I
nte
rna
t
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na
l J
o
urna
l o
f
P
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c
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ea
lt
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(
I
J
P
H
S)
Vo
l.
15
,
No
.
2
,
J
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20
26
,
p
p
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605
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h
ttp
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//
ijp
h
s
.
ia
esco
r
e.
co
m
H
o
ney
as
an a
lter
na
tive wo
und h
ea
ling
t
hera
py
:
a
sy
stema
tic
revi
ew of
clinica
l
a
nd preclini
ca
l evidence
(20
2
0
–
2
0
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)
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ni K
u
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y
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i
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ticle
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Dec
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ev
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Acc
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l
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e
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lt
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c
a
re
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o
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n
e
y
h
a
s
b
e
e
n
in
c
re
a
sin
g
l
y
in
v
e
stig
a
t
e
d
a
s
a
c
o
m
p
lem
e
n
tary
wo
u
n
d
c
a
re
a
g
e
n
t
d
u
e
to
it
s
a
n
ti
m
icro
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ial,
a
n
ti
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i
n
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a
m
m
a
to
ry
,
a
n
d
w
o
u
n
d
-
h
e
a
li
n
g
p
ro
p
e
rti
e
s.
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is
sy
ste
m
a
ti
c
re
v
iew
a
ime
d
to
sy
n
t
h
e
siz
e
a
n
d
c
rit
ica
ll
y
e
v
a
lu
a
te
th
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u
rre
n
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id
e
n
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e
o
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t
h
e
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se
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f
h
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e
y
a
s
a
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a
lt
e
rn
a
ti
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e
w
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n
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tre
a
tme
n
t.
A
sy
ste
m
a
ti
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re
v
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s
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o
n
d
u
c
ted
f
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A
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ix
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tro
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ic
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a
tab
a
se
s
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c
o
p
u
s,
Na
tu
re
,
P
r
o
Qu
e
st,
EBS
CO,
S
p
ri
n
g
e
r
Li
n
k
,
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n
d
S
c
ien
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e
Dire
c
t)
we
re
se
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rc
h
e
d
u
sin
g
p
re
d
e
fin
e
d
se
a
rc
h
term
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stu
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ies
p
u
b
li
sh
e
d
b
e
twe
e
n
2
0
2
0
a
n
d
2
0
2
4
.
In
c
l
u
sio
n
c
rit
e
ria
e
n
c
o
m
p
a
ss
e
d
h
u
m
a
n
stu
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ies
,
m
ix
e
d
-
m
e
th
o
d
s
o
r
q
u
a
n
ti
tati
v
e
d
e
sig
n
s
,
a
n
d
in
terv
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n
ti
o
n
s
u
si
n
g
h
o
n
e
y
f
o
r
wo
u
n
d
c
a
re
.
S
t
u
d
y
q
u
a
li
ty
wa
s
a
ss
e
ss
e
d
u
sin
g
t
h
e
Jo
a
n
n
a
Bri
g
g
s
In
stit
u
te
(JBI)
c
rit
ica
l
a
p
p
ra
isa
l
t
o
o
ls.
F
ro
m
3
0
2
in
it
ially
i
d
e
n
ti
f
ied
a
rti
c
les
,
1
6
st
u
d
ies
m
e
t
th
e
i
n
c
lu
si
o
n
c
rit
e
r
ia
a
fter
re
m
o
v
in
g
d
u
p
li
c
a
tes
a
n
d
s
c
re
e
n
in
g
.
Th
e
i
n
c
lu
d
e
d
st
u
d
ies
c
o
m
p
rise
d
ra
n
d
o
m
ize
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c
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tro
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led
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rials,
p
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sp
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c
ti
v
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c
o
n
tro
ll
e
d
stu
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ies
,
c
a
se
se
ries
,
a
n
d
in
v
i
tro
in
v
e
stig
a
ti
o
n
s.
T
h
r
e
e
th
e
m
e
s
e
m
e
rg
e
d
:
i)
H
o
n
e
y
a
s
a
wo
u
n
d
-
h
e
a
li
n
g
th
e
ra
p
y
,
d
e
m
o
n
stra
ti
n
g
a
n
ti
m
icro
b
ial,
a
n
ti
-
in
flam
m
a
to
ry
,
a
n
d
b
io
fi
lm
-
i
n
h
ib
it
in
g
p
ro
p
e
rti
e
s;
ii
)
B
e
n
e
fit
s
o
f
m
e
d
ica
l
-
g
ra
d
e
h
o
n
e
y
(M
G
H),
in
c
l
u
d
i
n
g
a
c
c
e
lera
ted
e
p
it
h
e
li
a
li
z
a
ti
o
n
,
re
d
u
c
e
d
in
fe
c
ti
o
n
ra
tes
,
a
n
d
s
h
o
rter
re
c
o
v
e
ry
ti
m
e
s;
a
n
d
ii
i)
R
e
c
o
m
m
e
n
d
a
ti
o
n
s
f
o
r
h
o
n
e
y
a
s
a
c
o
st
-
e
ffe
c
ti
v
e
,
a
c
c
e
s
sib
le
a
lt
e
rn
a
ti
v
e
trea
tme
n
t.
Th
e
e
v
i
d
e
n
c
e
su
p
p
o
rts
h
o
n
e
y
a
s
a
p
ro
m
isi
n
g
a
d
ju
n
c
ti
v
e
t
h
e
ra
p
y
fo
r
wo
u
n
d
m
a
n
a
g
e
m
e
n
t,
p
a
rti
c
u
larly
in
re
so
u
rc
e
-
li
m
it
e
d
se
tt
in
g
s
.
Ho
we
v
e
r,
t
h
e
h
e
tero
g
e
n
e
it
y
in
st
u
d
y
d
e
sig
n
s,
h
o
n
e
y
ty
p
e
s,
a
n
d
wo
u
n
d
c
a
teg
o
ries
li
m
it
s
d
e
fin
it
iv
e
c
o
n
c
lu
sio
n
s.
F
u
tu
re
lar
g
e
-
sc
a
le
ra
n
d
o
m
i
z
e
d
c
o
n
tr
o
ll
e
d
tr
ials
with
sta
n
d
a
rd
ize
d
o
u
tco
m
e
s
a
re
n
e
e
d
e
d
to
e
sta
b
li
sh
c
li
n
ica
l
g
u
id
e
li
n
e
s fo
r
h
o
n
e
y
-
b
a
se
d
wo
u
n
d
c
a
re
.
K
ey
w
o
r
d
s
:
Alter
n
ativ
e
th
er
ap
y
Ho
n
ey
Me
d
ical
-
g
r
ad
e
h
o
n
e
y
Sy
s
tem
atic
r
ev
iew
W
o
u
n
d
h
ea
lin
g
T
h
is i
s
a
n
o
p
e
n
a
c
c
e
ss
a
rticle
u
n
d
e
r th
e
CC B
Y
-
SA
li
c
e
n
se
.
C
o
r
r
e
s
p
o
nd
ing
A
uth
o
r
:
E
n
i K
u
s
y
ati
Dep
ar
tm
en
t o
f
Nu
r
s
in
g
,
Facu
lt
y
o
f
Nu
r
s
in
g
an
d
Hea
lth
Scien
ce
,
Un
iv
er
s
itas
Kar
y
a
Hu
s
ad
a
Sem
ar
an
g
J
l.
Ko
m
p
o
l R.
So
ek
an
to
N
o
4
6
,
Sem
ar
an
g
,
C
en
tr
al
J
av
a
,
I
n
d
o
n
esia
E
m
ail:
k
u
s
y
atien
i2
0
1
4
@
g
m
ail.
co
m
1.
I
NT
RO
D
UCT
I
O
N
W
o
u
n
d
s
r
ep
r
esen
t
a
m
ajo
r
g
l
o
b
al
p
u
b
lic
h
ea
lth
b
u
r
d
en
,
a
f
f
ec
tin
g
an
esti
m
ated
1
–
2
%
o
f
t
h
e
g
en
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r
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p
o
p
u
latio
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in
d
e
v
elo
p
ed
co
u
n
tr
ies
an
d
co
n
t
r
ib
u
tin
g
s
ig
n
if
ican
tly
to
d
is
ab
ilit
y
-
ad
ju
s
ted
life
y
ea
r
s
(
DAL
Ys)
an
d
h
ea
lth
ca
r
e
ex
p
en
d
itu
r
e
[
1
]
,
[
2
]
.
C
h
r
o
n
ic
an
d
ac
u
te
wo
u
n
d
s
p
o
s
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ch
allen
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,
in
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n
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p
ai
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,
in
f
ec
ti
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,
p
r
o
lo
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ed
m
o
r
b
id
ity
,
an
d
r
ed
u
ce
d
q
u
ality
o
f
life
[
3
]
.
T
h
e
e
co
n
o
m
ic
im
p
ac
t
is
s
u
b
s
tan
tial
;
wo
u
n
d
ca
r
e
co
s
ts
ex
ce
ed
$
2
5
b
illi
o
n
an
n
u
ally
in
th
e
U
n
ited
States
alo
n
e,
with
a
s
ig
n
if
ican
t
ad
d
itio
n
al
b
u
r
d
e
n
in
lo
w
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an
d
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id
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le
-
in
co
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co
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n
tr
ies (
L
M
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s
)
wh
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ac
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s
to
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v
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wo
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ca
r
e
p
r
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d
u
cts is
lim
ited
[
4
]
-
[
6
]
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
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:
2
2
5
2
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8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
15
,
No
.
2
,
J
u
n
e
20
26
:
6
0
5
-
6
1
4
606
W
o
u
n
d
h
ea
lin
g
is
a
co
m
p
l
ex
b
io
ch
em
ical
p
r
o
ce
s
s
in
v
o
lv
in
g
in
f
lam
m
atio
n
,
p
r
o
life
r
atio
n
,
an
d
r
em
o
d
elin
g
p
h
ases
th
at
r
eq
u
i
r
e
co
o
r
d
i
n
ated
ce
llu
lar
s
ig
n
al
in
g
[
3
]
,
[
7
]
.
Mu
ltip
le
f
ac
to
r
s
in
f
lu
en
ce
h
ea
lin
g
o
u
tco
m
es,
in
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d
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g
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s
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co
m
o
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b
i
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ities
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g
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e,
im
m
u
n
o
lo
g
ical
s
tatu
s
,
an
d
in
f
ec
tio
n
[
8
]
.
T
h
e
g
r
o
win
g
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d
er
ly
p
o
p
u
latio
n
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d
r
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s
tan
tially
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b
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r
d
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n
d
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h
ea
lth
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r
e
s
y
s
tem
s
wo
r
ld
wid
e
[
2
]
,
[
5
]
,
[
9
]
.
Po
o
r
ly
h
ea
lin
g
wo
u
n
d
s
ar
e
also
s
u
s
ce
p
tib
le
to
b
ac
ter
i
al
co
l
o
n
izatio
n
a
n
d
m
a
y
p
r
o
g
r
ess
t
o
s
e
p
s
is
,
a
life
-
th
r
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ten
in
g
c
o
n
d
itio
n
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f
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g
ap
p
r
o
x
im
ately
4
9
m
illi
o
n
p
eo
p
le
a
n
d
ca
u
s
in
g
1
1
m
illi
o
n
d
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th
s
an
n
u
ally
[
1
0
]
.
Sep
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ican
t
h
e
alth
p
r
o
b
lem
wo
r
l
d
wid
e
[
4
]
,
[
1
1
]
.
A
p
p
r
o
x
im
ately
8
5
%
o
f
s
ep
s
is
ca
s
es
oc
cu
r
in
L
MI
C
s
,
u
n
d
er
s
co
r
in
g
th
e
d
is
p
r
o
p
o
r
ti
o
n
ate
im
p
ac
t
on
v
u
ln
er
ab
le
p
o
p
u
latio
n
s
[
4
]
,
[
1
1
]
.
C
o
n
v
en
tio
n
al
wo
u
n
d
tr
ea
tm
e
n
ts
,
wh
il
e
e
ff
e
ctiv
e
,
ar
e
o
f
t
e
n
e
x
p
en
s
iv
e
,
ass
o
ciate
d
with
ad
v
er
s
e
ef
f
ec
ts
s
u
ch
as
aller
g
ic
r
ea
ctio
n
s
an
d
an
tim
icr
o
b
ial
r
esis
tan
ce
(
A
L
MR),
an
d
m
ay
b
e
u
n
r
eliab
le
i
n
u
n
d
e
r
s
er
v
ed
a
r
ea
s
[
3
]
,
[
1
2
]
.
T
h
e
r
is
e
o
f
AL
MR
h
as
cr
ea
ted
an
u
r
g
en
t
n
ee
d
f
o
r
alter
n
ativ
e
s
tr
ateg
ies
in
tr
ea
tin
g
all
ty
p
es
o
f
in
f
ec
tio
n
s
in
wo
u
n
d
m
an
a
g
e
m
en
t
[
12
]
,
[
1
3
]
.
