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LIVER TRANSPLANTATION 13:1582-1588, 2007


Streptococcus salivarius Bacteremia and

Spontaneous Bacterial Peritonitis in Liver
Transplantation Candidates
Manjushree Gautam,1 Kapil B. Chopra,1 David D. Douglas,1 Rebecca A. Stewart,2 and Shimon Kusne3
Division of Transplantation Medicine, Mayo Clinic, Scottsdale, AZ; 2Division of Laboratory Medicine, Mayo
Clinic, Scottsdale, AZ; 3Division of Infectious Diseases, Mayo Clinic, Scottsdale, AZ.

Bacterial infections are a serious complication of end-stage liver disease (ESLD) that occurs in 20% to 60% of patients. We
retrospectively reviewed medical records of patients with ESLD who were identied by our microbiology laboratory as having
Streptococcus salivarius bacteremia. Of 592 patients listed for transplantation between January 1998 and January 2006, 9
(1.5%) had 10 episodes of S salivarius bacteremia. Of 2 patients already receiving quinolone prophylaxis for spontaneous
bacterial peritonitis (SBP), 1 later presented with a second episode. The male-to-female ratio was 1:1.2. Medians for age,
Model for End-Stage Liver Disease score, and Child-Turcotte-Pugh score were 50 years, 17, and 10, respectively. Presenting
symptoms and signs in 10 episodes of infection were ascites (in 8 episodes), elevated temperature (6), abdominal pain (5), and
encephalopathy (4). Median laboratory values included: white blood cell count, 15.1 109/L; creatinine, 0.9 mg/dL; albumin,
3.1 gm/dL; aspartate aminotransferase, 64 U/L; alanine aminotransferase, 52.5 U/L; ammonia, 67 g/dL; and prothrombin
time, 17.3 seconds. Ascitic uid in patients with peritonitis showed a median white blood cell count of 466 cells/mm3 (range,
250-12,822 cells/mm3), with 66% polymorphs, protein of 0.9 gm/dL, and albumin of 0.4 gm/dL. S salivarius may cause primary
bacteremia and SBP in liver transplantation candidates despite quinolone prophylaxis. Liver Transpl 13:1582-1588, 2007.
2007 AASLD.
Received April 5, 2007; accepted June 24, 2007.

Bacterial infections are a common and serious complication of end-stage liver disease (ESLD). Their prevalence has been reported to range from 20 to 60%.1,2
They are associated with increased morbidity and overall in-hospital mortality.1,2 Proposed mechanisms for
increased risk of infection are changes in humoral immunity with a decreased synthesis in the complement
system,3 a decrease in the phagocytosis capability of
the hepatic reticuloendothelial system,4 an alteration
in the function of neutrophils,5,6 and a reduction in
opsonic activity of ascitic uid.7 In addition, rupture of
natural barriers induced by invasive diagnostic or therapeutic procedures may be involved in the pathogenesis of infections.
Commonly observed infections in cirrhotic patients
are pneumonia, urinary tract infection, spontaneous
bacterial peritonitis (SBP), and bacteremia. Most of

these infections are community acquired. In 1 series,

two-thirds of the episodes were caused by gram-negative bacteria, 21% by gram-positive bacteria, and 3% by
anaerobic bacteria.8 In a more recent series of 117
cases of bacteremia, about one-half of the infections
were caused by gram-negative bacteria and about onehalf by gram-positive bacteria.9
We have encountered cases of S salivarius bacteremia among patients listed for liver transplantation at
our tertiary care academic medical institution. Herein,
we present our experience with this infection in patients with ESLD who were managed at our institution.


