[email protected] (1).pdf
-
Upload
scribdscribd -
Category
Documents
-
view
223 -
download
0
Transcript of [email protected] (1).pdf
-
8/17/2019 [email protected] (1).pdf
1/5
ABR
thresholds
in
infants born
with
CLP
and
OME
and
infants
with
OME
H. Sundman a, T. Flynn b,*, B. Tengrotha, A. Lohmander b
aHearing and Balance Clinic, Karolinska University Hospital, Stockholm, SwedenbDivision of Speech and Language Pathology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
1. Introduction
Children born with cleft palate and/or lip (CP L) present with a
higher
prevalence
of
otitis
media
with
effusion
(OME)
than
children
born without CP L. Prevalence of OME has been reported to range
from 76 and 97 percent in children with CP L between the ages of
two and 24 months [1–11]. This high prevalence of OME is most likely
due
to
Eustachian
tube
dysfunction.
The
tensor
veli
palatini
and
the
levator veli palatini muscles are not able to contract properly and
open the Eustachian tube [1,12,13]. Therefore, the Eustachian tube is
unable to equalize pressure and leads to negative pressure in the
middle
ear.
This
negative
pressure
results
in
a
retracted
tympanic
membrane
and
secretion
of
mucous
from
the
tissues
through
osmosis
into the middle ear cavity [2,7].
OME is associated with a mild to moderate, fluctuating
conductive
hearing
impairment
across
the
speech
frequencies
[14].
A
few
studies
have
investigated
this
association
in
young
children [15–17]. Gravel and Wallace [15] demonstrated infants at
one year of age with an average of four episodes of bilateral OME
presented
with
elevated
thresholds
(37.8
dB
nHL)
as
compared
to
a
group of infants (20.3 dB nHL) with an average of less than one
episode. Other studies have investigated OME and the associated
hearing loss in relation to universal newborn hearing screening
(UNHS).
Aithal
and
colleagues
[17]
demonstrated
68
percent
of
newborns (average of 47.5 days), which had OME also had a
hearing loss. For those infants who presented with OME and a
hearing loss, an average threshold of 50 dBnHL was recorded when
the
infant
was
49
days
old
[16]. Second,
Boudewyns
and
colleagues
[16] demonstrated 55 percent of the newborns (average 49 days)
who failed screening had a hearing loss associated with OME
ranging between 40 and 60 dBnHL in both ears. These infants were
followed
longitudinally
and
presented
with
normal
hearing
by
4.8
months
of
age.
Five
of
the
64
infants
presented
with
a
CP L.
Furthermore, there have been several studies focusing on OME
and an associated hearing loss in children with CP L. Four studies
have
reported
young
children
with
CP L exhibit a higher prevalence
of
hearing
impairment
than
children
without
CP L. Broen et al. [2]
demonstrated young children with CP L were more likely to fail a
hearing screening between 9 and 30 months of age. The other three
studies
reported
a
range
between
55
and
93
percent
of
ears
of
infants
and
young
children
with
CP L and OME to demonstrate a mild to
moderate hearing loss [9,10,18]. On the contrary, Jocelyn et al. [6]
reported fewer children with CP L (25 percent) which exhibited
mild
to
moderate
hearing
impairment
at
12
and
24
months
of
age
as
International Journal of Pediatric Otorhinolaryngology 81 (2016) 21–25
A R T I C L E I N F O
Article history:Received 30 August 2015
Received in revised form 2 November 2015
Accepted 30 November 2015
Available online 12 December 2015
Keywords:
Auditory brain stem response
Cleft palate
Hearing loss
Otitis media with effusion
A B S T R A C T
Objectives:
The aim of this study was to investigate and compare auditory brainstem response (ABR)thresholds related to otitismediawith effusion (OME) in infants with andwithoutcleft palateand/or lip
(CP L).
Methods: Forty-seven infants with CP L
and 67
infants
with
OME
participated
in the
study.
Hearing
thresholds
of
ears
of
infants
with
OME
were
compared
between
groups
andwithin
the
group
with
CP
L.
