Download Assoc. Prof. Dimosthenis Sarigiannis, Chemical

Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
Cross-Mediterranean Environment and Health Network
CROME–LIFE
The CROME method
Prof. Denis Sarigiannis – Project coordinator
Environmental Engineering Laboratory
Department of Chemical Engineering,
Aristotle University of Thessaloniki
GR-54124, Thessaloniki, Greece
Chair of Environmental Health Engineering,
Institute of Advanced Study, Pavia 27100, Italy
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
1
LIFE12 ENV/GR/001040
Project consortium
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Lead Beneficiary:
Aristotle University of Thessaloniki (AUTH) - Greece
AUTH coordinates the scientific/technical and administrative/financial aspects of
the project
Project manager: Prof. Dimosthenis Sarigiannis
Associated beneficiaries:
– Agencia Estatal Consejo Superior de Investigaciones Cientificas (CSIC) –
Spain – Principal investigator: Prof. Joan Grimalt
– Istituto Superiore di Sanità (ISS) – Italy
Principal investigator: Dr. Gemma Calamandrei
– Jožef Stefan Institute (JSI) – Slovenia
Principal investigator: Prof. Milena Horvat
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
2
What is Exposome?
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
•
The record of all exposures, both internal and
external, an individual receives over his or her
lifetime, from conception onward. These
exposures range from chemicals in the
environment to the body’s response to
infection or psychological stress
(C. Wild, IARC, 2005)
•
It is important to keep an unbiased (agnostic)
stance to coupling chemical exposure to
health status
S M Rappaport, M T Smith Science 2010;330:460-461
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
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LIFE12 ENV/GR/001040
What is the exposome?
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Rappaport et al., 2014. Environmental
Health Perspectives122: 769-774.
CROME LIFE+ Closing Conference
December 20, 2016
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Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
The connectivity paradigm
LIFE12 ENV/GR/001040
Environmental
sensors
Remote
sensing
Exposure
modelling
metabol
ite
formati
on
GI tract – portal vein
Environmental
modeling / data
management
GI tract – portal vein
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Uterus - gonads
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L
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EWAS
B
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Uterus - gonads
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Community
Effects / Cohorts
Systems Effects /
Individual exposome
Environmental
analysis
Epigenetics
Cellular/tissue
effects
Human
biosampling
Molecular
initiating events
Metabolomics
Agent based
modelling
Ubiquitous
personal sensors
Fluxomics
(dynamic flux
balance analysis)
Transcriptomics
CROME LIFE+ Closing Conference
December 20, 2016
Bioinformatics /
systems biology
Athens, Greece
Pathway analysis
5
CROME towards new E & H paradigm Main technical innovation proposed
LIFE12 ENV/GR/001040
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
CROME facilitated the new E & H paradigm, proposing targeted innovation steps that include:
1. the operational use and demonstration of the validity of biology-based modeling tools that allow to mechanistically
link environmental exposure to biomonitoring and epidemiological data. This will be done by:
(a) linking environmental exposure to the biologically effective dose (BED) of xenobiotics at the main target
tissues;
(b) linking biomarker levels in biological fluids to the BED at target tissues; and
(c) linking target tissue BED with health outcomes. In this way, environment-wide associations with adverse health
effects or physiological perturbations will be established and mechanistic hypotheses regarding the mode and/or
mechanism of action can be investigated.
2. the operational use of an integrated approach to biomonitoring that combines the use of state-of the-art biomarkers
with reverse dosimetry and environmental data to reconstruct the effective dose human population is exposed to. The
results will allow moving towards an improved environmental health risk assessment in the EU and the world.
