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I
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58
s
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p
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ess
io
n
to
p
r
e
v
e
n
t
ac
u
te
a
n
d
c
h
r
o
n
ic
r
ejec
tio
n
.
T
h
is
n
ee
d
f
o
r
p
r
ec
is
e
co
n
tr
o
l
o
f
th
e
im
m
u
n
e
r
esp
o
n
s
e
h
as
s
h
ap
ed
m
o
d
er
n
p
o
s
t
-
tr
an
s
p
lan
t
m
a
n
ag
em
en
t
an
d
u
n
d
er
s
co
r
es
th
e
ce
n
tr
al
r
o
le
o
f
ca
lcin
eu
r
in
in
h
ib
ito
r
s
in
cu
r
r
en
t
p
r
ac
tice.
Am
o
n
g
th
ese
ag
en
ts
,
tac
r
o
li
m
u
s
h
as
lo
n
g
b
ee
n
estab
lis
h
ed
as
a
f
ir
s
t
-
lin
e
o
f
m
ain
ten
an
ce
im
m
u
n
o
s
u
p
p
r
ess
iv
e
th
er
ap
y
.
T
ac
r
o
lim
u
s
is
co
m
m
o
n
ly
ad
m
in
is
ter
ed
in
co
m
b
in
atio
n
with
m
y
co
p
h
en
o
late
m
o
f
etil
an
d
co
r
tico
s
ter
o
id
s
,
f
o
r
m
in
g
th
e
b
ac
k
b
o
n
e
o
f
s
tan
d
ar
d
p
o
s
t
-
tr
an
s
p
lan
t
r
eg
im
en
s
.
Desp
ite
th
is
estab
lis
h
ed
ef
f
icac
y
,
im
p
o
r
tan
t
c
o
n
ce
r
n
s
r
em
a
in
r
eg
ar
d
in
g
lo
n
g
-
ter
m
s
af
ety
,
in
clu
d
in
g
r
is
k
s
o
f
m
etab
o
lic
co
m
p
licatio
n
s
,
in
f
e
ctio
n
s
,
an
d
n
e
u
r
o
to
x
icity
,
as
well
as
s
u
b
s
tan
tial
v
ar
iab
ilit
y
in
clin
ical
o
u
tco
m
es
ac
r
o
s
s
d
if
f
er
e
n
t
p
atien
t
p
o
p
u
l
atio
n
s
an
d
tr
ea
tm
en
t
s
ettin
g
s
[
1
4
]
-
[
1
6
]
.
T
h
ese
p
er
s
is
ten
t
u
n
c
er
tain
ties
h
ig
h
lig
h
t
th
e
n
ee
d
f
o
r
a
m
o
r
e
c
o
m
p
r
e
h
e
n
s
iv
e
an
d
u
p
d
ated
s
y
n
th
esis
o
f
r
ec
en
t e
v
id
e
n
ce
.
Ho
wev
er
,
tacr
o
lim
u
s
clin
ical
p
er
f
o
r
m
an
ce
is
in
f
lu
en
ce
d
b
y
m
u
ltip
le
f
ac
to
r
s
,
in
clu
d
in
g
p
h
ar
m
ac
o
g
en
o
m
ic
v
ar
iab
ilit
y
,
eth
n
ic
d
if
f
er
en
ce
s
,
co
n
co
m
ita
n
t
im
m
u
n
o
s
u
p
p
r
ess
iv
e
r
eg
im
e
n
s
,
an
d
th
er
ap
e
u
tic
d
r
u
g
m
o
n
ito
r
in
g
(
T
DM
)
p
r
ac
tices
[
1
7
]
.
I
ts
n
ar
r
o
w
th
er
a
p
e
u
tic
in
d
ex
n
ec
ess
itates
p
r
ec
is
e
th
er
ap
e
u
tic
d
r
u
g
m
o
n
ito
r
in
g
to
ac
h
iev
e
o
p
tim
a
l
b
lo
o
d
co
n
ce
n
tr
atio
n
.
Su
b
th
e
r
ap
eu
tic
lev
els
in
cr
ea
s
e
th
e
r
is
k
o
f
g
r
af
t
r
ejec
tio
n
,
wh
er
ea
s
s
u
p
r
ath
er
a
p
eu
tic
lev
e
ls
m
ay
ca
u
s
e
s
ig
n
if
ica
n
t
to
x
ic
ity
[
1
5
]
,
[
1
8
]
,
[
1
9
]
.
R
ec
en
t
s
tu
d
ies
h
av
e
r
ep
o
r
ted
h
eter
o
g
en
e
o
u
s
r
esu
lts
r
eg
ar
d
in
g
s
af
ety
o
u
tco
m
es
s
u
ch
as
in
f
ec
ti
o
n
r
is
k
,
m
etab
o
lic
co
m
p
licatio
n
s
,
n
ep
h
r
o
to
x
icity
,
n
eu
r
o
to
x
icity
,
an
d
h
ep
ato
to
x
icity
,
d
u
e
to
im
m
u
n
o
s
u
p
p
r
ess
io
n
[
2
0
]
-
[
2
6
]
.
T
h
ese
ad
v
er
s
e
ef
f
ec
ts
u
n
d
er
s
co
r
e
th
e
im
p
o
r
ta
n
ce
o
f
b
ala
n
cin
g
ef
f
icac
y
an
d
s
af
ety
th
r
o
u
g
h
in
d
iv
id
u
alize
d
d
o
s
in
g
s
tr
ateg
ies,
s
u
g
g
esti
n
g
t
h
at
tacr
o
lim
u
s
th
e
r
ap
y
r
e
q
u
ir
es
o
n
g
o
in
g
r
ee
v
al
u
atio
n
as n
ew
ev
id
en
ce
em
er
g
e
s
.
Desp
ite
ex
ten
s
iv
e
clin
ical
ex
p
er
ien
ce
with
tac
r
o
lim
u
s
,
f
ew
r
ev
iews
h
av
e
s
y
n
th
esized
r
ec
e
n
t
ev
id
en
ce
o
n
b
o
th
its
ef
f
icac
y
a
n
d
lo
n
g
-
ter
m
s
af
ety
,
p
ar
ticu
l
ar
ly
ac
r
o
s
s
d
iv
er
s
e
p
o
p
u
la
t
io
n
s
an
d
ev
o
lv
in
g
im
m
u
n
o
s
u
p
p
r
ess
iv
e
p
r
ac
tices
[
2
7
]
.
E
x
is
tin
g
r
e
v
iews
h
av
e
al
s
o
n
o
t
f
u
lly
ad
d
r
ess
ed
th
e
s
af
e
ty
co
n
ce
r
n
s
r
elate
d
to
lo
n
g
-
te
r
m
co
m
p
licatio
n
s
,
s
u
ch
as
m
etab
o
lic,
i
n
f
ec
tio
u
s
,
an
d
n
e
u
r
o
to
x
ic
ef
f
ec
ts
,
th
at
h
av
e
b
ec
o
m
e
m
o
r
e
ev
id
en
t
in
co
n
tem
p
o
r
ar
y
s
tu
d
ies
[
2
8
]
-
[
3
0
]
.
Mo
r
eo
v
e
r
,
m
an
y
p
r
io
r
s
u
m
m
ar
ies
f
o
cu
s
o
n
r
estricte
d
o
u
tco
m
es,
o
ld
er
d
atasets
,
o
r
s
in
g
le
p
atien
t
g
r
o
u
p
s
,
leav
in
g
clin
ician
s
with
o
u
t
a
co
m
p
r
eh
e
n
s
iv
e
p
ictu
r
e
o
f
h
o
w
b
en
ef
its
an
d
r
is
k
s
v
ar
y
ac
r
o
s
s
clin
ical
s
ettin
g
s
.
T
h
is
lack
o
f
u
p
d
at
ed
an
d
i
n
teg
r
ated
ev
id
e
n
ce
c
o
m
p
licates
clin
ical
d
ec
is
io
n
-
m
ak
in
g
,
esp
ec
ially
wh
en
clin
ician
s
m
u
s
t
b
alan
c
e
r
ejec
tio
n
p
r
ev
e
n
tio
n
with
th
e
r
is
k
s
o
f
o
v
er
t
im
m
u
n
o
s
u
p
p
r
ess
io
n
.
Sev
er
al
s
y
s
tem
atic
an
d
n
ar
r
at
iv
e
r
ev
iews
h
a
v
e
e
x
am
in
ed
t
ac
r
o
lim
u
s
th
er
a
p
y
o
v
er
th
e
p
ast
d
ec
ad
e
.
Ho
wev
er
,
th
ese
s
y
n
t
h
eses
ty
p
ically
ad
d
r
ess
s
p
ec
if
ic
asp
ec
ts
-
s
u
ch
as
d
e
n
o
v
o
im
m
u
n
o
s
u
p
p
r
ess
iv
e
r
eg
im
en
s
,
f
o
r
m
u
latio
n
co
m
p
ar
is
o
n
s
,
o
r
l
o
n
g
-
ter
m
o
u
tco
m
es
-
r
at
h
er
th
a
n
p
r
o
v
id
i
n
g
a
u
n
if
ied
ev
al
u
atio
n
o
f
co
n
tem
p
o
r
a
r
y
ev
id
en
ce
ac
r
o
s
s
ef
f
icac
y
,
s
af
et
y
,
p
h
ar
m
ac
o
lo
g
ic
v
ar
iab
ilit
y
,
an
d
r
ea
l
-
wo
r
l
d
clin
ical
d
ata
[
2
1
]
,
[
2
7
]
,
[
3
1
]
,
[
3
2
]
.
C
o
n
s
eq
u
en
tly
,
n
o
r
ev
iew
h
as
y
et
co
n
s
o
lid
ated
f
in
d
in
g
s
f
r
o
m
th
e
m
o
s
t
r
ec
en
t
d
ec
ad
e
(
2
0
1
5
-
2
0
2
5
)
,
a
p
er
io
d
m
ar
k
ed
b
y
m
ajo
r
ad
v
an
ce
s
in
tr
an
s
p
lan
t
ca
r
e
an
d
th
e
a
v
ailab
ilit
y
o
f
in
cr
ea
s
in
g
l
y
d
iv
e
r
s
e
g
lo
b
al
p
atien
t
d
ata.
T
h
is
g
ap
u
n
d
er
s
co
r
es
th
e
n
ee
d
f
o
r
a
b
r
o
a
d
an
d
co
n
tem
p
o
r
ar
y
s
y
n
th
esis
to
g
u
id
e
in
d
iv
id
u
alize
d
,
ev
id
en
ce
-
b
ased
d
ec
is
io
n
-
m
ak
i
n
g
in
c
u
r
r
en
t tr
an
s
p
lan
t p
r
ac
tice.
T
h
er
ef
o
r
e,
th
is
n
ar
r
ativ
e
r
e
v
iew
aim
s
to
s
u
m
m
ar
ize
r
ec
en
t
ev
id
en
ce
o
n
t
h
e
ef
f
icac
y
a
n
d
s
af
ety
o
f
tacr
o
lim
u
s
in
a
d
u
lt
k
i
d
n
ey
tr
a
n
s
p
lan
t
r
ec
ip
ien
ts
,
i
d
en
tify
k
e
y
f
ac
to
r
s
co
n
tr
ib
u
tin
g
to
clin
i
ca
l
v
ar
iab
ilit
y
,
a
n
d
h
ig
h
lig
h
t
p
er
s
is
ten
t
g
ap
s
th
at
r
eq
u
ir
e
f
u
r
th
er
in
v
esti
g
atio
n
.