Results: Infants with CP L and OME presented with similar hearing thresholds as infants with OME and
not
CP L. Within the cleft group, infants with isolated cleft palate and OME demonstrated significantly
higher hearing thresholds than infants with unilateral cleft lip and palate and OME.
Conclusion: A high prevalence of infantswith CP L
present
with
OME
early
in
life.
Hearing
thresholds
of
these infants are similar to infants without CP L, but with OME. The ear status and hearing thresholds of
infants
with
CP L needs to be monitored to be able to provide the best access to hearing in order to fully
allow
speech
and
language
development.
2015
Elsevier Ireland Ltd. All rights reserved.
* Corresponding author.
E-mail address: [email protected] (T. Flynn).
Contents
lists
available
at
ScienceDirect
International Journal of Pediatric Otorhinolaryngology
jo urn al hom ep ag e: www.els evier . c om/locat e/ i jp o r l
http://dx.doi.org/10.1016/j.ijporl.2015.11.036
0165-5876/ 2015 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036mailto:[email protected]:[email protected]://www.sciencedirect.com/science/journal/01655876http://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://www.elsevier.com/locate/ijporlhttp://dx.doi.org/10.1016/j.ijporl.2015.11.036http://dx.doi.org/10.1016/j.ijporl.2015.11.036http://www.elsevier.com/locate/ijporlhttp://www.sciencedirect.com/science/journal/01655876mailto:[email protected]://dx.doi.org/10.1016/j.ijporl.2015.11.036http://crossmark.crossref.org/dialog/?doi=10.1016/j.ijporl.2015.11.036&domain=pdfhttp://crossmark.crossref.org/dialog/?doi=10.1016/j.ijporl.2015.11.036&domain=pdf
-
8/17/2019 [email protected] (1).pdf
2/5
compared to zero and six percent in the children without CP L. This
lower
percentage
of
children
with
hearing
impairment
may
be
due
to
the significantly higher number of children with ventilation tubes in
the group of children with CP L [6].
This contradicting evidence is also seen in the hearing screening
of
newborns
with
CP L. Three studies reported a range of 12 and
28
percent
of
newborns
with
CP L which failed their newborn
hearing screen [19–21]. On the contrary, four other studies described
a higher percentage of hearing impairment, between 70 and
84
percent,
in
newborns
with
CP L with a mild to moderate
conductive
hearing
loss
[10,22–24]. This
discrepancy
may
be
to
audiometry methodology. Newborn hearing screening was con-
ducted either with otoacoustic emission (OAEs) or automated
auditory
brainstem
response
(AABR)
[19–21].
These
methods,
which
utilized
a
pass/fail
criteria,
were
used
in
the
studies
reporting
a
lower
incidence of abnormal hearing. The other studies obtained a threshold
of hearing via an auditory brainstem response (ABR) [10,22,23]. De-
termining
a
threshold
is
a
more
detailed
definition
of
hearing
sensitivity
and
includes
newborns
with
mild
hearing
loss,
which
may
have been missed via screening or pass/fail methods. Another factor
which may have contributed to the discrepancy is age of the newborn.
In
the
studies
with
a
lower
rate
of
abnormal
hearing,
the
infants
were
screened
at
birth;
while
the
studies
with
a
higher
rate
of
abnormal
hearing, the infants were tested when they were older, rangingbetween an average of 43 days up to 14 months of age.
Furthermore,
these
studies
do
not
compare
the
hearing
in
newborns
with
CP L to newborns without CP L, but with OME.
Children with CP L and OME have been shown to present with
higher thresholds than children without CP L, but with OME
[7].
Flynn
et
al.
[7]
demonstrated
children
with
unilateral
cleft
lip
and
palate
(UCLP)
with
OME
and
a
hearing
impairment
exhibited
significantly higher hearing thresholds than children without UCLP,
but with OME and a hearing impairment [7]. Therefore, it is critical to
investigate
when
this
significant
difference
may
occur
as
this
is
a
sensitive period for the development of auditory, speech, and
language skills.
