GRACE: The First Network of Excellence on Primary Care in Europe Herman Goossens Coordinator

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GRACEThe First Network of Excellence on Primary
Care in EuropeHerman GoossensCo-ordinator
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GRACE

• From molecule to management in
  community-acquired LRTI
• GRACE as a model for translating scientific
  innovation into benefits for patients

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GRACE Aim

• The overall aim of GRACE is to combat
  antimicrobial resistance through integrating and
  strengthening centres of excellence for studying
  the application of genomics with primary care
  practitioners, to community-acquired lower
  respiratory tract infections (LRTI), which is the
  leading reason for seeking medical care and
  consuming antibiotics.
• GRACE will develop into a European Lower
  Respiratory Tract Infection Research Centre to
  investigate and improve the bed-site management
  of community-acquired LRTI.

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The Target Community-acquired LRTI in GRACE

• Acute cough syndrome
• Acute bronchitis
• Community-acquired pneumonia (CAP)
• Infective exacerbations of chronic obstructive
  pulmonary disease (COPD)
• Infective exacerbations of asthma

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GRACE Facts and Figures

• Period of funding March 1, 2006 February 28,
  2011
• Grant for integration 11.5 million Euro
• Co-ordinating centre University of Antwerp,
  Belgium
• Partners from 14 countries
• Full partners 24 from 10 countries (including 5
  SMEs from 3 countries)
• Primary Care Networks 13 from 11 countries

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GRACE Four Platforms

• GRACE-COMIT
• WP1 Co-ordination, Organisation, Management
• WP2 IT infrastructure
• GRACE-TECH
• WP3, WP4, WP5, WP6, WP7 Technical platform
• GRACE-PAT
• WP8, WP9, WP10, WP11 Patient platform
• GRACE-EDUT
• WP12 Education and Training platform

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GRACE-COMIT

• WP N Workpackage Lead Partner
• 1 Project co-ordination and Herman Goossens
• management University of Antwerp,
• Belgium
• (and University of Leiden,
• Netherlands)
• 2 Develop IT platform and tools for Robert Veen
• information technology University of Utrecht,
• Netherlands

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GRACE-TECH
WP N Workpackage Lead Partner 3 Microbial
genomics for diagnosis of Greet
Ieven community-acquired LRTI University of
Antwerp, Belgium 4 Human genomics for
studying Adrian Hill risk factors University
of Oxford, United Kingdom 5 Virus
discovery Willy Spaan University of
Leiden, Netherlands 6 Pneumococcal genomics
Birgitta Henriques-Normark, Swedish Institute
for Infectious Disease Control, Sweden
7 Haemophilus genomics Derrick
Crook University of Oxford, United Kingdom

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GRACE-PAT

• WP N Workpackage Lead Partner
• 8 Observational study on determinants
  Christopher Butler
• of antibiotic use Cardiff University,
• United Kingdom
• 9 Observational studies on aetiology, Theo
  Verheij
• diagnosis and prognosis University of Utrecht,
• Netherlands
• 10 Randomised control trials Paul Little
• University of Southampton,
• United Kingdom
• 11 Economics of resistance Joanna Coast,
• University of Birmingham,
• Richard Smith
• University of East Anglia,

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GRACE-EDUT

• WP N Workpackage Lead Partner
• 12 Education and training Francesco Blasi
• University of Milan,
• Italy
• Roger Finch
• University of Nottingham,
• United Kingdom

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WP1 Objectives

• To provide a secure framework to ensure that the
  objectives of the work programme are complied
  with
• To achieve the expected degree of integration
  through the joint programme of activities
• To interact with the Commission, press and public
• To setup a business centre
• To prepare financial contracts and consortium
  agreement
• To ensure the optimal use of the generated
  knowledge within the scientific community and the
  public
• To manage staff mobility within the Network
• To manage quality control
• To develop a durable network beyond the period of
  the Commissions financial support

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WP1 Description of the Work

• Provision of a secure framework for structural
  decisions
• Management of flow of patient samples and
  isolates
• Management of quality control
• Management of staff mobility
• Monitoring the progress of the workpackages
• Setting up a business centre
• Preparing financial contracts, consortium
  agreement
• External communication

