DOCSLIB.ORG

Next-Generation Sequencing and Viral Phylogenetics for Outbreak Control

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Next-Generation Sequencing and Viral Phylogenetics for Outbreak Control Next-Generation Sequencing and Viral Phylogenetics for outbreak control My VT Phan, DPhil Next Generation Sequencing (NGS) All viral pathogens are encoded by RNA or DNA genomes Their genome sequences provide a specific signature to identify and track transmissions Holmes et al. Nature 2016 Ebola virus genome evolves at a defined rate Virus genome sequence can reveal close virus ancestors and potential sources of the infection Background In December 2013, Ebola virus emerged and spread in Guinea, Liberia, and Sierra Leone, resulting in the largest recorded outbreak of Ebola virus disease in history. http://apps.who.int/ebola/current-situation/ebola-situation-report-30-march-2016 To stop Ebola virus transmission in a population 1. Vaccinate before exposure to the virus Problem: No vaccine at the time 2. Treat with antiviral drugs Problem: No effective drugs to stop EBOV 3. Isolate infected people to prevent transmitting the virus QUARANTINE 4. Identify the source and contacts of virus and QUARANTINE Is this a new virus? Where does it come from? How does it spread? Challenges for deep sequencing Ebola Bottleneck 1 Bottleneck 2 Approvals for shipping Data movement >24 hours Actual sample shipment to transfer raw data from Solved by local Sierra Leone to England sequencing facility Solved by rewriting software, performing assemblies in the tent Sequencing tent PHE diagnostic lab Mateneh Ebola Treatment Centre, Makeni, Sierra Leone Diagnostic labs: • Public Health England labs • European mobile labs • Dutch mobile labs Arias et al. Virus Evolution, 2016, 2 (1) Time-resolved phylogenetic tree of EBOV genomes in Sierra Leone Arias et al. Virus Evolution, 2016, 2 (1) Rapid NGS of Ebola cases to track movement of virus Without an open database of contemporary genomes placement of a genome from a new case is not possible http://virological.org/c/ebolavirus, Andrew Rambaut http://www.nextstrain.org/ebola, Richard Neher, Trevor Bedford Movement to Guinea from Sierra Leone Orange: cases from Liberia Where was patient infected? Sequence virus Patient likely to have been infected in village B Utility of outbreak sequencing July 2015, new virus infections in region free of Ebola for previous 130 days Virus sequenced within 48 hours Clustered with viruses from Freetown Patient had recently travelled from Freetown Excluded: 1. Unknown transmission chain 2. Movement from Guinea 3. New zoonosis Arias et al. Virus Evolution, 2016, 2 (1) Sexual transmission of Ebola virus 29 Aug 2015, a post-mortem swab from case K was positive for EBOV, ie. 50 days after the last confirmed case in this district. 5 additional cases in household Variant changes at specific site Rapid NGS of Ebola cases to track movement of virus Without an open database of contemporary genomes placement of a genome from a new case is not possible http://virological.org/c/ebolavirus, Andrew Rambaut http://ebola.nextflu.org/, Richard Neher, Trevor Bedford Movement to Guinea from Sierra Leone Orange: cases from Liberia Geographical movement of EBOV in West Africa Combined all 1,610 EBOV genomes Dudas et al. Nature 2017 (544) p309-315 & Holmes et al. Nature 2016 Spatial and temporal movements of Ebola virus Dudas et al., Nature 2017 (544), pp309-315 Dudas and Rambaut, virological.org/t/phylogeography-of-2014-2015-ebola-virus-epidemic/199 Summary 1. Utility of NGS in clinical and outbreak settings 2. Generated 554 full genomes: 1/3 of EBOV genomes available 3. Performed rapid sequencing and phylogenetic tracing in 24-72 hours of sample NA receipt. 4. Obtained full Ebola virus genomes from atypical sample types eg semen, breast milk 5. Defined a realistic local platform for future outbreak sequencing and phylogenetic analyses. Acknowledgements University of Cambridge Erasmus MC Ian Goodfellow , Armando Arias, Dutch Mobile Labs Lucy Thorne, Sarah Caddy, Matthew Cotten Jia Lu, Luke Meredith Marion Koopmans University of Makeni WHO Umaru Jah, Raoul Emeric, Dhamari Naidoo Alimamy Tarawalie Sierra Leone MOH, Public Health England, DfID, CDC, EM Labs, Wellcome Trust Sanger Institute Volunteer Clinicians, nurses, scientists Paul Kellam, Simon Watson And many others University of Edinburgh University of Oxford Andrew Rambaut, Gytis Dudas Oliver Pybus, Nuno Faria Comparison of assembled EBOV genomes sequenced by Ion Torrent and by MinION .
