alcohol misuse in bipolar disorder
TRANSCRIPT
-
8/10/2019 Alcohol Misuse in Bipolar Disorder.
1/8
Review
Alcohol
misuse
in
bipolar
disorder.
A
systematic
review
andmeta-analysis
of
comorbidity
rates
A. Di Florio *, N. Craddock, M. van den Bree
Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24
4HQ, United Kingdom
1. Introduction
Comorbidity has important implications for both research and
clinical practice [68]. Nevertheless, important issues about the
definition and evaluation of comorbidity remain to be elucidated in
psychiatric research [62,69].
From the classic phenomenological work of Emil Kraepelin [36]
to contemporary epidemiological studies [50] the comorbidity
between alcohol misuse and bipolar disorder (BD) has been
reported. Of all DSM-IV axis I disorders, BD has been reported to be
the most strongly linked with alcohol or drug abuse [25,41] and
compared with other primary psychiatric disorders, mania and
hypomania may have one of the highest associations with
alcoholism [25,41].
Although considerable research has been devoted to character-izing the link between alcohol related disorders and BD,
surprisingly, a preliminary search of MEDLINE, EMBASE and
PsychINFO did provide no evidence of any published systematic
reviews focusing on the comorbidity between the two disorders.
In this review, we explored the current state of knowledge on
the rates of alcohol use disorders (AUDs) in people affectedbyBD.
There are many definitions of alcohol related disorders. Here we
included in the definition of AUDs problem drinking (alcohol
abuse or harmful use) and addiction (alcoholism or alcohol
dependence).
We tested the following hypotheses:
AUDs are over-represented in people with BD compared to the
general population;
there is an effect of gender on the comorbidity between AUDs
and BD, with men having higher comorbidity rates than women.
Although it is a common observation in clinical practice that men
with BD are over-represented among patients with AUDs
comorbidity, evidence from both epidemiological and clinical
studies are contrasting;
methodological differences such as study design, geographical
location of the population, diagnostic criteria and instruments ofassessment have an effect on comorbidity rates reported in
studies. The rates of AUDs in the general population are
influenced by cultural [16] and genetic differences [65]. More-
over, diagnostic criteria and research protocol have been
implicated as additional sources of variability [53].
2. Methods
Search strategy and reporting are in accordance with the
recommendations of the Meta-analysis Of Observational Studies in
Epidemiology (MOOSE) group [57].
European Psychiatry 29 (2014) 117124
A R T I C L E I N F O
Article history:
Received 31 May 2013Received in revised form 18 July 2013
Accepted 27 July 2013
Available online 25 September 2013
Keywords:
Alcohol
use
disorders
Bipolar disorder
Comorbidity
Co-occurrence
A B S T R A C T
Aims:
To assess the comorbidity rates of alcohol use disorders (AUDs) in bipolar disorder (BD) and to
explore possible sources of heterogeneity.
Methods: Studieswere identified through database searches. Meta-analytic techniques were employed
to aggregate dataon lifetime comorbidity and to explore possible sourcesof heterogeneity. Funnel plots
were used to detect publication bias.
Results: In cl inical studies, AUDs affected more than one in three subjects with BD. Significant
heterogeneitywas found,whichwas largely explainedby thegeographical location of study populations
and gender ratio of participants. AUDs affected more than one in five women and two in five men.
Conclusion: AUDs are highly prevalent in BD. Our study revealed a substantial heterogeneity across
studies. Further research including control groups is needed. Patients with BD should be assessed for
current and previous AUDs.
2013 Elsevier Masson SAS. All rights reserved.
* Corresponding author. Tel.: +44 2920 744 826.
E-mail address: [email protected] (A. Di Florio).
Available
online
at
www.sciencedirect.com
0924-9338/$
see
front
matter
2013
Elsevier
Masson
SAS.
All
rights
reserved.
http://dx.doi.org/10.1016/j.eurpsy.2013.07.004
http://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://dx.doi.org/10.1016/j.eurpsy.2013.07.004mailto:[email protected]:[email protected]://www.sciencedirect.com/science/journal/09249338http://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://www.sciencedirect.com/science/journal/09249338mailto:[email protected]://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://crossmark.crossref.org/dialog/?doi=10.1016/j.eurpsy.2013.07.004&domain=pdfhttp://crossmark.crossref.org/dialog/?doi=10.1016/j.eurpsy.2013.07.004&domain=pdf -
8/10/2019 Alcohol Misuse in Bipolar Disorder.
