aztreonam (but are frequently accompanied by aztreonam hydrolyzing EBSLs). The first
known plasmid-borne MBL was IMP-1, originally identified
from Pseudomonas aeruginosa in Japan in 1988 [39]. The first
case outside Japan was identified in K. pneumoniae in Singapore in 1996 [40]. While now endemic in Japan, this mechanism accounts for only a small percentage of carbapenem
resistance in Enterobacteriaceae in Singapore today. Verona
integron-encoded MBL (VIM), was first identified in Italy in
1997 but has never reached significance in Asia [29]. Of more
concern is the recently identified NDM-1. NDM-1 plasmidcarrying organisms frequently possess multiple resistance
mechanisms to other classes of antibiotics, typically rendering
the bacteria resistant to all antibiotics except polymyxin and
occasionally tigecycline [41]. NDM-1 was first reported from
an Indian patient managed in 2008 in Sweden who had been
transferred from a New Delhi hospital [42]. The following
year, NDM-1 was identified in 29 patients in the United
Kingdom and 143 patients from multiple sites in the Indian
subcontinent [43]. NDM-1 has now spread by plasmid transfer into a wide range of bacteria (both environmental organisms and potential human pathogens), and been identified in
sewage and tap water in India and Vietnam [44, 45]. Many
other countries around the world, including the United States,
have now reported sporadic cases in individuals returning
from the Indian subcontinent (Figure 4) [46].
Singapore has a multicultural population with significant
movement of people to and from the Indian subcontinent. It
is therefore not surprising that in 2011 12 NDM-1–positive
isolates were identified in Singapore, which represented 23%
of all CRE [47]. The multilocus sequence typing strains were
diverse, indicating that the clones were genetically unrelated.
Most patients were of non-Indian ethnicity, and none had
traveled overseas in the previous 2 years [48]. It is possible
that in addition to KPC, NDM-1–positive Enterobacteriaceae
are also now endemic in Singapore.
The most recent introduction to Singapore was OXA-181, a
class D β-lactamase (oxacillinase). OXA-48 has caused a
number of outbreaks in Europe and the Mediterranean countries [49], but is not endemic in the Americas yet. In the last
year, OXA-181, an OXA-48 variant recently identified in
India [50], has been reported in Singapore in K. pneumoniae
bloodstream isolates from 2 Bangladeshi patients [51]. Further
unpublished data suggest that it is now well established in
Singapore.
Overall, <1% of hospital-associated Enterobacteriaceae infections in Singapore are carbapenem resistant, but numbers
are increasing. By comparison, India’s rates are 5%–8% [52].
In Singapore, clinical isolates that screen positive for carbapenem resistance are referred to a reference laboratory for
Figure 4. Global dissemination of Klebsiella pneumoniae carbapenemase–producing K. pneumoniae and New Delhi metallo-β-lactamase-1–producing
Enterobacteriaceae. The earliest reported cases in each continent are shown. Arrows indicate the significant international movements of these organisms. Abbreviations: KPC, Klebsiella pneumoniae carbapenemase; NDM-1, New Delhi metallo-β-lactamase–1; UK, United Kingdom.
carbapenemase detection by polymerase chain reaction. These
surveillance data reveal that of carbapenem-resistant isolates,
approximately 40% test positive for a carbapenemase, of which
approximately two-thirds are NDM-1, 20% are OXA-181, and
5%–10% are KPC. Sporadic detection of VIM and IMP continues. There are plans to introduce targeted admission screening
for CRE in all public hospitals in the coming year.
Recently in Thailand, the enhanced cleaning that was necessitated by widespread flooding of hospitals and intensive care
units resulted in the elimination of previously prevalent multidrug-resistant A. baumannii [55].
Although rates of resistance of Pseudomonas aeruginosa to
the most commonly used antibiotic classes are typically high
in Southeast Asia [29], rates in Singapore remain significantly
lower than those of A. baumannii.
Nonfermenters
Control of Antimicrobial Resistance
In tropical regions including Southeast Asia, nosocomial Acinetobacter baumannii infections are more frequent than in
Europe and the United States. In addition, communityacquired infections can also occur [53]. Singapore has witnessed
the stepwise loss of antibiotic classes for treating A. baumannii
infection including carbapenems. Resistance to 3 or more
classes (multidrug-resistant A. baumannii) represented 44%
of isolates in Singapore between 2004 and 2007, as compared
to the overall proportion across 9 Asia-Pacific countries of
34.2% [54]. Now 55% of Singapore’s isolates are multidrug resistant and infection rates are increasing both in intensive care
units and general wards. Of concern is a small number of isolates that are truly panresistant, including to polymyxins. It is
hoped that enhanced isolation and environmental cleaning processes will control the spread of multidrug-resistant A. baumannii.
