streptococcus bovis infection and colorectal neoplasia: a meta-analysis

Streptococcus bovis infection and colorectal neoplasia:a meta-analysis

S. Krishnan and G. D. Eslick

The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Penrith, New South Wales, Australia

Received 18 January 2014; accepted 29 April 2014; Accepted Article online 13 May 2014

Abstract

Aim A meta-analysis was conducted to determine the

risk associated with Streptococcus bovis infection and the

occurrence of colorectal neoplasia (CRN). The level of

risk remains unknown.

Method We conducted a search of MEDLINE,

PubMed and EMBASE up to January 2014. We used a

random-effects model to analyse the data.

Results We identified 48 studies concerning three main

topics: S. bovis septicaemia, S. bovis endocarditis and

S. bovis faecal carriage. The total sample sizes were

1729, 807 and 1145, respectively; the 48 studies

included 9 case–control studies and 39 case series.

Overall, the presence of S. bovis infection was found to

be significantly associated with the presence of CRN.

Streptococcus bovis endocarditis showed the strongest

association in analyses of case–control studies and case

series (OR 14.54, 95% CI 5.66–37.35, test for hetero-

geneity I2 = 43.53; event rate of 0.53, 95% CI 0.45–

0.61, test for heterogeneity I2 = 53.50). Similarly,

S. bovis septicaemia was also associated with a high level

of concurrence with CRN (OR 7.48, 95% CI 3.10–

18.06, test for heterogeneity I2 = 43.32; event rate

0.49, 95% CI 0.42–0.56, test for heterogeneity

I2 = 69.97). Patients with CRN were found to have a

higher incidence of S. bovis in faeces upon stool culture

(OR 2.52, 95% CI 1.14–5.58, test for heterogeneity

I2 = 69.17).

Conclusion The meta-analysis showed a statistically sig-

nificant association between the presence of S. bovis

endocarditis or S. bovis septicaemia and CRN. Further-

more, there is a statistically significant increase in likeli-

hood of finding S. bovis in the stool of individuals with

CRN.

Keywords Colorectal cancer, Streptococcus bovis, colon

cancer, rectal cancer, risk factor, meta-analysis

What does this paper add to the literature?

We provide conclusive data on the specific associationof Streptococcus bovis septicaemia and endocarditis withcolorectal neoplasia. We also provide data on the rela-tionship S. bovis faecal carriage and colorectal neoplasia.

Introduction

A possible relationship between Streptococcus bovis and

colorectal neoplasia (CRN) was first proposed in a case

report in 1951 [1]. Since then numerous case reports

and retrospective studies have been published regarding

this association [2–7]. Streptococcus bovis is a Gram-posi-

tive group D Streptococcus [8], and is found in the

digestive tract of approximately 11% of asymptomatic

individuals [9]. New taxonomic changes were proposed

to the S. bovis group by Schlegel et al. in 2003 which

proposed the following three subspecies: Streptococcus

gallolyticus subsp. gallolyticus subsp. nov., S. gallolyticus

subsp. pasteurianus subsp. nov. and S. gallolyticus subsp.

Macedonicus subsp. nov, which are also known as bio-

types I, II/1 and II/2 [10]. It most frequently presents

as septicaemia and infective endocarditis.

Neoplasms, or tumours, can be benign or malignant,

of which there are further histological subtypes such as

adenomas, which are benign, or carcinoma, which are

malignant [90] . Streptococcus bovis has been associated

with many histological types of neoplasia.

There are varying reports of the frequency of colo-

rectal tumours amongst patients with S. bovis infection,

with figures from anywhere between 25 and 80% being

reported by some authors [11], making it a significant

indicator of coexisting colorectal pathology. Whilst this

potential association has been detailed in numerous

Correspondence to: Associate Prof. Guy D. Eslick, The Whiteley-Martin

Research Centre, Discipline of Surgery, The University of Sydney, Nepean

Hospital, Level 3, Clinical Building, PO Box 63, Penrith, New South Wales

2751, Australia.

E-mail: [email protected]

Colorectal Disease ª 2014 The Association of Coloproctology of Great Britain and Ireland. 16, 672–680672

Meta-analysis doi:10.1111/codi.12662

studies, the underlying pathophysiology is still not fully

understood. Bacteria are becoming increasingly recog-

nized as a likely contributor to carcinogenesis, with

potential mechanisms including the induction of inflam-

mation or the production of mutagenic toxins [12].