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WP1 Expected Achievements

• A high quality organisation and management

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WP2 Objectives

• To co-ordinate and harmonise the IT platform.
• To develop a Data Processing Centre
• To develop a web-based content management system
• To develop the GRACE portal
• To develop a technical framework access control
  management
• To develop a technical security and privacy
  concept and framework
• To engineer support for the development of
  database schemata for repositories
• To engineer support for the development of
  web-based case report forms (CRFs)
• To develop data export functions for statistical
  evaluation
• Technical maintenance of Data Processing Centre

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WP2 Description of the Work

• Co-ordination and harmonisation of IT platform.
• Development of a Data Processing Centre
• Development of web-based content management
  system.
• Development of the GRACE portal
• Development of a technical platform for access
  control management
• Development of a technical security and privacy
  concept and framework
• Engineering support for the development of
  database schemata for repositories
• Engineering support for the development of
  web-based case report forms
• Support of data export functions for statistical
  evaluation
• Technical maintenance of Data Processing Centre

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WP2 Expected Achievements

• A high quality IT infrastructure

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WP3 Objectives

• To develop novel rapid genome based diagnostic
  tests for the detection of pathogens implicated
  in community-acquired LRTI
• To develop reference reagents and an external
  quality assessment programme for molecular
  diagnostic methods for patients with
  community-acquired LRTI
• To establish a European repository of specimens
  and strains linked to a database including
  microbial and patient information

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WP3 Description of the Work

• Diagnostics
• Inventory of diagnostic (molecular) methods in
  the participating laboratories
• Establishing banks of fully characterised
  respiratory pathogens
• Development of reference reagents, calibrated
  stocks and run controls
• Development and distribution of proficiency
  panels for external quality assessment
• Development and optimisation of molecular methods
  for aetiological diagnosis
• Clinical validation of the novel technology
• Repositories
• Development of a bank of clinical materials from
  well-defined patients with community-acquired
  LRTI
• Development of a bank of well characterised
  clinical isolates of respiratory pathogens

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WP3 Expected Achievements

• Novel rapid genome based diagnostic tests for the
  detection of pathogens implicated in
  community-acquired LRTI
• European repository of specimens and strains
  linked to a database including microbial and
  patient information

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WP4 Objectives

• To devise the potential genetic risk profile for
  community-acquired LRTI
• To assess whether these polymorphisms identify
  individuals at risk of various presentations and
  outcomes of community-acquired LRTI in several
  European populations
• To determine whether these human genetic risk
  factors interact with each other or with key
  microbial genetic or other environmental risk
  factors for community-acquired LRTI
• To identify potential target pathways for new
  immunomodulatory approaches

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WP4 Description of the Work

• Two case-control studies
• First case-control study (years 1-3)
• Genotyping of severe community-acquired LRTI
  cases and controls from the UK by Illumina
  Beadarray high throughput typing for 30,000
  coding SNPs with a minimum allele frequency gt5
  that span the entire human genome
• Define the 30 most strongly associated SNPs
• Define the causative variants in these relevant
  genes
• Second case-control study (years 3 - 5)
• Retesting of the 30 most strongly associated SNPs
  in a larger study of about 6000 cases and locally
  matched controls from 6 European sites by
  Sequenom mass spectrometry or microarray
• Genotyping of specific loci of particular
  interest such as Ig receptors, cytokines,
  cytokine receptors, acute phase reactants,
  collectins, toll receptors, chemokines,
  inflammatory signalling pathway components,
  macrophage and neutrophil receptors.

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WP4 Expected Achievements

• Genetic risk factors for (particular) phenotypes
  of community-acquired pneumonia (caused by
  certain pathogens)

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WP5 Objectives

• To align RNA viruses to identify conserved
  domains for primer selection
• To optimise the CODEHOP programme for the
  selection of degenerated CODEHOP primers
• To construct test systems using amplicons created
  with consensus and CODEHOP primers
• To validate test systems for screening clinical
  samples
• To identify the genomes and characterise new
  viruses

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WP5 Description of the Work

• Two amplification-based strategies
• Nested Primers Primagens PALM Method
• Generic and specific primers located within the
  first amplicon
• Sequencing of obtained second amplicon of about
  500 to 600 nucleotides
• CODEHOP-based approach
• Primers with a non-degenerate 5' end and
  degenerate 3' end
• Primers designed using a method based on the
  CODEHOP programme
• Bioinformatics-based improvements of the CODEHOP
• Principal target RNA dependent RNA polymerase of
  three major genera of the Nidovirales
• Validation of the developed techniques
• Adaptation to encompass other virus genera