2/8
2.1. Search strategy
An electronic search was conducted in databases MEDLINE,
EMBASE, PsychINFO by author A.D.F.
Keywords and Boolean operators employed (set by A.D.F.,
M.V.D.B. and N.C.) are listed in S1.
No language restrictions were applied to the search. Publica-
tions from 1978 to 2013 were retrieved.
The abstracts of the identified studies were independently
screened for inclusion in the review by two investigators (A.D.F.
and M.V.D.B.).
Bibliographies of eligible articles were checked for possible
other relevant studies (ancestor search).
2.2.
Inclusion
criteria
Studies were selected for inclusion if they met the following
criteria:
disorders defined according to DSM or ICD and RDC criteria;
for clinical studies, sample size greater than 50 individuals;
at least 95% of the sample older than 18;
study employed quantitative research methodology;
participants not selected on the basis of comorbidity with AUDs(probabilistic sample);
rates of AUDs in BD participants evaluated and reported;
study based on original research.
2.3. Data extraction
Data were extracted from full-text articles, with the exception
of a single conference abstract [8].
When a sample was reported in more than one paper, data were
extracted from the article reporting the largest sample, or from all
articles, in case they reported on different variables.
Information extracted from original publications is listed in S2.
Geographical locations were classified according to:
the continent where the study was conducted;
total per capita consumption of pure alcohol, in litres, for the
adult population, as reported by the World Health Organization
[70];
patterns of drinking score as calculated by the World Health
Organization [70].
In this review, comorbidity was defined as the association
between BD and AUDs within a given time frame and co-
occurrence as the cross-sectional association between disorders
i.e. both traits assessed and present at the same time [69].
2.4. Data analyses
Data analyses were conducted using R version 2.13.0 (Copyright
2011 The R Foundation for Statistical Computing, Vienna, Austria).
Meta-analytic techniques were employed to aggregate data on
lifetime comorbidity between AUDs and BD.
Firstly, the command metaprop was used to calculate the
pooled estimates of proportions with the corresponding 95%
confidence intervals on the base of the Freeman-Tukey double
arcsine transformation. A fixed as well as a random effects model
framework was used [21].
The association between gender and AUDs was also evaluated
using DerSimonian-Laird estimate (R metabin command) for
random effect models.
Heterogeneity of combined study results was assessed by
Q
test and inconsistency statistic (I
2
). A
P
value below
0.10 in
the
Q test was considered indicative of statistically significant
heterogeneity. Values of 25%, 50% and 75% were considered
to represent respectively low, medium and high heterogeneity
in the I2 statistic [29]. Since significant heterogeneity was
found across studies, only random effects estimates were
reported.
Possible sources of heterogeneity were explored using
univariate and multivariate random effects meta-regression
(R metafor package) [64].
Models were fitted using the rma function. For the purpose of
a reliable statistical analysis, Freeman-Tukey double arcsine
transformed proportions were calculated as outcome measure.
The random-effects models were fitted using the restricted
maximum-likelihood estimator and the empirical Bayes estimator.
The effects of the following independent covariates were
tested: geographical location of the study, diagnostic tools,
diagnostic criteria and sampling methods. Proportion of women
and average age at the interview were not included in the model, to
avoid aggregation bias (i.e., the relationship with patient
averages between trials may not be the same as the relationship
for patients within trial) [30]. Standard errors of the estimated
coefficients were adjusted with the Knapp and Hartung method
[35], to account for the uncertainty in the estimate of the amount of
(residual) heterogeneity.To evaluate publication bias, asymmetry in the funnel plots was
tested with mixed-effects meta-regression model (R regtest
command) using the standard error as the predictor [14].
3. Results
3.1. Search results
The flow chart of the search process is shown in Fig. 1. As a
result of the electronic and ancestor researches, 57 research
articles and one abstract [8], reporting on 46 original studies, were
included in the systematic review. Except for one paper in French
[59] and one paper in Flemish [63], all papers were in English.
Studies characteristics are summarised in Table 1.
3.2. Are alcohol use disorders over-represented in people suffering
with bipolar disorder compared to the general population?
The majority of epidemiological studies calculated the strength
of association with AUDs in BD compared to the general population
(Table 2).