Chronic inflammation has already been shown to

increase the risk of CRN in conditions such as ulcerative

colitis [13]. The underlying mechanism is thought to

be chronic stimulation of mucosal proliferation by the

inhibition of apoptosis and damage to DNA [14].

Therefore the increased frequency of CRN in patients

with S. bovis infection and colonization in faeces can be

explained by the effects of chronic inflammation. How-

ever, the gut is colonized by many species of bacteria,

and the specific role of S. bovis cannot therefore be thus

fully accounted for at this point.

Another hypothesis is that S. bovis induces oncogene-

sis through an immune-mediated response in the host

[15]. Animal studies have shown that the administration

of S. bovis or S. bovis wall extracted antigens (WEA) in

rats promotes progression of preneoplastic lesions, as

seen by increased hyperproliferative changes [16]. Spe-

cifically, the gut mucosa of rats exposed to S. bovis was

found to have increased levels of interleukin-8 (IL-8), a

chemokine which increases carcinogenesis by increasing

oxidative stress, mediating the formation of carcino-

genic compounds, promoting angiogenesis and tumour

cell proliferation and causing over expression of COX-2

[16–19]. Similarly Biarc et al. found that the gut

mucosa of rats exposed to WEA of S. bovis showed

increased production of pro-inflammatory mediators

such as IL-8 and COX-2 and also increased presence of

preneoplastic lesions [19]. Most studies that examine

this relationship focus on the role of S. bovis

septicaemia, S. bovis endocarditis and, to a smaller

degree, S. bovis faecal carriage rates and CRN.

In 2009 Gupta et al. [20] conducted a systematic

review of the evidence regarding the role of S. bovis

endocarditis and/or septicaemia as a silent sign for

colonic tumour, and concluded that it was an early clue

to colorectal cancer (CRC) and warranted rigorous

investigation. In 2011 Boleij et al. [21] conducted a

meta-analysis of the specific role of S. bovis biotype I in

CRC but also compared it with S. bovis biotype II.

Infection with Streptococcus bovis biotype I gives a statis-

tically significant increased risk of CRC compared with

biotype II infection. The study also found that patients

with S. bovis infective endocarditis were more likely to

have CRC than patients with other S. bovis infections.

We have conducted a comprehensive meta-analysis

to address the individual relationships of S. bovis septi-

caemia and endocarditis with CRN. Additionally, we

aimed to investigate the role of S. bovis faecal carriage

and CRN. All biotypes of S. bovis have been included to

determine the global relationship between this bacte-

rium and CRN.

Method

Study protocol

We followed the Preferred Reporting Items for System-

atic reviews and Meta-Analyses (PRISMA) guidelines

[22]. A systematic search was made of the MEDLINE

(from 1950), PubMed (from 1946) and EMBASE

(from 1949) databases to 27 March 2014 to identify

relevant articles. The search used the terms ‘streptococ-

cus’ AND ‘neoplasm’, which were searched as text word

and as exploded medical subject headings where possi-

ble. The reference lists of relevant articles were also

searched for appropriate studies. No language restric-

tions were used in either the search or the study selec-

tion. We did not search for unpublished literature.

Study selection

We included studies that met the following inclusion

criteria: (1) S. bovis septicaemia confirmed by blood cul-

ture, (2) S. bovis endocarditis diagnosed by the appro-

priate clinical protocol, (3) patients diagnosed with

CRN, (4) the risk point reported as an odds ratio (OR)

or data presented such that an OR could be calculated,

(5) 95% confidence interval (CI) reported or data pre-

sented such that the CI could be calculated and (6) an

internal comparison used when calculating the risk esti-

mate. Studies that did not meet these criteria were

excluded.