Load more

Recommended publications
  • Viruses in Food: Scientific Advice to Support Risk Management Activities
    For further information on the joint FAO/WHO activities on microbiological risk assessment, please contact: Nutrition and Consumer Protection Division Food and Agriculture Organization of the United Nations Viale delle Terme di Caracalla 00153 Rome, Italy Fax: +39 06 57054593 E-mail: [email protected] Web site: http://www.fao.org/ag/agn/agns or Department of Food Safety, Zoonoses and Foodborne Diseases World Health Organization 20 Avenue Appia CH-1211 Geneva 27 Switzerland Fax: +41 22 7914807 E-mail: [email protected] Web site: http//www.who.int/foodsafety Cover design: Food and Agriculture Organization of the United Nations and the World Health Organization Cover picture: © Dennis Kunkel Microscopy, Inc. MICROBIOLOGICAL RISK ASSESSMENT SERIES 13 Viruses in food: scientific advice to support risk management activities MEETING REPORT WORLD HEALTH ORGANIZATION FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS 2008 5IFEFTJHOBUJPOTFNQMPZFEBOEUIFQSFTFOUBUJPOPGNBUFSJBMJOUIJTJOGPSNBUJPO QSPEVDUEPOPUJNQMZUIFFYQSFTTJPOPGBOZPQJOJPOXIBUTPFWFSPOUIFQBSUPGUIF 'PPEBOE"HSJDVMUVSF0SHBOJ[BUJPOPGUIF6OJUFE/BUJPOT '"0 PSPGUIF8PSME )FBMUI0SHBOJ[BUJPO 8)0 DPODFSOJOHUIFMFHBMPSEFWFMPQNFOUTUBUVTPGBOZ DPVOUSZ UFSSJUPSZ DJUZPSBSFBPSPGJUTBVUIPSJUJFT PSDPODFSOJOHUIFEFMJNJUBUJPOPGJUT GSPOUJFSTPSCPVOEBSJFT5IFWJFXTFYQSFTTFEIFSFJOBSFUIPTFPGUIFBVUIPSTBOEEPOPU OFDFTTBSJMZSFQSFTFOUUIPTFPG'"0OPSPG8)0OPSPGUIFJSBGGJMJBUFEPSHBOJ[BUJPO T "MMSFBTPOBCMFQSFDBVUJPOTIBWFCFFOUBLFOCZ'"0BOE8)0UPWFSJGZUIFJOGPSNBUJPO DPOUBJOFEJOUIJTQVCMJDBUJPO)PXFWFS UIFQVCMJTIFENBUFSJBMJTCFJOHEJTUSJCVUFE
    [Show full text]
  • Speakers' Biographies 4Th Annual Short Course in Medical Virology Of
    Speakers’ Biographies 4th Annual Short Course in Medical Virology of the GVN Clement A. Adebamowo, BM, ChB, ScD, FWACS, FACS. As a member of the Population Sciences Program of the Cancer Center and a cancer epidemiologist, I conduct research on the epidemiology of cancer. At this time, I am the PI of the NIH funded African Collaborative Center for Microbiome and Genomics Research (ACCME) which is one of the NIH/Wellcome Trust funded Human Heredity and Health in Africa (H3Africa) initiative on genomics research and education in Africa. ACCME’s current project is enrolling 10,000 women in Nigeria and Zambia and following them up every 6 months for research focused on integrative epidemiology of persistent high risk HPV infection, host germline and somatic genomics and epigenomics, and vaginal microenvironment (cytokines and microbiome) and risk of cervical cancer. As part of this project, I established a comprehensive genomics laboratory in Nigeria including facilities for epigenetics and next generation sequencing using Illumina NextSeq500. The genomics lab is linked to an NIH funded biorepository at IHVN. I also direct the Fogarty funded West African Bioethics Training program which has provided medium term training leading to Certificates in Research Ethics for 842 biomedical researchers, Masters’ degree in Bioethics to 34 individuals and Online WAB-CITI Training program to 6115 participants in West Africa. In Baltimore, I am working with colleagues at the University of Maryland Greenebaum Cancer Center and University of Maryland College Park to develop a research program on cancer disparities among Africans in Africa, recent African immigrants to the United States and African Americans in order to better understand the role of genetics, environment cultural and socio- economic factors in cancer prevention, treatment seeking behavior and outcomes.