T
h
is
wo
r
k
co
n
tr
ib
u
tes
s
ev
er
al
ad
v
an
ce
s
th
at
d
is
tin
g
u
is
h
it
f
r
o
m
p
r
io
r
s
y
n
t
h
eses
.
First,
it
p
r
esen
ts
an
u
p
d
ated
an
d
c
o
m
p
r
e
h
en
s
iv
e
e
v
a
lu
atio
n
o
f
e
v
id
en
ce
f
r
o
m
2
0
1
5
–
2
0
2
5
,
ca
p
tu
r
in
g
t
h
e
m
o
s
t
r
ec
en
t
d
ec
ad
e
d
u
r
in
g
wh
ich
s
ig
n
if
ican
t
ad
v
a
n
ce
s
h
av
e
o
cc
u
r
r
ed
i
n
tr
an
s
p
lan
t
m
an
a
g
em
en
t.
Seco
n
d
,
t
h
is
r
ev
iew
o
f
f
er
s
a
q
u
an
ti
tativ
e
co
n
s
o
lid
atio
n
o
f
k
ey
ef
f
icac
y
a
n
d
s
af
ety
o
u
tco
m
es
,
in
clu
d
i
n
g
ac
u
te
r
ej
ec
tio
n
,
b
io
p
s
y
-
p
r
o
v
en
r
ejec
tio
n
,
g
r
af
t
lo
s
s
,
m
o
r
tality
,
c
y
to
m
eg
alo
v
ir
u
s
(
C
MV
)
in
f
ec
tio
n
,
n
ew
-
o
n
s
et
d
iab
etes
af
ter
tr
an
s
p
lan
tatio
n
(
NODA
T
)
,
an
d
tr
em
o
r
,
allo
win
g
r
ea
d
er
s
to
d
ir
ec
tly
co
m
p
ar
e
n
u
m
er
ical
r
a
n
g
es
a
cr
o
s
s
s
tu
d
ies
r
ath
er
th
an
r
el
y
o
n
d
escr
ip
tiv
e
s
u
m
m
a
r
ies
alo
n
e.
T
h
ir
d
,
b
y
in
teg
r
atin
g
f
in
d
in
g
s
ac
r
o
s
s
d
iv
er
s
e
tacr
o
lim
u
s
f
o
r
m
u
latio
n
s
an
d
im
m
u
n
o
s
u
p
p
r
ess
iv
e
r
e
g
im
en
s
,
th
e
r
ev
iew
h
ig
h
lig
h
ts
r
e
g
im
en
-
s
p
ec
if
ic
p
atter
n
s
th
at
h
av
e
n
o
t
b
e
en
t
h
o
r
o
u
g
h
ly
ex
a
m
in
ed
i
n
ea
r
lier
wo
r
k
.
B
y
a
p
p
ly
in
g
a
th
em
atic
n
ar
r
ativ
e
s
y
n
t
h
esis
an
d
h
ig
h
lig
h
tin
g
v
ar
iab
ilit
y
a
cr
o
s
s
s
tu
d
y
d
esig
n
s
,
m
o
n
ito
r
in
g
s
tr
ateg
ies,
an
d
p
o
p
u
latio
n
ch
ar
ac
ter
is
tics
,
th
is
r
ev
iew
p
r
o
v
id
es a
m
o
r
e
in
teg
r
ated
u
n
d
er
s
tan
d
i
n
g
o
f
tacr
o
lim
u
s
p
er
f
o
r
m
a
n
ce
in
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
Ta
cro
limu
s
o
u
tco
mes in
a
d
u
lt
kid
n
ey
tr
a
n
s
p
la
n
ts
:
a
d
ec
a
d
e
r
ev
iew
(
Lo
lita
)
59
co
n
tem
p
o
r
ar
y
tr
a
n
s
p
lan
t
p
r
ac
t
ice.
T
h
e
s
ig
n
if
ican
ce
o
f
t
h
is
wo
r
k
lies
in
its
p
o
ten
tial
to
s
u
p
p
o
r
t
in
d
iv
id
u
alize
d
im
m
u
n
o
s
u
p
p
r
ess
iv
e
m
an
ag
e
m
en
t,
in
f
o
r
m
clin
ical
d
ec
is
io
n
-
m
ak
i
n
g
,
an
d
g
u
id
e
f
u
tu
r
e
r
esear
ch
to
war
d
im
p
r
o
v
in
g
tr
an
s
p
lan
t
o
u
tco
m
e
s
ac
r
o
s
s
d
iv
er
s
e
p
atien
t p
o
p
u
la
tio
n
s
.
2.
M
E
T
H
O
D
2
.
1
.
Sea
rc
h str
a
t
eg
y
a
nd
da
t
a
s
o
urce
s
T
h
is
n
ar
r
ativ
e
r
ev
iew
was
co
n
d
u
cted
to
s
y
n
th
esize
r
ec
en
t
ev
id
en
ce
o
n
th
e
ef
f
icac
y
an
d
s
af
ety
o
f
tacr
o
lim
u
s
in
ad
u
lt
k
id
n
ey
tr
an
s
p
lan
t
r
ec
ip
ien
ts
.
Pu
b
Me
d
was
s
elec
ted
a
s
th
e
p
r
im
ar
y
d
atab
ase
d
u
e
to
its
co
m
p
r
eh
e
n
s
iv
e
a
n
d
au
th
o
r
itativ
e
in
d
e
x
in
g
o
f
b
i
o
m
ed
ical,
clin
ical,
p
h
ar
m
ac
o
lo
g
ical,
an
d
tr
an
s
p
la
n
t
-
r
elate
d
s
tu
d
ies,
wh
ich
alig
n
s
d
ir
ec
tly
with
th
e
s
co
p
e
o
f
th
is
r
e
v
iew
[
3
3
]
.
Ad
d
itio
n
al
d
atab
ases
with
o
v
er
lap
p
in
g
co
v
er
ag
e
wer
e
s
cr
e
en
e
d
to
en
s
u
r
e
co
m
p
leten
ess
.
Pu
b
M
ed
in
clu
d
es
ME
DL
I
NE
-
in
d
e
x
ed
clin
ical
tr
ials
,
o
b
s
er
v
atio
n
al
s
tu
d
ies,
tr
a
n
s
p
lan
t
r
eg
is
tr
ies,
an
d
p
h
ar
m
ac
o
t
h
er
ap
y
r
esear
ch
th
at
a
r
e
ess
en
tial
f
o
r
e
v
alu
atin
g
tacr
o
lim
u
s
o
u
tco
m
es.
T
o
en
s
u
r
e
c
o
m
p
leten
ess
an
d
av
o
id
p
o
ten
tial
d
ata
b
ase
b
ias,
we
also
s
cr
ee
n
ed
ad
d
itio
n
al
d
atab
ases
with
o
v
er
lap
p
in
g
co
v
er
ag
e
(
s
u
ch
as
Go
o
g
le
Sch
o
lar
a
n
d
Se
m
an
tic
Sch
o
lar
)
to
co
n
f
ir
m
t
h
at
n
o
m
ajo
r
s
tu
d
ies
wer
e
m
is
s
ed
.
Ho
wev
er
,
Pu
b
Me
d
r
em
ain
ed
t
h
e
ce
n
tr
al
s
o
u
r
ce
d
u
e
t
o
its
m
eth
o
d
o
l
o
g
ic
al
co
n
s
is
ten
cy
,
h
ig
h
-
q
u
ality
p
ee
r
-
r
ev
iewe
d
co
n
te
n
t
,
an
d
s
tan
d
ar
d
ize
d
in
d
ex
in
g
,
wh
ich
s
u
p
p
o
r
t
m
o
r
e
r
eliab
le
s
cr
ee
n
in
g
with
in
th
e
tim
ef
r
am
e.
T
h
e
s
ea
r
ch
c
o
v
er
e
d
s
tu
d
ies
p
u
b
lis
h
ed
b
etwe
en
2
0
1
5
to
2
0
2
5
u
s
in
g
th
e
f
o
llo
wi
n
g
Me
d
ical
Su
b
ject
Hea
d
in
g
s
(
Me
SH)
k
ey
wo
r
d
s
a
n
d
B
o
o
lean
c
o
m
b
in
at
io
n
s
:
(
“k
id
n
ey
tr
a
n
s
p
lan
tatio
n
”
[
Me
SH
T
er
m
s
]
OR
“r
en
al
tr
an
s
p
lan
tatio
n
”
[
Me
SH T
er
m
s
]
)
AND
“T
ac
r
o
lim
u
s
”
[
Me
SH T
er
m
s
]
AND
(
“tr
ea
tm
en
t”
[
Me
SH T
er
m
s
]
)
.
A
n
ar
r
ativ
e
r
ev
iew
ap
p
r
o
ac
h
was
s
elec
ted
f
o
r
th
is
s
tu
d
y
d
u
e
to
th
e
s
u
b
s
tan
tial
h
eter
o
g
en
eity
am
o
n
g
th
e
in
cl
u
d
ed
ar
ticles.
T
h
e
s
tu
d
ies
v
ar
ied
wid
ely
in
d
esig
n
(
r
an
d
o
m
ized
tr
ials
,
p
r
o
s
p
ec
tiv
e
co
h
o
r
ts
,
r
etr
o
s
p
ec
tiv
e
an
aly
s
es),
p
o
p
u
latio
n
ch
ar
ac
ter
is
tics
,
tacr
o
lim
u
s
f
o
r
m
u
latio
n
s
,
co
n
c
o
m
itan
t
im
m
u
n
o
s
u
p
p
r
ess
iv
e
r
eg
im
en
s
,
o
u
tco
m
e
d
e
f
in
itio
n
s
,
r
ep
o
r
tin
g
o
f
tr
o
u
g
h
co
n
ce
n
tr
atio
n
s
,
an
d
f
o
llo
w
-
u
p
d
u
r
atio
n
s
.
T
h
ese
d
if
f
er
en
ce
s
m
ad
e
it
m
eth
o
d
o
lo
g
ically
in
ap
p
r
o
p
r
iate
to
p
o
o
l
d
ata
q
u
an
titativ
ely
o
r
ap
p
ly
a
m
eta
-
an
aly
tic
m
o
d
el,
as
s
tatis
tical
ag
g
r
eg
ati
o
n
wo
u
ld
r
is
k
g
en
er
atin
g
m
is
lead
in
g
o
r
n
o
n
in
ter
p
r
etab
le
s
u
m
m
ar
y
esti
m
ates.
Alth
o
u
g
h
s
tr
u
ctu
r
e
d
f
r
am
ewo
r
k
s
s
u
ch
as
PR
I
SM
A
o
f
f
er
s
ta
n
d
ar
d
ized
p
r
o
ce
d
u
r
es
f
o
r
s
y
s
tem
atic
r
ev
iews,
th
e
o
b
jectiv
e
o
f
th
is
wo
r
k
was
to
in
teg
r
ate
d
iv
er
s
e
ev
id
e
n
ce
,
h
ig
h
lig
h
t
clin
ical
p
atter
n
s
,
an
d
lin
k
f
in
d
in
g
s
with
p
h
ar
m
ac
o
l
o
g
ical
m
ec
h
a
n
is
m
s
,
aim
s
th
at
ar
e
b
etter
s
u
ited
to
th
em
atic
n
ar
r
ativ
e
s
y
n
t
h
esis
.
