JPIAMR Network for Integrating Microbial Sequencing and Platforms for Antimicrobial Resistance (Seq4AMR)

Main Questions/Approach: How can we best identify and promote collaboration and implementation between AMR NGS stakeholders that link the individual fields of (new) NGS technologies, algorithms, quality standards, teaching/training and sequence databanks?

Ongoing project

Answer – By establishing an international and interdisciplinary OneHealth network of public and private experts to take the lead in identifying potential knowledge gaps and solutions. Further, by developing AMR NGS-dedicated quality and teaching/training materials. Finally, by promoting discussion and interactions between AMR NGS stakeholders and other working groups with cross-cutting priorities – including extensive use of JPIAMR VRI.

Objectives:

  1. Promote active collaboration between interdisciplinary OneHealth AMR NGS stakeholders
  2. Identify knowledge gaps and provide solutions to current/future AMR NGS issues
  3. Formulate recommendations on quality and quality materials
  4. Educate AMR NGS stakeholders via interdisciplinary-directed AMR NGS teaching/training materials

Activities:

  1. Dedicated website and access to network materials
  2. Face-to-face network meetings and regular teleconferences (in collaboration with other relevant JPIAMR working groups)
  3. Open access publications and collation of a Seq4AMR Strategic Roadmap
  4. Dedicated interdisciplinary Seq4AMR webinar(s) and course(s)
  5. Dedicated Seq4AMR workshop at a relevant international meeting
  6. Promotion of Seq4AMR and JPIAMR during conferences.

Expected Results:

  1. Establish new OneHealth AMR synergies between international and interdisciplinary experts for knowledge exchange, joint publications grant writing etc.
  2. Identify current knowledge gaps and how to best fill these gaps
  3. Formulate quality recommendations and access to materials
  4. Develop new interdisciplinary AMR teaching/training/ materials
  5. To publish a Seq4AMR Strategic Roadmap
  6. To contribute and strengthen the activities of JPIAMR VRI

Network partners

  • John Hays, Erasmus MC University Medical Center, Netherlands (Coordinator)
  • A. Stubbs, Erasmus MC University Medical Center, Netherlands
  • A. Heikema, Erasmus MC University Medical Center, Netherlands
  • A. van Belkum, BioMérieu France, Craponne, France
  • W. A. Valdivia, Orion Integrated Biosciences (OIB), Kansas, USA
  • Liping Ma, East China Normal University, Shanghai, China
  • E. Kristiansson, University of Gothenburg, Gothenburg, Sweden
  • S. Bruchmann, Cambridge University, Cambridge, UK
  • A. McArthur, McMaster University, Hamilton, Canada (CARD Database)
  • S. Emler, SmartGene GmbH, Lausanne, Switzerland
  • E. Claas, Leiden University Hospital, Leiden, the Netherlands
  • S. Beisken, Ares Genetics GmbH, Vienna, Austria
  • R. Stabler, London School for Hygiene and Tropical Medicine, London, UK
  • A. Lebrand, Swiss Institute of Bioinformatics, Lausanne, Switzerland
  • M. Petrillo, European Commission, Joint Research Centre (JRC), Ispra, Italy
  • S. Capella-Gutierrez, Barcelona Supercomputing Centre (BSC), Barcelona, Spain
  • L. Portell, Barcelona Supercomputing Centre (BSC), Barcelona, Spain
  • B. Grüning, Freiburg Galaxy Team, Freiburg, Germany
  • G. Cuccuru, Freiburg Galaxy Team, Freiburg, Germany
  • C. Carrillo, Canadian Food Inspection Agency, Ottawa, Canada
  • B. Blais, Canadian Food Inspection Agency, Ottawa, Canada
  • B. Gruening, University of Freiburg, Freiburg, Germany
  • W. Meier, University of Freiburg, Freiburg, Germany
  • B. Batut, University of Freiburg, Freiburg, Germany
  • K. Vanneste, Sciensano, Brussels, Belgium
  • J. Bengtsson-Palme, University of Gothenburg, Gothenburg, Sweden
  • T. Naas, Hopital de Bicêtre, Paris, France
  • N. Strepis, Erasmus University Medical Centre (Erasmus MC), the Netherlands
  • A. Rhod Larsen, Statens Serum Institut, Copenhagen, Denmark
  • B. Helwigh, National Food Institute, Lyngby, Denmark
  • H. Hasman, National Food Institute, Lyngby, Denmark
  • R. Hendriksen, National Food Institute, Lyngby, Denmark
  • S. Forslund, Max Delbrück Center for Molecular Medicine, Berlin, Germany 
  • L. Pedro Coelho, Institute of Science and Technology, Fudan University, Shanghai, China
  • A. Patak, Molecular Biology and Genomics Unit, Institute for Health and Consumer Protection, Ispra, Italy
  • M. Querci, Deputy Head of Unit, Joint Research Centre European Commission, Brussels, Belgium
  • G. van den Eede, Head of Unit, Health, Consumer and Reference Materials, European Union, Brussels, Belgium