Data extraction

The data extraction was performed using a standardized

data extraction form, collecting information on the

publication year, study design, number of cases, number

of controls, total sample size, country, continent, case–

control matching, mean age, number of adjusted vari-

ables, the risk estimates or data used to calculate the

risk estimates, CIs or data used to calculate CIs, the

diagnostic tool used to confirm the CRN and the type

of laboratory investigation used to confirm the S. bovis

infection. The quality of the studies was not assessed

and authors were contacted for missing data. Adjusted

ratios were extracted in preference to unadjusted ratios;

however, where ratios were not provided, unadjusted

ORs and CIs were calculated. Where more than one

adjusted ratio was reported, we chose the ratio with the

highest number of adjusted variables. Where multiple

Colorectal Disease ª 2014 The Association of Coloproctology of Great Britain and Ireland. 16, 672–680 673

S. Krishnan & G. D. Eslick Streptococcus bovis infection and colorectal neoplasia

risk estimates were available in the same study, for

example due to the use of different comparator groups,

they were included as separate risk estimates.

Statistical analysis

Pooled ORs and 95% CIs were calculated for the effect

of S. bovis on the risk CRN using a random effects

model [23]. We tested heterogeneity with Cochran’s

Q-statistic, with P < 0.10 indicating heterogeneity,

and quantified the degree of heterogeneity using the

I2-statistic, which represents the percentage of the total

variability across studies which is due to heterogeneity.

I2-values of 25, 50 and 75% corresponded to low,

moderate and high degrees of heterogeneity, respec-

tively [24]. We quantified publication bias using

Egger’s regression model [25], with the effect of bias

assessed using the fail-safe number method. The fail-

safe number was the number of studies that we would

need to have missed for our observed result to be nulli-

fied to statistical nonsignificance at the P < 0.05 level.

Publication bias was generally regarded as a concern if

the fail-safe number was less than 5n + 10, with

n being the number of studies included in the meta-

analysis [26]. All analyses were performed with

Comprehensive Meta-analysis (version 2.0), Biostat,

Englewood, NJ, USA (2005).

Results

Study characteristics

Of the 4303 studies screened, 48 were selected for the

meta-analyses, of which 40 dealt with S. bovis septicae-

mia and CRN, 23 with S. bovis endocarditis and CRN

and six with faecal carriage (Fig. 1). Of the S. bovis sep-

ticaemia group, three were case–control studies and the

remaining were case series. In the three case–control

studies the total number of cases was 140 and the total

number of controls was 482. The same three case–con-

trol studies were also relevant for the S. bovis endocardi-

tis analyses, with the remaining 17 studies being case

series. The majority of the studies in the endocarditis

group overlapped with the septicaemia group because

the diagnostic criteria for endocarditis included confir-

mation of the pathogen by blood culture [39]. All of

the faecal carriage studies were case–control studies. In

this group there were 515 cases and 642 controls.

The sample size was 1729 for the septicaemia group,

807 for the endocarditis group and 1145 for the faecal

carriage group. Forty two papers were published in

English and the remaining six in other languages. The

geographical distribution of the studies was as follows:

Europe 23, North America 17, Asia 6, Australia 3 and

South America 1 (Table S1).

Streptococcus bovis septicaemia and CRC

Data from the case series showed that of all patients

positive for CRN, only 18.3% had a carcinoma. Analysis

of the case–control studies shows a seven-fold increase

in the risk of having CRN in the presence of S. bovis

septicaemia (OR 7.48, 95% CI 3.10–18.06) (Fig. 2).

Heterogeneity was moderate (I2 = 43.32) and not sta-

tistically significant (P = 0.17). Based on Egger’s regres-

sion analysis there was no evidence of publication bias

(P = 0.81). The analysis of the cases series showed that

among patients with S. bovis septicaemia, 49% also had

CRN (event rate 0.49, 95% CI 0.42–0.56). Heteroge-

neity here was high (I2 = 69.97) and statistically signifi-

cant (P < 0.001). Streptococcus bovis septicaemia was

also associated with an increased risk of having a colonic

adenoma (OR 2.26, 95% CI 0.65–7.79); however, it

was not statistically significant. Analysis based on geog-

raphy revealed differences in the event rates of CRN

among those infected with S. bovis, which were statisti-

cally significant: Australia (event rate 0.65, 95% CI

0.37–0.85), Europe (event rate 0.51, 95% CI 0.41–

0.60), North America (event rate 0.46, 95% CI 0.32–

0.60), Asia (event rate 0.35, 95% CI 0.17–0.58) (Table

S2).