T
h
is
r
atio
n
ale
h
as
n
o
w
b
ee
n
clea
r
ly
ar
ticu
lated
t
o
en
h
a
n
ce
tr
an
s
p
ar
e
n
cy
r
e
g
ar
d
in
g
th
e
ch
o
s
en
m
eth
o
d
o
lo
g
ical
ap
p
r
o
ac
h
.
2
.
2
.
E
lig
ibi
lity
cr
it
er
ia
a
nd
s
t
ud
y
s
elec
t
io
n
Stu
d
ies
wer
e
in
clu
d
ed
i
f
th
ey
:
i
)
in
v
o
l
v
ed
a
d
u
lt
k
id
n
ey
tr
a
n
s
p
lan
t
r
ec
ip
ien
ts
,
ii
)
e
v
alu
ated
t
ac
r
o
lim
u
s
ef
f
icac
y
an
d
s
af
ety
,
eith
er
with
o
r
with
o
u
t
a
co
m
p
ar
is
o
n
g
r
o
u
p
,
iii
)
wer
e
o
r
ig
in
al
r
esear
ch
ar
ticles,
an
d
iv
)
wer
e
av
ailab
le
as
o
p
en
-
ac
ce
s
s
f
u
ll
tex
ts
.
E
x
clu
s
io
n
cr
it
er
ia
wer
e:
p
e
d
iatr
ic
p
o
p
u
lati
o
n
s
,
ca
s
e
r
e
p
o
r
ts
,
ed
ito
r
ials
,
n
o
n
-
E
n
g
lis
h
p
u
b
lic
atio
n
s
,
an
d
s
tu
d
ies
with
o
u
t
ta
cr
o
lim
u
s
-
s
p
ec
if
ic
o
u
tc
o
m
es.
Ad
d
itio
n
al
r
elev
a
n
t
s
tu
d
ies
wer
e
id
en
tifie
d
th
r
o
u
g
h
m
an
u
al
r
ef
er
e
n
ce
s
cr
ee
n
i
n
g
o
f
s
elec
ted
f
u
ll
-
tex
t
ar
tic
les.
Fo
llo
win
g
th
e
ex
am
in
atio
n
o
f
r
e
f
er
en
ce
s
f
r
o
m
th
e
s
elec
ted
f
u
ll
-
tex
t
ar
ticles,
ad
d
itio
n
al
s
tu
d
ies
wer
e
in
co
r
p
o
r
ate
d
u
s
in
g
id
en
tical
in
clu
s
io
n
cr
iter
ia.
T
h
is
r
ev
iew
also
co
n
s
id
er
ed
p
h
ase
I
I
,
I
I
I
,
o
r
I
V
clin
ical
tr
ials
th
at
ev
alu
ate
th
e
ef
f
ec
tiv
en
ess
an
d
s
af
ety
o
f
t
ac
r
o
lim
u
s
as
an
im
m
u
n
o
s
u
p
p
r
ess
iv
e
tr
ea
tm
en
t
in
k
id
n
ey
tr
an
s
p
lan
t
p
atien
ts
.
Ph
ase
I
I
tr
ials
wer
e
an
aly
ze
d
m
ain
ly
f
o
r
p
r
elim
in
ar
y
ef
f
icac
y
s
ig
n
als,
d
o
s
e
–
r
esp
o
n
s
e
p
atter
n
s
,
an
d
ea
r
l
y
s
af
ety
o
b
s
er
v
atio
n
s
.
Ph
ase
I
I
I
tr
ials
wer
e
co
m
p
ar
ed
th
em
atica
lly
t
o
ev
alu
ate
co
n
f
ir
m
e
d
ef
f
icac
y
,
r
ejec
tio
n
o
u
tco
m
es,
an
d
s
tan
d
a
r
d
ized
s
af
ety
e
n
d
p
o
in
ts
.
Ph
ase
I
V
a
n
d
r
ea
l
-
wo
r
ld
s
tu
d
ies
wer
e
s
y
n
th
esized
t
o
ass
ess
lo
n
g
-
ter
m
to
ler
ab
ilit
y
,
ad
v
e
r
s
e
-
ev
en
t
v
a
r
iab
ilit
y
,
an
d
ef
f
ec
tiv
en
ess
in
r
o
u
tin
e
clin
ical
p
r
ac
tice.
T
h
ese
f
in
d
in
g
s
wer
e
t
h
en
in
teg
r
ated
n
ar
r
ativ
ely
,
r
ath
e
r
th
an
n
u
m
er
ically
,
to
id
e
n
tify
co
n
s
is
ten
t
p
atter
n
s
ac
r
o
s
s
p
h
a
s
es
(
e.
g
.
,
r
ejec
tio
n
co
n
tr
o
l,
m
eta
b
o
lic
co
m
p
licatio
n
s
)
wh
ile
r
esp
ec
tin
g
th
e
m
eth
o
d
o
lo
g
ical
d
if
f
er
en
ce
s
o
f
ea
ch
t
r
ial
ty
p
e.
2
.
3
.
Da
t
a
e
x
t
ra
ct
i
o
n
As
th
is
was
a
n
ar
r
ativ
e
r
ev
iew,
n
o
f
o
r
m
al
p
r
o
to
co
l
r
e
g
is
tr
atio
n
o
r
s
y
s
tem
atic
PR
I
S
MA
-
b
ased
s
cr
ee
n
in
g
was
u
n
d
e
r
tak
en
.
I
n
s
tead
,
r
elev
an
t
s
tu
d
ies
wer
e
s
elec
ted
b
ased
o
n
t
h
eir
s
cien
tific
r
elev
an
ce
an
d
m
eth
o
d
o
l
o
g
ical
q
u
ality
to
p
r
o
v
id
e
a
co
m
p
r
eh
e
n
s
iv
e
o
v
er
v
iew
o
f
th
e
cu
r
r
en
t
ev
id
en
ce
.
T
h
e
s
elec
tio
n
p
r
o
ce
s
s
in
v
o
lv
ed
r
e
v
iewin
g
titl
es,
ab
s
t
r
ac
ts
,
an
d
f
u
ll tex
ts
to
en
s
u
r
e
s
u
itab
ilit
y
f
o
r
th
e
in
clu
s
io
n
cr
iter
ia.
T
h
e
d
ata
wer
e
th
en
ex
tr
ac
te
d
d
escr
ip
tiv
ely
,
f
o
cu
s
in
g
o
n
t
h
e:
i
)
s
tu
d
y
ch
a
r
ac
ter
is
tics
:
d
esig
n
,
s
ettin
g
,
a
n
d
s
am
p
le
s
ize;
ii
)
in
ter
v
en
tio
n
d
etails:
tacr
o
lim
u
s
r
eg
im
en
,
d
u
r
atio
n
,
an
d
co
m
p
ar
ato
r
d
r
u
g
s
(
if
ap
p
li
ca
b
le)
;
iii
)
clin
ical
o
u
tco
m
es: ef
f
icac
y
a
n
d
s
af
ety
en
d
p
o
i
n
ts
;
iv
)
k
ey
f
in
d
in
g
s
an
d
clin
ical
im
p
licatio
n
s
.
Fo
r
ea
ch
s
tu
d
y
in
clu
d
ed
,
d
ata
wer
e
ex
tr
ac
ted
o
n
s
tu
d
y
d
esig
n
,
p
o
p
u
latio
n
ch
ar
ac
ter
is
tics
,
tacr
o
lim
u
s
r
eg
im
en
,
ef
f
icac
y
,
an
d
s
af
ety
o
u
tco
m
es.
E
x
tr
ac
te
d
d
ata
w
er
e
r
ec
o
r
d
ed
in
s
tan
d
ar
d
ize
d
tab
les
to
s
u
p
p
o
r
t
co
m
p
ar
is
o
n
ac
r
o
s
s
s
tu
d
ies.
T
h
e
g
ath
er
ed
d
ata
wer
e
s
u
m
m
a
r
ized
an
d
o
r
g
an
ized
ac
c
o
r
d
i
n
g
to
m
ajo
r
o
u
tco
m
e
d
o
m
ain
s
,
in
clu
d
in
g
g
r
af
t f
u
n
ct
io
n
,
r
ejec
tio
n
r
ates,
p
atien
t su
r
v
iv
al,
an
d
ad
v
er
s
e
ef
f
ec
ts
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
15
,
No
.
1
,
M
ar
ch
20
26
:
57
-
71
60
2
.
4
.
Ana
ly
t
ica
l a
nd
s
y
nthesi
s
a
pp
ro
a
ch
A
th
em
atic
n
a
r
r
ativ
e
s
y
n
th
esis
was
ap
p
lied
to
in
teg
r
ate
f
i
n
d
in
g
s
ac
r
o
s
s
th
e
s
elec
ted
s
t
u
d
ies.
T
h
e
s
y
n
th
esis
p
r
o
ce
ed
ed
in
t
h
r
ee
s
tag
es:
i
)
th
em
atic
ca
teg
o
r
i
za
tio
n
,
in
wh
ich
s
tu
d
ies
wer
e
g
r
o
u
p
ed
in
to
k
ey
d
o
m
ain
s
in
clu
d
e
ef
f
icac
y
o
u
tco
m
es,
s
af
ety
,
an
d
f
ac
to
r
in
f
lu
en
cin
g
clin
ical
v
ar
iab
ilit
y
;
ii
)
n
ar
r
ativ
e
co
m
p
ar
is
o
n
,
wh
er
e
r
esu
lts
we
r
e
co
m
p
ar
ed
ac
r
o
s
s
s
tu
d
ies
with
in
ea
ch
th
em
atic
d
o
m
ai
n
to
id
en
tify
c
o
n
v
e
r
g
en
t
ev
id
en
ce
,
d
iv
e
r
g
en
t
f
in
d
in
g
s
,
an
d
p
o
ten
tial
ex
p
lan
ato
r
y
f
ac
to
r
s
;
an
d
iii
)
q
u
an
titativ
e
s
u
m
m
ar
y
,
in
wh
ic
h
n
u
m
er
ical
in
d
icat
o
r
s
,
s
u
ch
a
s
r
ates
o
f
ac
u
te
r
ejec
tio
n
,
i
n
cid
en
ce
o
f
ad
v
e
r
s
e
ev
en
ts
,
wer
e
s
u
m
m
ar
ized
d
escr
ip
tiv
ely
to
s
u
p
p
o
r
t
in
te
r
p
r
etatio
n
o
f
p
atter
n
s
id
e
n
tifie
d
in
th
e
th
e
m
atic
an
aly
s
is
[
3
4
]
,
[
3
5
]
.
T
h
e
r
esu
lts
wer
e
in
ter
p
r
eted
to
h
i
g
h
lig
h
t
th
e
p
atter
n
s
,
c
o
n
s
is
ten
cies,
an
d
g
a
p
s
in
th
e
e
x
is
tin
g
liter
atu
r
e
r
eg
a
r
d
in
g
th
e
clin
ical
p
er
f
o
r
m
an
ce
o
f
tacr
o
li
m
u
s
in
k
id
n
e
y
tr
an
s
p
lan
t
r
ec
ip
ien
ts
.
2
.
5
.