After we encountered 2 liver transplantation candidates
with S salivarius bacteremia, we reviewed the electronic

Abbreviations: ESLD, end-stage liver disease; SBP, spontaneous bacterial peritonitis; VGS, viridans group streptococci.
Address reprint requests to Shimon Kusne, MD, Division of Infectious Diseases, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259.
Telephone: 480-342-0115; FAX: 480-342-2324; E-mail:
DOI 10.1002/lt.21277
Published online in Wiley InterScience (

2007 American Association for the Study of Liver Diseases.


TABLE 1. Demographic Features of 9 Patients With Streptococcus salivarius Infection

Patient #

Age (yr)


Underlying liver disease

CTP score

MELD score

Prior SBP



Cryptogenic cirrhosis or NASH

Chronic hepatitis C
Alcoholic cirrhosis
Chronic hepatitis C
Chronic hepatitis C
Chronic hepatitis C
Chronic hepatitis C
Fulminant hepatic failure




CTP, Child-Turcotte-Pugh; F, female; M, male; MELD, Model for End-Stage Liver Disease; NA, not available; NASH,
nonalcoholic steatohepatitis; PSC, primary sclerosing cholangitis.

microbiology records of all patients admitted by the

transplant medicine service between January 1998 and
January 2006 to identify similar cases. Nine patients
with S salivarius bacteremia were identied. A retrospective review of their medical records was conducted
to abstract the following information: demographic factors (e.g., age and gender); underlying liver disease, its
severity, and complications; past medical history, including any history of SBP; prophylaxis for SBP; dates
of hospitalization; presenting signs and symptoms; laboratory data, including microbiology reports of blood
and ascitic uid; treatment received; course during
hospital stay; response to therapy; date of liver transplantation, if received, and outcome.
An episode of S salivarius SBP was dened either as
bacteremia together with positive ascitic uid culture or
as bacteremia together with an ascitic uid absolute
polymorphonuclear leukocyte count of 250 cells/mm3
or more. Infections were considered community acquired when diagnosed within the rst 48 hours of
hospitalization and hospital acquired when diagnosed
after 48 hours of hospitalization. A temperature elevation of 38.3C or above was considered as fever.
The organism was identied on an automated microbiology blood culture analyzer system (MicroScan
WalkAway-96; Dade Behring, West Sacramento, CA)
using modied conventional and chromogenic tests.
Identication was based on the detection of pH
changes, substrate utilization, and growth in the presence of antimicrobial agents after a 16- to 44-hour
incubation at 35C.
Continuous variables are presented as median and
range. Categorical variables are presented as percentages.

Of 592 patients with ESLD listed for liver transplantation between January 1998 and January 2006, 9 (1.5%;
4 men and 5 women) were identied as having 10 episodes of symptomatic S salivarius infection. The demographic features of these 9 patients are summarized in
Table 1. The median age of the group was 50 years
(range, 33-66 yr). Eight patients had underlying

chronic liver disease (5 with chronic hepatitis C and 1

each with primary sclerosing cholangitis, alcoholic liver
disease, and cryptogenic cirrhosis); 1 patient had fulminant hepatic failure of unknown cause. The median
Child-Turcotte-Pugh score of patients with chronic liver
disease was 10 (range, 6-10), and the median Model for
End-Stage Liver Disease score was 17 (range, 13-22).

Underlying Medical Conditions

Two patients (no. 1 and no. 4) were known to have
long-standing type 2 diabetes mellitus. One patient (no.
2) was receiving cephalexin for a fever with an unclear
pathogenesis at the time of the current illness. One
patient (no. 5) had a prior episode of SBP (organism
unknown) and was taking ciprooxacin hydrochloride
(500 mg/day) prophylaxis. One patient (no. 1) had undergone an upper gastrointestinal endoscopy with ligation of esophageal varices 1 week before the onset of the
current illness. One patient (no. 8) had large B-cell
non-Hodgkin lymphoma and had nished the rst
round of chemotherapy about 2 weeks before the onset
of his febrile illness. All patients had undergone dental
evaluation as part of their pretransplantation workup.

Presenting Signs and Symptoms

The clinical features and laboratory data for the 9 patients are summarized in Table 2. Fever (median temperature, 38.4C) was the most common presenting
symptom (6/10 episodes), followed by abdominal pain
(5 episodes), and nausea and vomiting (3 episodes).
Patient 2 had presented with fever immediately after a
screening upper gastrointestinal endoscopy. Other presenting symptoms were shortness of breath (3/10) and
cough, chest pain, and dysuria (1 episode each). Four
episodes of infection were complicated by the development of encephalopathy. Of 8 patients with chronic
liver disease, 7 had ascites.