There
is
insufficient
data
to
conclude
the
timing
and
possible
long-term benefits of the placement of ventilation tubes [25]. TheNICE guidelines specify, ventilation tubes should only be placed at
palatal closure after careful otological and audiological assess-
ment,
not
prophylactically
[26].
However,
Klockars
and
Rautio
[11]
demonstrated
the
majority
of
infants
with
ventilation
tubes
placed
at four months of age during time of soft palate repair resulted in a
lower prevalence of OME at 12 months of age as compared to
infants
who
received
ventilation
tubes
at
four
months
of
age
but
with
soft
palate
repair
at
12
months
of
age
[11].
It
was
hypothesized that the earlier repair of the soft palate aided the
Eustachian tube to function effectively and allow the ventilation
tubes
to
not
become
occluded.
Ventilation
tubes
were
placed
either
following
the
diagnosis
of
OME
by
otomicroscopy
or
paracentesis during surgery or prophylactically. Hearing levels
were
not
reported.As
it
is
controversial
when
to
place
ventilation
tubes,
it
is
crucial
to
define
the
possible
prevalence
of
an
associated
hearing
impairment in newborns with and without CP L. This may lead
to changes in protocol for the placement of ventilation tubes.
Therefore,
the
aim
of
this
study
was
to
investigate
and
compare
auditory
brainstem
response
(ABR)
thresholds
related
to
otitis
media
with effusion (OME) in infants with and without CP L.
2.
Materials
and
methods
2.1. Materials
The
study
was
a
retrospective
chart
review
at
a
single
hospital
(Karolinska
University
Hospital,
Sweden).
Medical
files
between
January 2011 and January 2013 were reviewed for two groups of
possible
participants.
The
two
groups
included
infants
with
CP L
(cleft group) and infants without cleft, but with OME (non-cleft
group). For the non-cleft group, all infants with a medical record
containing a diagnosis of OME and ABR threshold levels were
included
in
the
study.
Infants
in
the
non-cleft
groups
were
excluded
if
they
had
a
medical
diagnosis
or
syndrome,
a
malformation,
or
a
hearing impairment not caused by OME. Infants in the cleft group
were excluded if they had an additional medical diagnosis or
malformation,
a
syndrome,
or
a
sensori-neural
hearing
impairment.
The
first
group
(non-cleft
group)
included
infants
who
failed
the
newborn hearing screening and were diagnosed with OME. Sixty-
six infants (41 males and 25 females) with a mean age of 97 days
(range:
37–197
days)
were
diagnosed
with
either
unilateral
or
bilateral
OME.
The
second
group
(cleft
group)
consisted
of
50 infants (32 males and 14 females) with a mean age of 65 days
(range: 25–145 days). Twenty-six infants presented with an
isolated
cleft
of
the
palate
(ICP),
14
infants
with
unilateral
cleft
lip
and
palate
(UCLP),
and
ten
infants
with
bilateral
cleft
lip
and
palate
(BCLP).
2.2.
Methods
Data were collected from the medical records at the time of thediagnostic ABR during clinical routine visits between January
2011
and
January
2013.
Hearing
thresholds
from
the
ABR
and
otomicroscopy
examination
were
collected.
2.2.1. Hearing sensitivity
The
click
evoked
ABR
was
obtained
while
infants
were
sleeping
using
the
Interacoustics
EP25
(Denmark).
The
click
evoked
ABR
was utilized as it is clinical protocol at the Karolinska University
Hospital following a failed OAE screen. Rarefaction pulses were
delivered
at
a
rate
of
39.1
stimuli/second
through
ER-3A
ABR
insert
earphones. The recording window was 15 ms. Initial stimuli were
presented at 50 dBnHL. Stimuli intensity was increased or
decreased
in
10
dB
increments
and
5
dB
increments
when
necessary. Thresholds were tracked using wave V. A minimumof 1700 sweeps for each waveform were obtained. Twenty dBnHL
was the lowest stimuli presented and 90 dBnHL was the maximum
level
presented.