Na
rr
a
t
iv
e
qu
a
lity
a
pp
ra
is
a
l
A
b
r
ief
d
o
m
ai
n
-
b
ased
q
u
ality
ap
p
r
aisal wa
s
co
n
d
u
cted
to
e
n
h
an
ce
th
e
in
ter
p
r
etab
ilit
y
o
f
t
h
e
f
in
d
in
g
s
.
E
ac
h
in
clu
d
e
d
s
tu
d
y
was
ev
alu
ated
ac
r
o
s
s
s
ev
er
al
m
eth
o
d
o
lo
g
ical
cr
iter
ia:
clar
ity
o
f
s
tu
d
y
d
esig
n
a
n
d
p
o
p
u
latio
n
,
ad
e
q
u
ac
y
o
f
s
am
p
le
s
ize,
tr
an
s
p
ar
en
cy
in
r
ep
o
r
t
in
g
tacr
o
lim
u
s
d
o
s
in
g
,
co
m
p
l
eten
ess
o
f
ef
f
icac
y
an
d
s
af
ety
o
u
tco
m
e
r
e
p
o
r
tin
g
,
an
d
p
o
te
n
tial so
u
r
ce
s
o
f
b
ias s
u
ch
as c
o
n
f
o
u
n
d
in
g
o
r
s
elec
tio
n
b
ias
[
3
6
]
.
Ov
er
all,
r
an
d
o
m
ize
d
co
n
tr
o
lled
tr
ials
an
d
well
-
d
esig
n
ed
p
r
o
s
p
ec
tiv
e
co
h
o
r
ts
d
em
o
n
s
tr
ate
d
s
tr
o
n
g
er
m
eth
o
d
o
l
o
g
ical
clar
ity
,
with
ex
p
licit
d
escr
ip
tio
n
s
o
f
p
atien
t
p
o
p
u
latio
n
s
,
s
tan
d
a
r
d
ized
ta
cr
o
lim
u
s
r
e
g
im
en
s
,
an
d
co
m
p
r
e
h
en
s
iv
e
r
e
p
o
r
tin
g
o
f
b
o
th
e
f
f
icac
y
an
d
ad
v
e
r
s
e
ev
en
ts
.
T
h
ese
s
tu
d
ies
g
en
er
al
ly
ex
h
ib
ite
d
lo
wer
r
is
k
o
f
b
ias
an
d
p
r
o
v
id
ed
m
o
r
e
r
o
b
u
s
t
ev
id
en
c
e
r
eg
ar
d
in
g
th
e
ef
f
ec
ts
o
f
tacr
o
lim
u
s
o
n
r
ejec
tio
n
r
ates,
g
r
af
t
o
u
tco
m
es,
an
d
s
af
ety
p
r
o
f
iles
[
3
7
]
.
I
n
co
n
tr
ast,
s
ev
er
al
r
etr
o
s
p
e
ctiv
es
,
s
in
g
le
-
ce
n
ter
,
o
r
r
ea
l
-
wo
r
ld
o
b
s
er
v
atio
n
al
s
tu
d
ies
s
h
o
wed
m
eth
o
d
o
l
o
g
ical
lim
it
atio
n
s
,
in
clu
d
in
g
s
m
aller
s
am
p
le
s
izes,
in
co
n
s
is
ten
t
r
ep
o
r
tin
g
o
f
tr
o
u
g
h
co
n
ce
n
t
r
atio
n
s
o
r
d
o
s
in
g
ad
ju
s
tm
en
ts
,
an
d
in
co
m
p
lete
d
o
cu
m
e
n
tatio
n
o
f
s
af
ety
o
u
tco
m
es.
T
h
ese
g
ap
s
in
cr
e
ase
th
e
p
o
ten
tial
f
o
r
b
ias
an
d
m
ay
co
n
tr
i
b
u
te
to
t
h
e
h
eter
o
g
e
n
eity
o
b
s
er
v
ed
ac
r
o
s
s
s
tu
d
ies
[
3
8
]
.
T
h
e
p
u
r
p
o
s
e
o
f
th
is
ass
ess
m
en
t
i
s
n
o
t to
g
en
er
ate
a
f
o
r
m
al
s
co
r
e
o
r
h
ier
ar
ch
y
o
f
ev
id
en
ce
b
u
t to
h
ig
h
lig
h
t th
e
v
ar
iab
ilit
y
in
m
eth
o
d
o
lo
g
ical
r
ig
o
r
am
o
n
g
th
e
in
clu
d
ed
s
tu
d
ies.
R
ec
o
g
n
izin
g
th
ese
d
if
f
e
r
en
ce
s
is
es
s
en
tial f
o
r
co
n
tex
tu
alizin
g
t
h
e
r
ev
iew
f
in
d
in
g
s
an
d
u
n
d
er
s
tan
d
in
g
h
o
w
v
ar
iati
o
n
s
in
s
tu
d
y
d
esig
n
m
ay
in
f
lu
e
n
ce
r
ep
o
r
ted
clin
ical
o
u
tco
m
es
.
3.
RE
SU
L
T
S AN
D
D
I
SCU
SS
I
O
N
3
.
1
.
Rev
iew
o
f
t
he
re
s
ults o
f
t
he
a
rt
icles includ
e
d
A
liter
atu
r
e
s
ea
r
ch
o
f
t
h
e
Pu
b
Me
d
d
atab
ase,
c
o
v
er
in
g
th
e
la
s
t
1
0
y
e
ar
s
(
2
0
1
5
–
2
0
2
5
)
,
was
p
er
f
o
r
m
ed
an
d
ac
ce
s
s
ed
o
n
Ma
y
2
7
,
2
0
2
5
.
A
to
tal
o
f
9
1
r
elev
a
n
t,
o
p
en
-
ac
ce
s
s
ar
ticles
wer
e
in
itially
i
d
en
tifie
d
u
s
in
g
t
h
e
f
o
llo
win
g
Me
SH
T
er
m
s
:
(
k
i
d
n
ey
tr
a
n
s
p
lan
tatio
n
[
Me
SH
T
er
m
s
]
OR
r
en
al
tr
an
s
p
lan
tatio
n
[
Me
SH
T
er
m
s
]
)
AND
T
ac
r
o
lim
u
s
[
Me
SH T
er
m
s
]
AND
(
tr
ea
tm
en
t [
Me
SH T
er
m
s
]
)
.
Ar
ticles
wer
e
s
cr
ee
n
ed
ac
co
r
d
in
g
to
p
r
e
d
ef
in
ed
in
clu
s
io
n
cr
iter
ia.
Sev
en
ty
-
o
n
e
p
u
b
licat
io
n
s
wer
e
ex
clu
d
ed
f
o
r
th
e
f
o
llo
win
g
r
e
aso
n
s
:
lack
o
f
a
s
p
ec
if
ic
f
o
cu
s
o
n
tacr
o
lim
u
s
(
n
=
3
4
)
,
ab
s
en
ce
o
f
ef
f
icac
y
o
r
s
af
ety
ev
alu
atio
n
(
n
=
2
8
)
,
u
n
r
elate
d
to
k
i
d
n
ey
tr
an
s
p
lan
ta
tio
n
(
n
=
5
)
,
s
tu
d
y
d
u
r
atio
n
<6
m
o
n
th
s
(
n
=
2
)
,
p
o
p
u
latio
n
<1
8
y
ea
r
s
(
n
=
2
)
,
an
d
in
c
o
m
p
lete
d
ata
(
n
=
1
)
.
C
o
n
s
eq
u
en
tly
,
2
0
s
tu
d
ies f
u
lf
ill
ed
all
th
e
elig
ib
ilit
y
cr
iter
ia
an
d
wer
e
in
cl
u
d
ed
in
t
h
e
p
r
esen
t n
a
r
r
ativ
e
r
e
v
iew
(
Fig
u
r
e
1
)
.
B
ased
o
n
a
r
ev
iew
o
f
th
e
1
9
s
tu
d
ies
s
u
m
m
ar
ized
in
T
ab
le
1
,
m
o
s
t
tr
ials
em
p
lo
y
ed
an
o
p
en
-
lab
e
l
d
esig
n
(
n
=
1
9
)
,
wh
ich
f
ac
ili
tates
im
p
lem
en
tatio
n
b
u
t
m
a
y
in
tr
o
d
u
ce
p
er
ce
p
tio
n
b
ias.
On
ly
o
n
e
s
tu
d
y
b
y
R
o
s
tain
g
et
a
l
.
in
co
r
p
o
r
ated
a
b
lin
d
ed
d
esig
n
[
3
9
]
-
[
5
8
]
.
L
a
r
g
e
m
u
lticen
ter
in
v
esti
g
atio
n
s
,
in
clu
d
in
g
t
h
o
s
e
b
y
[
4
2
]
(
E
u
r
o
p
e,
n
=
1
,
1
9
8
)
an
d
[
4
5
]
(
m
u
lti
-
co
u
n
tr
y
,
n
=
8
6
1
)
,
h
a
v
e
d
em
o
n
s
tr
ated
th
e
g
lo
b
al
u
tili
za
tio
n
o
f
tacr
o
lim
u
s
.
T
h
e
m
aj
o
r
ity
o
f
s
tu
d
ies
co
m
p
ar
e
d
two
tr
ea
tm
e
n
t
ar
m
s
,
wh
er
ea
s
[
4
2
]
a
n
d
[
4
4
]
i
n
clu
d
ed
u
p
to
f
o
u
r
co
m
p
ar
ativ
e
g
r
o
u
p
s
.
E
x
ten
s
iv
e
m
u
lticen
ter
tr
ials
,
s
u
ch
a
s
th
o
s
e
b
y
[
4
6
]
en
co
m
p
ass
in
g
7
2
i
n
ter
n
atio
n
al
ce
n
ter
s
,
p
r
o
v
i
d
e
r
o
b
u
s
t
g
en
er
aliza
b
ilit
y
.
Ho
wev
er
,
th
e
p
r
e
d
o
m
in
an
ce
o
f
o
p
en
-
lab
el
d
es
ig
n
s
h
ig
h
lig
h
ts
th
e
n
ee
d
f
o
r
f
u
tu
r
e
tr
ials
with
s
tr
o
n
g
er
b
lin
d
i
n
g
to
r
e
d
u
ce
th
e
p
o
ten
tial
b
ias.
Alth
o
u
g
h
th
e
ef
f
i
ca
cy
o
f
tacr
o
lim
u
s
is
well
e
s
tab
lis
h
ed
g
lo
b
ally
,
f
u
r
th
er
r
esear
ch
em
p
h
asizin
g
lo
n
g
-
ter
m
s
af
ety
o
u
tco
m
es
an
d
r
ig
o
r
o
u
s
tr
ial
m
eth
o
d
o
l
o
g
y
r
em
ain
s
ess
en
tial to
s
u
p
p
o
r
t
ev
id
en
ce
-
b
ased
cli
n
ical
d
ec
is
io
n
s
(
T
ab
le
1
).
3
.
2
.
P
a
t
ient
dem
o
g
ra
ph
ics a
nd
cha
ra
ct
er
is
t
ics
T
a
b
l
e
2
p
r
e
s
e
n
ts
t
h
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d
e
m
o
g
r
a
p
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n
d
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l
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c
a
l
c
h
a
r
a
c
t
e
r
is
ti
c
s
o
f
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h
e
1
9
s
t
u
d
i
es
t
h
at
e
v
al
u
a
t
e
d
t
h
e
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a
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m
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s
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ased
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m
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n
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u
p
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iv
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im
en
s
.