Call

Yeast-based biosensors for the specific and accessible detection of pathogens and antimicrobial resistance (AntiRYB)

Early and specific detection of microbial infections is crucial for the containment of diseases and for reducing the dependence on the use of antibiotics. There is however a lack of reliable, cheap and easy to use detection methods for day-to-day monitoring of infection and antimicrobial resistances in samples from patients, animals and the environment. This deficinecy is critical for the abuse of antibiotics and the diffusion of antimicrobial resistance.

Ongoing project

The aim of this project is establishing a method based on yeast biosensors that can detect with high specificity pathogens from different sources to develop a new, fast and specific diagnostic tool for resistant pathogens. We will achieve this by joining together strong research groups on antimicrobial resistance, systems biology, and strain engineering at SINTEF, Chalmers University and National Medicines Institute. Particular focus will be given to the detection of ESBL or carbapenemase-producing strains belonging to the emerging ESKAPE group of resistant pathogens.

The biosensor is developed using the yeast Saccharomyces cerevisiae as host, which will be engineered to express specific receptors able to recognise unique molecules produced by the pathogens. The ligand-receptor binding initiates a cascade mechanism that activates the genes for the production of a red pigment visible to the naked eye. Using the biosensors, we aim to identify molecular markers specific for resistant pathogen strains, to enable fast, easy and inexpensive point-of-use profiling of resistant pathogens.

Project partners

  • Geir Klinkenberg, SINTEF, Norway (Coordinator)
  • Verena Siewers, Chalmers University of Technology, Sweden
  • Alicja Kuch, National Medicines Institute, Poland

Call

Concomitant IDentification and Antibiotic REsistance profile of bacteria in one hour with an adaptive targeted single Mass Spectrometry analysis (IDAREMS)

Blood stream infection (BSI) is annually responsible of hundred thousand estimated deaths worlwide. The time frame for identification and antimicrobial susceptibility testing of the causative agent(s) of BSI directly impact the delay in the administration of appropriate antimicrobial therapy and, consequently, the clinical outcome of patients.

Ongoing project

MALDI-TOF mass spectrometry obviously revolutionized routine microbial identification by drastically shortening the delay of the identification (ID). There is however no consensus on a universal and affordable tool for shortening the characterization of putative antibiotic resistance mechanisms. IDAREMS aims to introduce a disruptive tool for clinical diagnosis of blood stream infection (BSI) based on targeted proteomics carried out by tandem mass spectrometry (MS) to achieve concomitant pathogen identification and antibiotic resistance profiling directly from an aliquot of positive blood culture in less than one hour.

IDAREMS project is structured over three main work packages: WP1) the development by partner 1 (France) of a prototype assay for concomitant identification and rapid diagnostics of antimicrobial resistance in Gram-negative bacteria using a limited number of antibiotic-resistant bacterial isolates provided by partner 2 (France), partner 3 (Poland) and partner 4 (Thailand); WP2) the validation of the assay through blind testing of new clinical strains; WP3) technician training and deployment of the validated assay in the respective partner’s clinical platforms.

Project partners

  • Jérôme Lemoine, Jérôme Lemoine, France (Coordinator)
  • Frederic Robin, Université Clermont Auvergne, France
  • Marek Gniadkowski, National Medicines Institute, Poland
  • Visanu Thamlikitkul, Mahidol University, Thailand
  • Susan M. Poutanen, University of Toronto, Canada

Call

IDx: An exploration of regulatory, corporate, relational, and technical barriers to uptake of diagnostics in the fight against AMR (IDx)

Greater availability of fast and accurate diagnostics for infections would greatly reduce the over-prescription of antibiotics and slow the growth of antibiotic resistance which limits treatment options. It would also help prescribe the right drug at the right time, thus reducing suffering and increasing survival.