    [Show full text]
  • COVID-19 China Mission VPC 09 Feb 2021
    COVID-19 China Mission VPC 09 Feb 2021 Speaker key: MF Mi Feng LW Professor Liang Wannian PE Mr Peter Ben Embarek MK Madam Marion Koopmans QU Questioners 00:00:23 MF Ladies and gentlemen, dear friends, good afternoon. Welcome to the press conference of joint expert team of China WHO SARS-CoV-2 origin research. This is Mi Feng, the spokesperson of China National Health Commission. Since COVID-19 became a global pandemic, WHO has been actively promoting the international cooperation in terms of the COVID-19 response. China has always been showing firm support to WHO in terms of unleashing the role of WHO in the leadership of the global COVID-19 response. 00:01:55 With the consensus based on two-sides negotiation, China and WHO have conducted joint research of the SARS-CoV-2 global source-tracing including the China parts since the arrival of international expert teams in Wuhan from January 14, 2021. The joint expert team has been working from three groups, respectively, the group of epidemiology, molecular research, animal and environment. The experts have been working in the forms of video conferences, onsite interviews and visits, and also discussions. They have conducted systematic and full-fledged research. They have already concluded the China part of the source-tracing in Wuhan according to the original plan. During this period, Mr Ma Xiaowei, the minister of China National Health Commission, has been discussing and having abundant communication with Dr Tedros, the Director-General of WHO, through telephone. They have fully exchanged their ideas in terms of the scientific cooperation in the origin source-tracing.
    [Show full text]
  • COVID-19 Virtual Press Conference 12 February 2021
    COVID-19 Virtual Press conference 12 February 2021 Speaker key: FC Fadela Chaib TAG Dr Tedros Adhanom Ghebreyesus RO Robin PBE Dr Peter Ben Embarek PA Paulina TR Translator SS Dr Soumya Swaminathan MK Dr Maria Van Kerkhove HE Helen MR Dr Michael Ryan ME Megan MA Professor Marion Koopmans SI Simone DA David SO Sophie BA Dr Bruce Aylward SH Shoko DO Donato 00:00:48 FC Good afternoon, everyone. This is Fadela Chaib speaking to you from WHO headquarters in Geneva and welcoming you to our global COVID-19 press conference today, Friday 12th February. Simultaneous interpretation is provided in the six official UN languages plus Portuguese and Hindi. Let me introduce to you the participants at this press conference. Present in the room are Director-General of WHO, Dr Tedros, Dr Mike Ryan, Executive Director, Health Emergencies, Dr Maria Van Kerkhove, Technical Lead for COVID-19, Dr Soumya Swaminathan, Chief Scientist, Dr Bruce Aylward, Special Advisor to the Director-General and Lead on the ACT Accelerator. Joining us remotely are Dr Kate O'Brien, Director, Immunisation, Vaccines and Biologicals and Dr Janet Diaz, Team Lead, Healthcare Readiness. We also have present in the room a member of the international team to China, Dr Peter Ben Embarek. He's also an expert at WHO on food safety and zoonosis and team lead of the international team. Joining remotely is Professor Marion Koopmans, Head of the Department of Viroscience at the University of Rotterdam. Now without further delay I would like to hand over to Dr Tedros for his opening remarks.
    [Show full text]
  • The Scientists Investigating the Pandemic's Origins
    News in focus is on the table,” says Koopmans. Another member, Hung Nguyen, an environ- ment and food-safety researcher at the International Livestock Research Institute in Nairobi, will contribute his knowledge on how pathogens spread in wet markets, similar to the Huanan seafood market in Wuhan, which many of the first people reported to have COVID-19 had visited. Nguyen has investigated how salmonella and other bacteria spread through smallholder farms, slaughterhouses and live-animal markets in his home country of Vietnam and across southeast Asia. Also on the team is Peter Daszak, president of the non-profit research organization Ecohealth Alliance in New York City, who has spent more than a decade studying coronaviruses. He has worked closely with the Wuhan Institute of Virology (WIV) to test bats for coronaviruses with the potential to spill over into people. “It is an honour to be part of this team,” says Daszak. “There hasn’t been a pandemic on this scale since the 1918 flu, and we’re still close KONIG/IMAGEBROKER/SHUTTERSTOCK MARKO SARS-CoV-2 probably originated in bats, but how it passed to people is being investigated. enough to the origin to really find out more details about where it has come from.” Another team member, Fabian Leendertz, a veterinary researcher at the Robert Koch THE SCIENTISTS Institute in Berlin, will bring his expertise in spillover events. In April 2014, Leendertz vis- INVESTIGATING THE ited Meliandou village in Guinea, months after a two-year-old died of Ebola — the first person PANDEMIC’S ORIGINS reported to be infected in West Africa.