I
n
th
is
co
n
tex
t,
h
o
n
ey
h
as
em
er
g
ed
as
a
p
r
o
m
is
in
g
th
er
ap
e
u
tic
ag
en
t,
with
a
lo
n
g
h
is
to
r
y
o
f
u
s
e
in
tr
ad
itio
n
al
m
ed
icin
e
ac
r
o
s
s
cu
ltu
r
es
[
1
4
]
.
Ho
n
ey
p
o
s
s
ess
es
an
tim
icr
o
b
ial
,
an
ti
-
in
f
lam
m
ato
r
y
,
a
n
d
an
tis
ep
tic
p
r
o
p
er
ties
,
a
n
d
m
ed
ici
n
al
-
g
r
ad
e
h
o
n
ey
(
MG
H)
p
r
o
d
u
cts
h
a
v
e
b
ee
n
in
cr
ea
s
in
g
ly
ad
o
p
te
d
in
clin
ic
al
wo
u
n
d
ca
r
e
[
1
5
]
,
[
1
6
]
.
I
ts
af
f
o
r
d
a
b
ilit
y
,
ac
ce
s
s
ib
ilit
y
,
an
d
cu
ltu
r
al
f
am
iliar
ity
m
ak
e
it
p
ar
ticu
lar
ly
r
elev
an
t
f
o
r
lo
w
-
r
eso
u
r
ce
s
ettin
g
s
an
d
c
o
m
m
u
n
ity
-
b
ased
wo
u
n
d
ca
r
e
[
1
5
]
,
[
1
7
]
.
D
e
s
p
it
e
g
r
o
win
g
e
v
id
e
nc
e
,
n
o
r
e
c
e
n
t
s
y
s
t
e
m
a
tic
r
e
vi
e
w
h
a
s
co
m
p
r
e
h
e
n
s
iv
e
ly
s
y
n
th
e
s
iz
e
d
clin
ic
a
l
a
n
d
p
r
e
clin
ic
a
l
e
v
id
e
nc
e
o
n
h
o
n
e
y
a
s
a
wo
u
n
d
h
ea
lin
g
th
e
r
a
p
y
co
v
e
r
in
g
th
e
p
e
r
io
d
2
0
2
0
–
2
0
2
4
.
T
h
is
r
e
vi
e
w
a
im
s
to
ad
d
r
ess
th
is
g
ap
by
ev
alu
atin
g
th
e
c
u
r
r
en
t
e
v
id
en
ce
b
ase
,
id
en
tify
i
n
g
ef
f
ec
tiv
e
h
o
n
ey
-
b
ased
in
ter
v
en
tio
n
s
,
a
n
d
p
r
o
v
id
i
n
g
r
ec
o
m
m
en
d
atio
n
s
f
o
r
clin
ical
p
r
ac
tice
,
p
u
b
lic
h
ea
lth
p
o
licy
,
a
n
d
f
u
t
u
r
e
r
esear
ch
.
2.
M
E
T
H
O
D
2
.
1
.
Study
d
esig
n
A
s
y
s
tem
atic
r
ev
iew
was c
o
n
d
u
cted
f
o
llo
win
g
th
e
Pre
f
er
r
e
d
R
ep
o
r
tin
g
I
tem
s
f
o
r
Sy
s
tem
ati
c
R
ev
iew
s
an
d
Me
ta
-
An
aly
s
es
(
PR
I
SM
A)
g
u
id
elin
es.
T
h
e
r
ev
iew
aim
ed
to
s
y
n
th
esize
ev
id
en
ce
o
n
h
o
n
e
y
u
s
e
as
an
alter
n
ativ
e
wo
u
n
d
tr
ea
tm
e
n
t.
T
h
e
PR
I
SMA
f
r
am
ewo
r
k
was
ap
p
lied
to
en
s
u
r
e
a
s
tr
u
ctu
r
ed
an
d
tr
an
s
p
ar
e
n
t
r
ev
iew
p
r
o
ce
s
s
.
2
.
2
.
L
it
er
a
t
ure
s
ea
rc
h str
a
t
e
g
y
T
h
is
s
y
s
t
e
m
a
tic
r
e
vi
e
w
lo
o
k
e
d
a
t
o
r
ig
in
a
l
r
e
s
ea
r
ch
f
in
d
in
g
s
f
r
o
m
s
ix
d
atab
ases
:
Sco
p
u
s
,
Natu
r
e
,
Pro
q
u
est
,
E
B
SC
O
,
Sp
r
in
g
er
lin
k
,
an
d
Scien
ce
Dir
ec
t
.
T
h
e
s
ea
r
ch
w
a
s
co
n
d
u
ct
e
d
b
e
tw
ee
n
J
a
nu
a
r
y
a
n
d
M
a
r
ch
2
0
2
4
,
c
o
v
er
in
g
ar
ticles
p
u
b
lis
h
ed
f
r
o
m
J
an
u
ar
y
2
0
2
0
t
o
Dec
em
b
er
2
0
2
4
.
T
h
e
f
o
llo
win
g
s
ea
r
ch
s
tr
in
g
w
a
s
us
e
d
:
(
"wo
u
n
d
c
a
r
e
"
OR
"wo
u
n
d
h
ea
lin
g
"
OR
"wo
u
n
d
tr
ea
tm
e
n
t"
OR
"wo
u
n
d
m
a
n
a
g
e
m
e
n
t")
A
ND
(
"h
o
n
e
y
"
OR
"m
e
d
ic
a
l
g
r
a
d
e
hon
e
y
"
OR
"m
a
nuk
a
hon
e
y
"
)
A
ND
(
"
a
lt
e
rn
a
tiv
e
tr
ea
tm
en
t
"
OR
"
alter
n
ativ
e
th
er
ap
y
"
OR
"
co
m
p
lem
en
tar
y
th
er
a
p
y
")
.
T
h
e
s
ea
r
ch
was
lim
ited
to
E
n
g
lis
h
-
lan
g
u
ag
e
a
r
ticles
th
at
wer
e
av
ailab
le
in
f
u
ll
tex
t
,
o
p
en
ac
ce
s
s
,
an
d
p
u
b
lis
h
ed
b
etwe
en
2
0
2
0
an
d
2
0
2
4
.
2
.
3
.
I
nclus
io
n a
nd
ex
clus
io
n
cr
it
er
ia
I
n
clu
s
io
n
cr
iter
ia
:
i
)
S
tu
d
ies
i
n
v
o
lv
in
g
h
u
m
an
p
a
r
ticip
an
ts
o
r
in
v
itr
o
m
o
d
els
r
elev
an
t
t
o
wo
u
n
d
ca
r
e
;
ii
)
I
n
ter
v
en
tio
n
s
in
v
o
lv
in
g
h
o
n
e
y
f
o
r
wo
u
n
d
ca
r
e
;
iii
)
R
ep
o
r
ts
o
n
h
o
n
e
y
a
s
a
n
a
lt
e
rn
a
tiv
e
wo
u
n
d
tr
ea
tm
e
n
t;
an
d
iv
)
Q
u
a
n
tit
a
tiv
e
,
q
u
a
lit
a
tiv
e
,
o
r
m
i
x
e
d
m
e
th
o
d
s
s
tu
d
y
d
e
s
ig
n
s
.
Stu
d
i
e
s
in
v
o
lv
in
g
d
i
v
e
rs
e
wo
u
n
d
ty
p
e
s
(
s
u
r
g
ical
,
ch
r
o
n
i
c,
d
i
a
b
e
tic,
p
r
ess
u
r
e
u
lcer
s
,
in
f
e
ct
e
d
wo
u
n
d
s
)
w
e
r
e
in
clu
d
e
d
.
Ex
clu
s
io
n
cr
iter
ia
:
i
)
a
n
im
a
l
-
b
a
s
e
d
wo
u
n
d
c
a
r
e
s
tu
d
i
e
s
,
ii
)
s
tu
d
i
e
s
f
o
cu
s
in
g
e
x
clu
s
iv
e
ly
o
n
m
o
d
e
r
n
wo
u
n
d
d
r
ess
in
g
tech
n
iq
u
es
with
o
u
t
h
o
n
e
y
,
an
d
iii
)
s
y
s
tem
atic
r
ev
iews
,
liter
atu
r
e
r
ev
i
ews
,
o
r
e
d
ito
r
ials
.
T
h
e
PR
I
SM
A
f
lo
w
d
i
a
gr
a
m
o
u
tlin
e
s
th
e
s
ea
r
ch
s
tr
ate
gy
a
n
d
s
tu
d
y
s
e
l
e
ctio
n
p
r
o
c
e
s
s
(
s
e
e
Fig
u
r
e
1
)
.
2
.
4
.
Ris
k
o
f
bia
s
a
s
s
ess
m
ent
Stu
d
y
q
u
ality
was
ass
ess
ed
u
s
in
g
th
e
J
o
an
n
a
B
r
ig
g
s
I
n
s
titu
te
(
J
B
I
)
C
r
itic
al
Ap
p
r
aisal
T
o
o
ls
,
with
s
p
ec
if
ic
ch
ec
k
lis
ts
ap
p
lied
ac
co
r
d
in
g
to
s
tu
d
y
d
esig
n
:
th
e
J
B
I
ch
ec
k
lis
t
f
o
r
r
an
d
o
m
ized
c
o
n
tr
o
lled
tr
ials
,
th
e
ch
ec
k
lis
t
f
o
r
ca
s
e
s
er
ies,
a
n
d
th
e
c
h
ec
k
lis
t
f
o
r
a
n
aly
t
ical
cr
o
s
s
-
s
ec
tio
n
al
s
tu
d
ies.
E
ac
h
s
tu
d
y
was
in
d
ep
en
d
en
tly
a
p
p
r
ai
s
ed
b
y
two
r
e
v
iewe
r
s
(
DI
I
an
d
S
M)
,
an
d
d
is
ag
r
ee
m
en
ts
wer
e
r
eso
lv
ed
th
r
o
u
g
h
d
is
cu
s
s
io
n
with
a
th
ir
d
r
ev
iew
er
(
E
K)
.
2
.
5
.
Da
t
a
e
x
t
ra
ct
i
o
n a
nd
a
na
ly
s
is
Data
ex
tr
ac
tio
n
u
s
ed
s
tan
d
ar
d
i
ze
d
f
o
r
m
s
to
ca
p
t
u
r
e
s
tu
d
y
d
e
s
ig
n
,
s
ettin
g
,
p
ar
ticip
an
ts
,
in
te
r
v
en
tio
n
d
etails,
o
u
tco
m
es,
a
n
d
k
ey
r
esu
lts
.
Fo
u
r
r
e
v
iewe
r
s
(
E
K,
DI
I
,
SM,
DM
)
i
n
d
ep
e
n
d
en
tly
co
llected
d
ata,
r
eso
lv
in
g
d
is
ag
r
ee
m
en
ts
b
y
co
n
s
en
s
u
s
.
Du
e
to
s
u
b
s
tan
tial
h
e
ter
o
g
en
eity
in
s
tu
d
y
d
esig
n
s
,
wo
u
n
d
ty
p
es,
h
o
n
e
y
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
Ho
n
ey
a
s
a
n
a
lter
n
a
tive
w
o
u
n
d
h
ea
lin
g
th
era
p
y:
a
s
ystema
tic
r
ev
iew
o
f c
lin
ica
l
… (
E
n
i Ku
s
ya
ti
)
607
ty
p
es
an
d
co
n
ce
n
tr
atio
n
s
,
a
n
d
o
u
tco
m
e
m
ea
s
u
r
es,
a
q
u
an
titativ
e
m
eta
-
an
aly
s
is
was
n
o
t
f
ea
s
ib
le.
T
h
er
ef
o
r
e,
an
aly
s
is
r
elied
o
n
n
a
r
r
ativ
e
s
y
n
th
esis
to
in
ter
p
r
et
an
d
o
r
g
an
i
ze
f
in
d
in
g
s
th
e
m
atica
lly
.
Fig
u
r
e
1
.
Flo
w
d
ia
g
r
am
o
f
s
y
s
tem
atic
r
ev
iew
3.
RE
SU
L
T
S
A
to
tal
o
f
3
0
2
a
r
ticles
wer
e
id
en
tifie
d
ac
r
o
s
s
s
ix
d
atab
a
s
es,
an
d
1
8
0
d
u
p
licate
ar
ticl
es
wer
e
r
em
o
v
ed
.
T
itles
an
d
ab
s
tr
ac
ts
o
f
1
2
2
ar
ticles
wer
e
s
cr
ee
n
ed
,
r
esu
ltin
g
in
2
1
ar
ticles
d
ee
m
ed
elig
ib
le.
Af
ter
f
u
l
l
-
tex
t
s
cr
ee
n
in
g
an
d
ap
p
ly
i
n
g
ex
cl
u
s
io
n
cr
iter
ia,
1
6
s
tu
d
i
es
m
et
th
e
in
clu
s
io
n
cr
iter
ia
a
n
d
wer
e
in
clu
d
e
d
in
th
e
r
ev
iew
(
T
ab
le
1
(
s
ee
Ap
p
e
n
d
ix
)
)
[
1
8
]
-
[
3
2
]
.