Laboratory Data
The median white blood cell count for the group of 9
patients was 15.1 109/L (range, 0.6-21.2 109/L).
The median values of liver function tests were as fol-

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases


TABLE 2. Clinical and Laboratory Features of 9 Patients With Streptococcus salivarius Infection

Patient #


Signs and symptoms

Laboratory data


Recent upper GI bleed;

presented with
encephalopathy and
minimal ascites; no
prior SBP prophylaxis

Blood culture
grew S
salivarius (2 of
2 bottles)


Temperature 38.6C;
encephalopathy and
ascites; no prior SBP

Temperature 39.4C;
abdominal pain and
ascites; no prior SBP

Temperature 38.4C
and ascites; no prior
SBP prophylaxis

Presented with
abdominal pain,
nausea, vomiting,
ascites, and rightsided hydrothorax;
prior treatment of SBP
of unclear etiology
followed by
Temperature 38.4C;
abdominal pain,
nausea, vomiting,
SOB, cough, and
ascites; no prior SBP

Blood culture
grew S
salivarius (1
bottle each in
2 sets); ascitic
uid was
Blood culture
grew S
salivarius (1 of
3 bottles);
ascitic uid
culture was
Blood culture
grew S
salivarius (3 of
3 bottles);
ascitic uid
culture grew S
Blood culture
grew S
salivarius (1 of
2 bottles);
ascitic uid
culture was


WBC 7.9 109/L;

AST 50 U/L; ALT 53
U/L; ALP 80 U/L;
albumin 3.6 gm/dL;
ascitic uid not
WBC 17.4 109/L;
AST 71 U/L; ALT 52
U/L; ALP 180 U/L;
albumin 3.3 gm/dL;
ascitic uid 245
nucleated cells/mm3
with 34% polymorphs
WBC 21.2 109/L;
AST 41 U/L; ALT 36
U/L; ALP 600 U/L;
albumin 1.7 gm/dL;
ascitic uid 1,650
nucleated cells/mm3
with 90% polymorphs
WBC 13.3 109/L;
AST 31 U/L; ALT 32
U/L; ALP 1,470 U/L;
albumin 2.3 gm/dL;
ascitic uid 12,822/L
nucleated cells/mm3
with 95% polymorphs
WBC 16.8 109/L;
AST 57 U/L; ALT 43
U/L; ALP 127 U/L;
albumin 3.4 gm/dL;
ascitic uid 466
nucleated cells/mm3
with 66% polymorphs

WBC 16.7 109/L;

AST 165 U/L; ALT 116
U/L; ALP 105 U/L;
albumin 3 gm/dL;
ascitic uid 3,850
nucleated cells/mm3
with 87% polymorphs
WBC 12 109/L; AST
178 U/L; ALT 107 U/
L; ALP 122 U/L;
albumin 2.9 gm/dL;
ascitic uid 286
nucleated cells/mm3
with 31% polymorphs
WBC 13.6 109/L;
AST 56 U/L; ALT 35
U/L; ALP 229 U/L;
albumin 3.7 gm/dL;
ascitic uid 72
cells/mm3 with 43%
WBC .6 109/L; AST
99 U/L; ALT 162
U/L; ALP 258 U/L;
albumin 3.3 gm/dL

Blood culture
grew S
salivarius (2 of
2 bottles);
ascitic uid
culture grew S
Blood culture
grew S
salivarius (2 of
2 bottles);
ascitic uid
culture grew S
Blood culture
grew S
salivarius (3
of 4 bottles);
ascitic uid
grew S
Blood culture
grew S
salivarius (3
of 3 bottles);
no ascites
Blood culture
grew S
salivarius (1
of 3 bottles);
no ascites



Presented 1 month
after initial episode
with temperature
40.4C, nausea,
abdominal pain,
ascites, and
Temperature 38.1C;
abdominal pain,
nausea, vomiting,
hypotension, and
ascites; no prior
SBP prophylaxis
Temperature 38.8C
with neutropenia
after therapy for
NHL; no prior SBP
Temperature 37.8C
encephalopathy; no
prior SBP

WBC 19.3 109/L;