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h
e
s
tu
d
y
p
o
p
u
latio
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s
h
o
wed
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n
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id
er
ab
l
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iatio
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,
with
a
me
an
ag
e
r
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g
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g
f
r
o
m
2
9
.
9
7
to
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9
.
6
y
ea
r
s
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n
d
a
m
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p
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o
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ce
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6
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m
o
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co
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ts
.
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h
e
m
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o
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y
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ass
in
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ex
(
B
MI
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r
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g
ed
f
r
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m
2
5
to
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9
k
g
/m
².
T
h
e
m
ajo
r
ity
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p
a
r
ticip
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ts
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ia
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>7
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ile
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ly
a
s
m
all
p
r
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tio
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ig
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ate
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Asi
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ar
g
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m
u
lticen
ter
tr
ials
,
s
u
ch
as
th
o
s
e
b
y
[
4
2
]
an
d
[
4
5
]
en
r
o
lled
t
h
o
u
s
an
d
s
o
f
p
atien
ts
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o
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ltip
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ies,
r
ef
lectin
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tac
r
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e,
wh
er
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s
m
aller
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g
le
-
o
r
d
u
al
-
ce
n
ter
s
tu
d
ies,
s
u
ch
as
[
4
0
]
an
d
[
5
8
]
in
v
o
lv
ed
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
Ta
cro
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s
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tco
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a
d
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lt
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a
n
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61
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atien
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s
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ap
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tic
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en
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ied
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b
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tially
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clu
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tan
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ar
d
tacr
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s
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STD
T
ac
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m
b
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atio
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s
with
m
y
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p
h
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o
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etil
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MM
F),
p
r
ed
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im
m
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iate
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R
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ed
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R
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ad
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en
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ch
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asil
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d
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r
tico
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ter
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h
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eg
im
en
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lect
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n
g
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ts
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o
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tim
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ef
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icac
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ile
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in
im
izin
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er
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e
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ec
ts
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Nev
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eless
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th
e
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r
e
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o
m
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ian
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ticip
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ies
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r
an
ts
ca
u
tio
n
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h
en
ex
tr
ap
o
latin
g
th
e
r
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lts
to
f
e
m
ale
an
d
Asi
an
p
o
p
u
latio
n
s
.
Var
iatio
n
s
in
th
e
d
em
o
g
r
ap
h
i
c
co
m
p
o
s
itio
n
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d
tr
ea
tm
en
t
p
r
o
t
o
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ls
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em
ain
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r
itical
f
o
r
in
ter
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etin
g
th
e
d
if
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er
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ce
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th
e
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f
icac
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d
s
af
ety
o
u
tco
m
es
o
f
tacr
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lim
u
s
th
er
ap
y
(
T
ab
le
2
)
.
Dif
f
er
en
ce
s
b
etwe
en
im
m
ed
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ate
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r
elea
s
e
an
d
p
r
o
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n
g
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d
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r
e
lease
tacr
o
lim
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s
f
o
r
m
u
latio
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s
p
r
o
v
id
e
im
p
o
r
tan
t
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tex
t
f
o
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n
d
e
r
s
tan
d
in
g
th
e
v
ar
iab
ilit
y
o
b
s
er
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ed
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th
e
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ted
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tco
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es.
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m
m
e
d
iate
-
r
elea
s
e
tacr
o
lim
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s
,
g
iv
en
twice
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aily
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is
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o
ciate
d
with
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r
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ter
p
ea
k
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o
u
g
h
f
lu
ct
u
atio
n
s
,
wh
ich
m
ay
co
n
tr
ib
u
te
to
n
eu
r
o
to
x
ic
ev
en
ts
s
u
ch
as
tr
e
m
o
r
an
d
i
n
cr
ea
s
e
th
e
r
is
k
o
f
s
u
b
th
er
ap
eu
tic
ex
p
o
s
u
r
e
lead
i
n
g
to
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ejec
tio
n
.
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n
co
n
tr
ast,
o
n
ce
-
d
aily
p
r
o
lo
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g
e
d
-
r
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s
e
f
o
r
m
u
latio
n
s
o
f
f
er
s
m
o
o
th
er
p
h
ar
m
ac
o
k
in
etic
p
r
o
f
iles
with
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ed
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ce
d
p
ea
k
c
o
n
ce
n
tr
atio
n
s
,
p
o
ten
tially
im
p
r
o
v
in
g
to
ler
a
b
ilit
y
an
d
ad
h
er
e
n
ce
[
5
9
]
,
[
6
0
]
.
Sev
e
r
al
s
tu
d
ies
in
clu
d
ed
in
th
is
r
ev
iew
s
h
o
wed
th
at
p
r
o
lo
n
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ed
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s
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o
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ated
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ar
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le
r
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n
r
ates
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m
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iate
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s
e
f
o
r
m
u
latio
n
s
b
u
t
with
lo
wer
r
ates
o
f
n
eu
r
o
to
x
icity
an
d
m
o
r
e
s
tab
le
t
r
o
u
g
h
le
v
els
[
4
5
]
,
[
6
0
]
.
T
h
ese
p
atter
n
s
ar
e
co
n
s
is
ten
t
with
estab
lis
h
ed
p
h
ar
m
ac
o
k
in
etic
th
eo
r
y
,
w
h
ich
p
r
ed
icts
th
at
r
e
d
u
ce
d
v
a
r
iab
ilit
y
in
ex
p
o
s
u
r
e
lead
s
to
im
p
r
o
v
e
d
s
a
f
ety
an
d
m
o
r
e
p
r
e
d
ictab
le
im
m
u
n
o
s
u
p
p
r
ess
iv
e
ef
f
ec
ts
.
T
h
e
in
teg
r
atio
n
o
f
th
ese
f
o
r
m
u
latio
n
-
s
p
ec
if
ic
f
in
d
in
g
s
ad
d
s
im
p
o
r
ta
n
t d
ep
th
to
th
e
in
t
er
p
r
etatio
n
o
f
th
e
tab
le
d
r
esu
lt
s
.
Fig
u
r
e
1
.
Flo
wch
ar
t
o
f
ar
ticle
s
ea
r
ch
an
d
id
e
n
tific
atio
n
3
.
3
.
E
f
f
ec
t
iv
eness
o
f
t
a
cr
o
lim
us
3
.
3
.
1
.
Acut
e
re
j
ec
t
io
n a
nd
bio
ps
y
-
pro
v
en
a
cut
e
re
j
ec
t
io
n
T
ab
le
3
(
s
ee
Ap
p
en
d
ix
)
s
u
m
m
ar
izes
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e
in
cid
en
ce
o
f
ac
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te
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ejec
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n
(
AR
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d
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p
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en
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te
r
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tio
n
(
B
PAR
)
ac
r
o
s
s
1
9
s
tu
d
ies
th
at
ev
alu
ated
v
ar
io
u
s
tacr
o
lim
u
s
-
b
ased
im
m
u
n
o
s
u
p
p
r
ess
iv
e
r
eg
im
en
s
.
Mo
s
t
tr
ials
ad
o
p
ted
an
in
ten
tio
n
-
to
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tr
ea
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(
I
T
T
)
ap
p
r
o
ac
h
an
d
r
ep
o
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te
d
a
f
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ll
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aly
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is
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et
(
FAS)
p
o
p
u
latio
n
.
T
h
e
in
cid
en
ce
o
f
B
PAR
v
ar
ies wid
ely
,
r
an
g
in
g
f
r
o
m
0
% to
2
3
.
5
%
[
4
2
]
,
[
4
7
]
,
[
5
0
]
.
I
n
a
m
u
lticen
ter
tr
ial
b
y
Alb
a
n
o
et
a
l.
[
4
2
]
,
th
e
B
PAR
r
ate
r
ea
ch
ed
1
9
.
6
%
in
t
h
e
ex
te
n
d
ed
-
cr
iter
ia
d
o
n
o
r
(
E
C
D)
g
r
o
u
p
r
ec
ei
v
in
g
a
p
r
o
lo
n
g
ed
-
r
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s
e
(
PR
)
tacr
o
lim
u
s
0
.
3
m
g
/
k
g
+
m
y
c
o
p
h
en
o
late
m
o
f
etil
+
co
r
tico
s
ter
o
id
r
eg
im
en
.
T
h
is
h
ig
h
er
r
ate
was
attr
ib
u
ted
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o
th
e
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r
ea
ter
h
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in
ju
r
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c
o
m
m
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ly
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E
C
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m
p
ar
e
d
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r
iter
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d
o
n
o
r
(
SC
D)
g
r
af
ts
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wh
ich
co
n
tr
ib
u
tes
to
p
o
o
r
er
p
o
s
t
-
tr
an
s
p
lan
t
r
en
al
f
u
n
ctio
n
.
Mo
r
eo
v
e
r
,
r
ec
ip
ien
ts
o
f
E
C
D
k
id
n
ey
s
ar
e
t
y
p
ically
o
ld
er
an
d
h
a
v
e
ad
d
it
io
n
al
co
m
o
r
b
i
d
ities
th
at
p
r
ed
is
p
o
s
e
th
em
to
u
n
f
av
o
r
ab
le
o
u
tco
m
es
.
T
h
e
h
ig
h
est
B
PA
R
in
cid
en
ce
(
2
3
.
5
%)
o
c
cu
r
r
ed
in
th
e
lo
w
-
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
15
,
No
.
1
,
M
ar
ch
20
26
:
57
-
71
62
d
o
s
e
tacr
o
lim
u
s
+
o
th
er
an
ti
h
y
p
er
ten
s
iv
e
th
e
r
ap
y
(
OAHT
)
g
r
o
u
p
co
m
p
ar
ed
to
t
h
e
n
o
n
-
AC
E
i/AR
B
-
b
ased
an
tih
y
p
er
ten
s
iv
e
r
eg
im
e
n
s
.
Gr
ea
ter
in
ter
s
titi
al
in
f
lam
m
atio
n
an
d
f
ib
r
o
s
is
in
th
e
OAHT
g
r
o
u
p
wer
e
th
o
u
g
h
t
to
u
n
d
er
lie
th
is
f
in
d
i
n
g
,
as
r
en
i
n
–
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g
i
o
ten
s
in
s
y
s
tem
in
h
ib
itio
n
in
th
e
AC
E
i/AR
B
g
r
o
u
p
m
iti
g
ated
T
ce
ll
-
m
ed
iated
r
ejec
tio
n
[
4
4
]
.
B
PA
R
-
f
r
ee
o
u
tco
m
es
(
0
%)
wer
e
r
ep
o
r
ted
i
n
two
s
tu
d
ies
u
tili
zin
g
im
m
ed
iate
-
r
elea
s
e
tacr
o
lim
u
s
(
I
R
-
T
ac
)
an
d
lo
w
-
d
o
s
e
tacr
o
lim
u
s
+
m
y
co
p
h
en
o
late
m
o
f
etil
+
p
r
ed
n
is
o
n
e
(
L
o
w
T
ac
+
MM
F
+
Pre
d
)
r
eg
im
e
n
s
[
4
7
]
,
[
5
0
]
.