3.2.1. Epidemiological studies
Information was extracted from eight epidemiological studies,
from ten published papers (table S3a).
Epidemiological studies conducted in Europe [41] and
North America [50,25,34,17,20,26] univocally reported that
the prevalence of
AUDs was significantly
increased amongparticipants with BD, regardless the diagnostic criteria (i.e.
DSM-III, DSM-III-R, DSM-IV) and the time window (i.e. current,
lifetime, other Table 2) employed. Results were heterogeneous
when alcohol abuse (AA) and alcohol dependence (AD) were
analysed separately. Only one study reported on the 12 month
incidence of AUDs [26]. This study found no differences between
BD and the general population and furthermore that partici-
pants with bipolar II disorder (BD-II) had a lower risk of AA
compared to the general population. Kessler et al. [34] reported
a similar finding for lifetime AA incidence in men with mania,
despite the fact that this study used different definitions
(lifetime prevalence) compared to Grant et al. [26] (12 months
incidence) as well as different diagnostic criteria (DSM-III-R
versus
DSM-IV).
A. Di Florio et al./European Psychiatry 29 (2014) 117124118
-
8/10/2019 Alcohol Misuse in Bipolar Disorder.
3/8
The only epidemiological survey conducted in Asia reported no
effect of BD on the 12 months prevalence of any AUDs [10]
compared to the general population.
It was not possible to calculate a combined odds ratio for
epidemiological studies, because of the small number of studies
using
the
same
diagnostic
criteria
and
time
frames
(Table
2).
3.2.2.
Clinical
studies
Only one clinical study included a random control group. This
study found an excess of AUDs in BD [7].
Because of the lack of random control groups, it was not
possible to estimate the pooled effect of BD on AUDs in clinical
samples.
However,
lifetime
prevalence
of
AUDs
was
reported
by
31
Fig. 1. Flow chart of the selection process. Electronic search in grey, ancestor search in white. aStudies could be excluded because meeting more than one exclusion criterion.
A. Di Florio et al./ European Psychiatry 29 (2014) 117124 119
-
8/10/2019 Alcohol Misuse in Bipolar Disorder.
4/8
independent
clinical
studies
[8,63,7,3,5,4,9,12,15,18,22,24,28,32,33,55,3840,4247,49,56,58,60,61,67], including 8309 subjects
with BD, allowing us to calculate pooled lifetime prevalence.
Overall, the pooled lifetime prevalence of AUDs in BD in these
31 studies was 35.1% [95%CI: 30.3%; 40.0%] using a random effect
model. Significant heterogeneity across studies emerged from both
Q test (Q = 615.27, df = 30, P
-
8/10/2019 Alcohol Misuse in Bipolar Disorder.
5/8
4.
Discussion
In this systematic review, the currently available literature on
the burden of AUDs in BD was assessed.
We tested the hypotheses that AUDs are over-represented in
people suffering fromBDand that, amongparticipants with BD,men
have higher comorbidity rates than women. Moreover, we explored
the causes of heterogeneity in comorbidity rates between studies.
We found only one clinical study including a random control
group of participants without BD [7]. Epidemiological studies
conducted in North America and Europe unanimously found
significantly increased odds of AUDs in participants with BDcompared to the general population. However, sub-analyses
examining AA, AD or genders separately, produced greater
variability in findings. AUDs affected more than one in three
participants in clinical studies of BD, with men having 23 times
higher rates of AUDs than women. Prevalence estimates of AUD in
BD-I and of AD in BD were similar at about 3035%.
A large variability across studies was reported, with geogra-
phical location and gender ratio of participants explaining the
majority of the heterogeneity.
4.1. Rates of alcohol use disorders in bipolar disorder
To the best of our knowledge, this is the first systematic review
and meta-analysis on the comorbidity rates with AUDs in patients
with BD. We found a previously unreported large variability in
definitions, methodology and results between studies. Our reviewof the epidemiological studies indicated clear evidence of
increased odds of AUDs in BD only for studies conducted in
Western countries. Due to the differences in the outcome
measured and in the stratification of the samples, it was not
Table 2
Odds ratio for the associations with alcohol use disorders in bipolar disorders compared to the general population in epidemiological studies.