4303 potentially relevantreferences screened• PubMed, EMBASE,

MEDLINE searched• includes 8 hand searched

references

3808 references excluded because they were not relevant (not about S. bovis or CRN)

495 abstracts retrievedfor more detailed analysis

294 full-texts reviewed to be included in the meta-analysis

52 Studies suitable for meta-analyses

48 studies with usable information

201 references excluded (duplicates)

242 Studies excluded (was not about S. bovis septicaemia,endocarditis or faecal carriage, did not relate it to CRN,inappropriate study type e.g. case reports)

4 studies withdrawn (unable to extract data)

Figure 1 Study flow diagram. CRN: colorectal neoplasia;

S. bovis: Streptococcus bovis.


Streptococcus bovis infection and colorectal neoplasia S. Krishnan & G. D. Eslick

Streptococcus bovis endocarditis and CRC

Data from the case series showed that of all the patients

positive for CRN only 14.4%, on average, had a carci-

noma. However, the case–control studies showed that

there is a significantly increased risk of having CRN in

patients who have S. bovis endocarditis (OR 14.54, 95%

CI 5.66–37.35) (Fig. 3). The heterogeneity was moder-

ate (I2 = 43.53) but not statistically significant

(P = 0.17). The case series, similarly, showed a signifi-

cant increase in risk with an event rate of 0.53 (95% CI

0.45–0.61). The heterogeneity is moderate

(I2 = 53.50) but statistically significant (P = 0.003).

Streptococcus bovis endocarditis was associated with an

increased risk of formation of a colonic adenoma (OR

5.13, 95% CI 0.27–98.69), but this was not statistically

significant. Analysis based on geography revealed differ-

ences in the event rates of CRN among those infected

with S. bovis in Europe (event rate 0.57, 95% CI 0.50–

0.64), and North America (event rate 0.42, 95% CI

0.26–0.60). Based on Egger’s regression analysis there

was no evidence of publication bias (P = 0.47).

Faecal carriage

The rate of patients carrying S. bovis in their faeces is

two times greater in patients with CRN (OR 2.52, 95%

CI 1.14–5.58) (Table S2). The heterogeneity in this

analysis was statistically significant (I2 = 69.17,

P = 0.006). Faecal carriage of S. bovis was similarly

increased in patients with colonic adenoma (OR 1.50,

95% CI 0.77–2.91) and colon carcinoma (OR 2.46,

95% CI 0.72–8.46), but neither was statistically signifi-

cant. The heterogeneity of both these analysis were at

null (I2 = 0.00) with P-values of 0.89 and 0.43, respec-

tively. Based on Egger’s regression analysis there was no

evidence of publication bias (P = 0.0.5).

Discussion

Summary of evidence

The meta-analysis shows that the presence of S. bovis

infection in the form of septicaemia or endocarditis is

associated with an increased risk of finding CRN. It is

also seen that in patients with CRN the rate of finding

S. bovis in faeces is doubled. The analysis clearly shows

the significant association between S. bovis infection and

CRN. It also shows that 50% of patients with S. bovis

endocarditis are likely to have a concurrent CRN.

Infective endocarditis is defined as an endovascular

infection of cardiovascular structures including cardiac

valves, atrial and ventricular endocardium, large intra-

thoracic vessels and intracardiac foreign bodies [27]. In

the general population, S. bovis is estimated to the aeti-

ological source of infective endocarditis in approxi-

mately 14% [28]. The underlying mechanism of the

association between CRN and S. bovis endocarditis spe-

cifically is not fully understood but is thought to be tied

in with the increased affinity of S. bovis to extracellular

Study name

Corredoira-Sanchez 5.99 3.54 10.12 0.00

Hoen 3.21 0.51 20.23 0.21

Sharara 21.58 5.40 86.20 0.00

7.48 3.10 18.06 0.00

0.01 0.1 1 10 100

Statistics for each study Odds ratio and 95% CI

Oddsratio

Lowerlimit

Upperlimit P-value

Figure 2 Forest plot of Streptococcus bovis septicaemia and colorectal neoplasia.

Study name

Corredoira-Sanchez 20.53 10.18 41.40 0.00

Hoen 3.21 0.51 20.23 0.21

Sharara 21.58 5.40 86.20 0.00

14.54 5.66 37.55 0.00

0.01 0.1 1 10 100

Statistics for each study Odds ratio and 95% CI

Oddsratio

Lowerlimit

Upperlimit P-value

Figure 3 Forest plot of Streptococcus bovis endocarditis and colorectal neoplasia.



matrix (ECM) proteins such as collagens and fibronec-

tin; these are known to be exposed in higher rates at

sites of tissue injury such as tumours and the vegeta-

tions on affected heart valves [29,30].