T
h
e
1
6
in
clu
d
ed
s
tu
d
ies
c
o
m
p
r
is
ed
s
ix
r
an
d
o
m
ized
co
n
tr
o
lled
tr
ials
,
th
r
ee
p
r
o
s
p
ec
tiv
e
s
tu
d
ies,
f
o
u
r
ca
s
e
s
er
ies,
an
d
th
r
ee
in
v
itr
o
/lab
o
r
ato
r
y
s
tu
d
ies.
Stu
d
ies
co
v
er
ed
d
iv
er
s
e
w
o
u
n
d
ty
p
es
in
clu
d
in
g
s
u
r
g
ical
wo
u
n
d
s
(
p
alato
p
last
y
,
th
i
r
d
m
o
lar
ex
tr
ac
ti
o
n
,
ca
esar
ea
n
s
ec
tio
n
,
p
ilo
n
id
al
cy
s
t
e
x
cisi
o
n
,
g
in
g
iv
al
g
r
af
ts
)
,
ch
r
o
n
ic
wo
u
n
d
s
(
p
r
ess
u
r
e
u
lcer
s
,
in
f
ec
ted
wo
u
n
d
s
)
,
a
n
d
d
iab
etic
wo
u
n
d
s
.
Var
io
u
s
h
o
n
ey
ty
p
es
we
r
e
in
v
esti
g
ated
,
in
clu
d
i
n
g
m
e
d
ical
-
g
r
ad
e
h
o
n
e
y
(
MG
H)
,
Ma
n
u
k
a
h
o
n
ey
,
ch
estn
u
t
h
o
n
ey
,
h
ea
th
er
h
o
n
ey
,
an
d
r
eg
io
n
-
s
p
ec
if
ic
Nig
e
r
ian
h
o
n
e
y
s
.
3
.
1
.
T
hem
e
1
:
H
o
ney
a
s
a
w
o
un
d hea
lin
g
t
hera
p
y
T
h
e
r
ev
iew
d
em
o
n
s
tr
ated
t
h
at
h
o
n
ey
is
a
co
m
p
lex
m
atr
ix
co
n
tain
in
g
o
v
er
2
0
0
ch
em
ical
co
m
p
o
u
n
d
s
with
s
ig
n
if
ican
t
co
m
p
o
s
itio
n
al
v
ar
iatio
n
s
d
ep
en
d
in
g
o
n
g
eo
g
r
ap
h
ical
o
r
ig
in
[
3
2
]
.
Sev
e
r
al
in
v
esti
g
atio
n
s
h
av
e
f
o
u
n
d
th
at
h
ea
th
er
h
o
n
ey
h
as
p
o
ten
tial
as
an
an
tib
ac
ter
ial
ag
en
t
f
o
r
u
s
e
in
wo
u
n
d
d
r
ess
in
g
co
m
p
o
s
itio
n
s
[
3
0
]
.
A
r
an
d
o
m
i
ze
d
co
n
tr
o
lled
s
tu
d
y
d
is
co
v
er
e
d
th
at
io
d
in
e
an
d
Ma
n
u
k
a
h
o
n
ey
-
b
ased
d
r
ess
in
g
s
ca
n
r
ed
u
ce
t
h
e
b
ac
ter
ial
lo
ad
in
h
ig
h
ly
c
o
n
tam
in
ated
s
o
f
t
tis
s
u
e
wo
u
n
d
s
[
2
2
]
.
L
o
ca
l
M
G
H
th
er
ap
y
r
e
d
u
ce
d
th
e
b
ac
ter
ial
b
u
r
d
e
n
,
r
esu
ltin
g
in
s
ter
ile
cu
ltu
r
es in
s
o
m
e
in
s
t
an
ce
s
[
2
6
]
,
wh
ich
p
r
ev
e
n
ted
b
ac
ter
ial
g
r
o
wth
an
d
b
io
f
ilm
d
ev
el
o
p
m
en
t
[
2
9
]
.
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
.
2
,
J
u
n
e
20
26
:
6
0
5
-
6
1
4
608
Acr
o
s
s
th
e
in
clu
d
ed
s
tu
d
ies,
an
tim
icr
o
b
ial
o
u
tco
m
es
v
a
r
ied
b
y
h
o
n
e
y
ty
p
e
an
d
co
n
ce
n
tr
atio
n
.
Ma
n
u
k
a
h
o
n
ey
an
d
MG
H
p
r
o
d
u
cts
co
n
s
is
ten
tly
d
em
o
n
s
tr
ated
b
r
o
ad
-
s
p
ec
tr
u
m
an
tib
ac
te
r
ial
ac
tiv
ity
,
wh
ile
th
e
ef
f
icac
y
o
f
o
th
er
h
o
n
e
y
ty
p
e
s
(
e.
g
.
,
ch
estn
u
t,
h
ea
th
er
)
was
m
o
r
e
s
p
ec
if
ic
to
ce
r
tain
b
a
cter
ial
s
tr
ain
s
.
T
h
is
h
eter
o
g
en
eity
in
an
tim
icr
o
b
i
al
p
r
o
f
iles
r
ef
lect
s
co
m
p
o
s
itio
n
al
d
if
f
er
en
ce
s
in
f
lu
e
n
ce
d
b
y
f
lo
r
al
s
o
u
r
ce
,
g
eo
g
r
a
p
h
ic
o
r
ig
in
,
a
n
d
p
r
o
ce
s
s
in
g
m
eth
o
d
s
.
3
.
2
.
T
hem
e
2
:
T
he
a
dv
a
nta
g
es o
f
m
edica
l
-
g
r
a
de
ho
ney
(
M
G
H
)
in wo
un
d hea
li
ng
C
lin
ical
s
tu
d
ies
d
em
o
n
s
tr
ated
th
at
h
o
n
ey
d
r
ess
in
g
s
m
ad
e
s
u
b
s
tan
tial
d
if
f
er
en
ce
s
in
wo
u
n
d
h
ea
lin
g
o
u
tco
m
es.
W
o
u
n
d
ca
r
e
u
tili
zin
g
h
o
n
e
y
d
r
ess
in
g
s
r
esu
lted
i
n
clin
ically
s
ig
n
i
f
ican
t
e
p
ith
elializa
tio
n
o
f
later
al
p
alata
l
d
ef
ec
ts
in
6
6
.
7
%
o
f
te
s
t
g
r
o
u
p
p
ar
ticip
an
ts
at
two
w
ee
k
s
p
o
s
t
-
s
u
r
g
er
y
[
1
8
]
.
A
ca
s
e
s
er
ies
f
o
u
n
d
t
h
at
MG
H
p
r
o
v
id
es
a
m
o
is
t
wo
u
n
d
en
v
ir
o
n
m
en
t,
in
d
u
ce
s
a
u
t
o
ly
tic
d
eb
r
id
em
en
t,
ex
h
i
b
its
an
ti
-
in
f
lam
m
ato
r
y
ac
tiv
ity
,
an
d
p
r
o
m
o
tes
an
g
io
g
en
esis
an
d
r
e
-
ep
ith
elializa
tio
n
[
2
5
]
.
MG
H
d
em
o
n
s
tr
ated
s
ig
n
if
ican
tly
f
aster
r
ec
o
v
er
y
u
p
to
d
ay
4
2
p
o
s
t
-
c
ae
s
ar
ea
n
s
ec
tio
n
[
2
3
]
,
r
ed
u
ce
d
b
ac
ter
ial
b
u
r
d
e
n
an
d
in
f
ec
t
io
n
r
is
k
[
2
8
]
,
an
d
im
p
r
o
v
e
d
s
u
r
g
ical
o
u
tco
m
es
with
s
h
o
r
ten
ed
r
ec
o
v
er
y
tim
e
[
2
1
]
.
N
o
tab
ly
,
th
e
s
tr
en
g
th
o
f
ev
id
en
ce
v
ar
ied
ac
r
o
s
s
s
tu
d
ies.
R
C
T
s
p
r
o
v
id
e
d
m
o
r
e
r
o
b
u
s
t
e
v
id
en
ce
f
o
r
h
o
n
ey
’
s
e
f
f
icac
y
in
s
u
r
g
ical
w
o
u
n
d
h
ea
lin
g
,
wh
ile
cas
e
s
er
ies
o
f
f
er
ed
p
r
elim
in
ar
y
s
u
p
p
o
r
t
f
o
r
its
u
s
e
in
ch
r
o
n
i
c
wo
u
n
d
m
an
ag
em
e
n
t.
I
n
v
itr
o
s
tu
d
ies
elu
cid
ated
p
o
ten
tial m
ec
h
an
is
m
s
b
u
t
h
av
e
lim
ited
d
ir
ec
t c
lin
ical
ap
p
lic
ab
ilit
y
.
3
.
3
.
T
hem
e
3
:
Rec
o
m
m
enda
t
io
ns
f
o
r
t
he
us
e
o
f
ho
ney
a
s
a
n a
lt
er
na
t
iv
e
wo
un
d t
re
a
t
ment
T
h
e
r
e
v
iew
id
en
tifie
d
th
at
h
o
n
ey
ca
n
b
e
u
s
ed
as
a
n
alter
n
ativ
e
wo
u
n
d
t
r
ea
tm
en
t.
A
ca
s
e
s
er
ies
s
tu
d
y
r
ec
o
m
m
e
n
d
s
h
o
n
e
y
as
an
alter
n
ativ
e
o
r
co
m
p
le
m
en
tar
y
th
er
a
p
y
in
wo
u
n
d
h
ea
lin
g
[
2
5
]
.
C
o
s
t
co
n
s
id
er
atio
n
s
ar
e
also
a
r
ea
s
o
n
f
o
r
u
s
in
g
h
o
n
e
y
,
with
q
u
a
n
ti
tativ
e
s
tu
d
ies
s
h
o
win
g
th
at
h
o
n
ey
ca
n
b
e
a
co
s
t
-
ef
f
ec
tiv
e
an
d
ea
s
y
-
to
-
u
s
e
alter
n
ativ
e
f
o
r
tr
ea
tin
g
ch
r
o
n
ic
wo
u
n
d
in
f
ec
tio
n
s
[
2
6
]
.
T
h
i
s
is
r
ein
f
o
r
ce
d
b
y
Ko
lo
h
et
a
l
.
[
2
9
]
,
wh
o
s
tate
th
at
ch
estn
u
t
h
o
n
e
y
is
an
alter
n
a
tiv
e
tr
ea
tm
en
t
f
o
r
r
esis
tan
t
in
f
ec
tio
n
s
a
n
d
ch
r
o
n
ic
wo
u
n
d
s
.
T
h
e
ea
s
e
o
f
u
s
e
o
f
h
o
n
ey
d
r
ess
in
g
s
is
an
o
th
er
r
ea
s
o
n
,
as
h
o
n
ey
is
a
p
r
ac
tical,
s
im
p
le,
an
d
a
f
f
o
r
d
ab
le
m
eth
o
d
f
o
r
wo
u
n
d
ca
r
e
i
n
v
a
r
io
u
s
o
r
t
h
o
p
ae
d
ic
co
n
d
itio
n
s
,
ev
en
with
e
x
p
o
s
ed
b
o
n
es
o
r
ten
d
o
n
s
[
1
5
]
.
T
h
e
f
in
d
in
g
s
o
f
th
is
s
y
s
tem
atic
r
ev
ie
w
r
ein
f
o
r
ce
m
ed
ical
-
g
r
a
d
e
h
o
n
ey
(
MG
H)
as
a
p
o
wer
f
u
l
alter
n
ativ
e
tr
ea
tm
en
t
to
r
ep
lace
an
tib
io
tics
an
d
p
o
v
id
o
n
e
-
io
d
in
e,
wh
ile
ac
ce
ler
ati
n
g
h
ea
lin
g
[
2
3
]
.
Ad
d
itio
n
ally
,
h
o
n
ey
a
cc
eler
ates
th
e
wo
u
n
d
h
ea
lin
g
p
r
o
ce
s
s
,
le
ad
in
g
to
a
s
h
o
r
ter
r
ec
o
v
er
y
p
e
r
io
d
an
d
r
ed
u
c
e
d
p
o
s
t
-
o
p
er
ativ
e
m
o
r
b
id
ity
[
2
0
]
.
4.
DIS
CU
SS
I
O
N
T
h
is
s
y
s
tem
atic
r
ev
iew
p
r
o
v
i
d
es
a
co
m
p
r
eh
e
n
s
iv
e
s
y
n
th
esis
o
f
clin
ical
an
d
p
r
ec
li
n
ical
ev
i
d
en
ce
o
n
h
o
n
ey
as
an
alter
n
ativ
e
wo
u
n
d
h
ea
lin
g
th
er
a
p
y
p
u
b
lis
h
ed
b
etwe
en
2
0
2
0
an
d
2
0
2
4
.