3. development of new and validation of existing biomarkers for environmental health risk assessment and
environmental human biomonitoring
Exposure
source
Transport
fate
CROME LIFE+ Closing Conference
External
contact
Internal
dose
December 20, 2016
Biologically
effective
dose
Early
biological
response
Altered
function
Athens, Greece
Clinical
disease
6
Exposure modelling
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
Oral exposure –
Non Dietary
Oral exposure –
Dietary
Skin
exposure
Inhalation takes into account
Dietary ingestion takes into
account
Object to mouth
Hand to mouth
- The chemical concentration of food
category i in μg/g
- The daily average consumption in g/d
of food category i, age category j and
gender category k
Instant
application
Food residues are estimated
- Through the food web (multimedia
model)
Inhalation
exposure
Migration from
skin contact
- The concentration from the several
locations encountered during the
exposure regimes
- The intensity of activity, gender and
age dependent inhalation rate
For particles and the
compounds adsorbed,
deposition across the HRT is
considered
Soil and dust ingestion
- Accounting also for migration through
food contact materials
Rubbing off
Personal care
products ingestion
Constant rate
CROME LIFE+ Closing Conference
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LIFE12 ENV/GR/001040
Biokinetic modeling
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Lifetime evolving parameters
•
•
•
Organ volumes
Blood flows
Age-dependent clearance
Mother – Fetus interaction
Breast feeding
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
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LIFE12 ENV/GR/001040
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Expanding the chemical
space - use of QSARs
According to Abraham’s solvation equation, a biological property SP can
be described by the following equation
log SP  c  r  R2  s   2  a   2  b   2  v  log Vx
Where:
R2
R2 is an excess molar refraction that can be determined simply from
π2Η
a knowledge of the compound refractive index
π2Η is the compound dipolarity/polarizability
Σα2Η is the solute effective or summation hydrogen-bond acidity
Σβ2Η is the solute effective or summation hydrogen-bond basicity
Vx is the McGowan characteristic volume
1
2
3
Σα2Η
Σβ2Η
n
LogSP
4
Vx
5
6
Input
layer
CROME LIFE+ Closing Conference
December 20, 2016
Hidden
layer
Athens, Greece
Output
layer
9
What does a spot
sample represent?
LIFE12 ENV/GR/001040
20
Concentration in human specimen
(μg/L)
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
16
Exposure scenario 1
Exposure scenario 2
Exposure scenario 3
12
Spot sampling
8
4
0
0
4
8
12
16
20
24
Time (h)
CROME LIFE+ Closing Conference
December 20, 2016
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Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Exposure reconstruction
LIFE12 ENV/GR/001040
Optimal methodological scheme for exposure
Distribution of exposure
reconstruction
values consistent with
biomarker data
Potential exposure
estimation
Improved
sampling
En
B*n
PBTK model
run with E*n
input
E3
B*3
E2
B*2
E1
PBTK model
run with E*1
input
Exposure
model
CROME LIFE+ Closing Conference
Companion
data
B*1
Comparison with biomarker data
Optimization
algorithm
Small
proportion
of rejected
model
simulations
Biomarker
data
(Exposure related)
December 20, 2016
Athens, Greece
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LIFE12 ENV/GR/001040
CROME LIFE+ Closing Conference
Application: reconstructing
Arsenic exposure from HBM data
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
As →
PROBE- Italy
As →
PHIME Slovenia
December 20, 2016
Athens, Greece
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LIFE12 ENV/GR/001040
CROME LIFE+ Closing Conference
Application: reconstructing HCB
and DDT exposure from HBM data
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
HCB →
INMA - Spain
DDT →
INMA - Spain
December 20, 2016
Athens, Greece
13
LIFE12 ENV/GR/001040
CROME LIFE+ Closing Conference
Application: reconstructing
MeHg exposure from HBM data
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
MeHg →
PHIME - Croatia
MeHg →
PHIME - Slovenia
December 20, 2016
Athens, Greece
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LIFE12 ENV/GR/001040
•
•
Association of biomonitoring
data to health effects
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
To estimate the health impact we will use a statistical approach based on
survey-weighted logistic multivariate regression adjusted for different covariates
(age, sex, socio-economic status (SES) etc.) linking internal doses with health
effect considering the interdependence of the covariates (using as metric an
analogy of the “linkage disequilibrium” metric used in genome-wide association
studies).
The general formulation of the approach is based on the following mathematical
linkage of health end points (expressed in terms of odds ratio, p) with different
covariates (age sex, SES etc.) and the internal dose in the target tissue
(XFactor):
where cov represents the different covariates used in the model and α and β
are the regression coefficients which take into account the interdependence
between the covariates.