In a study conducted by Sillanpaa et al. [29] it was

seen that 13 out of 17 isolates of S. bovis showed adher-

ence to one or more ECM proteins, with the greatest

affinity being to type I collagen. Indeed, the locus in

the S. bovis genome which codes for a pilus protein with

collagen-binding properties has been identified [33].

Similarly, Boleij et al. [31] showed that S. bovis biotype

I had an ability to form biofilms on collagen type I and

type IV, unlike most other Gram-positive gut bacteria.

Heart valves are composed of various types of collagen,

but mainly type I and type IV [32], the types that S. bo-

vis is most adherent to. Furthermore, it has been shown

that the formation of a biofilm is critical to the patho-

genicity of infective endocarditis [34]. This helps to

explain the possible mechanisms which underpin the

unique and significant association between S. bovis

infectious endocarditis and CRN.

Our study showed that S. bovis septicaemia is also a

significant predictor of the presence of CRN. Although

there is some debate as to whether the role of S. bovis

in CRN is really aetiological or incidental, the general

hypothesis is that the infection occurs by translocation

of the bacterium secondary to tumour development

[12]. This is evidenced by the fact that whilst our study

shows that up to a third of patients with S. bovis bacter-

aemia may have CRN, the incidence of S. bovis in

patients who have CRN is estimated to be 3–6% [28],

indicating the likely causative, rather than incidental,

role of S. bovis. In a study comparing the colonization

of S. bovis in patients with CRC with and without bac-

teraemia, it was found that the rate was significantly

higher in tumourous lesions than in nontumourous

lesions, and more so in patients with CRC than controls

[35]. The study found that the rate of colonization was

highest amongst those who had S. bovis bacteraemia

along with CRC. From this association, the authors

inferred that there is a possibility of a host–bacterium

interaction where S. bovis plays an aetiological role

through mechanisms such as chronic inflammation and

induction of oncogenesis. Indeed, the study by Abdula-

mir et al. [36] also found that the levels of IL-8

mRNA, a key mediator in colorectal carcinogenesis, was

highest in tumour lesions of CRC patients with S. bovis,

further confirming the oncogenic role of S. bovis. The

mechanism of translocation is proposed to be secondary

to the ability of S. bovis common antigen to promote

tumour attachment [36] and the role of histone-like

protein A in binding to the HCT116 and HT-29 colon

tumour cell lines [37]. Furthermore, it is aided by the

vasodilatation caused by the release of local chemical

mediators at the site of the tumour, which allow for the

passage of bacteria into the blood to cause septicaemia

[38].

Diagnosis of S. bovis endocarditis requires confirma-

tion of the pathogen in the blood [40], effectively mak-

ing it a diagnosis of septicaemia as well. However, the

rates of CRN associated with septicaemia, according to

our analysis, are lower than those for endocarditis. This

may be due to the fact that S. bovis biotype 1, the one

most associated with the presence of CRN, is also the

biotype which is most likely to cause infective endocar-

ditis [21]. Our study included all biotypes because our

aim was to gather comprehensive information about the

general significance of S. bovis in CRN, and the scarcity

of studies which differentiate between the biotypes,

acknowledged by Boleij et al. [21], would not have

allowed us to do this.

The third component of our analysis, looking at the

prevalence of faecal carriage of S. bovis in patients with

CRN, showed that there is a statistically significant posi-

tive association compared with controls. The first study

was performed by Klein et al. in 1977 [41] and since

then a case series [41] and a few case–control studies

have been published reporting this association. To our

knowledge, no meta-analysis has been performed on

this topic. Whilst most of the studies demonstrate a

positive association with CRN, Potter et al. showed a

negative association [87]. In that study, 24 individuals

with colon carcinoma were tested for the presence of

S. bovis in faeces. Of these 24 patients, only two were

found have the bacterium in their faeces (11%), and this

was comparable to the 13% in the control group.