First author, year of publication BD Criteria Time window AUD OR
(95%CIs)
AA OR
(95%CIs)
AD OR
(95%CIs)
Regier, 1990 [50] Any DSM-III Lifetime 5.1a 4.6a 3.3a
BD-I 5.6a 5.5a 3.0a
BD-II 4.2a 3.1a 3.9a
Fogarty, 1994 [17] BD-I DSM-III Lifetime 2.5 (1.225.34)
Kessler,
1997
[34]
Mania
in
women
DSM-III-R
Lifetime
incidence
1.8
(0.74.7)
4.7
(0.828.2)Mania in men 0.1 (0.0030.5) 8.0 (4.514.5)
Merikangas 2008 [41];
Angst, 1998 [2]
BD-II DSM-III-R 18 years incidence 9.1 (2.731.2) 21.1 (6.667.5)
Grant, 2005 [50];
Goldstein, 2006 [23]
BD-I DSM-IV 12 months prevalence 3.5 (2.84.3) 1.3 (0.91.8) 5.9 (4.67.7)
Lifetime 3.3 (2.93.8) 1.0 (0.81.2) 5.2 (4.56.1)
Any 12 months prevalence 2.7 (2.223.31) 1.0 (0.81.4) 4.2 (3.25.3)
Glantz 2009 [26] BD DSM-IV Lifetime 2.7 (1.84.0) 5.6 (4.17.7)
Grant, 2009b [26] BD-I DSM-IV 12 months incidence 0.4 (0.151.24) 1.4 (0.752.71)
BD-II 0.2 (0.030.99) 1.3 (0.553.10)
Chou, 2012 [10] BD DSM-IV 12 months prevalence 0.38 (0.043.46) 2.04 (0.2318.25) c
Positive associations in bold, negative association in italics. BD: bipolar disorder; BD-I: bipolar I disorder; BD-II: bipolar II disorder; AA: alcohol abuse; AD: alcohol
dependence; AUD: alcohol use disorders.a Confidence
intervals
not
given.b 99% confidence intervals.c OR could not be calculated because the prevalence was too low.
Study
Randomeffectsmodel
Cardosoetal2008 (29)
Cassidy
et
al
2001 (57)
Dalton
et
al
2003
(32)
Escamillaetal2002(34)
Hendricketal2000(37)
Kawaetal2005(38)
Fryeetal2003 (58)
Lydall
et
al
2011
(42)Maier
et
al
1995
(43)
Morganetal2005(44)
Nivolietal2011(48)
Ostacheretal2010 (50)
Strakowskietal2005(51)
Suominenetal2009(52)
Tsaietal1997(53)
Tsai
et
al
2012
(54)
VanRoyetal2010(21)
Events
25
114
51
25
31
32
117
8018
23
143
429
40
56
8
31
9
Total
2610
54
191
129
92
64
90
162
19341
59
272
880
75
90
36
147
35
Males
Events
28
76
47
5
12
20
96
6311
4
99
518
21
37
2
10
6
Total
3462
132
201
207
113
59
121
188
31341
53
332
1274
69
101
65
159
34
Females
0.75
1.5
OddsRatio
OR
2.76
3.20
2.44
2.23
8.06
3.68
2.79
2.49
2.812.13
7.83
2.61
1.39
2.61
2.85
9.00
3.98
1.62
95%-CI
[2.17; 3.50]
[1.62; 6.31]
[1.62;
3.65]
[1.38;
3.60]
[2.94;22.07]
[1.65; 8.20]
[1.46; 5.31]
[1.59; 3.90]
[1.89;
4.18][0.85;
5.39]
[2.49;24.61]
[1.87; 3.65]
[1.17; 1.65]
[1.32; 5.18]
[1.58; 5.13]
[1.80;45.12]
[1.88;
8.45]
[0.51; 5.17]
W(random)
100%
5.7%
8.1%
7.4%
3.7%
4.8%
6.0%
7.8%
8.2%4.1%
3.1%
8.8%
10.1%
5.7%
6.5%
1.8%
5.2%
3.0%
Fig. 2. Forest plot of the association between lifetime comorbidity and gender in 17 clinical studies. OR indicates the increased risk of lifetime alcohol use disorders (AUDs) in
male
participants
with
bipolar
disorder
(BD)
compared
to
female
participants
with
BD.
A. Di Florio et al./ European Psychiatry 29 (2014) 117124 121
-
8/10/2019 Alcohol Misuse in Bipolar Disorder.