Threshold
was
determined
when
two
recordings
were
repeated.
The click evoked ABR was performed during natural sleep on
both ears of the infant. If the infant woke during the measurement,
any
further
collection
of
data
was
discontinued
until
the
infant
went
back
to
sleep.
Fourteen
infants
in
this
study
underwent
two
ABR assessments. The second ABR was performed due to an
incomplete assessment due to lack of sleep or restlessness. The
lowest
estimated
threshold
obtained
was
used
during
the
analysis.
2.2.2. Ear status
A
pediatric
otolaryngologist
performed
otomicroscopy
on
theday
of
ABR
testing
to
determine
ear
status.
Results
were
classified
as
normal
or
abnormal
(fluid
filled
middle
ear
cavity
or
retracted
tympanic membrane).
2.3.
Statistical
description
and
analysis
Statistical analysis of the results was performed using the t -test
to compare the mean hearing thresholds between the cleft and
non-cleft
groups
and
the
ANOVA
to
compare
cleft
types
within
the
cleft
group.
Effect
size
was
analyzed
with
Cohen’s
d.
The
data
were
analyzed using SPSS for Windows (Version 22).
Data collection and analyses were carried out according to
ethical
principles
for
medical
research
involving
human
subjects
and
with
permission
from
the
Head
of
the
Clinical
Department
of
H. Sundman et al. / International Journal of Pediatric Otorhinolaryngology 81 (2016) 21–2522
-
8/17/2019 [email protected] (1).pdf
3/5
Hearing and Balance at Karolinska University Hospital, Solna,
Stockholm, Sweden (Swedish Ethical Law 2003:460).
3. Results
The
data
analysis
focused
on
the
individual
ears
of
the
participating
infants.
There
are
a
total
of
116
infants
providing
232 ears for examination in the cleft and non-cleft groups. Within
the cleft group, there were 100 ears. Of those 100 ears, 88 presented
with
OME
on
the
day
of
testing.
Twelve
ears
were
excluded
from
the
study
including
four
children
with
no
OME
bilaterally
(one
infant with BCLP and three infants with ICP). Therefore, data from
88 ears with OME was gathered for further analysis (Table 1). In thenon-cleft
group,
66
infants
providing
132
potential
ears
were
studied.
Of
the
132
possible
ears,
105
presented
with
OME
on
the
day of testing and were designated for further analysis. In total,
193 ears from infants with OME in the cleft (n = 88) and non-cleft
group
(n
=
105)
were
included.
The
data
were
analyzed
and
compared
between
the
cleft
group
and
non-cleft
group
and
within
the cleft group by type of cleft.
The non-cleft group exhibited a mean threshold of 41.4 dBnHL
(SD:
8.8)
and
the
cleft
group
exhibited
a
mean
threshold
of
40.1
dBnHL
(SD:
9.5)
(see
Fig.
1).
There
was
no
significant
difference between the cleft and non-cleft groups on hearing
sensitivity (F (1, 190) = 0.047, p = 0.829).
Within the cleft group, the mean ABR threshold value for infants
with UCLP was 37.5 dBnHL (SD: 7.9; range: 20–50), 44.2 dBnHL
(SD: 8.9; range: 30–60) for infants with ICP and 40.3 dBnHL (SD: 7.6;
range: 30–55) for infants with BCLP (see Fig. 2). There was a
significant difference within the cleft group when the group was
divided by cleft type (F (1, 84) = 5.44, p = 0.006). A significant
difference was present between the UCLP and ICP groups, with
infants with ICP presenting with worse hearing thresholds ( p = 0.005)
(see Table 2). This significant difference had a large effect size
(d = 0.796).
4. Discussion
Eight-eight
percent
of
infants
with
CP L presented with OME.
These
infants
did
not
demonstrate
significantly
worse
hearing
thresholds as compared to infants with OME. However, the infants
with ICP, exhibited significantly higher thresholds than the infants
with
UCLP.