Unlike the work of Potter et al., most of the remaining

studies in this meta-analysis included patients with not

just carcinoma but other neoplastic changes as well,

such as adenomas. On the other hand, Burns et al.

reported that in their study there appeared to be a trend

towards increasing rates of faecal carriage of S. bovis

corresponding to increasing malignant potential of the

neoplasm, albeit statistically not significant [86]. This

correlation can be explained, once again, by the ability

of S. bovis to attach to tumours and promoting the

growth of the tumour as well.

The bowel contains a huge variety of microflora

[43], but S. bovis clearly plays a greater role than

others in the pathogenesis of CRC. We have shown that

S. bovis fulfils the requirements for consideration as a

causative organism in CRC in accordance with the

Bradford-Hill criteria, which we demonstrate in Table

S3. Abdulamir et al. [44] conducted a study comparing

the IgG seroprevalence of S. bovis biotype I compared

with Bacteroides fragilis, a bacterium which is far more



prevalent in the bowel than S. bovis, and found the for-

mer to be more significantly associated with CRN than

B. fragilis. Clearly, the generic properties of all bacteria,

such as the ability to cause chronic inflammation, do

not suffice to explain the unique role of S. bovis in

CRN. In a study in which the complete nucleotide

sequence of a strain of S. bovis was analysed, it was

shown that the bacterium contains a number of features

which contribute to its resilience in the human bowel

[44]. These include its simple nutritional requirements,

allowing it to grow in hostile environments, its ability

to withstand certain toxic substances such as tannins

and bile salts and its ability to defend itself against a

large variety of viruses and thus compete with the other

microflora in the gut.

Limitations of the study

The main limitation of the meta-analysis is the paucity

of studies with controls and the quality of the studies

included. Most are observational and have inherent con-

founding factors that have not been adjusted for in the

analysis. Moreover, there were no prospective cohort

studies available, thus limiting the ability to determine

cause and effect. The meta-analysis was also limited by

the small sample sizes of individual studies, conse-

quently decreasing the power. Another common source

of sampling bias in some of the studies included in the

meta-analyses was that colonoscopies were not per-

formed on all participants. Since only those with clinical

indications for a colonoscopy had the procedure carried

out, the issue remains that the presence of CRN cannot

be conclusively determined without the use of colonos-

copy. We calculated the sample size to include only the

patients who underwent colonoscopy, but this does not

fully abolish sampling bias.

We can conclude from our analysis that the presence

of S. bovis is a convincing indicator of the probability of

concurrent CRN. We recommend that all patients who

are diagnosed with S. bovis septicaemia or endocarditis

undertake colonoscopy to exclude the presence of neo-

plasia.

Whilst our analysis demonstrates the significance of

the presence of S. bovis in the faeces of CRN patients, it

not yet known whether it is efficient to perform stool

culture to identify S. bovis as a predictor of underlying

CRN. Another avenue of early detection of CRN is

through serological investigation. Tjalsma et al. [46]

conducted a study analysing serum antibodies to S. bovis

in CRC patients by immunocapture and found that

S. bovis antigen profiles could distinguish 11 out of 12

colon cancer patients from eight control subjects. Other

studies have found similar results with enzyme-linked

immunosorbent assay measurement of IgG [45] and

Western blot identification of two proteins of approxi-

mately of approximately 30 and 22 kDa identified as

potential markers. Boleij et al. [47] conducted a study

where CRC antigen RpL7/L12 was used to identify

that IgG levels were most pronounced in patients with

early stage colonic tumours, highlighting a possible

mechanism of detecting CRN at an early stage [47].

We recommend that further investigations be performed

to identify a reliable immunological marker for early

detection of CRC. We also recommend that future

studies in this field of research should conduct case–

control or prospective cohort studies and ensure a

higher quality of study design to contribute more valid

data.

Author contributions

Study conception and design: Guy D. Eslick; acquisition

of data: Sailakshmi Krishnan; analysis and interpretation

of data: Guy D. Eslick; Writing manuscript: Sailakshmi

Krishnan.

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Supporting Information

Additional Supporting Information may be found in the

online version of this article:

Table S1. Study characteristics.

Table S2. Meta-analysis by different study characteris-

tics.

Table S3. Bradford-Hill Criteria relating S. bovis to

CRN.



streptococcus bovis infection and colorectal neoplasia: a meta-analysis

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