AST 590 U/L; ALT
1,750 U/L; ALP 445
U/L; albumin 3.0



Vancomycin HCl
and piperacillin
sodium (14
sodium, then
metronidazole (7

underwent DDLT
11 months later

underwent DDLT
2 months later


sodium, then
oral amoxicillin

underwent LDLT
3 months later


sodium (5 days)

Responded; later
lost to follow-up


sodium, then
sodium (15

underwent LDLT
3 weeks later


sodium (5 days),
then started on
prophylaxis dose
of ciprooxacin
sodium (14


underwent LDLT
4 months later


Vancomycin HCl
sodium (21

months later


sodium (28

awaiting liver



Died after 8 days

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DDLT, deceased
donor liver transplantation; GI, gastrointestinal; LDLT, living donor, liver transplantation; NHL, non-Hodgkin lymphoma;
SOB, shortness of breath; WBC, white blood cell count.

lows: aspartate aminotransferase, 64 U/L (range, 31590 U/L); alanine aminotransferase, 52.5 U/L (range,
32-1,750 U/L); and alkaline phosphatase, 204.5 U/L

(range, 80-1,470 U/L). Other median values were as

follows: glucose, 145.5 mg/dL (range, 89-231 mg/dL);
serum creatinine, 0.9 mg/dL (range, 0.1-5.5 mg/dL);

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases


total protein, 5.2 gm/dL (range, 4.0-7.5 gm/dL); albumin, 3.1 gm/dL (range, 1.7-3.7 gm/dL); bilirubin, 2.5
gm/dL (range, 0.5-31.6 gm/dL); prothrombin time,
17.3 seconds (range, 13.7-150 seconds); international
normalized ratio, 1.38 (range, 1.0-2.58); and ammonia,
67 g/dL (range, 31-619 g/dL). All blood cultures
from the group grew S salivarius. Paracentesis was performed in all but 1 patient (no. 1). Ascitic uid showed:
466 nucleated white blood cells/mm3 (range,
250-12,822 nucleated white blood cells/mm3); 66%
polymorphs (range, 1%-95%); total protein, 0.9 gm/dL
(range, 0.8-1.0 gm/dL); and albumin, and 0.4 gm/dL
(range, 0.2-0.6 gm/dL). Ascitic uid culture from 3 patients (nos. 4, 6, and 7) grew S salivarius, which was
sensitive to penicillin, vancomycin hydrochloride, levooxacin, and ceftriaxone sodium, and resistant to
erythromycin. Five patients were diagnosed with 6 episodes (including 1 relapse) of SBP on the basis of our
denition as detailed in the Patients and Methods section.

Of 10 episodes, 8 were community-acquired, 1 was
hospital-acquired, and 1 was a relapse within 1 month
of prior S salivarius peritonitis. Six episodes were diagnosed as secondary to SBP. One patient (no. 8) had
signs indicative of possible vegetations on the aortic
valve on a transthoracic echocardiogram and was
treated for a presumptive diagnosis of endocarditis. He
was not known to have any preexisting valvular disease. The source of infection was not clear in the remaining patients and hence was labeled as primary
bacteremia. All patients were treated with appropriate
antibiotics for a median of 14 days (range, 5-28 days).

Follow-up blood culture and paracentesis were conducted before patients were discharged from the hospital. All but 1 patient was cured after treatment. One
patient (no. 6) had a relapse of S salivarius bacterial
peritonitis 1 month after the initial episode while taking
ciprooxacin prophylaxis. She was initially treated with
intravenous cefotaxime sodium for 5 days. She then
was continued on 750 mg ciprooxacin every week for
prophylaxis. However, the organism responsible for the
second episode was susceptible to quinolones. During
the second episode, this patient was treated with intravenous ceftriaxone for 14 days and had a good response
to therapy. The patient who was admitted for fulminant
hepatic failure died 8 days after admission due to multiple organ failure. There were no mortalities related to
S salivarius bacterial infection. One patient (no. 4) was
lost to follow-up within 3 months. Of the other 7 patients with chronic liver disease still on the liver transplant list, 6 had undergone liver transplantation (3 deceased donor and 3 living donor) at follow-up. One
patient (no. 8) was awaiting liver transplantation as of
this writing.