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
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LIFE12 ENV/GR/001040
CROME LIFE+ Closing Conference
Association of biomonitoring
data to health effects
December 20, 2016
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Athens, Greece
16
Explore causality in EWAS
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
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LIFE12 ENV/GR/001040
Explore causality in EWAS
using linkage disequilibrium
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Red: positive 
Blue: negative 
Thickness: | |
CROME LIFE+ Closing Conference
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LIFE12 ENV/GR/001040
Name
Country/Region
INMA
Spain (Valencian
Community)
Available cohort data
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Questionnaires
available
People targeted
HBM matrices
Health end-points
Chemicals
500 mother-infant pairs
venous blood serum,
cord blood serum
Bayley test for infant
development
Mercury, Organochlorine
compounds, polybromodiphenyl
ethers (including
decabromodiphenyl ether)
yes
venous blood serum,
cord blood serum
McCarthy Scales of
Children’s Abilities.
Tests for the California
Mercury, organochlorine
Preschool Social
compounds, polybromodiphenyl
Competence Scale
ethers
and Attention-Deficit
Hyperactivity Disorder
(ADHD)
yes
480 cord blood
300 blood at 4 years
INMA
Spain (Menorca)
JSI
Slovenia – 12 regions
included in the
national human
600 pairs, mother-child,
biomonitoring survey,
man
including rural, urban
and contaminated
sites
Breast milk, blood,
urine, hair
Reproductive and
neurodevelopmental
toxicity and effects of
endocrine disruptors
BPA, phthalates, pesticides,
PCBs, metals and As
yes
PHIME
Slovenia
Brest milk, bllood
urine, hair
neurodevelopmental
toxicity and effects of
endocrine disruptors
BPA, phthalates, pesticides,
PCBs, Hg and other metals and
As
yes
PROBE
Italy - various Regions
1500 adults 500
Latium for
adolescents
adolescents
HM (focus on Arsenic)
yes
CROME LIFE+ Closing Conference
225 mother-child pairs
Blood and serum
December 20, 2016
Athens, Greece
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LIFE12 ENV/GR/001040
Additional data
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
The CROME-LIFE Cross-Mediterranean study (or Common case study) is a follow
up study of pre-existing Children Mediterranean cohorts based on:
PHIME, involving Slovenia, Croatia, Italy, Greece
INMA (Environment and Childhood), Spain
Aim: to find those gene polymorphisms that could modulate the effects of metals,
particularly Hg, at low exposure in the Mediterranean cohort:





glutathione-related genes
metal binding protein genes
genes involved in scavenging of ROS
genes implicated in brain development
others, identified by GWAS
CROME LIFE+ Closing Conference
December 20, 2016
MERCURY
MINING
Athens, Greece
20
Additional case studies - Greece
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
Greece – Aspropyrgos plastic recycling
plant fire → PCDDs / PCDFs
Greece – Asopos basin → Cr+6
Greece – Biomass burning in large
cities → PM / PAHs
CROME LIFE+ Closing Conference
December 20, 2016
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LIFE12 ENV/GR/001040
Asopos region – Cr(VI)
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Health impact
 A total of 474 deaths were observed over an 11-year period (1999 - 2009). The
standardized mortality ratios (SMR) for all cause mortality was 98 (95% CI 89107) and for all cancer mortality 114 (95% CI 94-136).
 The SMR for primary liver cancer was 1104 (95% CI 405-2403, p-value <
0.001).
 Statistically significantly higher SMRs were identified for lung cancer (SMR =
145, 95% CI 100-203, p-value = 0.047) and cancer of the kidney and other
genitourinary organs among women (SMR = 368, 95% CI 119-858, p-value =
0.025).
 Elevated SMRs for several other cancers were also noted (lip, oral cavity and
pharynx 344, stomach 121, female breast 134, prostate 128, and leukaemias
168), but these did not reach statistical significance.
 In addition, increased morbidity related to asthma and allergies have been
observed
*Linos et al (2011). Oral ingestion of hexavalent chromium through drinking water and cancer
mortality in an industrial area of Greece - An ecological study. Environ. Health. 10.