Ongoing project

However, despite advances in technology, few useful diagnostics for bacterial infections have come to market and we are seeing a downward trend in innovation. This study proposes to identify the key barriers that remain once a new diagnostic has been developed, looking at recent technological advances that ultimately failed to be authorized, adopted, or able to change prescribing. It will also look at technologies that have helped in the fight against antimicrobial resistance. Are there any features or particularities that seem to have improved their chance of success?

Lessons from the failures and few successes will be used to assess chances for products in the pipeline, examining how regulation, reimbursement, technology transfer, and organizational characteristics might be improved to make them succeed within the clinical setting. The work will focus on each of these themes in developed world settings but also use them as a lens (in addition to a technical lens) to examine determinants of uptake in rural parts of South Africa, which are to some extent a proxy for LMIC.

Project partners

  • Olof Lindahl, Uppsala University, Sweden (Coordinator)
  • Marc Mendelson, University of Cape Town, South Africa
  • Eve Dubé, Université Laval, Canada
  • Volkan Özenci, Karolinska Institutet, Sweden
  • Florence Séjourné, BEAM Alliance, France

Call

Prevention of antibiotic resistance by TARGEted Treatment of pneumonia in children (TARGET)

Lower respiratory tract infections (LRTI), such as pneumonia, are a leading cause of death especially in children below the age of 5 years. Low and middle-income countries (LMIC) suffer the highest burden of childhood pneumonia.

Ongoing project

Most LRTIs are caused by viruses, but differentiating viral from bacterial causes is frequently impossible in LMIC due to lack of diagnostics. As a consequence, most cases are treated empirically with antibiotics leading to overuse and misuse of antibiotics, which is an important driver of the global epidemic of antimicrobial resistance.

Therefore, we propose to apply a newly developed diagnostic device, the modular breath sampler (MBS), which is based on the entrapment of aerosols from the lower respiratory tract to identify the etiological agent in children with LRTI. Because the MBS is a non-invasive, patient-friendly device and easy applicable for repeated measurements, it allows direct monitoring of the effect of antibiotic treatment. In addition, the identification of pathogens will not only be determined by PCR but also by loop-mediated isothermal amplification (LAMP) that amplifies DNA with high specificity, efficiency and rapidity in a single tube under isothermal conditions, and does not require a thermal cycler, which would make it easy to apply in LMICs.

Project partners

  • Marien de Jonge, Radboud University Medical Center, Netherlands (Coordinator)
  • Markéta Martinkova, Charles University, Czech Republic
  • Blandina Mmbaga, Kilimanjaro Christian Medical Centre, United Republic of Tanzania
  • Corne van den Kieboom, Xheal Diagnostics, Netherlands

Call

A K-mer Based Approach for Institutional AMR Surveillance, Transmission Monitoring, and Rapid Diagnostics (K-STaR)

Antibiotic resistant organisms (AROs) have become increasingly difficult to treat, with rising morbidity and mortality worldwide. Healthcare institutions are often the epicenter for outbreaks of these antibiotic resistant organisms, and are also windows into their circulation within the broader community.

Ongoing project

Transmission of antibiotic resistant organisms within hospitals is under appreciated. Moreover, identification of linked strains that may be causing occult outbreaks is often not systematically performed. Genomic approaches can provide a better understanding of within-hospital transmission of AROs, which can be used to guide infection control practices. Some institutions have augmented their ARO surveillance with whole genome sequencing, but this is both expensive and time consuming, making it unsuitable for routine use.

However, new approaches that use k-mer based algorithms along with genomic reference databases can provide rapid evaluation of pathogen lineage and potential for linked transmission. These same approaches can also be used to provide important rapid diagnostic information about the pathogen and likelihood of resistance to a given antibiotic. While there is much potential in these approaches, they need to be formally evaluated across care settings and geography before they can be trialled in the clinical setting. Here we propose a multi-continental prospective evaluation of the performance of a k-mer based approach for institutional surveillance of common multidrug resistant Gram-negative pathogens as well rapid prediction of antibiotic resistance patterns.