T
h
e
f
in
d
in
g
s
s
u
p
p
o
r
t
h
o
n
ey
’
s
ef
f
icac
y
ac
r
o
s
s
m
u
lt
ip
le
wo
u
n
d
t
y
p
es,
with
ev
id
en
ce
f
o
r
a
n
tim
icr
o
b
ial,
an
ti
-
i
n
f
lam
m
ato
r
y
,
a
n
d
wo
u
n
d
-
h
ea
lin
g
-
p
r
o
m
o
tin
g
p
r
o
p
er
ties
.
Ho
wev
er
,
th
e
ev
i
d
en
ce
b
ase
r
em
ain
s
h
eter
o
g
e
n
eo
u
s
,
an
d
s
ev
er
al
im
p
o
r
tan
t c
o
n
s
id
er
atio
n
s
war
r
an
t d
is
cu
s
s
io
n
[
3
3
]
.
4
.
1
.
Rec
o
mm
enda
t
io
ns
f
o
r
us
ing
ho
ney
a
s
a
n a
lt
er
na
t
iv
e
wo
un
d t
re
a
t
m
ent
Ho
n
e
y
alt
er
n
ati
v
es
f
o
r
w
o
u
n
d
ca
r
e
a
r
e
b
ec
o
m
i
n
g
t
h
e
p
r
ef
er
r
ed
c
h
o
ic
e
f
o
r
v
ar
io
u
s
r
ea
s
o
n
s
,
in
cl
u
d
i
n
g
af
f
o
r
d
a
b
i
lit
y
,
co
n
v
e
n
i
en
ce
o
f
u
s
e
a
n
d
ac
q
u
is
it
io
n
,
k
i
n
d
o
f
wo
u
n
d
,
w
o
u
n
d
le
n
g
t
h
,
i
n
f
ec
ti
o
n
c
o
n
tr
o
l
,
a
n
d
m
a
x
i
m
u
m
a
n
d
f
aste
r
w
o
u
n
d
h
ea
l
in
g
p
r
o
ce
s
s
.
Ho
n
ey
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as
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p
o
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ar
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m
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ic
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e
as
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"p
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i
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li
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ti
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a
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i
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p
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o
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co
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t
ai
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s
s
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r
a
l
a
n
t
io
x
i
d
an
ts
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i
n
c
lu
d
in
g
f
l
av
o
n
o
i
d
s
,
m
o
n
o
p
h
e
n
o
ls
,
p
o
l
y
p
h
en
o
ls
,
v
it
a
m
i
n
C
,
a
n
d
m
et
h
y
ls
y
r
in
g
ate
,
w
h
i
ch
i
n
h
ib
i
t
th
e
a
m
p
li
f
i
ca
ti
o
n
o
f
i
n
f
la
m
m
at
io
n
ca
u
s
e
d
b
y
r
ea
cti
v
e
o
x
y
g
e
n
s
p
ec
ies
(
R
OS
)
.
T
h
ese
a
n
ti
o
x
i
d
a
n
ts
a
r
e
r
es
p
o
n
s
ib
l
e
f
o
r
t
h
e
m
et
h
o
d
t
h
a
t
h
o
n
e
y
u
s
es
t
o
all
ev
iat
e
wo
u
n
d
p
a
in
[
3
4
]
,
[
3
5
]
.
Ho
n
ey
,
i
n
ad
d
it
io
n
t
o
b
ei
n
g
a
s
o
l
u
ti
o
n
h
ig
h
in
s
u
g
a
r
,
is
als
o
a
b
i
o
l
o
g
i
ca
l
w
o
u
n
d
d
r
ess
in
g
t
h
a
t
co
n
t
a
in
s
m
an
y
b
i
o
ac
ti
v
e
co
m
p
o
n
e
n
ts
th
at
c
an
s
t
im
u
l
at
e
w
o
u
n
d
h
e
ali
n
g
t
h
r
o
u
g
h
v
a
r
io
u
s
p
at
h
wa
y
s
.
H
o
n
ey
ca
n
s
p
ee
d
u
p
t
h
e
h
e
ali
n
g
p
r
o
ce
s
s
o
f
w
o
u
n
d
s
b
y
wo
r
k
i
n
g
o
n
t
h
e
t
h
r
ee
p
h
ases
o
f
g
r
o
w
th
:
p
r
o
li
f
e
r
at
io
n
,
r
e
m
o
d
elli
n
g
,
a
n
d
i
n
f
la
m
m
at
io
n
[
7
]
.
Ho
n
e
y
is
k
n
o
w
n
t
o
e
n
h
a
n
ce
t
h
e
p
r
o
d
u
cti
o
n
o
f
c
o
ll
a
g
e
n
,
as
w
ell
as a
n
g
i
o
g
e
n
esis
a
n
d
g
r
an
u
l
ati
o
n
tis
s
u
e
c
r
e
ati
o
n
.
Ad
d
it
io
n
a
ll
y
,
h
o
n
ey
b
o
o
s
ts
w
o
u
n
d
c
o
n
t
r
ac
ti
o
n
an
d
p
r
o
m
o
te
s
e
p
it
h
eli
ali
za
ti
o
n
.
I
n
a
d
d
iti
o
n
t
o
al
le
v
ia
ti
n
g
p
a
in
an
d
r
e
m
o
v
i
n
g
o
d
o
r
f
r
o
m
t
h
e
ar
ea
,
h
o
n
ey
als
o
h
as
a
d
e
b
r
i
d
em
e
n
t
e
f
f
ec
t,
m
ea
n
i
n
g
i
t
r
e
m
o
v
es
d
eb
r
is
f
r
o
m
t
h
e
lesi
o
n
[
1
5
]
.
Al
le
r
g
ies
t
o
h
o
n
e
y
a
r
e
r
ar
e,
b
u
t
all
er
g
i
c
r
ea
c
ti
o
n
s
to
h
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n
e
y
p
r
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te
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s
a
n
d
all
e
r
g
en
s
a
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p
o
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s
i
b
l
e.
4
.
2
.
H
o
ney
a
s
a
wo
un
d hea
li
ng
t
hera
py
A
c
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h
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p
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2
0
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p
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d
i
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r
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[
3
2
]
.
S
e
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[
3
0
]
.
A
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Evaluation Warning : The document was created with Spire.PDF for Python.
I
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N:
2252
-
8
8
0
6
Ho
n
ey
a
s
a
n
a
lter
n
a
tive
w
o
u
n
d
h
ea
lin
g
th
era
p
y:
a
s
ystema
tic
r
ev
iew
o
f c
lin
ica
l
… (
E
n
i Ku
s
ya
ti
)
609
s
e
v
e
r
e
l
y
c
o
n
ta
m
i
n
a
t
e
d
s
o
f
t
t
is
s
u
e
w
o
u
n
d
s
[
2
2
]
.
L
o
c
a
l
M
GH
th
e
r
a
p
y
r
e
d
u
c
e
d
t
h
e
b
a
c
te
r
i
a
l
lo
a
d
,
i
n
s
o
m
e
c
a
s
es
r
e
s
u
l
t
i
n
g
i
n
s
t
e
r
i
l
e
c
u
lt
u
r
e
s
[
2
6
]
,
a
n
d
i
n
h
i
b
i
t
e
d
b
a
c
t
e
r
ia
l
g
r
o
w
t
h
a
n
d
b
i
o
f
i
l
m
p
r
o
d
u
c
t
i
o
n
[
2
9
]
.
T
h
e
f
in
d
in
g
s
s
u
g
g
est
th
at
alter
in
g
h
o
n
e
y
co
n
ce
n
tr
a
tio
n
ca
n
h
in
d
er
g
r
o
wth
an
d
r
ed
u
ce
th
e
n
u
m
b
er
o
f
g
er
m
s
.
T
h
is
n
o
tio
n
is
b
ased
o
n
th
e
f
ac
t
th
at
ch
r
o
n
ic
a
n
d
p
er
s
is
ten
t
wo
u
n
d
s
ar
e
f
r
eq
u
en
tly
ca
u
s
ed
b
y
b
ac
ter
ial
co
lo
n
izatio
n
o
f
th
e
a
f
f
licted
ti
s
s
u
e.
T
h
is
m
ec
h
an
is
m
ca
n
r
es
u
lt
in
b
ac
ter
ial
r
esis
tan
ce
to
a
n
tim
ic
r
o
b
ials
,
b
o
th
to
p
ical
an
d
s
y
s
tem
ic.
As
a
r
esu
lt,
th
is
h
as
th
e
p
o
ten
tial
to
r
aise
m
o
r
b
id
ity
an
d
m
o
r
tality
r
at
es.
Ho
n
ey
h
as
b
ee
n
s
h
o
wn
to
in
clu
d
e
an
tib
ac
ter
ial
an
d
an
ti
-
in
f
lam
m
ato
r
y
ef
f
ec
ts
[
1
4
]
,
[
3
6
]
.
Ho
n
ey
'
s
ca
p
ac
ity
t
o
h
ea
l
wo
u
n
d
s
ca
n
b
e
attr
ib
u
te
d
to
s
ev
er
al
m
ec
h
an
is
m
s
,
in
clu
d
in
g
its
an
ti
-
in
f
l
am
m
ato
r
y
an
d
an
tio
x
id
an
t
p
r
o
p
er
ties
.
Ho
n
e
y
n
o
t
o
n
ly
en
co
u
r
ag
es
r
e
-
ep
ith
eliali
za
tio
n
an
d
an
g
io
g
en
esis
,
b
u
t
it
also
s
tim
u
lates
s
k
in
ce
ll
g
r
o
wth
an
d
b
o
o
s
ts
th
e
im
m
u
n
e
s
y
s
tem
.
Ho
n
e
y
'
s
d
is
t
in
ct
p
r
o
p
e
r
ties
,
in
clu
d
in
g
h
ig
h
o
s
m
o
lality
,
lo
w
wate
r
c
o
n
t
en
t,
an
d
ac
i
d
ic
p
H,
wh
en
co
m
b
in
ed
with
s
p
ec
if
ic
ch
em
icals
s
u
ch
as
h
y
d
r
o
g
e
n
p
er
o
x
id
e,
p
h
e
n
o
lic
co
m
p
o
u
n
d
s
,
m
eth
y
lg
l
y
o
x
al,
an
d
b
ee
d
e
f
en
s
in
-
1
p
e
p
tid
es,
h
av
e
a
d
ir
ec
t
im
p
ac
t
o
n
b
ac
te
r
ial
g
r
o
wth
an
d
s
u
r
v
iv
al.
Fu
r
th
er
m
o
r
e
,
h
o
n
ey
h
as
in
d
ir
ec
t
an
tim
icr
o
b
ial
ef
f
ec
ts
b
y
en
h
an
cin
g
ly
m
p
h
o
c
y
te
p
r
o
life
r
atio
n
,
an
tib
o
d
y
p
r
o
d
u
ctio
n
,
cy
to
k
in
e
r
elea
s
e,
an
d
im
m
u
n
o
m
o
d
u
latio
n
,
as we
ll a
s
s
tim
u
latin
g
n
itric
o
x
id
e
(
NO)
g
en
er
atio
n
[
1
3
]
,
[
1
4
]
.
Hy
d
r
o
g
e
n
p
e
r
o
x
i
d
e,
a
n
a
tu
r
a
l
an
t
ib
ac
te
r
ia
l
a
g
e
n
t
,
is
wi
d
el
y
u
s
e
d
t
o
cl
ea
n
wo
u
n
d
s
.
T
h
is
c
h
e
m
ic
al
is
b
el
ie
v
e
d
t
o
p
l
ay
a
c
r
u
c
ial
r
o
l
e
i
n
h
o
n
e
y
'
s
a
b
ili
ty
t
o
i
n
h
ib
it
b
a
cte
r
i
al
g
r
o
w
th
.
H
o
w
e
v
e
r
,
t
h
e
co
n
ce
n
t
r
at
io
n
o
f
h
y
d
r
o
g
e
n
p
e
r
o
x
i
d
e
c
o
m
m
o
n
l
y
u
t
ili
ze
d
i
n
w
o
u
n
d
ca
r
e
is
m
o
r
e
h
a
r
m
f
u
l
t
h
a
n
th
at
f
o
u
n
d
i
n
h
o
n
e
y
.
T
h
e
co
n
c
e
n
tr
ati
o
n
o
f
p
e
r
o
x
i
d
e
in
h
o
n
e
y
is
s
i
g
n
if
ic
an
tl
y
l
o
w
er
a
n
d
m
o
r
e
co
m
p
a
ti
b
le
wit
h
ce
lls
,
y
et
i
t
s
t
ill
e
f
f
ec
t
iv
el
y
in
h
i
b
its
b
ac
te
r
ia
l
d
ev
el
o
p
m
e
n
t
[
3
7
]
,
[
3
8
]
.
H
o
n
e
y
'
s
a
n
ti
-
i
n
f
l
am
m
at
o
r
y
p
r
o
p
e
r
t
ies
als
o
li
m
it
t
h
e
s
y
n
t
h
esis
o
f
p
las
m
i
n
o
g
e
n
ac
t
iv
at
o
r
i
n
h
i
b
it
o
r
(
PA
I
)
b
y
m
ac
r
o
p
h
ag
es
[
1
5
]
.