6/8
possible to investigate patterns of variability. Interestingly, the
epidemiological studies conducted over the past two decades
didnt find any association with AA, or even that BD might be
protective against incident AA [34,26].
4.2. Gender
In our meta-analysis of the clinical studies (Fig. 2) male gender
was associated with a higher lifetime prevalence of AUDs (44%),
compared to female gender (22%). Male BD patients had between 2
3 times greater risk of lifetime AUDs (pooled OR between 2 and 3).
We werent able to compare comorbidity estimates stratified by
gender with those in the general population, because of the lack of
clinical studies including a control sample. [28,19]. Gender
differences in alcohol consumption and AUDs, in fact, have been
reported in the general population. In an American survey, ethanol
consumptionandproportion ofheavydrinkers werealmost twice as
high inmen than inwomen [71].According to theAmericanNational
Comorbidity Survey, AUDs are more prevalent in men (19.6%) than
women (7.5%) (http://www.hcp.med.harvard.edu/ncs/ftpdir/NCS-
R_Lifetime_Prevalence_Estimates.pdf). Two previous clinical stu-
dies hypothesized that, although women with BD had lower risk of
AUDs than men with BD, the comorbidity rates may actually be
greater in women than in men, when compared to healthy controls.Contrary to this hypothesis, Kessler found that women with BD
didnt have an increased risk of incident AUDs compared to the
general population, while men with BD did have an increased risk of
AD, but not of AA.
Despite alcohol problems being related to male gender in the
general population and in the majority of clinical studies,
comorbidity with AUDs in women with BD is clinically relevant
with more than one in five reporting lifetime AUDs.
Gender may affect the identifications of patients with AUDs,
leading to overestimation in men. Recognition of AUDs by general
physicians is, in fact, higher for men and for women [13].
Further studies including control groups are needed to
elucidate the effect of gender on comorbidity with AUDs in BD.
4.3.
Geographical
location
We found that pooled comorbidity estimates for Asia were
significantly lower than those for North America and Europe. It is
well established thatAsianpopulations have a reduced riskofAUDs.
Criteria such as intoxication, dependence, impairment and abuse
can be challenged by cultural and genetic [65] differences between
populations. Genetic variations especially of ADH and ALDH2
(mitochondrial ALDH2 aldehyde dehydrogenase 2 family, http://
omim.org/entry/100650) [1] have been associated with the varia-
tion in risk of AD between populations. Environmental as well as
other genetic factors have been hypothesised to explain this
heterogeneity [65].
Interestingly,
we
found
a
positive
correlation
between
comor-bidity rates and pro capita consumption of alcohol, but no
correlation with risky patterns of drinking in the general
population. However, the majority of studies considered in this
review were conducted in the US, with a lack of data on Africa and
the vast majority of Asian countries (the ones included in this
review were conducted in South Korea and Taiwan only).
Further studies are needed to disentangle the cultural and
biological factors mediating the geographical differences in the
comorbidity risk of AUD.
4.4. Quality of studies
Although considerable literature has addressed the comorbid-
ity rates of AUDs in BD (we selected 131 pertinent papers), only 46
original studies (from 58 papers) were retrieved according to our
quality inclusion criteria (sample size larger than 50 subjects,
employment of main diagnostic system criteria, assessment
methods reported). The paucity of evidence may be related to
the fact that some studies with negative results may not have been
published (so called file drawer effect). Publication bias is a
greater factor in observational studies than in clinical trials [21].
However, we didnt find any evidence of publication bias, although
the results should be treated with some caution. Statistically
pooled information from observational data may produce precise
but spurious results [14]. In our analyses, we emphasized the
examination of possible sources of heterogeneity, as it has been
suggested that this, rather than the numerical combination of data,
should be the primary aim of reviews of observational studies [14].
4.5. Limitations and further directions
Our results need to be interpreted in the light of several
methodological limitations:
we did not use unpublished material;
we did not employ quality scoring to report and assess the
quality of the studies included, as this is still controversial [57].
Instead, we postulated a priori quality inclusion criteria.