The management of complications from cirrhosis has
been revolutionized in the past decade. With the extension of liver transplant programs, more invasive diagnostic procedures are being performed more frequently.
These may have predisposed the patients to infections
with more common and usually nonpathogenic inhabitants of skin, oropharyngeal areas, and the gastrointestinal tract. Another problem is emergence of resistant infections in patients who are on long-term
selective intestinal decontamination.10
S salivarius is a gram-positive organism that belongs
to viridans group streptococci (VGS).11 It is a relatively
nonvirulent bacterium that is part of the normal oral
ora.12 It is rarely isolated from blood and is usually
considered a contaminant. In 1 study, 68% of the isolates were considered either contaminants or of unclear
signicance.13 There are case reports of S salivarius
infection involving the eyes,14 the endocardium,15 the
bloodstream in neutropenic patients,16,17 and the central nervous system in patients with neoplasia or iatrogenia.18,19
There are few reports of S salivarius SBP in patients
with underlying liver disease. Peterson20 reported a
case of S salivarius SBP in a 50-yr-old male patient with
ESLD due to chronic hepatitis C. The patient was
treated with ciprooxacin hydrochloride for 3 days, followed by levooxacin for 7 days (10 days of total treatment), with the intention of maintaining him on prophylactic noroxacin. There was no reported
information on cure. A second case report was of a
61-yr-old male patient with alcohol-related ESLD who
was diagnosed with S salivarius SBP.21 He was treated
with intravenous third-generation cephalosporin and
oral amoxicillin. He responded to treatment and was
maintained on noroxacin prophylaxis.
We identied 10 episodes of symptomatic S salivarius
infection in 9 (1.5%) of 592 patients with ESLD who
were managed in our institution. Six episodes were due
to SBP. In the other 3 patients, the source of bacteremia
was unclear. One patient had a diagnostic upper gastrointestinal endoscopy without any intervention before
the onset of the symptoms. Bacteremia after an upper
gastrointestinal endoscopy is not rare. Carley22 reported a case of S salivarius bacteremia after upper
gastrointestinal endoscopy and cauterization for gastric bleeding. Meningitis later developed in this patient.
S sanguis bacteremia and peritonitis have been reported after sclerotherapy.23 One patient in our series
had S salivarius bacteremia 1 week after endoscopic
variceal ligation. Endoscopic variceal ligation has been
associated with asymptomatic bacteremia in 16% of
patients.24 The isolated organisms in that series were
gram-positive oral or skin commensals. However, no
case of peritonitis was reported by those authors. Dental evaluation was conducted as part of the pretransplantation workup. None of our patients had any dental
procedure before the onset of S salivarius infection.
Kiddy et al.25 reported 4 cases of VGS peritonitis in
patients receiving continuous ambulatory peritoneal