Project partners

  • Derek MacFadden, Ottawa Hospital Research Institute, Canada (Coordinator)
  • Allison McGeer, Mt. Sinai Hospital, University of Toronto, Canada
  • Hajo Grundmann, University of Freiberg, Germany
  • Martin Antonio, Medical Research Council Unit, The Gambia, Gambia
  • William Hanage, Harvard Chan School of Public Health, USA

Call

Management of animal diseases and antimicrobial use by information and communication technology to control AMR in East Africa (MAD-tech-AMR)

In low-income countries (LICs), patterns of livestock diseases and antimicrobial use (AMU) are largely unknown, and there are few high-quality laboratory facilities. Robust and actor-centred surveillance systems are needed and surveillance of the dynamics leading to antimicrobial resistance (AMR) should precede more advanced systems.

Ongoing project

The project is designed to provide proof of concept, applying a framework for surveillance of: AMU, diseases that trigger AMU and perceived problems with AMR, in East African poultry production systems. Information and Communication Technology (ICT) will be coupled with veterinary epidemiology and social science methods. The originality lies in using frontline technology particularly suited for challenges in resource-poor settings. The overall objective is to provide an ICT framework for monitoring and control of AMU and AMR in livestock in LICs. The project will assess if veterinary “telemedicine” coupled with ICT systems can change AMU. Baseline data on AMU practices and actors involved will be collected, followed by a Knowledge-Attitudes-Practices study. A platform to register drug purchases and a database to monitor drug sales will be developed along with a mobile application for delivery of animal health advice and information about AMR. The ICT framework will be pilot-tested in selected poultry production systems in Kenya and Uganda. The framework can be expanded in the future to allow inclusion of diagnostic tools, but the initial focus is on clinical diagnosis based on tele-consultation and evidence-based therapeutic strategies.

Project partners

  • Susanna Sternberg Lewerin, Swedish University of Agricultural Sciences, Sweden (Coordinator)
  • Florence Mutua, International Livestock Research Institute, Kenya
  • Lawrence Mugisha, Makerere University, Uganda
  • Joshua Onono, University of Nairobi, Kenya

Call

Design, synthesis and lead generation of novel siderophore conjugates for the detection and treatment of infections by Gram-negative pathogens (SCAN)

There is a strong need for novel, innovative therapeutic solutions for infections caused by Gramnegative pathogens. In addition, there is a lack of tools to diagnose bacterial infections at deep body sites, e.g. on implant surfaces.

Ongoing project

In the project SCAN (Siderophore Conjugates Against Gram-Negatives), we apply a rational design approach to establish a targeting conjugate platform that can be used to both diagnose as well as treat bacterial infections (‘theranostics’ principle). The conjugates are actively transported into bacteria through their iron transport machinery that accepts siderophores as substrates.

This concept has recently been validated clinically and addresses a key issue of Gramnegative pathogens, the impaired translocation into the cell. We will design and synthesise novel siderophores that employ novel central scaffolds and combinations of iron-binding motifs. Those will be coupled with hitherto unexplored effectors: RNA polymerase inhibitors are employed as potent antibiotics, and dioxetane-based chemiluminescent probes will be used for imaging.

As a linkage between siderophore and antibiotic, cleavable, self-immolative linkers (e.g. trimethyl lock) will be constructed. The conjugates will be characterised in cellular assays and in infection models in mice. Their translocation and resistance mechanisms will be investigated by genetic and proteomic methods. The project should yield novel antibiotic lead structures with proven efficacy in vivo.

Project partners

  • Mark Brönstrup, Helmholtz Centre for Infection Research, Germany (Coordinator)
  • Doron Shabat, Tel-Aviv University, Israel
  • Isabelle Schalk, CNRS – Université de Strasbourg, France

Infections caused by multidrug-resistant Gram-negative bacteria result in significant mortality and morbidity worldwide. In line with this, all pathogens that received a ‘critical’ status by the recently established WHO priority list were drug-resistant Gram-negative species. The reasons for limited success of pharmaceutical research programs in the area of antibiotics have been carefully analyzed: the main hurdle is the limited understanding how to get drugs into Gram-negative bacteria. Thus, there is a strong need for novel, innovative drugs against infections caused by Gram-negative pathogens. There is also a lack of tools to diagnose bacterial infections at deep body sites, e.g. on implant surfaces.