PAI
p
r
e
v
e
n
ts
t
h
e
c
o
n
v
e
r
s
i
o
n
o
f
p
l
asm
i
n
o
g
e
n
,
a
n
en
zy
m
a
tic
all
y
in
ac
t
iv
e
p
r
ec
u
r
s
o
r
o
f
p
l
asm
in
,
i
n
t
o
ac
ti
v
e
p
l
asm
i
n
.
I
n
f
l
am
m
a
ti
o
n
p
r
o
m
o
t
e
s
PAI
d
ev
el
o
p
m
en
t,
h
e
n
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e
h
o
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ey
'
s
m
et
h
o
d
f
o
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r
ed
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ci
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PA
I
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n
t
h
esis
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m
o
s
t
li
k
el
y
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n
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n
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i
-
in
f
l
a
m
m
a
t
o
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r
o
p
e
r
t
ies
[
3
9
]
.
S
e
v
e
r
al
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t
u
d
i
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b
o
t
h
in
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it
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o
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h
a
v
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em
o
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t
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th
at
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ty
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es
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n
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d
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t
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H
o
n
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s
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ig
h
v
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it
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r
e
ates
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p
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ec
ti
v
e
b
ar
r
i
er
a
g
ai
n
s
t
in
f
ec
tio
n
[
1
4
]
.
An
tim
icr
o
b
ial
p
ep
tid
es
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d
p
h
en
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f
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it
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ty
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ically
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A
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5
%
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r
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ter
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m
m
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n
icatio
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n
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m
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g
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h
is
p
ath
way
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cr
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r
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llin
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ir
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p
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ch
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co
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s
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en
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e
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es
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csg
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)
,
as
well
as
q
u
o
r
u
m
-
s
en
s
in
g
g
en
es
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in
cl
u
d
in
g
AI
-
2
im
p
o
r
ter
s
an
d
in
d
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le
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s
y
n
th
esis
)
an
d
v
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r
u
len
ce
g
e
n
es (
s
u
ch
as L
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E
g
e
n
es)
in
E
s
ch
erich
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co
li
[
4
0
]
,
[
4
1
]
.
4
.
3
.
B
enef
it
s
o
f
m
edi
ca
l g
ra
de
ho
ney
(
M
G
H
)
o
n t
he
wo
un
d hea
lin
g
pro
ce
s
s
Pre
v
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s
r
esear
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h
as sh
o
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th
at
h
o
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d
r
ess
in
g
s
m
ak
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s
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b
s
tan
tial d
if
f
er
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ce
in
im
p
r
o
v
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g
wo
u
n
d
h
ea
lin
g
.
T
h
is
r
ev
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r
ev
ea
le
d
h
o
n
e
y
d
r
ess
in
g
s
as
a
wo
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n
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ca
r
e
m
eth
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d
,
with
th
e
r
e
s
u
lt
th
at
co
m
p
lete
ep
ith
elializa
tio
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o
f
later
al
p
al
atal
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ef
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ts
was
clin
ically
ev
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d
en
t
in
6
6
.
7
%
o
f
test
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u
p
p
ar
ticip
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ts
2
wee
k
s
f
o
llo
win
g
s
u
r
g
er
y
[
1
8
]
.
Ho
n
ey
tr
ea
tm
en
t
p
r
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m
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ea
r
ly
ep
ith
elializa
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p
alata
l
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r
g
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n
d
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f
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llo
win
g
p
alate
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ep
air
an
d
lo
wer
s
th
e
r
is
k
o
f
p
alata
l f
i
s
tu
las
[
1
8
]
.
A
C
ase
Ser
ie
s
in
v
esti
g
at
io
n
d
is
co
v
er
ed
th
at
m
ed
ical
g
r
ad
e
h
o
n
ey
(
MG
H)
p
r
o
v
id
es
a
m
o
is
t
wo
u
n
d
e
n
v
ir
o
n
m
en
t,
ac
ce
ler
ates
au
to
ly
tic
d
eb
r
id
em
en
t,
ex
h
ib
its
an
ti
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in
f
lam
m
ato
r
y
ac
tiv
ity
,
an
d
p
r
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m
o
tes
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n
g
io
g
e
n
esis
an
d
r
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-
ep
ith
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tio
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[
2
5
]
,
r
esu
ltin
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i
n
s
ig
n
if
ican
tly
f
aster
h
ea
lin
g
u
p
to
d
ay
4
2
p
o
s
t
-
ca
esar
ea
n
s
ec
t
io
n
[
2
3
]
.
MG
H
ca
n
also
r
ed
u
c
e
b
ac
ter
ial
b
u
r
d
en
,
lo
wer
th
e
r
is
k
o
f
in
f
ec
tio
n
,
a
n
d
im
p
r
o
v
e
h
ea
lin
g
o
u
tco
m
e
s
[
2
8
]
.
Fu
r
th
er
m
o
r
e,
in
cu
b
atin
g
h
o
n
e
y
with
th
e
s
tr
o
n
g
est
wo
u
n
d
ex
u
d
ate
ca
u
s
es
co
n
s
id
er
ab
le
d
eg
r
ad
atio
n
o
f
th
e
GOX
en
zy
m
e,
a
q
u
ick
an
d
p
o
ten
t
H
2
O2
p
r
o
d
u
ce
r
[
3
1
]
.
H
o
n
ey
im
p
r
o
v
e
s
s
u
r
g
ical
r
esu
lts
an
d
s
h
o
r
ten
s
r
ec
o
v
er
y
tim
e
[
2
1
]
.
T
h
e
wo
u
n
d
h
ea
lin
g
p
r
o
ce
s
s
in
v
o
lv
es
3
8
ty
p
es
o
f
wo
u
n
d
s
wo
r
ld
wid
e,
af
f
ec
tin
g
t
h
e
ep
id
em
i
o
lo
g
y
a
n
d
ec
o
n
o
m
i
c
im
p
ac
t
o
n
h
ea
lth
c
ar
e
s
y
s
tem
s
.
T
r
ea
tin
g
wo
u
n
d
s
in
clu
d
es
r
ed
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ci
n
g
in
f
lam
m
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n
,
p
r
ev
e
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tin
g
in
f
ec
tio
n
,
ed
em
a
,
an
d
ed
em
a
,
en
h
an
cin
g
ce
ll
s
y
n
th
esis
,
an
d
in
cr
ea
s
in
g
DNA
d
am
ag
e
in
th
e
wo
u
n
d
.
Ho
n
ey
,
a
ty
p
e
o
f
wo
u
n
d
tr
ea
tm
en
t,
h
as a
n
tib
ac
ter
ial
an
d
an
ti
-
in
f
lam
m
at
o
r
y
p
r
o
p
er
ties
,
wh
ich
h
elp
p
r
ev
en
t
s
k
in
d
am
ag
e
an
d
in
f
lam
m
atio
n
.
I
t
also
tr
ea
ts
d
iab
etic
wo
u
n
d
s
,
p
r
ev
e
n
tin
g
co
m
p
licatio
n
s
lik
e
am
p
u
tatio
n
o
r
in
f
ec
tio
n
[
1
7
]
.
R
o
y
al
jelly
,
a
n
atu
r
al
s
u
p
p
lem
en
t,
h
as
b
ee
n
f
o
u
n
d
to
e
n
h
an
c
e
s
k
in
wo
u
n
d
h
ea
lin
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b
y
m
o
d
u
latin
g
Glu
ta
th
io
n
e
Per
o
x
id
ase
ac
tiv
ity
an
d
C
C
L
2
ch
em
o
k
i
n
e
g
en
e
tr
an
s
cr
ip
ti
o
n
.
T
h
is
tr
ea
tm
en
t
ca
n
ef
f
ec
ti
v
ely
r
ed
u
ce
wo
u
n
d
h
ea
lin
g
tim
e
an
d
c
o
s
ts
co
m
p
ar
ed
to
p
ar
af
f
in
an
d
p
o
v
i
d
o
n
e
-
i
o
d
in
e
[
4
2
]
.
Ho
n
e
y
’
s
an
ti
-
in
f
la
m
m
ato
r
y
p
r
o
p
e
r
ties
in
clu
d
e
th
e
in
h
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itio
n
o
f
p
lasmin
o
g
en
a
ctiv
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r
in
h
ib
ito
r
(
PAI
)
s
y
n
th
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b
y
m
ac
r
o
p
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wh
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f
ac
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ates
f
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r
in
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ly
s
is
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d
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ar
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d
u
ct
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.
I
n
v
itr
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d
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v
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tu
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ies
d
em
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n
s
tr
ate
th
at
h
o
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d
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ce
s
C
OX
-
1
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d
C
OX
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2
ac
tiv
ity
,
in
ter
f
er
in
g
with
p
r
o
s
tag
lan
d
in
s
y
n
th
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an
d
th
er
eb
y
d
ec
r
ea
s
in
g
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a
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im
p
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n
an
d
n
u
tr
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n
t a
v
ailab
ilit
y
f
o
r
tis
s
u
e
r
ep
ai
r
[
4
2
]
-
[
4
5
]
.
Evaluation Warning : The document was created with Spire.PDF for Python.
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4
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4
.
Rec
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o
r
us
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a
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t
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Acc
o
r
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in
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to
th
e
r
ev
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h
o
n
e
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ca
n
b
e
u
tili
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d
as
a
n
alter
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at
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tr
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en
t
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o
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s
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A
c
ase
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aly
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ested
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ay
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er
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m
p
lem
en
tar
y
tr
ea
tm
en
t
f
o
r
wo
u
n
d
h
ea
lin
g
[
2
5
]
.
H
o
n
ey
is
also
u
s
ed
f
o
r
f
in
an
cial
r
ea
s
o
n
s
,
as
q
u
an
titati
v
e
s
tu
d
ies
h
av
e
s
h
o
wn
th
at
it
is
a
co
s
t
-
ef
f
ec
tiv
e
an
d
s
tr
aig
h
tf
o
r
war
d
alter
n
ativ
e
f
o
r
t
r
ea
tin
g
p
er
s
is
ten
t
wo
u
n
d
in
f
ec
tio
n
s
[
2
6
]
.
Acc
o
r
d
in
g
to
Ko
lo
h
et
a
l
.
[
2
9
]
,
ch
estn
u
t
h
o
n
ey
is
an
alter
n
ati
v
e
tr
ea
tm
en
t
f
o
r
r
esis
tan
t
in
f
ec
tio
n
s
an
d
c
h
r
o
n
ic
wo
u
n
d
s
.
A
n
o
th
er
a
d
v
an
ta
g
e
o
f
h
o
n
ey
d
r
ess
in
g
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is
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eir
ea
s
e
o
f
u
s
e
,
as
h
o
n
e
y
is
a
p
r
ac
tical,
s
im
p
le,
an
d
in
ex
p
en
s
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way
t
o
h
ea
l
wo
u
n
d
s
in
a
v
ar
iety
o
f
o
r
th
o
p
ed
ic
d
is
ea
s
es,
in
clu
d
in
g
th
o
s
e
with
ex
p
o
s
ed
b
o
n
es
o
r
te
n
d
o
n
s
[
1
5
]
.
T
h
e
f
in
d
in
g
s
o
f
th
is
s
y
s
tem
atic
r
ev
iew
s
u
p
p
o
r
t
th
e
u
s
e
o
f
m
ed
ical
-
g
r
ad
e
h
o
n
e
y
(
MG
H)
as
an
ef
f
ec
tiv
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alter
n
ativ
e
tr
ea
tm
en
t
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tib
io
tics
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e,
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ile
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atin
g
r
ec
o
v
er
y
[
2
3
]
.
Fu
r
th
e
r
m
o
r
e
,
h
o
n
ey
h
as
b
ee
n
s
h
o
wn
to
ex
p
ed
ite
wo
u
n
d
h
ea
lin
g
,
r
esu
ltin
g
in
a
q
u
ick
er
r
ec
o
v
e
r
y
ti
m
e
an
d
lo
wer
p
o
s
t
-
o
p
er
ativ
e
m
o
r
b
id
ity
[
2
0
]
.
Ho
n
ey
co
n
tain
s
s
ev
er
al
an
tio
x
id
an
ts
,
in
clu
d
in
g
f
la
v
o
n
o
id
s
,
m
o
n
o
p
h
e
n
o
ls
,
p
o
ly
p
h
en
o
ls
,
v
itam
in
C
,
an
d
m
et
h
y
ls
y
r
in
g
ate,
wh
ich
i
n
h
ib
it
th
e
am
p
lific
atio
n
o
f
in
f
lam
m
atio
n
ca
u
s
ed
b
y
r
ea
cti
v
e
o
x
y
g
en
s
p
ec
ies
(
R
OS)
.
T
h
ese
an
tio
x
id
an
ts
ar
e
r
esp
o
n
s
ib
le
f
o
r
th
e
m
eth
o
d
th
at
h
o
n
e
y
u
s
es
to
allev
iate
wo
u
n
d
p
ain
[
3
5
]
.