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WP5 Expected Achievements

• New tools to detect novel or previously unknown
  viral pathogens in clinical specimens form
  patients with community-acquired LRTI

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WP6 Objectives

• To correlate antibiotic resistance, virulence
  characteristics and pneumococcal genotype to
  severity of community-acquired LRTI
• To identify pneumococcal genes important for
  virulence and for antibiotic resistance
  development

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WP6 Description of the Work

• Collection of isolates with resistance profiles
  and clinical information through WP9 and WP10
• Genotypic determination of new resistance
  determinants
• Serotyping and genotyping of relevant (virulent)
  pneumococci
• Correlating antibiotic resistance profile and
  genotype to clinical parameters with the aim of
  finding certain clones that are more virulent and
  prone to spread
• Study of known pathogenicity islands as well as
  horizontally acquired genes important for
  resistance development by comparative genomics
  using microarray chips, and correlate to
  clonality and clinical information.
• Deletion of relevant genes by performing knockout
  mutants and study for virulence in various models
  (tissue culture, animal, etc)

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WP6 Expected Achievements

• Pneumococcal genes important for virulence and
  for antibiotic resistance development

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WP7 Objectives

• To determine the relationship between antibiotic
  usage and prevalence of resistance in Europe
  among infecting and colonising haemophili, as
  determined by resistance genes encoded by
• integrating conjugative mobile elements, and
• chromosomal genes
• Determine the phylogenetic relationships between
  conjugative elements and their host bacteria
• Determine the prevalence and distribution of
  hypermutable H. influenzae clinical isolates in
  Europe
• Determine the European variation in the
  prevalence in clinical settings and carriers of
  capsulated isolates, their molecular epidemiology
  and their resistance mechanism

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WP7 Description of the Work

• Collection of H. influenzae from clinical samples
  and Haemophilus species from throat samples,
  through WP9 (prevalence of resistance) and WP10
  (impact of use)
• Determination of species by conventional methods
  and 16S RNA sequence analysis
• Phenotypic characterisation of antibiotic
  resistance (MIC)
• Genotypic characterisation of antibiotic
  resistance by multiplex PCR (conjugative
  elements), PCR and sequencing (chromosomal
  elements)
• Multi-locus sequence analysis of the resistance
  elements and host bacteria
• Study of the prevalence of mechanisms of
  hypermutability (i.e. mutations in the DNA repair
  system, mutS and mutL).
• Capsular typing of representative H. influenzae
  isolates by molecular procedures

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WP7 Expected Achievements

• Relationship between antibiotic usage and
  prevalence of antibiotic resistance encoded by a
  conjugative and chromosomal genes
• Phylogenetic relationships between conjugative
  elements and their host bacteria
• Prevalence of hypermutable H. influenzae clinical
  isolates in Europe
• Prevalence and characterisation of capsulated H.
  influenzae isolates

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Flow of Specimens and Isolates among Academic
Participants and SMEs
Instituto de tecnologia Quimica e Biologica H.
De Lencastre
Universität Kaiserslautern R. Hakenbeck
Instituto de Salud Carlos III J. Campos
MRC-Holland The Netherlands J.P. Schouten
University of Leiden E. Claas
University of Utrecht A. Van Loon
AmpTec GmbH Germany G. Krupp
PathoFinider The Netherlands G. Simons
Coris BioConcept Belgium T. Leclipteux
Primagen The Netherlands P. van den Broek
Rigshospitalet P. Garred
Karolinska Institute S. Normark
University of Oxford WP4 A. Hill
University of Antwerp WP3 M. Ieven
University of Leiden WP5 W. Spaan
Swedish Institute for Infectious
Disease Control WP6 B. Henriques-Normark
University of Oxford WP7 D. Crook
Human specimens
Human specimens
S. pneumoniae
Human specimens
H. influenzae
Project Managemant Office University of
Antwerp WP1 H. Goossens
Human specimens
Microbial isolates
National Co-ordinating Diagnostic
Laboratories WP9, WP10
Human specimens
Human specimens
Primary Care Networks
Hospitals
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WP8 Objectives