In the project SCAN (Siderophore Conjugates Against gram-Negatives), we apply a rational design approach to establish a targeting conjugate platform that can be used to both diagnose and treat bacterial infections (‘theranostics’ principle). The conjugates are actively transported into bacteria through their iron transport machinery that accepts siderophores as substrates. As this resembles the strategy of ancient Trojan warriors, the approach has been named the ‘Trojan Horse Strategy’. This concept has recently been validated clinically, a first drug (Fetroja) has been approved and is available to patients.

We will design and synthesize artificial siderophores that employ novel central scaffolds and combinations of iron-binding motifs. Those will be coupled with hitherto unexplored effectors: RNA polymerase inhibitors are employed as potent antibiotics, and chemiluminescent probes will be used for imaging. As a linkage between siderophore and antibiotic, cleavable, self-immolative linkers will be constructed. The conjugates will be characterized in cellular assays and in animal infection models. Their translocation and resistance mechanisms will be investigated by genetic and proteomic methods.

The project should yield novel antibiotic lead structures as well as activatable bacterial probes with proven efficacy in vivo to detect and treat infections. Taken together, the afforded antimicrobials and moreover the novel theranostics could be tools that allow for strain-specific, potent treatment and monitoring of bacterial infections, addressing a major medical need expressed by the WHO.

Project resources

Call

TRANSLOCATION-transfer (TT)

There is an urgent need for discovery and development of new drugs to combat multi-resistant organisms. The search for new drugs is cumbersome, particularly because the current business model for antibiotics in the pharmaceutical industry has been stalled because of the poor return on investment.

Ongoing project

In response to the pharmaceutical industry stepping back from antibiotic discovery, multiple public efforts, including the JPIAMR and IMI ND4BB, as well as the efforts of Biomedical Science (BMS) European Research Infrastructures community have stepped in to fill the gap. In this project, the TT network will set up a knowledge sharing network, Translocation-Transfer bringing together experts from with two major publically funded programs, with the goal to improve the process of academically driven antibiotic drug discovery by capitalising on recently gained insights into a key bottleneck in anti-bacterial research, namely how compound penetration properties determine efficacy and resistance properties.

Three existing communities forming the TT network are:
1) the partners associated with the multinational program Translocation (www.translocation.eu), part of IMI ND4BB;
2) partner sites from EU-OPENSCREEN, the European Research Infrastructure for chemical biology and screening (www.eu-openscreen.eu);
3) partners from the wider global community working on AMR issues and research.

Translocation (1/2013-6/2018) was one of the largest antibiotic research programs in the world specifically devoted to understanding and to devising ways of increasing antibiotic penetration into bacteria. EUOPENSCREEN began operations in April 2018 and from 2019 onwards will run some 50 chemical biology and academic drug discovery projects per year, across a network of 25 screening sites, based in eight European countries on behalf of users from across Europe. It is anticipated that at least 20% of EU-OPENSCREEN projects will involve antibiotic drug discovery element. The initial goal of the TT network will be to transfer knowledge between Translocation and EU-OPENSCREEN to fully incorporate compound permeation and efflux considerations into academic antibiotic drug discovery. We have the active participation of the Pew Charitable Trust, which will contribute to the long-term systematic dissemination of findings from the co-funded funded Translocation project to help academic antibiotic drug discovery efforts on a global scale.

Network partners

  • Mathias Winterhalter, Jacobs University Bremen, Germany (Coordinator)

This network includes 22 partners, please click on the following link to see complete network composition: Network composition TRANSLOCATION-transfer (TT)

Translocation-transfer aims to improve academically driven antibiotic drug discovery on a key bottleneck in anti-bacterial research, namely how compound penetration determine efficacy and resistance properties. There is an urgent need for discovery and development of new drugs to combat multi-resistant organisms. The search for new drugs is cumbersome, particularly because the current business model for antibiotics in the pharmaceutical industry has stalled because of the poor return on investment. In response to the pharmaceutical industry stepping back from antibiotic discovery, multiple public efforts, including the JPIAMR and IMI ND4BB, as well as the efforts of Biomedical Science (BMS) European Research Infrastructures community have stepped in to fill the gap. Translocation-transfer (TT) brings together experts from with two major publically funded programs, with the goal to improve the process of academically driven antibiotic drug discovery by capitalising on recently gained insights into a key bottleneck in anti-bacterial research, namely how compound penetration properties determine efficacy and resistance properties.