Ho
n
ey
,
in
a
d
d
itio
n
t
o
b
ein
g
a
s
o
lu
tio
n
h
ig
h
in
s
u
g
a
r
,
is
also
a
b
i
o
lo
g
ical
wo
u
n
d
d
r
ess
in
g
th
at
co
n
tain
s
m
an
y
b
io
ac
tiv
e
co
m
p
o
n
en
ts
th
at
ca
n
s
tim
u
late
wo
u
n
d
h
ea
lin
g
th
r
o
u
g
h
v
a
r
io
u
s
p
ath
way
s
.
Ho
n
e
y
ca
n
s
p
ee
d
u
p
th
e
h
ea
lin
g
p
r
o
ce
s
s
o
f
wo
u
n
d
s
b
y
wo
r
k
in
g
o
n
t
h
e
th
r
ee
p
h
ases
o
f
g
r
o
w
th
:
p
r
o
life
r
atio
n
,
r
em
o
d
ellin
g
,
an
d
in
f
lam
m
atio
n
.
Ho
n
ey
is
k
n
o
wn
to
en
h
an
ce
t
h
e
p
r
o
d
u
ctio
n
o
f
co
llag
e
n
,
as
well
as
an
g
io
g
en
esis
an
d
g
r
an
u
latio
n
tis
s
u
e
cr
ea
tio
n
.
Ad
d
itio
n
ally
,
h
o
n
e
y
b
o
o
s
ts
wo
u
n
d
co
n
tr
ac
tio
n
a
n
d
p
r
o
m
o
tes
ep
ith
elializa
tio
n
[
4
6
]
.
I
n
ad
d
itio
n
t
o
allev
iatin
g
p
ain
a
n
d
r
em
o
v
in
g
o
d
o
r
f
r
o
m
th
e
ar
ea
,
h
o
n
ey
also
h
as
a
d
eb
r
id
em
e
n
t
ef
f
ec
t,
m
ea
n
in
g
it
r
em
o
v
es
d
eb
r
is
f
r
o
m
th
e
lesi
o
n
[
1
5
]
.
Aller
g
ies
to
h
o
n
ey
a
r
e
r
a
r
e,
b
u
t
aller
g
ic
r
ea
ctio
n
s
to
h
o
n
ey
p
r
o
tein
s
an
d
aller
g
en
s
ar
e
p
o
s
s
ib
le.
4
.
5
.
H
et
er
o
g
eneit
y
a
cr
o
s
s
s
t
ud
ies
A
cr
itical
co
n
s
id
er
atio
n
is
t
h
e
s
u
b
s
tan
tial
h
eter
o
g
e
n
eity
o
b
s
er
v
ed
ac
r
o
s
s
th
e
in
clu
d
ed
s
tu
d
ies.
Var
iatio
n
s
in
h
o
n
ey
ty
p
es (
Ma
n
u
k
a,
ch
estn
u
t,
h
ea
th
er
,
m
ed
ic
al
-
g
r
ad
e)
,
co
n
ce
n
tr
atio
n
s
,
wo
u
n
d
ty
p
es
(
s
u
r
g
ical
,
ch
r
o
n
ic,
d
iab
etic,
p
r
ess
u
r
e
u
lcer
s
)
,
p
atien
t
p
o
p
u
latio
n
s
,
an
d
o
u
tco
m
e
m
ea
s
u
r
es
lim
it
th
e
ab
ilit
y
to
d
r
aw
d
ef
in
itiv
e
c
o
n
clu
s
io
n
s
r
eg
ar
d
in
g
o
p
tim
al
p
r
o
to
c
o
ls
.
T
h
e
co
m
p
o
s
itio
n
o
f
h
o
n
e
y
v
ar
ies
s
ig
n
if
ican
tly
b
ased
o
n
f
lo
r
al
s
o
u
r
ce
an
d
g
eo
g
r
ap
h
ic
al
o
r
ig
in
,
wh
ich
m
ay
ac
c
o
u
n
t
f
o
r
d
if
f
e
r
en
ce
s
in
th
er
ap
e
u
tic
ef
f
icac
y
.
T
h
is
v
ar
iab
ilit
y
u
n
d
er
s
co
r
es th
e
n
ee
d
f
o
r
s
tan
d
ar
d
ized
h
o
n
ey
p
r
o
d
u
cts an
d
tr
ea
tm
en
t
p
r
o
to
c
o
ls
in
f
u
tu
r
e
r
esear
ch
.
4
.
6
.
P
ub
lic
hea
lt
h,
po
licy
,
a
n
d e
co
no
m
ic
im
pli
ca
t
io
ns
Ho
n
ey
’
s
af
f
o
r
d
ab
ilit
y
a
n
d
ac
c
ess
ib
ilit
y
m
ak
e
it
p
ar
ticu
lar
ly
r
elev
an
t
f
o
r
wo
u
n
d
ca
r
e
in
L
MI
C
s
an
d
r
u
r
al
a
r
ea
s
,
wh
er
e
ac
ce
s
s
to
ad
v
a
n
ce
d
wo
u
n
d
ca
r
e
p
r
o
d
u
cts
is
o
f
ten
lim
ited
[
1
5
]
.
Me
d
ical
-
g
r
ad
e
h
o
n
ey
p
r
o
d
u
cts
h
av
e
d
em
o
n
s
tr
ated
co
s
t
-
ef
f
ec
tiv
en
ess
co
m
p
a
r
ed
to
co
n
v
en
tio
n
al
d
r
ess
in
g
s
in
s
ev
er
al
s
tu
d
ies
[
2
6
]
.
T
h
e
cu
ltu
r
al
f
am
ili
ar
ity
o
f
h
o
n
ey
as a
tr
ad
itio
n
al
m
ed
icin
e
ac
r
o
s
s
m
an
y
co
m
m
u
n
ities
wo
r
ld
wid
e
m
ay
im
p
r
o
v
e
p
atien
t
ad
h
er
en
c
e
an
d
ac
ce
p
tan
ce
,
p
ar
ticu
lar
ly
i
n
s
ettin
g
s
wh
er
e
m
o
d
e
r
n
wo
u
n
d
ca
r
e
p
r
o
d
u
cts
ar
e
p
er
ce
iv
ed
as f
o
r
eig
n
o
r
in
ac
ce
s
s
ib
le
[
1
5
]
.
Fro
m
a
p
o
licy
p
er
s
p
ec
tiv
e,
th
e
g
r
o
win
g
e
v
id
en
ce
b
ase
s
u
p
p
o
r
ts
co
n
s
id
er
atio
n
o
f
h
o
n
ey
-
b
ased
th
er
ap
ies
f
o
r
in
cl
u
s
io
n
in
n
at
io
n
al
wo
u
n
d
ca
r
e
g
u
id
elin
es
an
d
p
o
te
n
tially
in
W
HO
ess
en
tial
wo
u
n
d
ca
r
e
r
ec
o
m
m
en
d
atio
n
s
.
I
n
te
g
r
atio
n
o
f
h
o
n
ey
in
to
co
m
m
u
n
ity
h
e
alth
p
r
o
m
o
tio
n
p
r
o
g
r
a
m
s
,
s
ch
o
o
l
h
ea
lth
f
ir
s
t
-
ai
d
p
r
o
to
co
ls
,
a
n
d
o
cc
u
p
atio
n
al
h
ea
lth
p
r
o
g
r
a
m
s
f
o
r
ag
r
ic
u
ltu
r
al
an
d
in
d
u
s
tr
ial
wo
r
k
er
s
i
n
u
n
d
e
r
s
er
v
ed
ar
ea
s
co
u
ld
ex
te
n
d
th
e
r
ea
ch
o
f
ef
f
e
ctiv
e
wo
u
n
d
ca
r
e
[
1
5
]
.
T
h
e
r
elev
a
n
ce
o
f
h
o
n
e
y
-
b
ase
d
wo
u
n
d
ca
r
e
e
x
ten
d
s
ac
r
o
s
s
p
o
p
u
latio
n
s
,
i
n
clu
d
in
g
eld
e
r
ly
p
atien
ts
with
ch
r
o
n
ic
wo
u
n
d
s
,
d
iab
e
tic
p
atien
ts
with
f
o
o
t
u
lce
r
s
an
d
p
r
ess
u
r
e
s
o
r
es
[
2
4
]
,
[
4
7
]
,
an
d
p
ed
iatr
ic
p
o
p
u
latio
n
s
r
eq
u
ir
in
g
s
af
e
an
d
ac
ce
p
tab
le
wo
u
n
d
ca
r
e
o
p
tio
n
s
[
4
8
]
,
[
4
9
]
.
Ho
we
v
er
,
s
p
ec
if
ic
ev
id
en
ce
f
o
r
p
ed
iatr
ic
p
o
p
u
latio
n
s
r
em
ai
n
s
lim
i
ted
an
d
war
r
a
n
ts
f
u
r
th
er
in
v
esti
g
atio
n
.
5.
CO
NCLU
SI
O
N
T
h
is
s
y
s
tem
atic
r
ev
iew
d
e
m
o
n
s
tr
ates
th
at
h
o
n
e
y
,
p
ar
ticu
lar
ly
m
ed
ical
-
g
r
ad
e
h
o
n
ey
,
s
h
o
ws
co
n
s
id
er
ab
le
p
r
o
m
is
e
as
an
a
lter
n
ativ
e
wo
u
n
d
h
ea
lin
g
th
er
ap
y
with
an
tim
icr
o
b
ial,
an
ti
-
i
n
f
lam
m
ato
r
y
,
a
n
d
tis
s
u
e
-
r
eg
en
er
atin
g
p
r
o
p
er
ties
.
T
h
e
ev
id
en
ce
s
u
p
p
o
r
ts
its
ef
f
icac
y
ac
r
o
s
s
d
iv
er
s
e
wo
u
n
d
ty
p
es
in
clu
d
in
g
s
u
r
g
ical,
ch
r
o
n
ic,
d
iab
etic,
a
n
d
in
f
ec
ted
wo
u
n
d
s
.
Ho
wev
e
r
,
th
e
cu
r
r
en
t
e
v
id
en
ce
b
ase
is
lim
ited
b
y
s
tu
d
y
h
eter
o
g
en
eity
,
s
m
all
s
am
p
le
s
izes,
v
ar
iab
ilit
y
in
h
o
n
e
y
t
y
p
es
an
d
p
r
o
to
co
ls
,
an
d
th
e
p
r
e
d
o
m
in
an
ce
o
f
s
tu
d
ies
f
r
o
m
h
i
g
h
-
in
c
o
m
e
s
ettin
g
s
.
T
h
e
f
in
d
in
g
s
ca
n
n
o
t
b
e
g
en
er
alize
d
with
o
u
t
ca
u
tio
n
,
p
a
r
ticu
lar
ly
to
p
o
p
u
latio
n
s
an
d
s
ettin
g
s
u
n
d
er
r
ep
r
esen
ted
i
n
th
e
cu
r
r
e
n
t
liter
atu
r
e.
W
h
ile
h
o
n
e
y
-
b
as
ed
th
er
ap
ies
o
f
f
er
a
c
o
s
t
-
ef
f
ec
tiv
e
an
d
cu
ltu
r
ally
ac
ce
p
tab
le
ap
p
r
o
ac
h
to
wo
u
n
d
ca
r
e,
th
e
ev
id
en
ce
is
n
o
t
y
e
t
s
u
f
f
icien
t
to
r
ec
o
m
m
en
d
th
e
ir
r
o
u
tin
e
u
s
e
as
a
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
Ho
n
ey
a
s
a
n
a
lter
n
a
tive
w
o
u
n
d
h
ea
lin
g
th
era
p
y:
a
s
ystema
tic
r
ev
iew
o
f c
lin
ica
l
… (
E
n
i Ku
s
ya
ti
)
611
s
tan
d
alo
n
e
r
e
p
lace
m
en
t
f
o
r
co
n
v
en
tio
n
al
tr
ea
tm
en
ts
.
R
ath
er
,
h
o
n
ey
s
h
o
u
ld
b
e
co
n
s
id
er
e
d
a
s
a
co
m
p
lem
en
tar
y
th
er
ap
y
with
in
a
n
in
teg
r
ated
w
o
u
n
d
m
an
ag
e
m
en
t a
p
p
r
o
ac
h
.
Hea
lth
ca
r
e
p
r
ac
titi
o
n
er
s
s
h
o
u
ld
co
n
s
id
er
m
ed
ical
-
g
r
ad
e
h
o
n
ey
p
r
o
d
u
cts
as
ad
ju
n
ctiv
e
th
er
ap
y
i
n
wo
u
n
d
ca
r
e,
p
a
r
ticu
lar
ly
in
s
ettin
g
s
wh
er
e
co
n
v
en
tio
n
a
l
tr
ea
tm
en
ts
ar
e
co
s
tly
o
r
u
n
av
ailab
le.
Fam
ily
en
g
ag
em
e
n
t
an
d
cu
ltu
r
all
y
s
en
s
itiv
e
ap
p
r
o
ac
h
es
to
w
o
u
n
d
ca
r
e
e
d
u
ca
tio
n
s
h
o
u
l
d
b
e
in
co
r
p
o
r
ated
in
t
o
p
r
ac
tice.