• To establish a collaboration of primary care
  research networks in Europe
• To describe current presentation, investigation,
  management and outcomes for patients with
  community-acquired LRTI in primary care in Europe
• To achieve a deep understanding of the
  micro-level determinants and contextual factors
  that influence antibiotic prescription/management
  for community-acquired LRTI
• To develop evidence-based definitions for
  community-acquired LRTI

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Primary Care Networks
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Primary Care Networks Participating in WP8 (I)

• Country N practices/ Co-ordinator Facilitator
• N GPs
• Belgium 25/50 Samuel Coenen Samuel Coenen
• Finland 5-10/50-150 Ulla-Maija Rautakorpi
  Ulla-Maija Rautakorpi
• Germany 15-25/15-25 Tom Schaberg Konstanze
  Voigt
• Hungary 25/20 Bernadette Kovacs Bernadette
  Kovacs
• Italy 20/15 Francesco Blasi Francesco Blasi
• Netherlands 7/35 Theo Verheij Eelko Hak

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Primary Care Networks Participating in WP8 (II)
Country N practices/ Co-ordinator Facilitator
N GPs Norway 8/32 Carol Pascoe Hasse
Melbye Poland 5/10 Maciek Godycki-Cwirko Maci
ek Godycki-Cwirko Spain 20/6 Jordi Almirall
Jordi Almirall 15/6 Antoni Torres Ruano
Nuria Sanchez Sweden 10/40 Bo-Eric Sigvard
Mölstad Malmvall Futurum UK 25/60
Christopher Butler Richard Hibbs 8/24
Michael Moore Michael Moore
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WP8 Description of the Work Quantitative,
registration study

• 13 PC networks in 11 countries have been selected
  (minimum of 20,000 patients)
• Computerised or paper standardised formats
• Consecutive enrolment of 300 patients/network
  consulting with acute cough
• Data collection (patients and primary care
  clinicians) over two one-month periods (February
  and September)

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WP8 Description of the WorkQualitative in depth
study

• Stratification of practices and samples to
  maximise variation
• Training of researchers in qualitative
  interviewing
• Interview study, exploring
• PC Clinicians accounts of management of patients
  with community-acquired LRTI
• Patients accounts of their experiences and
  beliefs about medical management of LRTI
• Data analysis according to the procedures of
  Grounded Theory

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WP8 Description of the Work Developing
definitions

• Multi-step evidence-based development of
  definitions with
• internationally agreed clinical (signs and
  symptoms) and technical
• (radiological and microbiological) criteria for
  the target diseases
• Empirical research (the quantitative study will
  provide the platform to
• describe syndromes and clinical presentation)
• ?
• Literature searching
• ?
• Expert opinion to enhance the empirical research
  and literature
• searching
• ?
• Consensus groups (using modified Delphi
  technique)
• ?
• Face validity (the qualitative study will provide
  the platform to confront
• the definitions with clinical reality)

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WP8 Expected Achievements

• Description and a deep understanding of the
  variation in presentation, investigation,
  management and outcomes of community-acquired
  LRTI
• Pilot specimen collection, procedures and inform
  study methods for WP9, WP10, WP11
• Identification of good practice and factors which
  predispose and maintain this good practice, that
  may be generalised in later intervention studies
  (WP10) and education and training initiatives
  (WP12)
• Areas in which practice could be enhanced and
  targets for interventions aimed at improving
  antibiotic prescribing/management, and inform the
  prioritising, the nature and location of the
  intervention studies (WP10)
• An instrument to measure change in attitude,
  knowledge and beliefs about common infections and
  their management (WP10)
• Provide data for modelling studies (WP11)
• Definitions on which to base later
  observational, intervention and modelling studies
  (WP9, WP10 and WP11)

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WP9 Objectives

• To study the role of atypical bacteria and
  viruses, including novel pathogens, in patients
  with community-acquired LRTI
• To assess risk factors for infection with
  (resistant) S. pneumoniae and H. influenzae in
  patients with community-acquired LRTI
• To develop clinical models to differentiate viral
  from bacterial infections and identify pneumonia
• To develop clinical models to identify patients
  at risk for adverse outcomes including severe and
  prolonged illness

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WP9 Description of the WorkSetting

• Same cohort for all objectives of WP9 (and for
  the randomised clinical trial of WP10)
• About 6 large computerised primary care research
  networks across the EU
• representative populations for the main regions
  in Europe
• affiliated with major hospitals.
• Protocols for inclusion of study subjects and
  data collection developed in other WP
• Inclusion criteria will be tailored to the
  definitions developed in WP8