Three main communities form the TT network: i) the partners associated with the multinational program Translocation (www.translocation.eu), part of IMI ND4BB;ii) partner sites from EU-OPENSCREEN, the European Research Infrastructure for chemical biology and screening (www.eu-openscreen.eu) and iii) partners from the wider global community working on AMR issues and research.

Project resources

Publications

Call

inCreasing cOmmunicatioN, awareNEss and data sharing in a global approaCh against resisTance (CONNECT)

The CONNECT network is based on the need for defining and implementing an integrated research strategy to facilitate the necessary studies and investigations for an innovative response to AMR. The CONNECT network output will contribute to the development of the JPIAMR-VRI by aligning stakeholders to share values on AMR with a One Health approach.

Completed project

The CONNECT network will provide an opportunity for stakeholders to consolidate around a common sets of goals, share their lesson learned and identify synergic work and effectively contribute to the collective impact of research. Recognising the complexity and scale of AMR is emphasised by the amount of resources needed to address the issue, and the limits of available resources and organisational capacities of governments, civil society, and philanthropy/charities.

Through partnerships, resources across sectors have the potential to complement one another and create more effective and sustained change. To have increased meaningful and sustainable impact, community engagement is needed. To develop trust, institutions and communities in the network should be involved in design and implementation of research. Developing member interoperability is expected to contribute to a strong and coherent globally connected effort based on exchange data, information, services and/or outputs, align their activities, policies and procedures and effectively operate together.

As an ultimate goal, the platform will encourage the development of priorities on strategic focuses, the engagement of brains thinking out of the box innovative solutions, and will represent the virtual and unique point for governing the research in Europe on the fight against AMR on a One Health approach.

Network partners

  • Nicola Petrosillo, National Institute for Infectious Diseases “Lazzaro Spallanzani”, IRCCS, Italy (Coordinator)

This network includes 20 partners, please click on the following link to see complete network composition: Network composition inCreasing cOmmunicatioN, awareNEss and data sharing in a global approaCh against resisTance (CONNECT)

Antimicrobial resistance (AMR) is one of the biggest public health challenges of our time. AMR is the ability of a microorganism to survive and grow in the presence of antimicrobial drugs, this phenomenon implies that antimicrobials are no longer effective to treat infectious diseases. The AMR problem is very complex and caused by multiple factors; an important cause is represented by the excessive use of antibiotics, not only in humans but also in food animal production and in agriculture. Addressing the growing threat of AMR requires a holistic and multidisciplinary approach – referred to as One Health – which includes all sectors such as hospitals, communities, farm animals, human and animal waste, wastewater systems.

To fight AMR, collaboration between researchers coming from different countries as well as from different scientific fields is essential. For this purpose, the JPIAMR established a virtual research institute (JPIAMR-VRI) with the main scope to improve visibility of the AMR research and facilitate knowledge exchange and capacity development across the globe, covering the full One Health spectrum. The CONNECT (inCreasing cOmmunicatioN, awareNEss and data sharing in a global approaCh against resistance) is one of the eight pillars that lay the foundation of the JPIAMR-VRI. In order to improve knowledge on AMR research and to allow findings sharing, and avoid duplication of research, the CONNECT network prepared a list of main projects and networks related to research on AMR in a One Health Approach. Moreover, links with other networks involved in the AMR research on a One Health approach were established, this will be the basis for a deeper cooperation between researchers across Europe and beyond and, importantly, for an exchange of findings and a sharing of research objectives with scientists working on animal health and on agricultural research.

Our network also prepared a proposal for a communication, dissemination and exploitation (CDE) plan to be used by all the VRI networks. The scope of this plan is to improve communication and dissemination of ideas on research projects and on the findings of projects. This is a tool that will allow to join efforts, minimize duplication and maximize potential of AMR research on a One Health approach. Moreover, the CDE plan will ensure that both the scientific community and the broad public understand the value of the JPIAMR –VRI and the importance of the One Health approach. In fact, to have meaningful and sustainable impact, community engagement is needed. The CONNECT network, along with the VRI networks, laid the foundation stone for developing scientists interoperability.

Publications

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