C
lin
ician
s
s
h
o
u
ld
b
e
awa
r
e
o
f
th
e
v
ar
iab
ilit
y
in
h
o
n
ey
p
r
o
d
u
cts
an
d
p
r
e
f
er
en
tiall
y
u
s
e
s
tan
d
ar
d
ized
,
m
ed
ical
-
g
r
ad
e
f
o
r
m
u
latio
n
s
.
Fu
tu
r
e
r
esear
ch
s
h
o
u
l
d
p
r
io
r
itize
lar
g
e
-
s
ca
le,
m
u
lti
-
ce
n
t
er
r
an
d
o
m
ized
co
n
tr
o
lled
tr
ials
with
s
tan
d
ar
d
ized
h
o
n
e
y
p
r
o
d
u
cts,
tr
ea
tm
en
t
p
r
o
to
co
ls
,
a
n
d
o
u
tc
o
m
e
m
ea
s
u
r
es
(
h
ea
lin
g
tim
e,
i
n
f
ec
tio
n
r
ates,
p
ain
s
co
r
es,
co
s
t
-
ef
f
ec
tiv
en
ess
)
to
en
ab
le
q
u
an
titativ
e
s
y
n
th
esis
an
d
g
u
id
elin
e
d
e
v
elo
p
m
e
n
t.
C
o
m
p
ar
ativ
e
s
tu
d
ies
ac
r
o
s
s
d
if
f
er
en
t
h
o
n
e
y
ty
p
es
an
d
co
n
ce
n
tr
atio
n
s
,
in
v
esti
g
atio
n
s
in
d
iv
er
s
e
clin
ical
s
ettin
g
s
in
clu
d
in
g
L
MI
C
s
,
an
d
s
tu
d
ies s
p
ec
if
ically
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d
r
es
s
in
g
p
ed
iatr
ic,
g
e
r
iatr
ic,
an
d
d
i
ab
etic
p
o
p
u
latio
n
s
ar
e
n
ee
d
ed
.
RE
F
E
R
E
NC
E
S
[
1
]
E.
M
.
T
o
t
t
o
l
i
,
R
.
D
o
r
a
t
i
,
I
.
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e
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t
a
,
E.
C
h
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s
a
,
S
.
P
i
sa
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i
,
a
n
d
B
.
C
o
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,
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S
k
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t
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h
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rm
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r
mac
e
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s
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0
7
3
5
.
[
2
]
H
.
D
i
n
g
,
Z
.
Y
u
,
H
.
Y
a
o
,
X
.
X
u
,
Y
.
Li
u
,
a
n
d
M
.
C
h
e
n
,
“
G
l
o
b
a
l
b
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a
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d
s o
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b
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y
‐
a
d
j
u
st
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d
l
i
f
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y
e
a
r
s a
n
d
m
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r
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f
o
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u
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s
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:
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s
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st
e
ma
t
i
c
a
n
a
l
y
si
s
,
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n
t
e
r
n
a
t
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o
n
a
l
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u
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d
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o
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l
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l
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o
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o
i
:
1
0
.
1
1
1
1
/
i
w
j
.
1
4
6
0
4
.
[
3
]
D
.
B
a
l
d
e
r
a
s
-
C
o
r
d
e
r
o
,
O
.
C
a
n
a
l
e
s
-
A
l
v
a
r
e
z
,
R
.
S
á
n
c
h
e
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-
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n
c
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e
z
,
A
.
C
a
b
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r
a
-
W
r
o
o
ma
n
,
M
.
M
.
C
a
n
a
l
e
s
-
M
a
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t
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n
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z
,
a
n
d
M
.
A
.
R
o
d
r
i
g
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e
z
-
M
o
n
r
o
y
,
“
A
n
t
i
-
i
n
f
l
a
mm
a
t
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d
h
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st
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d
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t
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n
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f
M
e
x
i
c
a
n
pr
o
p
o
l
i
s
,
”
I
n
t
e
r
n
a
t
i
o
n
a
l
J
o
u
rn
a
l
o
f
M
o
l
e
c
u
l
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c
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,
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l
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o
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4
,
p
.
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,
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l
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0
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:
1
0
.
3
3
9
0
/
i
j
ms
2
4
1
4
1
1
8
3
1
.
[
4
]
W
o
r
l
d
H
e
a
l
t
h
O
r
g
a
n
i
z
a
t
i
o
n
(
W
H
O
)
,
“
S
e
p
s
i
s
,
k
e
y
f
a
c
t
s
.
”
[
O
n
l
i
n
e
]
.
A
v
a
i
l
a
b
l
e
:
h
t
t
p
s
:
/
/
w
w
w
.
w
h
o
.
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n
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/
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e
w
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-
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/
f
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-
s
h
e
e
t
s
/
d
e
t
a
i
l
/
s
e
p
s
i
s
.
[
5
]
D
.
G
.
A
r
ms
t
r
o
n
g
,
M
.
A
.
S
w
e
r
d
l
o
w
,
A
.
A
.
A
r
ms
t
r
o
n
g
,
M
.
S
.
C
o
n
t
e
,
W
.
V
.
P
a
d
u
l
a
,
a
n
d
S
.
A
.
B
u
s,
“
F
i
v
e
y
e
a
r
m
o
r
t
a
l
i
t
y
a
n
d
d
i
r
e
c
t
c
o
s
t
s
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f
c
a
r
e
f
o
r
p
e
o
p
l
e
w
i
t
h
d
i
a
b
e
t
i
c
f
o
o
t
c
o
m
p
l
i
c
a
t
i
o
n
s
a
r
e
c
o
m
p
a
r
a
b
l
e
t
o
c
a
n
c
e
r
,
”
J
o
u
r
n
a
l
o
f
Fo
o
t
a
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d
A
n
k
l
e
R
e
se
a
rc
h
,
v
o
l
.
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3
,
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o
.
1
,
J
a
n
.
2
0
2
0
,
d
o
i
:
1
0
.
1
1
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6
/
s
1
3
0
4
7
-
0
2
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0
0
3
8
3
-
2.
[
6
]
C
.
K
.
S
e
n
,
“
H
u
ma
n
w
o
u
n
d
a
n
d
i
t
s
b
u
r
d
e
n
:
u
p
d
a
t
e
d
2
0
2
5
c
o
m
p
e
n
d
i
u
m o
f
e
st
i
m
a
t
e
s
,
”
A
d
v
a
n
c
e
s
i
n
W
o
u
n
d
C
a
re
,
v
o
l
.
1
4
,
n
o
.
9
,
p
p
.
4
2
9
–
4
3
8
,
S
e
p
.
2
0
2
5
,
d
o
i
:
1
0
.
1
1
7
7
/
2
1
6
2
1
9
1
8
2
5
1
3
5
9
5
5
4
.
[
7
]
C
.
C
.
F
.
P
l
e
e
g
i
n
g
,
F
.
A
.
D
.
T.
G
.
W
a
g
e
n
e
r
,
H
.
d
e
R
o
o
s
t
e
r
,
a
n
d
N
.
A
.
J.
C
r
e
mers
,
“
R
e
v
o
l
u
t
i
o
n
i
z
i
n
g
n
o
n
-
c
o
n
v
e
n
t
i
o
n
a
l
w
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n
d
h
e
a
l
i
n
g
u
si
n
g
h
o
n
e
y
b
y
si
m
u
l
t
a
n
e
o
u
sl
y
t
a
r
g
e
t
i
n
g
mu
l
t
i
p
l
e
m
o
l
e
c
u
l
a
r
me
c
h
a
n
i
sms
,
”
D
ru
g
Re
s
i
st
a
n
c
e
U
p
d
a
t
e
s
,
v
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l
.
6
2
,
p
.
1
0
0
8
3
4
,
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y
2
0
2
2
,
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:
1
0
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1
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1
6
/
j
.
d
r
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p
.
2
0
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2
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1
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0
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3
4
.
[
8
]
R
.
H
o
ssa
i
n
e
t
a
l
.
,
“
P
r
o
p
o
l
i
s
:
a
n
u
p
d
a
t
e
o
n
i
t
s
c
h
e
mi
s
t
r
y
a
n
d
p
h
a
r
ma
c
o
l
o
g
i
c
a
l
a
p
p
l
i
c
a
t
i
o
n
s
,
”
C
h
i
n
e
se
Me
d
i
c
i
n
e
,
v
o
l
.
1
7
,
n
o
.
1
,
p
.
1
0
0
,
A
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g
.
2
0
2
2
,
d
o
i
:
1
0
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1
1
8
6
/
s
1
3
0
2
0
-
0
2
2
-
0
0
6
5
1
-
2.
[
9
]
X
.
La
n
e
t
a
l
.
,
“
G
l
o
b
a
l
,
r
e
g
i
o
n
a
l
,
a
n
d
n
a
t
i
o
n
a
l
b
u
r
d
e
n
o
f
p
r
e
ss
u
r
e
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l
c
e
r
s
f
r
o
m
1
9
9
0
t
o
2
0
2
1
a
n
d
p
r
o
j
e
c
t
i
o
n
s
o
v
e
r
t
h
e
n
e
x
t
d
e
c
a
d
e
:
r
e
su
l
t
s fr
o
m t
h
e
2
0
2
1
G
B
D
s
t
u
d
y
,
”
W
o
u
n
d
R
e
p
a
i
r
a
n
d
R
e
g
e
n
e
r
a
t
i
o
n
,
v
o
l
.
3
3
,
n
o
.
4
,
Ju
l
.
2
0
2
5
,
d
o
i
:
1
0
.
1
1
1
1
/
w
r
r
.
7
0
0
6
4
.
[
1
0
]
W
o
r
l
d
H
e
a
l
t
h
O
r
g
a
n
i
z
a
t
i
o
n
(
W
H
O
)
,
“
S
e
p
si
s
s
y
mp
t
o
ms,
o
v
e
r
v
i
e
w
s
e
p
s
i
s,
t
r
e
a
t
m
e
n
t
.
”
[
O
n
l
i
n
e
]
.
A
v
a
i
l
a
b
l
e
:
h
t
t
p
s
:
/
/
w
w
w
.
w
h
o
.
i
n
t
/
h
e
a
l
t
h
-
t
o
p
i
c
s/
s
e
p
si
s.
[
1
1
]
K
.
E.
R
u
d
d
e
t
a
l
.
,
“
G
l
o
b
a
l
,
r
e
g
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o
n
a
l
,
a
n
d
n
a
t
i
o
n
a
l
se
p
si
s
i
n
c
i
d
e
n
c
e
a
n
d
m
o
r
t
a
l
i
t
y
,
1
9
9
0
–
2
0
1
7
:
a
n
a
l
y
si
s
f
o
r
t
h
e
G
l
o
b
a
l
B
u
r
d
e
n
o
f
D
i
sea
s
e
S
t
u
d
y
,
”
T
h
e
L
a
n
c
e
t
,
v
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l
.
3
9
5
,
n
o
.
1
0
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1
9
,
p
p
.
2
0
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1
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,
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n
.
2
0
2
0
,
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o
i
:
1
0
.
1
0
1
6
/
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0
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4
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6
7
3
6
(
1
9
)
3
2
9
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9
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7.
[
1
2
]
E
.
T
a
c
c
o
n
e
l
l
i
e
t
a
l
.
,
“
D
i
s
c
o
v
e
r
y
,
r
e
s
e
a
r
c
h
,
a
n
d
d
e
v
e
l
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p
m
e
n
t
o
f
n
e
w
a
n
t
i
b
i
o
t
i
c
s
:
t
h
e
W
H
O
p
r
i
o
r
i
t
y
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i
s
t
o
f
a
n
t
i
b
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r
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s
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s
t
a
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t
b
a
c
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a
a
n
d
t
u
b
e
r
c
u
l
o
s
i
s
,
”
T
h
e
L
a
n
c
e
t
I
n
f
e
c
t
i
o
u
s
D
i
s
e
a
s
e
s
,
v
o
l
.
1
8
,
n
o
.
3
,
p
p
.
3
1
8
–
3
2
7
,
M
a
r
.
2
0
1
8
,
d
o
i
:
1
0
.
1
0
1
6
/
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1
4
7
3
-
3
0
9
9
(
1
7
)
3
0
7
5
3
-
3.
[
1
3
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lth
Sci
I
SS
N:
2252
-
8
8
0
6
Ho
n
ey
a
s
a
n
a
lter
n
a
tive
w
o
u
n
d
h
ea
lin
g
th
era
p
y:
a
s
ystema
tic
r
ev
iew
o
f c
lin
ica
l
… (
E
n
i Ku
s
ya
ti
)
613
T
ab
le
1
.
C
h
ar
ac
ter
is
tics
o
f
in
c
lu
d
ed
s
tu
d
ies
(
co
n
tin
u
ed
)
N
o
.