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases


dialysis 2 to 7 days after dental surgery or the onset of

a lesion in the mouth. Four patients underwent transthoracic echocardiogram during the workup of their
illness. One patient had signs suggestive of vegetations
on the cardiac valves and was treated for bacterial endocarditis. Given the adherence properties of grampositive bacteria, the consequences of S salivarius bacteremia may be concerning with regard to endovascular
seeding and subsequent embolization of infected clots.
Of 10 isolates in our series, 5 were resistant to erythromycin. One was resistant to quinolones; that patient
was receiving ciprooxacin prophylaxis for a previous
episode of SBP (information not available on earlier
organism). Another patient had a second episode of SBP
with a quinolone-sensitive organism after receiving cefotaxime for 5 days during the rst episode and weekly
ciprooxacin prophylaxis thereafter. Corredoira et al.13
reported that 51% of S salivarius isolates were resistant
to erythromycin, 29% to clindamycin, 22% to trimethoprim sulfamethoxazole, and 7% to cefotaxime.
Furthermore, they reported a greater rate of resistance
of S salivarius to penicillin (31%) compared with other
members of VGS. Smith et al.26 reported that 60% of S
salivarius isolates were resistant to erythromycin,
whereas none were resistant to penicillin and clindamycin. Most isolates in both of these studies were from
patients undergoing treatment for malignancy.
Use of antibiotic prophylaxis as well as use of previous courses of empiric therapy may inuence the susceptibility of bacteria. Han et al.17 reported that 92% of
levooxacin-resistant streptococci cases had either
prophylaxis or treatment with one of the quinolones
within a week of a positive culture. In another series, all
isolates of VGS were susceptible to levooxacin and
moxioxacin, and minimum inhibitory concentrations
of uoroquinolones did not differ in patients with or
without noroxacin prophylaxis.27 An increased incidence of quinolone resistance was reported among patients with gram-positive bacterial infections than
among those with gram-negative bacterial infections
(P 0.01) without long-term antibiotic prophylaxis. In
our series, S salivarius peritonitis developed in 2 patients who were taking ciprooxacin prophylaxis for
SBP. In 1 patient (no. 6), the isolate was susceptible to
levooxacin, whereas in the other patient (no. 5), the
isolate was resistant to levooxacin.
One patient (no. 6) had a relapse of S salivarius peritonitis after being treated with intravenous cefotaxime
for 5 days during the rst episode. Another patient (no.
8) showed signs of possible vegetation on echocardiogram. He was treated with intravenous ceftriaxone for
28 days for a presumptive diagnosis of infective endocarditis and responded to treatment. It is possible that
the 5-day duration usually offered for SBP treatment is
not adequate and that longer treatment is needed to
eradicate this organism.
The incidence of VGS SBP has been reported to vary
from 3 to 23%.28,29 The various species encountered
are bovis, sanguis, mitis, and oralis. In patients who are
receiving uoroquinolone prophylaxis, gram-positive
cocci (mainly streptococci) have been reported to cause

SBP more frequently than gram-negative bacilli.28,30,31

However, Fernandez et al.29 did not report any difference in the incidence of gram-positive or gram-negative
bacterial infections in patients with cirrhosis who either
were or were not receiving noroxacin prophylaxis.
They found a higher proportion of quinolone-resistant
gram-negative bacilli infections among patients receiving noroxacin prophylaxis but found no difference by
duration of noroxacin therapy. Cholongitas et al.32
reported that gram-positive bacteria caused SBP in
their patients signicantly more frequently during
2000-2002 than during 1998-1999 (P 0.04). Interestingly, none of their patients had been receiving prophylactic antibiotic therapy. This increased incidence of
gram-positive bacterial infections may have been associated with the increasing frequency of invasive procedures or hospitalizations. It may be worthwhile to initiate empiric coverage with antibiotics and to
specically expand coverage of gram-positive organisms in cirrhotic patients with suspected infection, especially if they are receiving quinolone prophylaxis.
Quinolones are widely used for primary and secondary SBP prophylaxis. A daily dose of noroxacin has
been reported to have a failure rate of about 15%.33 A
once-weekly dose of ciprooxacin has been found to
have a failure rate of 4%.34 Ciprooxacin has been reported to be the least active agent in vitro against VGS
isolated from the bloodstream.35 VGS isolates from the
blood of patients with neutropenic cancer have been
found to have a resistance rate of 23% against ciprooxacin.16 An increased incidence of VGS bacteremia
has been reported in neutropenic patients receiving ciprooxacin prophylaxis.36-38 Mutations in the topoisomerase gene parC of S pneumoniae have been reported
after exposure to quinolones, and this mutation along
with the gyrA mutation has been thought to cause resistance to higher levels of quinolones.39 S salivarius
bacteremia has also been reported during ciprooxacin
therapy for osteomyelitis.40 Therefore, treatment as
well as prophylaxis with ciprooxacin may not prevent
future episodes of S salivarius SBP. On the other hand,
gatioxacin has been reported to be highly active in
vitro against VGS isolates.35 Emergence of resistance to
newer quinolones has also been reported.41 Use of
newer quinolones with broadened gram-positive activity may be required to prevent future SBP episodes with

S salivarius, a nonpathogenic and commensal organism, may cause symptomatic infection in patients with
ESLD. This streptococcal infection may be associated
with increased morbidity. We did not observe any mortality among our patients. A high proportion of patients
with liver failure who present with S salivarius bacteremia may have SBP. Prophylaxis with quinolones may
not be adequate to prevent future episodes of S salivarius peritonitis.

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases


Editing, proofreading, and reference verication were
provided by the Section of Scientic Publications, Mayo

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