T
h
e
f
a
v
o
r
ab
l
e
o
u
tco
m
es
in
th
e
I
R
-
T
ac
g
r
o
u
p
we
r
e
attr
ib
u
te
d
to
its
lo
wer
b
io
a
v
ailab
ilit
y
,
wh
ich
is
ass
o
ciate
d
with
r
ed
u
ce
d
p
o
s
t
-
tr
an
s
p
lan
t
ad
v
er
s
e
ef
f
ec
ts
an
d
im
p
r
o
v
ed
g
r
a
f
t
f
u
n
ctio
n
[
4
7
]
.
I
n
g
e
n
er
al,
th
ese
f
in
d
in
g
s
u
n
d
e
r
s
co
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m
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p
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k
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y
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a
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s
[
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4
]
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M
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lity
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ab
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3
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s
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m
m
ar
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d
p
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k
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ates
v
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ly
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r
an
g
in
g
f
r
o
m
0
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in
tr
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s
u
ch
as
[4
1]
,
wh
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h
ev
alu
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en
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to
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th
e
s
tu
d
y
b
y
[
5
5
]
.
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n
th
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s
tu
d
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b
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[
4
1
]
,
tacr
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lim
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s
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tr
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s
r
em
ain
ed
with
in
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[
5
5
]
r
ep
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with
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ased
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est
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if
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er
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ce
s
in
im
m
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p
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iv
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s
tr
ateg
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o
b
s
er
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s
,
an
d
b
aselin
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p
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t
ch
ar
ac
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is
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m
ay
in
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lu
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m
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ates.
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ir
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t
in
ter
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p
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ter
p
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with
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s
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th
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p
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p
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latio
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p
r
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f
iles
an
d
s
tu
d
y
d
esig
n
s
.
T
ab
le
1
.
L
is
t o
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s
tu
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u
t
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r
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c
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l
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B
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N
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t
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R
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g
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n
To
t
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samp
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s
O
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t
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f
f
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t
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n
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ss
S
a
f
e
t
y
o
u
t
c
o
me
G
r
o
u
p
[
4
0
]
-
O
p
e
n
-
l
a
b
e
l
1
c
e
n
t
e
r
s
N
e
t
h
e
r
l
a
n
d
s
40
Y
N
2
[
4
1
]
4
O
p
e
n
-
l
a
b
e
l
7
c
e
n
t
e
r
s
K
o
r
e
a
3
4
5
Y
N
2
[
4
2
]
3b
O
p
e
n
-
l
a
b
e
l
M
u
l
t
i
c
e
n
t
e
r
Eu
r
o
p
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1
1
9
8
Y
Y
4
[
4
3
]
-
O
p
e
n
-
l
a
b
e
l
4
c
e
n
t
e
r
s
K
o
r
e
a
77
Y
Y
2
[
4
4
]
3b
O
p
e
n
-
l
a
b
e
l
1
3
c
e
n
t
e
r
s
C
a
n
a
d
a
2
8
1
Y
N
4
[
4
5
]
3
O
p
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-
l
a
b
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l
M
u
l
t
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c
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t
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t
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t
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n
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l
8
6
1
Y
N
2
[
4
6
]
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O
p
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l
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b
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l
7
2
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t
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o
n
a
l
7
1
5
Y
Y
2
[
4
7
]
3
O
p
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l
a
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4
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c
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55
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N
2
[
4
8
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2
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2
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3
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c
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s
A
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st
r
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87
Y.
Y
2
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5
4
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20
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2
Evaluation Warning : The document was created with Spire.PDF for Python.
I
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Hea
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Sci
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N:
2252
-
8
8
0
6
Ta
cro
limu
s
o
u
tco
mes in
a
d
u
lt
kid
n
ey
tr
a
n
s
p
la
n
ts
:
a
d
ec
a
d
e
r
ev
iew
(
Lo
lita
)
63
T
ab
le
2
.
Ma
in
c
h
ar
ac
ter
is
tics
o
f
p
u
b
licatio
n
s
A
u
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h
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R
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i
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e
n
P
o
p
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l
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M
e
d
i
a
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(
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e
a
r
)
M
a
l
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(
%)
F
e
mal
e
(
%)
B
M
I
(
k
g
/
m²
)
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h
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(
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B
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/
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n
A
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(
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s
(
%)
[
4
0
]
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l
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[
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1
]
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[
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TA
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13
55
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-
Evaluation Warning : The document was created with Spire.PDF for Python.
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4
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Sa
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3
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4
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1
.
Cy
t
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eg
a
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v
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(
CM
V)
infe
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T
ab
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4
(
s
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Ap
p
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d
ix
)
s
u
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ar
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in
cid
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C
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by
[
4
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[
5
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all
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[
4
9
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ra
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(
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T
ab
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4
(
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ased
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2
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ies
[
4
2
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[
4
9
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.
L
ar
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as
Alb
an
o
et
a
l.
[4
2]
,
d
e
m
o
n
s
tr
ated
s
ig
n
if
ican
t
v
ar
iab
ilit
y
in
NODA
T
o
cc
u
r
r
en
ce
,
with
a
h
ig
h
er
i
n
cid
en
ce
o
b
s
er
v
ed
in
th
e
im
m
ed
iate
-
r
el
ea
s
e
tacr
o
lim
u
s
0
.
2
m
g
/k
g
+
MM
F
+
co
r
tic
o
s
ter
o
id
(
E
C
D)
r
eg
im
e
n
,
lik
ely
r
ela
ted
to
tacr
o
lim
u
s
-
in
d
u
ce
d
in
s
u
lin
r
esis
tan
ce
[
4
2
]
,
[
4
3
]
,
[
5
0
]
.
T
h
ese
f
in
d
in
g
s
s
u
g
g
est
th
at
th
e
im
m
u
n
o
s
u
p
p
r
ess
iv
e
r
eg
im
en
t
y
p
e,
tacr
o
lim
u
s
d
o
s
ag
e,
an
d
p
atien
t
-
s
p
ec
if
ic
m
etab
o
lic
p
r
o
f
iles
p
lay
cr
itical
r
o
les in
d
eter
m
i
n
in
g
th
e
r
is
k
o
f
NODA
T
.
3.
4
.
3
.
T
re
m
o
r
T
ab
le
4
(
s
ee
Ap
p
e
n
d
ix
)
p
r
esen
ts
th
e
d
ata
o
n
th
e
i
n
cid
en
c
e
o
f
tr
em
o
r
s
r
ep
o
r
ted
in
s
ev
e
r
al
s
tu
d
ies
ev
alu
atin
g
tacr
o
lim
u
s
-
b
ased
r
eg
im
en
s
.
I
n
th
e
6
-
m
o
n
th
tr
ia
l
b
y
[
4
2
]
,
tr
em
o
r
o
cc
u
r
r
ed
i
n
7
.
2
%
–
1
3
.
5
%
o
f
p
atien
ts
ac
r
o
s
s
g
r
o
u
p
s
r
ec
eiv
in
g
im
m
ed
iate
-
r
elea
s
e
tacr
o
lim
u
s
(
I
R
-
T
ac
0
.
2
/0
.
3
m
g
/k
g
)
a
n
d
p
r
o
lo
n
g
ed
-
r
elea
s
e
tacr
o
lim
u
s
(
PR
-
T
ac
0
.
2
m
g
/k
g
)
in
co
m
b
in
atio
n
with
MM
F
an
d
co
r
tico
s
ter
o
id
s
.
Qaz
i
et
a
l
.
[
5
4
]
r
ep
o
r
ted
a
h
ig
h
er
in
cid
en
ce
(
2
8
.
6
%)
wi
th
th
e
MM
F
+
s
tan
d
ar
d
tacr
o
lim
u
s
r
eg
im
e
n
o
v
er
1
2
m
o
n
th
s
,
wh
er
ea
s
[
5
5
]
o
b
s
er
v
ed
tr
em
o
r
r
ates
o
f
1
8
.
5
%
an
d
2
2
%
with
th
e
I
R
-
T
ac
an
d
L
C
PT
r
eg
im
en
s
,
r
esp
ec
tiv
ely
,
d
u
r
i
n
g
a
2
4
-
m
o
n
th
f
o
llo
w
-
up
.
T
h
e
h
ig
h
est
in
cid
en
ce
(
2
8
.
6
%)
w
as
o
b
s
er
v
ed
in
th
e
MM
F
+
s
tan
d
a
r
d
tacr
o
lim
u
s
g
r
o
u
p
[
5
4
]
.
T
r
em
o
r
i
n
th
ese
s
tu
d
ies
was
attr
ib
u
ted
to
tacr
o
lim
u
s
-
r
elate
d
n
eu
r
o
to
x
icity
af
f
ec
tin
g
th
e
ce
n
tr
al
n
er
v
o
u
s
s
y
s
tem
[
6
1
]
-
[
6
3
]
.
Alth
o
u
g
h
n
o
t
all
s
tu
d
ies
r
ep
o
r
ted
tr
em
o
r
d
ata,
th
e
av
ailab
le
ev
id
en
ce
in
d
ica
tes
th
at
n
eu
r
o
lo
g
ic
ad
v
er
s
e
ef
f
ec
ts
,
s
u
ch
as
tr
em
o
r
,
ca
n
o
cc
u
r
in
a
clin
ically
s
ig
n
if
ican
t
p
r
o
p
o
r
tio
n
o
f
p
atien
ts
r
ec
eiv
in
g
tacr
o
lim
u
s
,
with
v
ar
i
ab
le
f
r
eq
u
en
cy
ac
r
o
s
s
r
eg
im
en
s
.
T
h
e
v
ar
ia
b
ilit
y
o
b
s
er
v
e
d
in
a
cu
te
r
ejec
tio
n
a
n
d
b
io
p
s
y
-
p
r
o
v
en
ac
u
te
r
ejec
tio
n
r
ef
lects
f
u
n
d
am
en
tal
d
if
f
er
en
ce
s
i
n
im
m
u
n
o
l
o
g
ical
r
is
k
p
r
o
f
iles
,
ce
n
ter
-
s
p
ec
if
ic
p
r
o
to
co
ls
,
a
n
d
th
er
ap
e
u
tic
d
r
u
g
m
o
n
ito
r
in
g
(
T
DM
)
p
r
ac
tices
[
6
4
]
.
Fr
o
m
a
m
ec
h
a
n
is
tic
p
er
s
p
ec
tiv
e,
tacr
o
lim
u
s
ac
ts
b
y
in
h
ib
itin
g
ca
lcin
e
u
r
in
an
d
s
u
p
p
r
ess
in
g
I
L
-
2
–
m
ed
iated
T
-
ce
ll
ac
tiv
atio
n
;
th
er
ef
o
r
e,
in
a
d
eq
u
ate
t
r
o
u
g
h
lev
els
o
r
f
l
u
ctu
atin
g
d
r
u
g
ex
p
o
s
u
r
e
ca
n
lead
t
o
b
r
ea
k
th
r
o
u
g
h
r
ejec
tio
n
[
6
5
]
.
T
h
is
alig
n
s
with
p
r
ev
io
u
s
p
h
ar
m
ac
o
k
in
etic
s
tu
d
ies
d
em
o
n
s
tr
atin
g
th
at
tacr
o
lim
u
s
ex
h
ib
its
a
n
ar
r
o
w
th
er
a
p
eu
tic
in
d
ex
an
d
h
ig
h
in
ter
in
d
i
v
id
u
al
v
ar
iab
ilit
y
in
f
lu
en
ce
d
b
y
C
YP3
A5
g
en
o
ty
p
e
,
d
r
u
g
–
d
r
u
g
in
ter
ac
tio
n
s
,
an
d
a
d
h
er
en
ce
p
atter
n
s
[
6
6
]
.