The reduction in rates of nosocomial MRSA, and until recently
VRE, was achieved with a coordinated interhospital infection
control response. A care-bundle approach was introduced,
which includes a checklist for routine hand hygiene and
aseptic technique during line care or invasive procedures
(which had not been optimally practiced in Singapore for
many years [56]). With this approach, Singapore now seems to
be following global trends in reducing central line–associated
bloodstream infections, although there are no peer-reviewed
data published. Enhanced environmental cleaning and active
surveillance of high-risk patients with electronic tagging of colonized patients’ medical records were introduced [25], with
isolation and cohorting of identified patients [25]. Now all new
patients are screened for MRSA and cohorted appropriately
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without contact precautions except for specific indications.
Targeted patients undergo decolonization. However, the
background rate of MRSA is high, so unlike some parts of
Europe, widespread decolonization and eradication of MRSA
from the hospitals is not yet an achievable goal. Isolation of
patients with multidrug-resistant gram-negative organisms
aims to curtail nosocomial transmission, although the existing burden locally plus the contribution of community outbreaks from regional countries where these organisms have
been found in environmental sources will make control
challenging.
Antimicrobial stewardship is not well developed in Asia.
Broad-spectrum antimicrobial use in Singapore is higher than
in most developed countries, but so is antimicrobial resistance [57]. It is difficult to tease out cause and effect. Up to
38% of antibiotic prescriptions in Singaporean hospitals could
be considered inappropriate (mostly failure to de-escalate after
culture results were available) [58]. Antimicrobial stewardship
is now practiced in all major Singaporean hospitals, with evidence of a resulting shorter length of stay and fewer infectionrelated readmissions [59]. The effect on antimicrobial resistance
is yet to be shown. No data currently exist on community prescribing. In the community in Singapore, antibiotics require a
prescription, in contrast to most other countries in Asia.
Surveillance remains undeveloped in most Asian countries.
Singapore has escalated surveillance to provide leadership in
the region, and help to identify emerging resistance patterns.
All hospitals report rates to the Ministry of Health for MRSA,
VRE, carbapenem-resistant A. baumannii and P. aeruginosa,
and third-generation cephalosporin-resistant and carbapenem-resistant E. coli and K. pneumoniae, as well as levels of
broad-spectrum antibiotic use. A National Antimicrobial Task
Force coordinates the response to antimicrobial resistance in
hospitals and long-term care facilities. This initiative aims to
monitor the clinical and molecular epidemiology and formalize lines of communication between the healthcare facilities to
better prepare for future challenges.
We can expect future resistant organisms to spread quickly,
independent of international boundaries. Containment requires a coordinated global approach. As well as improving
infection control, surveillance, and antimicrobial stewardship,
a recent World Health Organization report recommends reducing antimicrobial use in animal husbandry [60]. Although
ESBL-producing gram-negative organisms have repeatedly
been identified on fresh meat and vegetables, the true implications of this for human health are not known [61]. Almost all
meat for human consumption in Singapore is imported from
farms that are preaccredited through a process which includes
screening for antibiotic residues. Finally, the development of
new antibiotics, diagnostics, and vaccines can no longer be
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relied upon. The approval of new antibiotics in the United
States has fallen from 30 between 1983 and 1992, to just 12
between 1998 and 2009 [62].
While historically, antibiotic resistance has followed the introduction of novel antibiotics in the West, the recent trend
toward the emergence of highly drug-resistant community associated strains in developing Asian countries where medical
resources are scarce is a cause for concern. There is potential
for unrecognized global spread of these organisms. Globally
connected cities such as Hong Kong and Singapore are
uniquely positioned to act as sentinels for the emergence of
resistant strains. At the same time, their modern healthcare
facilities offer unique opportunities for research into novel approaches to controlling the spread of these organisms.
Notes
Acknowledgments. We thank Dr Michelle Balm and Dr Hsu Li Yang
for provision of data and kind review of the manuscript.
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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