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
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Cr(VI) in water
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
1,000
5%-95%
Cr(VI) in water
Median
Εξασθενές χρώμιο (μg/L)
Mean
100
10
1
0
Tap water
CROME LIFE+ Closing Conference
December 20, 2016
Underground water
Athens, Greece
23
Exposure biomarkers
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
5
Total Cr
5%-95%
Median
Urine (μg/L) / Hair (μg/g)
4
Mean
3
2
1
0
Childrern
Adults
Urine
CROME LIFE+ Closing Conference
Childrern
Adults
Hair
December 20, 2016
Athens, Greece
24
LIFE12 ENV/GR/001040
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Biomarkers analysis
Integrated biology workflow
LC-MS/MS
GC-MS/MS
MassHunter Qual/Quant
ChemStation AMDIS
Microarrays
Feature Extraction
NGS
CROME LIFE+ Closing Conference
GeneSpring Platform
Biological
Pathways
Alignment to Reference Genome
December 20, 2016
Athens, Greece
25
LIFE12 ENV/GR/001040
Biomarkers analysis
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Cancer
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
26
LIFE12 ENV/GR/001040
Biomarkers analysis
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Allergies and asthma
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
27
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
Health risks of recycling
The case of Aspropyrgos recycling plant
fire – dioxin/furan release
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
28
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
Recycling plant accidental event
LIFE12 ENV/GR/001040
10,000
Concentration (fg/m3)
1,000
5%-95%
Median
PCDDs and PCDFs (TEQ)
100
10
1
Rural areas
City centre
Industrial area
Landfield fires Aspropyrgos fire
24
Conc. (pg/g lipid_TEQ)
20
16
12
Background
levels
8
4
0
8 6 7 8 9 6 11 8 9 10 7 6 9 11 9 273841552941324225394231293942255836474930364924342936483839443842274449344148534953483934
Children
Adults
Individuals age (years)
5%-95%
Median
Risk
Cancer risk
1.E-06
1.E-07
1.E-08
Background risk
CROME LIFE+ Closing Conference
December 20, 2016
Post-accidental risk / Post-accidental risk / Post-accidental risk /
adults
neonates
breast fed
Athens, Greece
29
Metabolomics and pathway analysis
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
Increased levels of unsaturated vs saturated fatty acids, compared to
controls → cholesterol homeostasis perturbation → AhR deregulation
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
30
LIFE12 ENV/GR/001040
Biomass smoke
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
The environmental problem
In Greece, the use of biomass for space heating was introduced in 2011 as a CO2-neutral
means to foster global warming mitigation
However, a series of austerity measures combined with the excessive rise in the taxation
of light heating diesel, resulted in irrational use of biomass for residential heating in the
winter of 2012-2013
This was followed by a significant increase of ambient and indoor air levels and, as a
result of the lack of technological readiness of Greek households to use biomass for
space heating; the vast majority of the appliances included use of open fireplaces or
woodstoves
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
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Study design
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
– integrating detailed environmental information into
enhanced exposure and health impact assessment
LIFE12 ENV/GR/001040
25
20
15
15
Indoor concentrations
Index
Meteorological
parameters
prediction
Lung cancer risk
25
20
Index
Temperature
Humidity
Wind speed
Wind direction
Precipitation
Region specific oxidative
potential index
10
10
5
5
0
0
Nasopharyng eal
Trach eo bro nchial
Pulmonary bronchioles
Nasopharyng eal
Traffic
Trach eo bro nchial
Pulmonary bronchioles
Nasopharyng eal
Trach eo bro nchial
Traffic
Urban backgroun d
Pulmonary bronchioles
Nasopharyng eal
Trach eo bro nchial
Pulmonary bronchioles
Urban backgroun d
1
Dynamics in time
2
PM
PM day before
Forecasted
ANN
Ambient air PM
HRT deposition
+
INTERA comp.
platform
Measured
Population exposure
n
Ambient air
PM
monitoring
network
Database
Health impact



Training loop
150
Urban background
Anthropometric data
Time activity data
Housing data
Other sources
Biomass
Chemical analysis
• Source apportionment
(e.g. Levoglucosan, BC, metals)
• Refined risk assessment
(e.g. PAHs analysis, redox
activity)
Monetary impact
120
90
60
30
0
Sarigiannis et al. Total exposure to airborne particulate matter in cities: The
effect of biomass combustion. Science of the Total Environment 2014; 493:
795-805.
Sarigiannis et al. Lung cancer risk from PAHs emitted from biomass
combustion. Environmental Research 2015; 137: 147-156.
Sarigiannis et al. Health impact and monetary cost of exposure to particulate
matter emitted from biomass burning in large cities. Science of the Total
Environment 2015; 524-525: 319-330.