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WP9 Description of the WorkThree types of
investigations

• An aetiological study
• A case-control study nested in the predefined
  cohorts of each national network
• - cohorts of approximately 2,400 adults and
  elderly/network
• - nested random sample of 25 of the cohort
  (approximately 600/network)
• Blood and urine sampling, nose-throat swabs for
  GRACE-TECH
• Pulmonary measurements
• A diagnostic cross-sectional study
• Starting point baseline of the aetiological
  study
• Cases with suspected community-acquired LRTI (max
  of about 500 cases/network)
• Blood and urine sampling, nose-throat swabs for
  GRACE-TECH
• Pulmonary measurements
• A prognostic study
• Starting point baseline of the diagnostic study
• Cases with confirmed community-acquired LRTI
• Follow up prospectively during 3 months
• All studies Web-based data collection

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WP9 Expected Achievements

• A simple clinical algorithm that can help the
  primary care clinician to distinguish viral from
  bacterial infections, and acute bronchitis
• A simple clinical algorithm that can support the
  primary care clinician to detect
  community-acquired pneumonia.
• A simple algorithm that will enable the primary
  care clinician to discern patients with
  community-acquired LRTI at risk for complications
  from patients with self-limiting disease with low
  risk for poor outcome
• Provide data for economic modelling (WP11)

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WP10 Objectives

• To assess the effectiveness of antibiotics among
  patients with community-acquired LRTI in order to
  understand which subgroups selectively benefit
  from antibiotic treatment
• To develop and assess a practice based
  intervention based on improvements of antibiotic
  prescribing behaviour in patients with
  community-acquired LRTI and explore the effect on
  antibiotic resistance

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WP10 Description of the workTwo clinical trials

• Antibiotic randomised placebo-controlled
  double-blind trial
• Starting point nested in the diagnostic study
• Cases with community-acquired LRTI, not CAP (max
  of about 500 cases/network)
• Intervention antibiotic or placebo patients
  stratified by three age groups
• Bed-side patient testing
• Blood and urine sampling, nose-throat swabs for
  GRACE-TECH
• Pulmonary measurements
• Web-based data collection.
• Outcomes deterioration of illness symptom
  severity and duration,
• Outreach RCT of optimal package of care
• 30 practices/network of not low AB prescribers
• randomly chosen in each of the 6 networks (i.e.
  180 practices)
• Intervention academic detailing/outreach and
  controls
• Outcomes AB prescribing, hospitalisation, length
  of illness,

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WP10 Expected Achievements

• Identification of subgroups of patients with
  community-acquired LRTI who benefit from
  antibiotic treatment
• A practice based validated intervention for
  improving antibiotic prescribing in patients with
  community-acquired LRTI

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WP11 Objectives

• To model the macroeconomic impact of antibiotic
  resistance and policies to contain it
• To model the cost-effectiveness of the management
  strategies developed in the observational studies
  
• To conduct economic evaluations in parallel with
  the intervention studies
• To conduct economic evaluations of molecular
  diagnostics

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WP11 Description of the Work

• Macro-economic modelling of impact of resistance
  and policies to contain it
• Model Computable General Equilibrium UK
  approach, extended to other European countries
• Policy options derived mainly from exploration
  of WP8
• Estimating costs and health outcomes associated
  with resistant and susceptible disease
• Methods
• comparisons between subjects infected with AB
  resistant or susceptible bacteria, with
  appropriate statistical modelling
• Event History Models
• Resource use data questionnaires in WP9 and
  WP10 existing routine data systems
• Economic evaluation alongside intervention
  studies
• First 18 months develop protocols for primary
  (reduction in antibiotic prescribing) and other
  outcome parameters
• Remainder economic evaluation
• Economic evaluation of molecular diagnostics

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WP11 Expected Achievements

• A model for the macroeconomic impact of
  antibiotic resistance and policies to contain
  resistance
• Cost-effectiveness of the management strategies
  developed in the observational and intervention
  studies
• Economic evaluation of molecular diagnostics

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WP12 Objectives

• To contribute information aimed at increasing
  awareness among the public and policy makers of
  the importance, economic impact and threat of
  antimicrobial resistance
• To develop education and training support to
  disseminate awareness and knowledge relevant to
  antibiotic resistance and its control
• To develop educational packages including
  web-based resources and workshops to inform
  postgraduate lifelong learning needs of
  prescribing professionals