This
has
not
been
previously
reported
in
the
literature.
The
prevalence
of
OME
in
the
cleft
group
(88
percent)
is
in
the
higher range of the previously reported prevalence of between
18 and 94 percent. However, when examining the literature, there
are
two
groups
of
results:
18
to
28
percent
and
65
to
94
percent.
This
study
has
similar
results
to
other
studies
stating
a
prevalence
of OME ranging from 65 to 94 [10,11,23,24]. In contrast, the
present results are considerably higher than the 18 to 28 percent
Table 1
Number of infants and ears with OME included in the data analysis.
Non-cleft group Cleft group
UCLP ICP BCLP
Infants Ears Infants Ears Infants Ears Infants Ears
Bilateral OME 39 (59%) 78 (74%) 12 (86%) 24 (92%) 22 (96%) 44 (98%) 8 (89%) 16 (94%)
Unilateral OME 27 (41%) 27 (26%) 2 (14%) 2 (8%) 1 (4%) 1 (2%) 1 (11%) 1 (6%)
Total number of infants and ears 66 105 14 26 23 45 9 17
Table
1
Number
of
infants
and
ears
included
in
the
data
analysis
by
group.
Unilateral
Cleft
Lip
and
Palate
(UCLP),
Isolated
Cleft
Palate
(ICP),
Bilateral
Cleft
Lip
and
Palate
(BCLP).
Fig. 1. Box plots showing maximum, median, and minimum hearing thresholds in dB nHL and first and third quartile for all ears in the cleft and non-cleft groups with otitis
media with effusion (OME).
H. Sundman et al. / International Journal of Pediatric Otorhinolaryngology 81 (2016) 21–25 23
-
8/17/2019 [email protected] (1).pdf
4/5
reported when examining hearing screening results in infants with
CP L [19–21]. This discrepancy in prevalence may be due to
methodological
differences
and
aims
of
the
studies.
The
studies
reporting a lower prevalence were investigating hearing in infants
with CP L with a focus on the hearing screening results or
thresholds.
However,
OME
is
not
always
associated
with
a
hearing
loss
or
a
fail
on
a
hearing
screen.
Andrews
and
colleagues
[10]
illustrated the hearing thresholds and tympanometry results in theirstudy. Fifteen percent of ears (10/67) exhibited flat tympanometry
and
mean
hearing
levels,
which
passed
screening
(range:
25–
35
dBnHL).
In
the
present
study,
30
percent
of
ears
with
OME
exhibited mean hearing levels, which passed screening (range: 20–
35
dBnHL).
The
noted
difference
between
15
and
30
percent
may
be
due
to
methodological
methods
of
defining
OME.
Andrews
and
colleagues [10] utilized high-frequency tympanometry (flat tympa-
nograms) to indicate the presence of OME while the present study
defined
the
presence
of
OME
by
visualization
of
the
tympanic
membrane
by
an
experienced
otolaryngologist
who
performed
otomicroscopy. OME may be present with other types of tympano-
metry [27]. The inclusion of infants with syndromes does not explain
the
discrepancy,
as
studies
reporting
lower
and
higher
prevalence
of
OME
included
infants
with
syndromes
[10,19,21].In the present study, there was no significant difference in
hearing thresholds between infants with CP L and infants without
CP L. One study has reported hearing thresholds of infants with a
conductive
hearing
loss
due
to
OME
[16].
In
this
study,
an
average
hearing threshold of 50 dBnHL was reported in infants without
CP L, but with OME; while the present study demonstrated average
hearing
thresholds
of
41.4
dBnHL
and
the
cleft
group
and
40.1
dBnHL
in the non-cleft group. The differences in thresholds may be due to
inclusion criteria. In the Boudewyns et al. [16] study, 25 percent of the
infants
presented
with
a
known
risk
factor
for
hearing
loss
(6
of
them
with
craniofacial
anomalies)
while
infants
with
additional
malforma-
tions or sensorineural hearing loss were excluded in the presentstudy. Infants with CP L in the present study presented with similar
hearing
thresholds
of
infants
with
CP L in a previously reported
study
[22].