A
u
t
h
o
r
a
n
d
y
ear
S
t
u
d
y
d
e
si
g
n
W
o
u
n
d
t
y
p
e
H
o
n
e
y
t
y
p
e
K
e
y
f
i
n
d
i
n
g
s
JB
I
q
u
a
l
i
t
y
a
p
p
r
a
i
s
a
l
2
O
n
u
o
h
a
e
t
a
l
.
(
2
0
2
3
)
[
1
9
]
R
a
n
d
o
m
i
z
e
d
c
o
n
t
r
o
l
l
e
d
t
r
i
a
l
S
u
r
g
i
c
a
l
(
t
h
i
r
d
mo
l
a
r
e
x
t
r
a
c
t
i
o
n
)
M
a
n
u
k
a
h
o
n
e
y
M
a
n
u
k
a
h
o
n
e
y
a
c
c
e
l
e
r
a
t
e
d
h
e
a
l
i
n
g
o
f
e
x
t
r
a
c
t
i
o
n
so
c
k
e
t
s
a
n
d
si
g
n
i
f
i
c
a
n
t
l
y
r
e
d
u
c
e
d
c
o
m
p
l
i
c
a
t
i
o
n
r
a
t
e
s
c
o
m
p
a
r
e
d
t
o
c
o
n
t
r
o
l
.
JB
I
R
C
T
c
h
e
c
k
l
i
st
:
1
0
/
1
3
c
r
i
t
e
r
i
a
m
e
t
.
3
A
l
a
sq
a
h
e
t
a
l
.
(
2
0
2
2
)
[
2
0
]
P
r
o
sp
e
c
t
i
v
e
r
a
n
d
o
m
i
z
e
d
c
a
se
-
c
o
n
t
r
o
l
st
u
d
y
S
u
r
g
i
c
a
l
(
f
r
e
e
g
i
n
g
i
v
a
l
g
r
a
f
t
d
o
n
o
r
si
t
e
)
N
a
t
u
r
a
l
h
o
n
e
y
H
o
n
e
y
a
c
c
e
l
e
r
a
t
e
d
w
o
u
n
d
h
e
a
l
i
n
g
,
r
e
su
l
t
i
n
g
i
n
s
h
o
r
t
e
r
r
e
c
o
v
e
r
y
d
u
r
a
t
i
o
n
a
n
d
r
e
d
u
c
e
d
p
o
s
t
-
o
p
e
r
a
t
i
v
e
m
o
r
b
i
d
i
t
y
.
JB
I
R
C
T
c
h
e
c
k
l
i
st
:
9
/
1
3
c
r
i
t
e
r
i
a
met
.
4
S
a
l
e
h
i
e
t
a
l
.
(
2
0
2
2
)
[
2
1
]
P
r
o
sp
e
c
t
i
v
e
r
a
n
d
o
m
i
z
e
d
p
l
a
c
e
b
o
-
c
o
n
t
r
o
l
l
e
d
c
l
i
n
i
c
a
l
t
r
i
a
l
S
u
r
g
i
c
a
l
(
p
i
l
o
n
i
d
a
l
c
y
s
t
e
x
c
i
si
o
n
)
N
a
t
u
r
a
l
h
o
n
e
y
H
o
n
e
y
a
p
p
l
i
c
a
t
i
o
n
i
m
p
r
o
v
e
d
su
r
g
i
c
a
l
o
u
t
c
o
m
e
s wi
t
h
sec
o
n
d
a
r
y
w
o
u
n
d
h
e
a
l
i
n
g
,
sh
o
r
t
e
n
i
n
g
r
e
c
o
v
e
r
y
p
e
r
i
o
d
a
n
d
t
i
m
e
t
o
r
e
su
m
e
r
e
g
u
l
a
r
a
c
t
i
v
i
t
i
e
s.
JB
I
R
C
T
c
h
e
c
k
l
i
st
:
1
0
/
1
3
c
r
i
t
e
r
i
a
m
e
t
5
G
u
t
h
r
i
e
e
t
a
l
.
(
2
0
1
4
)
[
2
2
]
R
a
n
d
o
m
i
z
e
d
c
o
n
t
r
o
l
l
e
d
t
r
i
a
l
Tr
a
u
m
a
t
i
c
e
x
t
r
e
mi
t
y
w
o
u
n
d
s
(
c
o
n
t
a
mi
n
a
t
e
d
)
M
a
n
u
k
a
h
o
n
e
y
I
o
d
i
n
e
a
n
d
M
a
n
u
k
a
h
o
n
e
y
-
b
a
se
d
d
r
e
ssi
n
g
s m
i
n
i
m
i
z
e
d
b
a
c
t
e
r
i
a
l
b
u
r
d
e
n
o
n
e
x
t
e
n
si
v
e
l
y
c
o
n
t
a
mi
n
a
t
e
d
s
o
f
t
t
i
ssu
e
w
o
u
n
d
s,
p
a
r
t
i
c
u
l
a
r
l
y
w
h
e
n
s
u
r
g
i
c
a
l
t
r
e
a
t
me
n
t
w
a
s
d
e
l
a
y
e
d
.
JB
I
R
C
T
c
h
e
c
k
l
i
st
:
9
/
1
3
c
r
i
t
e
r
i
a
met
.
6
B
o
c
o
u
m
e
t
a
l
.
(
2
0
2
3
)
[
2
3
]
P
r
o
sp
e
c
t
i
v
e
c
o
n
t
r
o
l
l
e
d
t
r
i
a
l
S
u
r
g
i
c
a
l
(
C
a
e
s
a
r
e
a
n
sec
t
i
o
n
)
M
e
d
i
c
a
l
g
r
a
d
e
h
o
n
e
y
(
M
G
H
)
M
G
H
d
e
m
o
n
s
t
r
a
t
e
d
s
u
b
s
t
a
n
t
i
a
l
l
y
f
a
st
e
r
h
e
a
l
i
n
g
u
p
t
o
d
a
y
4
2
p
o
st
-
su
r
g
e
r
y
.
Ef
f
e
c
t
i
v
e
a
l
t
e
r
n
a
t
i
v
e
t
o
a
n
t
i
b
i
o
t
i
c
s
a
n
d
p
o
v
i
d
o
n
e
-
i
o
d
i
n
e
.
JB
I
q
u
a
si
-
e
x
p
e
r
i
me
n
t
a
l
c
h
e
c
k
l
i
st
:
7
/
9
c
r
i
t
e
r
i
a
me
t
.
7
P
a
p
a
n
i
k
o
l
a
o
u
e
t
a
l
.
(
2
0
2
3
)
[
2
4
]
P
r
o
sp
e
c
t
i
v
e
c
a
se
seri
e
s
C
h
r
o
n
i
c
(
i
n
f
e
c
t
e
d
h
e
e
l
p
r
e
ss
u
r
e
u
l
c
e
r
s)
M
e
d
i
c
a
l
g
r
a
d
e
h
o
n
e
y
(
M
G
H
,
L
-
M
e
s
i
t
r
a
n
)
W
o
u
n
d
s
t
r
e
a
t
e
d
w
i
t
h
M
G
H
r
e
so
l
v
e
d
i
n
f
e
c
t
i
o
n
s wi
t
h
i
n
3
–
4
w
e
e
k
s
a
n
d
h
e
a
l
e
d
c
o
m
p
l
e
t
e
l
y
w
i
t
h
o
u
t
c
o
mp
l
i
c
a
t
i
o
n
s.
R
e
c
o
mm
e
n
d
e
d
a
s
a
l
t
e
r
n
a
t
i
v
e
/
c
o
m
p
l
e
me
n
t
a
r
y
t
r
e
a
t
me
n
t
.
JB
I
c
a
se
s
e
r
i
e
s
c
h
e
c
k
l
i
st
:
8
/
1
0
c
r
i
t
e
r
i
a
me
t
.
8
P
a
p
a
n
i
k
o
l
a
o
u
e
t
a
l
.
(
2
0
2
3
)
[
2
5
]
C
a
se
s
e
r
i
e
s
C
h
r
o
n
i
c
(
H
e
e
l
p
r
e
ss
u
r
e
u
l
c
e
r
s)
M
e
d
i
c
a
l
g
r
a
d
e
h
o
n
e
y
(
M
G
H
)
M
G
H
c
r
e
a
t
e
d
mo
i
st
w
o
u
n
d
e
n
v
i
r
o
n
m
e
n
t
,
a
c
c
e
l
e
r
a
t
e
d
a
u
t
o
l
y
t
i
c
d
e
b
r
i
d
e
m
e
n
t
,
e
x
h
i
b
i
t
e
d
a
n
t
i
-
i
n
f
l
a
mm
a
t
o
r
y
p
r
o
p
e
r
t
i
e
s,
a
n
d
p
r
o
m
o
t
e
d
a
n
g
i
o
g
e
n
e
si
s
a
n
d
re
-
e
p
i
t
h
e
l
i
a
l
i
z
a
t
i
o
n
.
JB
I
c
a
se
s
e
r
i
e
s
c
h
e
c
k
l
i
st
:
7
/
1
0
c
r
i
t
e
r
i
a
me
t
.
9
A
h
me
d
e
t
a
l
.
(
2
0
2
2
)
[
1
5
]
C
a
se
seri
e
s
/
c
l
i
n
i
c
a
l
r
e
v
i
e
w
O
r
t
h
o
p
a
e
d
i
c
w
o
u
n
d
s
(
i
n
c
l
u
d
i
n
g
e
x
p
o
s
e
d
b
o
n
e
s
/
t
e
n
d
o
n
s)
N
a
t
u
r
a
l
h
o
n
e
y
H
o
n
e
y
ser
v
e
d
a
s
a
n
e
f
f
i
c
i
e
n
t
,
st
r
a
i
g
h
t
f
o
r
w
a
r
d
,
a
n
d
e
c
o
n
o
mi
c
a
l
w
o
u
n
d
t
r
e
a
t
me
n
t
f
o
r
v
a
r
i
o
u
s
o
r
t
h
o
p
a
e
d
i
c
d
i
so
r
d
e
r
s
.
JB
I
c
a
se
s
e
r
i
e
s
c
h
e
c
k
l
i
st
:
6
/
1
0
c
r
i
t
e
r
i
a
me
t
.
10
C
h
r
y
so
s
t
o
mo
u
e
t
a
l
.
(
2
0
2
3
)
[
2
6
]
C
a
se
s
e
r
i
e
s
C
h
r
o
n
i
c
(
P
e
r
si
st
e
n
t
w
o
u
n
d
i
n
f
e
c
t
i
o
n
s)
M
e
d
i
c
a
l
g
r
a
d
e
h
o
n
e
y
(
M
G
H
)
F
o
l
l
o
w
i
n
g
l
o
c
a
l
M
G
H
t
h
e
r
a
p
y
,
b
a
c
t
e
r
i
a
l
l
o
a
d
d
i
mi
n
i
s
h
e
d
;
i
n
c
e
r
t
a
i
n
i
n
s
t
a
n
c
e
s c
u
l
t
u
r
e
s wer
e
st
e
r
i
l
e
.
M
G
H
i
s
c
o
st
-
e
f
f
e
c
t
i
v
e
a
n
d
u
ser
-
f
r
i
e
n
d
l
y
a
l
t
e
r
n
a
t
i
v
e
.
JB
I
c
a
se
s
e
r
i
e
s
c
h
e
c
k
l
i
st
:
7
/
1
0
c
r
i
t
e
r
i
a
me
t
.
11
A
g
b
a
g
w
a
e
t
al
.
(
2
0
2
2
)
[
2
7
]
Ex
p
e
r
i
m
e
n
t
a
l
S
t
u
d
y
D
i
a
b
e
t
i
c
w
o
u
n
d
s
(
a
n
i
m
a
l
m
o
d
e
l
)
M
o
r
i
n
g
a
-
i
n
f
u
se
d
N
i
g
e
r
i
a
n
h
o
n
e
y
H
o
n
e
y
i
n
f
u
s
e
d
w
i
t
h
mo
r
i
n
g
a
e
x
h
i
b
i
t
e
d
s
u
p
e
r
i
o
r
e
f
f
i
c
a
c
y
a
n
d
f
a
st
e
r
h
e
a
l
i
n
g
o
f
d
i
a
b
e
t
i
c
w
o
u
n
d
s
c
o
m
p
a
r
e
d
t
o
o
t
h
e
r
h
o
n
e
y
v
a
r
i
a
n
t
s
a
n
d
s
i
l
v
e
r
s
u
l
f
a
d
i
a
z
i
n
e
.
JB
I
q
u
a
si
-
e
x
p
e
r
i
me
n
t
a
l
c
h
e
c
k
l
i
st
:
6
/
9
c
r
i
t
e
r
i
a
me
t
.
12
Mc
A
r
d
l
e
e
t
al
.
(
2
0
2
3
)
[
2
8
]
I
n
V
i
t
r
o
S
t
u
d
y
F
o
o
t
a
n
d
a
n
k
l
e
w
o
u
n
d
i
s
o
l
a
t
e
s
M
e
d
i
c
a
l
g
r
a
d
e
h
o
n
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Evaluation Warning : The document was created with Spire.PDF for Python.