The comorbidity between BD and AUDs is a broad research
topic, with many important aspects. For reasons of focus and
clarity, in this systematic review we used a limited set of
hypotheses, leaving several issues unaddressed:
we focused on BD as the primary diagnosis. The differences
between primary and secondary diagnosis were not
examined, neither was the causality between co-occurring AUDs
and BD. In a rare longitudinal study [66], 37% of participants with
BD reported co-occurring AUDs at intake, but only 3% had AUDs
at the 10-year follow-up. This suggests that AUDs in BD may be
secondary to the mood disorder, rather than independent or
primary. Recent analyses from the National Comorbidity SurveyReplication support this hypothesis, showing that active, but not
remitting, BD predicted incident AD [20];
due to the limited amount of data, it was not possible to conduct
separate analyses for problem drinking (AA or harmful use) and
addiction (alcoholism or AD). Notwithstanding, the differentia-
tion between the two sets of behaviours has important research
and clinical implications. There are two main views: one
supporting the hierarchical approach to the classification of
AUDs (where a diagnosis of AA is made only in absence of AD);
the other maintains that problem drinking and addiction are two
separate disorders. In the general population, there are clear
differences in family history and early childhood experiences
between subjects with AD and those with non-dependent
alcohol
disorders.
A
recent
genetic
linkage
study
reported
a
riskvariant for BD in families with AA, but not in families with AD,
supporting the second of the two views [51]. Methodologically,
alcohol abuse and harmful alcohol use are psychometrically less
robust than dependence, and it has been argued they represent
unsatisfactory constructs [27]. This may be particularly the case
of BD, where excessive alcohol use can be either a manifestation
of the impulse dyscontrol observed in acute mania or of self-
medication for both mania and depression;
although we had initially aimed to establish the odds ratio of
AUDs in BD compared to the general population, only one clinical
study included this information and the epidemiological studies
were too heterogeneous for meta-analysis;
geographical location and gender ratio explained about 70% of
heterogeneity.
However,
the
test
for
residual
heterogeneity
A. Di Florio et al./European Psychiatry 29 (2014) 117124122
http://www.hcp.med.harvard.edu/ncs/ftpdir/NCS-R_Lifetime_Prevalence_Estimates.pdfhttp://www.hcp.med.harvard.edu/ncs/ftpdir/NCS-R_Lifetime_Prevalence_Estimates.pdfhttp://omim.org/entry/100650http://omim.org/entry/100650http://omim.org/entry/100650http://omim.org/entry/100650http://www.hcp.med.harvard.edu/ncs/ftpdir/NCS-R_Lifetime_Prevalence_Estimates.pdfhttp://www.hcp.med.harvard.edu/ncs/ftpdir/NCS-R_Lifetime_Prevalence_Estimates.pdf -
8/10/2019 Alcohol Misuse in Bipolar Disorder.
7/8
suggests that there were other covariates not considered in the
model influencing the comorbidity rates, such as the level of
training of interviewers, other variables assessed and current
mood. Potential explanatory variables that we did not consider,
but that can contribute in explaining the association between BD
and AUDs, include:
comorbidity with anxiety disorder. It has for example been
reported that women, but not men, with BD and comorbid
social phobia have four-fold increased risk of AA compared to
those without social phobia [52],
duration of BD. It has been previously reported that medical
comorbidity in BD varies with age and duration of illness, with
systematic differences between patients at different stages of
the disease [54].
It has recently been advocated that substance use disorders and
psychiatric conditions are complicated and are probably best in
the realm of future research rather than nosology at this point [3].
The current nosological systems have been challenged by
comorbidity between disorders. Advances in neuroscience may
offer new insights into phenotypes [37]. In particular, one of the
specific objectives of the Psychiatric GWAS Consortium [11] is the
analysis of comorbidities between major psychiatric disorders.
This approach may lead to a better understanding of the biologicalmechanisms underpinning the relationship between AUDs and BD.
However, while we are waiting for more biological grounded
diagnostic and clinical approaches, clinical and epidemiological
studies may provide some important clues for the management of
patients with BD and AUDs.
Patients with BD in comorbidity with AUDs are usually
excluded from clinical trials. A recent research found that current
AUDs were the leading exclusion criterion in trials for acute mania
[31]. Our results indicate that the exclusion of patient with current
AUDs limits the generalizability and clinical utility of trials.
Moreover, due to the influence of gender on comorbidity rates, our
meta-analysis emphasises the need of systematically assessment
of gender differences among participants.