T
h
ese
m
ec
h
an
is
tic
f
ac
to
r
s
h
elp
e
x
p
la
in
wh
y
ce
n
te
r
s
with
r
ig
o
r
o
u
s
T
DM
an
d
g
en
o
ty
p
e
-
i
n
f
o
r
m
e
d
d
o
s
in
g
r
ep
o
r
t lo
wer
r
ejec
tio
n
r
ates.
T
h
e
wid
e
r
an
g
e
o
f
g
r
af
t
lo
s
s
an
d
m
o
r
tality
p
ar
allels
f
in
d
in
g
s
f
r
o
m
lo
n
g
-
ter
m
tr
an
s
p
lan
t
r
eg
is
tr
ies,
wh
ich
r
ep
o
r
t
th
at
o
u
tco
m
es
d
ep
en
d
n
o
t
o
n
ly
o
n
im
m
u
n
o
s
u
p
p
r
ess
iv
e
p
o
ten
cy
b
u
t
also
o
n
ca
r
d
io
v
ascu
la
r
co
m
o
r
b
i
d
ities
,
in
f
ec
tio
n
co
n
tr
o
l,
an
d
ea
r
l
y
p
o
s
t
-
tr
an
s
p
lan
t
co
m
p
licatio
n
s
[
6
7
]
.
T
h
e
r
e
lati
v
ely
lo
w
m
o
r
tality
r
ates
ac
r
o
s
s
th
e
r
ev
iewe
d
s
t
u
d
ies
ar
e
co
n
s
is
ten
t
with
g
lo
b
al
im
p
r
o
v
em
e
n
ts
in
p
o
s
t
-
tr
an
s
p
lan
t
ca
r
e,
y
et
d
if
f
er
en
ce
s
in
f
o
llo
w
-
u
p
d
u
r
atio
n
an
d
p
atien
t r
is
k
p
r
o
f
iles
m
a
y
s
till
in
f
lu
en
ce
o
u
tc
o
m
es.
Saf
ety
ev
en
ts
also
d
em
o
n
s
tr
ated
s
u
b
s
tan
t
ial
h
eter
o
g
en
eity
.
C
MV
in
f
ec
tio
n
is
b
io
lo
g
icall
y
p
lau
s
ib
le
g
iv
en
th
at
ca
lcin
e
u
r
in
i
n
h
ib
ito
r
s
alter
ce
llu
lar
im
m
u
n
ity
an
d
m
ay
in
cr
ea
s
e
s
u
s
ce
p
tib
ilit
y
t
o
v
ir
al
r
ea
ctiv
atio
n
[
6
8
]
.
Similar
ly
,
th
e
in
ci
d
en
ce
o
f
NODA
T
s
u
p
p
o
r
ts
ex
is
tin
g
ev
id
en
ce
th
at
tacr
o
lim
u
s
im
p
a
ir
s
p
an
cr
ea
tic
β
-
ce
ll
f
u
n
ctio
n
a
n
d
r
ed
u
ce
s
in
s
u
lin
s
ec
r
etio
n
,
p
ar
ticu
lar
ly
at
h
ig
h
er
tr
o
u
g
h
co
n
ce
n
tr
atio
n
s
[
6
9
]
.
T
h
e
v
ar
iab
ilit
y
in
tr
em
o
r
r
ef
lects
th
e
n
eu
r
o
to
x
ic
p
o
ten
tial
o
f
tacr
o
lim
u
s
,
wh
ich
is
k
n
o
wn
to
co
r
r
elate
with
p
ea
k
lev
els
an
d
ce
n
tr
al
n
er
v
o
u
s
s
y
s
tem
p
en
etr
atio
n
[
7
0
]
.
T
h
ese
f
in
d
in
g
s
alig
n
with
p
r
io
r
co
m
p
ar
ativ
e
s
tu
d
ies
s
h
o
win
g
th
at
tacr
o
lim
u
s
h
as
a
h
ig
h
e
r
n
e
u
r
o
t
o
x
ic
an
d
d
iab
eto
g
en
ic
r
is
k
th
a
n
cy
clo
s
p
o
r
i
n
e
[
7
1
]
.
T
h
e
h
eter
o
g
e
n
eity
ac
r
o
s
s
ef
f
ic
ac
y
an
d
s
af
ety
o
u
tc
o
m
es
ca
n
b
e
in
ter
p
r
eted
th
r
o
u
g
h
a
co
m
b
in
atio
n
o
f
p
h
ar
m
ac
o
l
o
g
ical
th
eo
r
y
,
g
en
e
tic
v
ar
iab
ilit
y
,
d
if
f
er
en
ce
s
in
co
n
co
m
itan
t
im
m
u
n
o
s
u
p
p
r
ess
iv
e
r
eg
im
en
s
,
an
d
ce
n
ter
-
lev
el
p
r
ac
tices.
I
n
te
g
r
at
in
g
th
ese
elem
en
ts
p
r
o
v
i
d
es
a
m
o
r
e
co
h
e
r
en
t
u
n
d
er
s
tan
d
in
g
o
f
h
o
w
tacr
o
lim
u
s
p
er
f
o
r
m
s
ac
r
o
s
s
d
iv
er
s
e
clin
ical
s
ettin
g
s
an
d
h
ig
h
lig
h
ts
th
e
n
ee
d
f
o
r
in
d
iv
i
d
u
alize
d
d
o
s
in
g
s
tr
ateg
ies,
g
en
o
ty
p
e
-
g
u
i
d
ed
th
e
r
ap
y
,
an
d
s
tan
d
ar
d
ized
m
o
n
ito
r
in
g
p
r
o
to
co
ls
[
7
2
]
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
Ta
cro
limu
s
o
u
tco
mes in
a
d
u
lt
kid
n
ey
tr
a
n
s
p
la
n
ts
:
a
d
ec
a
d
e
r
ev
iew
(
Lo
lita
)
65
W
h
en
co
m
p
ar
ed
with
alter
n
ativ
e
im
m
u
n
o
s
u
p
p
r
ess
an
ts
,
tacr
o
lim
u
s
co
n
tin
u
es
to
d
em
o
n
s
tr
ate
s
u
p
er
io
r
r
ejec
tio
n
p
r
ev
e
n
tio
n
c
o
m
p
ar
e
d
with
cy
clo
s
p
o
r
i
n
e,
co
n
s
is
ten
t
with
f
in
d
in
g
s
f
r
o
m
m
aj
o
r
tr
ials
an
d
m
eta
-
an
aly
s
es.
Ho
wev
er
,
tacr
o
lim
u
s
is
a
s
s
o
ciate
d
wi
th
a
h
ig
h
er
r
is
k
o
f
n
eu
r
o
to
x
icity
an
d
NODA
T
,
wh
ile
cy
clo
s
p
o
r
in
e
ex
h
i
b
its
m
o
r
e
p
r
o
n
o
u
n
ce
d
co
s
m
etic
ad
v
e
r
s
e
ef
f
ec
ts
an
d
less
f
av
o
r
ab
le
g
r
a
f
t
-
s
u
r
v
iv
al
t
r
en
d
s
[
7
3
]
.
Me
an
wh
ile,
b
elata
ce
p
t
o
f
f
er
s
im
p
r
o
v
ed
r
en
al
f
u
n
ctio
n
an
d
m
etab
o
lic
p
r
o
f
iles
b
u
t
ca
r
r
ies
a
h
ig
h
er
ea
r
ly
r
ejec
tio
n
r
is
k
an
d
r
e
q
u
ir
es
in
t
r
av
en
o
u
s
ad
m
in
is
tr
atio
n
,
lim
itin
g
its
g
lo
b
al
ap
p
licab
ilit
y
[
7
4
]
.
I
n
cl
u
d
in
g
t
h
ese
co
m
p
ar
is
o
n
s
s
itu
ates
tacr
o
lim
u
s
with
in
th
e
b
r
o
ad
er
th
e
r
ap
e
u
tic
lan
d
s
ca
p
e
an
d
clar
if
ies
wh
y
it
r
em
ain
s
th
e
p
r
im
ar
y
a
g
en
t in
c
o
n
tem
p
o
r
ar
y
tr
an
s
p
lan
t p
r
ac
tice
d
esp
ite
r
e
co
g
n
ized
s
af
ety
ch
allen
g
es.
Ov
er
all,
wh
ile
tacr
o
lim
u
s
r
em
ain
s
a
p
r
im
ar
y
th
er
ap
y
f
o
r
im
p
r
o
v
in
g
g
r
af
t
an
d
p
atien
t
s
u
r
v
iv
al
in
k
id
n
ey
tr
an
s
p
lan
tatio
n
,
a
d
v
er
s
e
ef
f
ec
ts
,
in
clu
d
in
g
in
f
ec
tio
n
,
p
o
s
t
-
tr
an
s
p
lan
t
d
iab
etes,
a
n
d
tr
e
m
o
r
s
,
r
em
ai
n
m
ajo
r
clin
ical
ch
allen
g
es.
T
h
e
f
in
d
in
g
s
o
f
th
is
r
ev
iew
s
h
o
u
ld
b
e
in
ter
p
r
eted
ca
u
tio
u
s
ly
d
u
e
to
th
e
co
n
s
id
er
ab
le
h
eter
o
g
en
e
ity
ac
r
o
s
s
th
e
in
clu
d
ed
s
tu
d
ies.
W
h
ile
r
ed
u
ctio
n
s
in
ac
u
te
r
ejec
tio
n
wer
e
g
e
n
er
ally
co
n
s
is
ten
t,
th
e
wid
e
v
ar
iab
ilit
y
in
b
io
p
s
y
-
p
r
o
v
en
r
ejec
tio
n
,
g
r
af
t
lo
s
s
,
an
d
ad
v
er
s
e
ev
en
t
r
ates
r
ef
lects
d
if
f
er
en
ce
s
in
s
tu
d
y
d
esig
n
,
p
o
p
u
latio
n
ch
ar
ac
ter
i
s
tics
,
m
o
n
ito
r
in
g
s
tr
ateg
ies,
an
d
o
u
tco
m
e
d
ef
in
itio
n
s
.
T
h
ese
in
co
n
s
is
ten
cies
in
d
icate
th
at
th
e
r
esu
lts
r
ep
r
es
en
t o
v
er
all
tr
e
n
d
s
r
ath
er
t
h
an
d
ef
in
itiv
e
co
m
p
a
r
ativ
e
esti
m
ates.
L
o
n
g
-
te
r
m
s
af
et
y
o
u
t
c
o
m
es
al
s
o
v
ar
ie
d
s
u
b
s
ta
n
ti
all
y
,
p
ar
tic
u
la
r
l
y
r
e
g
a
r
d
i
n
g
c
h
r
o
n
ic
n
e
p
h
r
o
to
x
i
cit
y
,
C
MV
i
n
f
ec
t
io
n
,
a
n
d
N
ODA
T
,
wh
ic
h
w
er
e
i
n
f
l
u
e
n
c
ed
b
y
d
i
f
f
er
e
n
ce
s
i
n
f
o
ll
o
w
-
u
p
d
u
r
ati
o
n
,
p
r
o
p
h
y
l
a
x
is
p
r
o
t
o
co
ls
,
a
n
d
t
r
o
u
g
h
-
le
v
el
s
t
ab
i
lit
y
[
2
2
]
.