In
the
present
study,
the
infants
with
CP L exhibited an
average threshold of 41.4 dBnHL while infants in the Viswanathan
et
al.
[22]
study
presented
with
40
dBnHL
right
ear
and
39.7
dBnHL
for
left
ear.
On
the
contrary,
Andrews
and
colleagues
[10]
presented
higher thresholds for infants with CP L with thresholds of 53 dBnHL
in the left ear and 49 dBnHL in the right ear. This difference may be
due
to
the
inclusion
criteria.
The
infants
in
the
present
study
did
not
present
with
additional
malformations
and/or
syndromes
and
22 percent of the infants in the Viswanathan et al. [22] study
presented with syndromes; while 30 percent of the infants included
in
the
Andrews
et
al.
[10]
study
presented
with
syndromes.
The
elevated
thresholds
in infants
with
ICP
and
OME
in
thepresent study does not follow previous literature on hearing
thresholds in individuals with CP L. There is no other study that
compares
the hearing
thresholds
of
infants
with
different
cleft types.
However,
there
are
two
studies
which
report
typeof
cleft
in
relation to
the degree of hearing impairment [22] and hearing screening results
[20]. Both studies present similar results with infants with ICP and UCLP
presenting
withworse
hearing
than
those
with
BCLP.
Infants
with ICP
and
UCLP
exhibited
a
higher
prevalence
of
moderate
to
severe
hearing
impairment (12 and 10 percent) or failure on hearing screening
(13 percent) than infants with BCLP (5 percent). A larger difference
between
the
ICP
and
UCLP
group
may
have
been
seen
if
Viswanathan
and
colleagues [22]
and
Szabo
and
colleagues
[20]
had
compared
hearing thresholds instead of categories of hearing impairment or
failure
of
hearing
screening.
Both
studies
did
not
mention
ear status.
Fig. 2. Box plots showing maximum, median, and minimum hearing thresholds in dB nHL and first and third quartile for all ears in the cleft group with otitis media with
effusion (OME). Cleft types include: Unilateral Cleft Lip and Palate (UCLP), Isolated Cleft Palate (ICP), Bilateral Cleft Lip and Palate (BCLP).
Table 2
Comparison of hearing sensitivity within the cleft group.
Cleft groups Mean difference Standard error P value
ICP-UCLP 6.71 2.07 0.005
ICP-BCLP 3.91 2.39 0.236
BCLP-UCLP 2.79 2.61 0.535
Results from Post-doc Tukey test comparing hearing sensitivity between cleft
groups: Unilateral Cleft Lip and Palate (UCLP), Isolated Cleft Palate (ICP), Bilateral
Cleft Lip and Palate (BCLP).
H. Sundman et al. / International Journal of Pediatric Otorhinolaryngology 81 (2016) 21–2524
-
8/17/2019 [email protected] (1).pdf
5/5
http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0360http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0360http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0360http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0355http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0355http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0355http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0350http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0350http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0350http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0345http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0345http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0345http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0340http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0340http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0340http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0335http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0335http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0330http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0330http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0330http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0325http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0325http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0320http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0320http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0315http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0315http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0315http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0310http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0310http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0305http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0305http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0305http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0300http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0300http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0300http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0300http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0295http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0295http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0295http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0290http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0290http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0290http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0285http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0285http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0280http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0280http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0280http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0275http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0275http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0270http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0270http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0265http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0265http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0265http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0260http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0260http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0260http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0255http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0255http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0250http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0250http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0245http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0245http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0245http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0240http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0240http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0240http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0235http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0235http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0235http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0230http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0230http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0230http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0230http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0225http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0225http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0225http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0220http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0220http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0215http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0215http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0215http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0210http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0210http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0210http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0205http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0205http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0200http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0200http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0195http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0195http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0190http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0190http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0190http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0185http://refhub.elsevier.com/S0165-5876(15)00620-5/sbref0185