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
32
Biomass
contribution to PM10
LIFE12 ENV/GR/001040
150
150
Traffic site
PM concentration (μg/m3)
Urban background
Other sources
Other sources
Biomass
Biomass
120
120
90
90
60
60
30
30
0
0
CROME LIFE+ Closing Conference
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
December 20, 2016
Athens, Greece
33
ICR among
age groups
LIFE12 ENV/GR/001040
1.E-04
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
5%-95%
Median
Mean
Lung cancer risk
Lung cancer risk
1.E-05
1.E-06
3
7
1.E-07
1.E-08
0-3
3-23 23m.-3 3-8
months months years years
8-14
years
14-18
years
18-21
years
Adult
Urban background
Lower SES area
CROME LIFE+ Closing Conference
December 20, 2016
IUR
0-3
3-23 23m.-3 3-8
months months years years
8-14
years
14-18
years
18-21
years
Adult
IUR
Traffic
Higher SES area
Athens, Greece
34
CROME related interventions
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
A tiered measure strategy was proposed and adopted by the Hellenic government in the form of a Joint
Ministerial Decree (KYA 3272, 23/12/2013) under the title “Short-term action plans to address air
pollution by particulate matter” among Ministries of Health, Financial, Internal Affairs, Development And
Competitiveness, Education And Religious, Administrative Reform And Government - Wellness Infrastructure, Transport And Networks - Environment, Energy And Climate Change - Public Order And
Protection Citizen - Shipping And Islands
-
Information of the public
- Reducing exposure of susceptible groups
- Avoiding intensive exercise
- Avoiding effort…..
-
Actions for restricting emissions
- Reducing traffic emissions
- Use of telematics systems – routes optimization
- Speed limits
- More passengers per vehicles
- Restricted zones……..
- Reducing industrial emissions
- Shifting into less polluting activities
- Use of alternative fuels
- Reducing activity and electricity production
- Reducing household emissions
- Reducing energy consumption
- Use of cleaner energy
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
35
0
CROME LIFE+ Closing Conference
December 20, 2016
2/8/2014
Athens, Greece
2/22/2014
2/20/2014
2/18/2014
2/16/2014
2/14/2014
2/12/2014
2/10/2014
125
2/6/2014
150
2/4/2014
-26%
2/2/2014
1/31/2014
1/29/2014
1/27/2014
1/25/2014
PM10 : 92.3
PM2.5: 70.7
1/23/2014
1/21/2014
1/19/2014
1/17/2014
1/15/2014
1/13/2014
1/11/2014
1/9/2014
1/7/2014
1/5/2014
1/3/2014
1/1/2014
12/30/2013
12/28/2013
Date of
intervention
PM10 : 68.6
PM2.5: 51.3
PM10 Urban background
20
PM10 Traffic
Precipitation (mm)
T (0C)
Wind speed (km/h)
15
100
75
10
50
5
25
0
T (0C) - Wind speed (km/h) - Precipitation (mm)
200
12/26/2013
12/24/2013
12/22/2013
12/20/2013
12/18/2013
12/16/2013
12/14/2013
175
12/12/2013
12/10/2013
12/8/2013
12/6/2013
PM concentration (μg/m3)
CROME related interventions
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
25
36
CONCLUDING REMARKS
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
The methodology applied in CROME
- Takes stock of biomonitoring data in the health impact assessment process
- Accounts for the internal dosimetry in the target tissues, setting the
biological basis for understanding the interaction between environmental
exposure and disease
- Demonstrates in real-life environmental-health problems, what the targeted
interventions should be for improving public health and protecting
vulnerable groups
CROME outcomes, will be disseminated as follows:
• Transferring the outcomes (practices and technologies) of the project to the
rest of the EU Member States.
• Informing all stakeholders and general public of the demonstration sites on
the resulted benefits.
• Promoting the adopted practices and protocols to the key stakeholders.
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
37
Department of Chemical Engineering
School of Engineering
Aristotle University of Thessaloniki
LIFE12 ENV/GR/001040
Thank you for your kind
attention
www.enve-lab.eu
A new perspective to environment-health interactions
CROME LIFE+ Closing Conference
December 20, 2016
Athens, Greece
38