To conclude, clinicians should be aware of the high comorbidityof AUDs not only in men, but also in women with BD. Patients with
BD should be assessed for current and previous alcohol use and
misuse. Clinical trials should also take into account the high rates
and gender differences in comorbidity with AUDs in participants
with BD.
Disclosure
of
interest
The authors declare that they have no conflicts of interest
concerning this article.
Appendix
A.
Supplementary
data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.eurpsy.2013.
07.004.
References
[1] Agarwal DP, Goedde HW. Pharmacogenetics of alcohol metabolism and alco-holism. Pharmacogenetics 1992;2(2):4862.
[2] Angst J. The emerging epidemiology of hypomania and bipolar II disorder. JAffect
Disord
1998;50(2-3):14351.[3] Bizzarri JV, Sbrana A, Rucci P, Ravani L, Massei GJ, Gonnelli C, et al. The
spectrum of substance abuse in bipolar disorder: reasons for use, sensationseeking and substance sensitivity. Bipolar Disord 2007;9(3):21320.
[4] Brown GR, McBride L, Bauer MS, Williford WO. Impact of childhood abuse onthe
course
of
bipolar
disorder:
a
replication
study
in
U.S.
veterans.
J Affect
Disord
2005;89(13):5767.
[5] Cardoso BM, Kauer SantAnna M, Dias VV, Andreazza AC, Cereser KM, Kapc-zinski F. The impact of co-morbid alcohol use disorder in bipolar patients.Alcohol 2008;42(6):4517.
[6] Cassidy F, Ahearn EP, Carroll BJ. Substance abuse in bipolar disorder. BipolarDisord 2001;3(4):1818.
[7] Castilla-Puentes RC,Secin R, GrauA, Galeno R, De Mello F, Castilla-Puentes S,etal. A multicenter study of bipolar disorder among emergency departmentpatients in Latin-American countries. Int J Psychiatry Med 2011;42(1):4967.
[8] Cha B, Moon ES, Jeong CY, Ha K. Axis I psychiatric comorbidity in Koreanpatients with bipolar disorder: Prevalence and response to treatment.Journal
of
Cancer
Education
[Internet].
2009
[cited
2012
Apr
16];
Available
from:http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&-D=emed9&AN=70044745.
[9] Chengappa KN, LevineJ, Gershon S, Kupfer DJ. Lifetime prevalence of substanceor alcohol abuse and dependence among subjects with bipolar I and II dis-orders in a voluntary registry. Bipolar Disord 2000;2(3 Pt 1):1915.
[10] Chou SP, Lee HK, Cho MJ, ParkJI, Dawson DA, Grant BF. Alcohol use disorders,nicotine
dependence,
and
co-occurring
mood
and
anxiety
disorders
in
theUnited States and South Korea a cross-national comparison. Alcohol Clin ExpRes 2012;36(4):65462.
[11] Craddock N, Kendler K, Neale M, Nurnberger J, Purcell S, Rietschel M, et al.Dissecting the phenotype in genome-wide association studies of psychiatricillness.
Br
J
Psychiatry
2009;195(2):979.[12] Dalton EJ, Cate-Carter TD, Mundo E, Parikh SV, Kennedy JL. Suicide risk in
bipolar patients: the role of co-morbid substance use disorders. Bipolar Disord2003;5(1):5861.
[13] Dawson NV, Dadheech G, Speroff T, Smith RL, Schubert DS. The effect of patientgender on the prevalence and recognition of alcoholism on a general medicineinpatient service. J Gen Intern Med 1992;7(1):3845.
[14]
Egger
M, Schneider
M,
Davey
Smith
G.
Spurious
precision?
Meta-analysis
ofobservational studies. BMJ 1998;316(7125):1404.
[15] Escamilla MA,Batki S, Reus VI, Spesny M, MolinaJ, Service S, et al. Comorbidityof bipolar disorder and substance abuse in Costa Rica: pedigree- and popula-tion-based
studies.
J
Affect
Disord
2002;71(13):7183.[16] Escobar JI, Vega WA. Cultural issues and psychiatric diagnosis: providing a
general background for considering substance use diagnoses. Addiction2006;101(Suppl. 1):407.
[17] Fogarty F, Russell J, Newman S, Bland R. Mania. Acta Psychiatr Scand Suppl1994;376:1623.