Ad
d
i
ti
o
n
all
y
,
tac
r
o
li
m
u
s
ex
p
o
s
u
r
e
is
h
i
g
h
l
y
a
f
f
ec
t
ed
b
y
d
r
u
g
–
d
r
u
g
in
t
er
ac
t
io
n
s
i
n
v
o
lv
in
g
C
YP3
A
4
/
5
m
o
d
u
l
at
o
r
s
a
n
d
b
y
p
h
a
r
m
a
co
g
e
n
o
m
ic
f
ac
t
o
r
s
s
u
ch
as
C
Y
P3
A
5
a
n
d
AB
C
B
1
p
o
l
y
m
o
r
p
h
is
m
s
[
7
5
]
.
T
h
ese
e
le
m
e
n
ts
c
o
n
t
r
i
b
u
te
to
i
n
t
er
p
a
tie
n
t
v
a
r
i
ab
ili
ty
i
n
ef
f
i
c
ac
y
a
n
d
to
x
i
cit
y
,
u
n
d
er
s
co
r
i
n
g
th
e
n
e
e
d
f
o
r
in
d
i
v
i
d
u
ali
ze
d
d
o
s
i
n
g
an
d
s
ta
n
d
a
r
d
ize
d
m
o
n
it
o
r
in
g
f
r
a
m
e
wo
r
k
s
[
7
6
]
.
F
u
t
u
r
e
r
es
ea
r
ch
s
h
o
u
l
d
m
o
v
e
b
e
y
o
n
d
d
es
c
r
i
p
t
iv
e
o
b
s
e
r
v
a
ti
o
n
al
w
o
r
k
a
n
d
i
n
c
o
r
p
o
r
at
e
m
o
r
e
r
i
g
o
r
o
u
s
s
t
u
d
y
d
esi
g
n
s
t
h
at
ca
n
cla
r
i
f
y
ca
u
s
al
it
y
an
d
r
e
d
u
ce
b
i
as.
M
u
lti
ce
n
t
er
r
a
n
d
o
m
i
ze
d
c
o
n
t
r
o
lle
d
t
r
ia
ls
wit
h
b
l
in
d
i
n
g
a
r
e
n
e
ed
e
d
to
e
v
al
u
at
e
tac
r
o
li
m
u
s
r
eg
im
e
n
s
a
cr
o
s
s
d
i
v
e
r
s
e
p
o
p
u
lat
io
n
s
a
n
d
h
ea
lt
h
ca
r
e
s
y
s
t
em
s
,
en
a
b
li
n
g
m
o
r
e
r
eli
ab
l
e
co
m
p
a
r
is
o
n
s
o
f
ef
f
ic
ac
y
a
n
d
s
a
f
e
ty
.
P
h
a
r
m
ac
o
g
e
n
o
m
i
c
in
v
esti
g
a
ti
o
n
s
,
p
a
r
ti
c
u
la
r
l
y
i
n
v
o
lv
in
g
C
YP
3
A
5
a
n
d
AB
C
B
1
p
o
l
y
m
o
r
p
h
is
m
s
,
s
h
o
u
l
d
b
e
e
x
p
a
n
d
e
d
t
o
s
u
p
p
o
r
t
i
n
d
iv
id
u
a
lize
d
d
o
s
i
n
g
al
g
o
r
i
th
m
s
an
d
ex
p
l
ai
n
i
n
t
er
p
atie
n
t
v
a
r
i
ab
ilit
y
[
1
7
]
.
A
d
d
iti
o
n
al
ly
,
co
m
p
a
r
at
iv
e
e
f
f
ec
ti
v
e
n
ess
tr
ial
s
th
at
i
n
c
lu
d
e
e
m
e
r
g
in
g
im
m
u
n
o
s
u
p
p
r
ess
a
n
ts
s
u
c
h
as
b
ela
tac
e
p
t
o
r
n
ex
t
-
g
e
n
er
a
tio
n
ca
l
ci
n
e
u
r
in
i
n
h
ib
it
o
r
s
—
m
a
y
c
la
r
i
f
y
wh
et
h
e
r
a
lte
r
n
at
iv
e
a
g
e
n
ts
p
r
o
v
i
d
e
ad
v
a
n
t
a
g
es
in
l
o
n
g
-
t
e
r
m
g
r
a
f
t
s
u
r
v
i
v
a
l
o
r
m
et
a
b
o
lic
s
a
f
et
y
.
R
e
al
-
wo
r
l
d
r
eg
is
t
r
y
-
b
as
ed
s
tu
d
ies
c
o
u
l
d
h
el
p
m
o
n
i
to
r
l
o
n
g
-
t
er
m
a
d
v
er
s
e
ev
en
ts
an
d
i
d
e
n
t
if
y
p
r
a
cti
ce
d
if
f
e
r
en
ce
s
a
cr
o
s
s
t
r
a
n
s
p
la
n
t
c
en
te
r
s
.
Fi
n
a
ll
y
,
im
p
le
m
e
n
t
ati
o
n
r
es
ea
r
c
h
is
n
e
ed
ed
t
o
e
v
al
u
a
te
h
o
w
s
ta
n
d
a
r
d
iz
e
d
t
h
er
ap
e
u
ti
c
d
r
u
g
m
o
n
it
o
r
i
n
g
a
n
d
g
e
n
o
t
y
p
e
-
g
u
i
d
e
d
d
o
s
i
n
g
ca
n
b
e
f
e
asi
b
l
y
i
n
te
g
r
a
te
d
in
to
c
li
n
ic
al
w
o
r
k
f
l
o
ws,
es
p
ec
ial
ly
i
n
r
eso
u
r
c
e
-
lim
i
ted
s
e
tti
n
g
s
.
4.
CO
NCLU
SI
O
N
T
ac
r
o
lim
u
s
co
n
tin
u
es
to
d
em
o
n
s
tr
ate
a
f
av
o
r
a
b
le
ef
f
i
ca
cy
-
s
af
ety
b
alan
ce
in
ad
u
lt
k
id
n
ey
tr
an
s
p
lan
tatio
n
,
y
e
t
its
clin
ical
p
er
f
o
r
m
an
ce
r
em
ain
s
h
eter
o
g
en
o
u
s
ac
r
o
s
s
p
o
p
u
latio
n
an
d
tr
ea
tm
en
t
s
ettin
g
s
.
T
h
ese
f
in
d
in
g
s
h
ig
h
lig
h
t th
e
n
ee
d
f
o
r
m
o
r
e
in
d
iv
id
u
alize
d
i
m
m
u
n
o
s
u
p
p
r
ess
iv
e
s
tr
ateg
ies,
in
clu
d
in
g
o
p
tim
ized
th
er
ap
eu
tic
d
r
u
g
m
o
n
ito
r
in
g
,
e
ar
ly
id
en
tific
atio
n
o
f
p
atie
n
ts
at
r
is
k
f
o
r
m
etab
o
lic
o
r
in
f
ec
tio
u
s
co
m
p
licatio
n
s
,
an
d
ca
r
ef
u
l
ad
j
u
s
tm
en
t
o
f
c
o
n
co
m
itan
t
im
m
u
n
o
s
u
p
p
r
ess
iv
e
r
eg
im
en
s
.
Fo
r
clin
ical
p
r
ac
tice,
co
n
s
is
ten
t
im
p
lem
en
tatio
n
o
f
s
tan
d
ar
d
iz
ed
tacr
o
lim
u
s
tar
g
et
le
v
els
an
d
in
teg
r
atio
n
o
f
p
h
ar
m
ac
o
g
e
n
o
m
ic
co
n
s
id
er
at
io
n
s
m
ay
im
p
r
o
v
e
p
atien
t
o
u
tco
m
e
s
an
d
r
ed
u
c
e
v
ar
iab
ilit
y
in
th
er
ap
y
r
esp
o
n
s
e.
Fro
m
a
p
o
licy
a
n
d
s
y
s
tem
p
er
s
p
ec
tiv
e,
s
tr
en
g
th
e
n
in
g
n
ati
o
n
al
an
d
r
e
g
io
n
al
tr
a
n
s
p
lan
t
r
eg
is
tr
ies,
im
p
r
o
v
in
g
ac
ce
s
s
to
h
ig
h
-
q
u
a
lity
lab
o
r
ato
r
y
m
o
n
ito
r
in
g
,
a
n
d
h
ar
m
o
n
izin
g
clin
ical
p
r
ac
t
ice
g
u
id
elin
es
will
h
elp
s
u
p
p
o
r
t
m
o
r
e
eq
u
itab
le
a
n
d
d
ata
-
d
r
iv
e
n
t
r
an
s
p
lan
t
ca
r
e.
E
x
p
a
n
d
in
g
tr
a
n
s
p
lan
t
d
ata
f
r
o
m
Asi
an
an
d
o
th
er
u
n
d
er
r
ep
r
esen
ted
p
o
p
u
latio
n
s
is
p
ar
ticu
lar
ly
im
p
o
r
tan
t
to
en
h
an
ce
g
lo
b
al
g
e
n
er
ab
izab
il
ity
an
d
en
s
u
r
e
th
at
d
o
s
in
g
r
ec
o
m
m
en
d
atio
n
s
r
e
f
lect
d
iv
er
s
e
g
e
n
etic
an
d
clin
ical
p
r
o
f
iles
.
T
h
is
r
ev
iew
also
ac
k
n
o
wled
g
es
s
ev
er
al
lim
itatio
n
s
with
in
th
e
a
v
ailab
le
liter
atu
r
e.
Ma
n
y
s
tu
d
ies
v
ar
ied
in
d
esig
n
,
h
a
d
r
elativ
ely
s
h
o
r
t
f
o
llo
w
-
u
p
d
u
r
atio
n
s
,
lac
k
ed
s
tan
d
a
r
d
ize
d
r
ep
o
r
tin
g
o
f
tr
o
u
g
h
c
o
n
ce
n
tr
atio
n
s
,
o
r
in
v
o
lv
ed
h
o
m
o
g
en
o
u
s
p
o
p
u
latio
n
s
,
p
r
ed
o
m
i
n
an
tly
C
au
ca
s
ian
c
o
h
o
r
ts
.
T
h
ese
lim
itatio
n
s
r
estrict
th
e
ec
ten
t
to
wh
ic
h
f
i
n
d
in
g
s
ca
n
b
e
ex
tr
ap
o
lated
to
b
r
o
ad
er
clin
ical
s
ettin
g
s
.
Fu
tu
r
e
r
esear
ch
s
h
o
u
ld
f
o
cu
s
o
n
lar
g
e,
m
u
lticen
ter
s
tu
d
ies
with
d
iv
er
s
e
p
o
p
u
latio
n
s
,
s
tan
d
ar
d
ized
m
o
n
ito
r
in
g
p
r
o
to
c
o
ls
,
an
d
l
o
n
g
e
r
-
ter
m
o
u
tco
m
e
ass
ess
m
en
t
to
r
ef
in
e
tac
r
o
lim
u
s
o
p
tim
izatio
n
an
d
s
u
p
p
o
r
t p
r
ec
i
s
io
n
-
b
ased
im
m
u
n
o
s
u
p
p
r
ess
iv
e
m
an
ag
em
e
n
t.
ACK
NO
WL
E
DG
M
E
N
T
S
W
e
g
r
a
t
ef
u
l
ly
a
ck
n
o
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