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WP12 Description of the Work

• Participating scientific societies ERS and
  ESCMID (organising committee)
• Target audience hospital practitioners, primary
  care clinicians, community pharmacists, Public
  Health practitioners, and laboratory researchers
• Instruments
• Teaching courses and workshops at changing
  location
• Educational web site Virtual Learning Centre
  (VLC) consisting of a web based learning and
  assessment package

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WP12 Expected Achievements

• Increasing awareness among the public and policy
  makers of the threat of antimicrobial resistance
• Dissemination of knowledge relevant to antibiotic
  resistance and its control
• Educational (web-based) postgraduate learning
  packages

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Joint Programme of Activities (first 18 months)

• Establishment of the platforms
• Development and sharing of common research and
  molecular diagnostic tools and methods (WP3-7)
• Development of questionnaires and databases for
  reagents, strains, patient specimens and data
  (WP2-7)
• Observational studies on current management of
  community-acquired LRTI in European primary care
  (WP8)
• Selection of the primary care networks for WP9
  and WP10
• Development and integration of data collection
  for economic models (WP11)

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Joint Programme of Activities (18 months to 5
years)

• Development and application of molecular
  technologies (WP3, WP5-7)
• Studies on genetic risk factors (WP4)
• Observational (WP9) and intervention (WP10)
  studies
• Integrating the data to develop innovative
  management strategies
• Development and promotion of evidence-based
  recommendations for an optimal treatment of
  community-acquired LRTI through cost-effective
  strategies
• Application of economic models into microbial and
  human research (WP11)

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Joint Programme of Activities(full duration)

• Spreading the excellence
• Development of computer programmes and
  educational tools for continued training
• Enhancing and strengthening the network
  activities through looking for new partners and
  finding funding sources
• Collaboration with other (EU-funded) research
  programmes

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Potential Applications of GRACE (I)

• Novel rapid genome based diagnostic tests for the
  detection of pathogens implicated in
  community-acquired LRTI
• A European repository of research tools, strains,
  and patient specimens linked to a database
  including microbial and patient information, for
  genomic diagnostics
• Pneumococcal genes important for virulence and
  for antibiotic resistance development
• Optimal pneumococcal treatment and prevention
  strategy linked to severity of community-acquired
  LRTI
• Human susceptibility genes affecting severe
  community-acquired LRTI
• Potential human target pathways for new
  immunomodulatory approaches
• Potential genetic risk profiles for various
  presentations and outcomes of community-acquired
  LRTI in several European populations
• Evidence-based definitions of the major
  community-acquired LRTI

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Potential Applications of GRACE (II)

• Clinical models to differentiate viral from
  bacterial infections and identify pneumonia.
• Clinical models to identify patients at risk for
  adverse outcomes including severe and prolonged
  illness
• More focused management of patients with
  community-acquired LRTI, through new genomic
  tools, thereby resulting in better resource
  utilisation
• Clinical outcome measures for evaluating
  interventions
• Feasible, acceptable and cost-effective practise
  based intervention in reducing inappropriate
  antibiotic use in patients with
  community-acquired LRTI
• A model for the macroeconomic impact of
  antibiotic resistance and policies to contain
  resistance
• A model for economic evaluations of molecular
  diagnostics
• Educational packages to inform postgraduate
  lifelong learning needs of prescribing
  professionals

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Long-term Impact of GRACE

• Establish the principle and practice of linking
  basic science with clinical care for
  community-acquired LRTI
• Enhance the competitiveness of European
  translational research
• Link science with education and provide a focus
  for spreading of excellent practice throughout
  Europe
• Cement future international research
  collaborations linking international experts in
  primary and secondary care research in
  community-acquired LRTI
• Contribute to EC policy developments
• Strengthen European excellence and achieve a
  leadership on community-acquired LRTI

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Conclusion

• GRACE will serve as model of how different but
  relevant disciplines in health care can be
  integrated and combined and of how the full cycle
  of translating basic science innovation into
  clinical care can be achieved efficiently and
  seamlessly.
• GRACE will develop into a European Lower
  Respiratory Tract Infection Research Centre to
  investigate and improve the bed-side management
  of community-acquired LRTI.