[18] Frank E, Boland E, Novick DM, BizzarriJV, Rucci P. Association between illicitdrug and alcohol use and first manic episode. Pharmacol Biochem Behav2007;86(2):395400.
[19] Frye MA, Altshuler LL, McElroy SL, Suppes T, Keck PE, Denicoff K, et al. Genderdifferences
in
prevalence,
risk,
and
clinical
correlates
of
alcoholism
comorbid-ity in bipolar disorder. Am J Psychiatry 2003;160(5):8839.
[20] Glantz MD, Anthony JC, Berglund PA, Degenhardt L, Dierker L, Kalaydjian A,et al. Mental disorders as risk factors for later substance dependence: esti-mates of optimal prevention and treatment benefits. Psychol Med2009;39(8):
136577.[21]
Glasser
SP,
Duval
S.
Essentials
of
Clinical
Research.
Springer
Netherlands;
2008[cited 2012 Mar 26]. p. 15977. Available from: http://www.springerlink.co-m.abc.cardiff.ac.uk/content/k531021571444176/abstract/.
[22] Goldberg JF, Garno JL, Leon AC, Kocsis JH, Portera L. A history of substanceabuse complicates remission from acute mania in bipolar disorder. J ClinPsychiatry
1999;60(11):73340.[23] Goldstein BI, Levitt AJ. Factors associated with temporal priority in comorbid
bipolar I disorder and alcohol use disorders: Results from the national epide-miologic survey on alcohol and related conditions. J Clin Psychiatry2006;67(4):6439.
[24]
Gonzalez-Pinto
A,
Alberich
S,
Barbeito
S,
Alonso
M, Vieta
E,
Martnez-Aran A,et al. Different profile of substance abuse in relation to predominant polarity inbipolar disorder: The Vitoria long-term follow-up study. J Affect Disord2010;124(3):2505.
[25] Grant BF, Stinson FS, Hasin DS, Dawson DA, Chou SP, Ruan WJ,et al. Prevalence,correlates, and comorbidity of bipolar I disorder and axis I and II disorders:results from the National Epidemiologic Survey on Alcohol and Related Con-
ditions.
J
Clin
Psychiatry
2005;66(10):120515.[26] Grant BF, Goldstein RB, Chou SP, Huang B, Stinson FS, Dawson DA, et al.Sociodemographic and psychopathologic predictors of first incidence of DSM-IV substance use, mood and anxiety disorders: results from the Wave 2National Epidemiologic Survey on Alcohol and Related Conditions. Mol Psy-chiatry 2009;14(11):105166.
[27] Hasin D, Hatzenbuehler ML, Keyes K, Ogburn E. Substance use disorders:Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV)and International Classification of Diseases, tenth edition (ICD-10). Addiction2006;101(Suppl. 1):5975.
[28] Hendrick V, Altshuler LL, Gitlin MJ,Delrahim S, Hammen C. Gender and bipolarillness. J Clin Psychiatry 2000;61(5):3936. quiz 397.
[29] HigginsJPT. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):55760.
[30] HigginsJP, Whitehead A, Turner RM,Omar RZ, Thompson SG. Meta-analysis ofcontinuous outcome data from individual patients. Stat Med 2001;20(15):221941.
[31] Hoertel N, Le Strat Y, Lavaud P, Dubertret C, Limosin F. Generalizability ofclinical trial results for bipolar disorder to community samples: findings from
A. Di Florio et al./ European Psychiatry 29 (2014) 117124 123
http://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://dx.doi.org/10.1016/j.eurpsy.2013.07.004http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0005http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0350http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0010http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0015http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0020http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0025http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0030http://ovidsp.ovid.com/ovidweb.cgi%3FT=JS%26CSC=Y%26NEWS=N%26PAGE=fulltext%26D=emed9%26AN=70044745http://ovidsp.ovid.com/ovidweb.cgi%3FT=JS%26CSC=Y%26NEWS=N%26PAGE=fulltext%26D=emed9%26AN=70044745http://ovidsp.ovid.com/ovidweb.cgi%3FT=JS%26CSC=Y%26NEWS=N%26PAGE=fulltext%26D=emed9%26AN=70044745http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0040http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0045http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0050http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0055http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0060http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0065http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0070http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0075http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0080http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0085http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0090http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924-9338(13)00100-4/sbref0095http://refhub.elsevier.com/S0924