    [Show full text]
  • Human Monkeypox – Epidemiological and Clinical Characteristics, Diagnosis and Prevention
    1 Chapter/Review 12 Clinical Review for IDCNA IDC 33.4 Emerging and Re-Emerging Infectious Diseases Title: Human Monkeypox – Epidemiological and Clinical characteristics, Diagnosis and Prevention Authors*: Eskild Petersen, Anu Kantele, Marion Koopmans, Danny Asogun, Adesola Ogunlete, Chikwe Ihekweazu and Alimuddin Zumla (* All authors contributed equally) Institutional affiliations: Eskild Petersen: Institute of Clinical Medicine, University of Aarhus, Denmark and The Royal Hospital, Muscat, Oman. European Society for Clinical Microbiology and Infectious Diseases Task Force for Emerging Infections, Basel, Switzerland. Email: [email protected] Anu Kantele: Inflammation Center, Helsinki University Hospital and Helsinki University, Helsinki, Finland. Email: [email protected] Marion Koopmans: Viroscience Department, Erasmus Medical Centre, Rotterdam, The Netherlands. Email: [email protected] Danny Asogun: Department of Public Health, Faculty of Clinical Sciences, College of Medicine, Ambrose Alli University, Ekpoma, Nigeria. Email: [email protected] Adesola Ogunleye: Nigeria Centre for Disease Control, Jabi, Abuja, Nigeria. Email: [email protected] Chikwe Ihekweazu: Nigeria Centre for Disease Control, Jabi, Abuja, Nigeria. Email: [email protected] Alimuddin Zumla: Division of Infection and Immunity, Center for Clinical Microbiology, University College London, and the National Institute of Health Research Biomedical Research Centre at UCL Hospitals, London, UK. Email. [email protected] Mailing Addresses:
    [Show full text]
  • Infectious Disease Detection in the Era of Next Generation Sequences: Opportunities, Challenges, and the COMPARE Project
    COllaborative Management Platform for detection and Analyses of (Re-) emerging and foodborne outbreaks in Europe Infectious disease detection in the era of next generation sequences: opportunities, challenges, and the COMPARE project Prof. Marion Koopmans, (Erasmus Medical Center, the Netherlands) @MarionKoopmans Prof Frank Aarestrup (DTU, Denmark) This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement 643476 Enterovirus 68 MERS CoV Avian influenza H7N9 China H5N1 Egypt Infectious disease situation 2015 • Dynamics of common infectious diseases are changing – Demographic change, population density, anti vaccine movement, AMR, etc. • New diseases emerge frequently – Deforestation, population growth, health systems inequalities, travel, trade, climate change • Effects are difficult to predict due to complexity of problems • Public health and clinical response depend on global capacity for disease surveillance Start outbreak EBOV • March 10, 2014 notification unknown disease characterized by fever, severe diarrhea, vomiting and high fatality rate in Guéckédou and Macenta in Guinea. • March 22, EVD reported by Guinea to WHO. • March 27, EVD suspected cases in Liberia and Sierra Leone related to outbreak in Guinea. • April 3d: ZEBOV Dx * Diagnosis < 2 yr old seeding through funeral > < seeding through HCW Animal surveillance, Gabon 2001-3 Fruit bats Duikers Primates Outbreaks in animals detected prior to (4/5) human disease outbreaks Convincing evidence for bushmeat related
    [Show full text]
  • Avian Influenza a Virus (H7N7) Associated with Human Conjunctivitis and a Fatal Case of Acute Respiratory Distress Syndrome
    Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome Ron A. M. Fouchier†‡, Peter M. Schneeberger§, Frans W. Rozendaal§, Jan M. Broekman§, Stiena A. G. Kemink§, Vincent Munster†, Thijs Kuiken†, Guus F. Rimmelzwaan†, Martin Schutten†, Gerard J. J. van Doornum†, Guus Koch¶, Arnold Bosmanʈ, Marion Koopmansʈ, and Albert D. M. E. Osterhaus† †Department of Virology and National Influenza Center, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands; §Jeroen Bosch Hospital, Nieuwstraat 34, 5211 NL, Den Bosch, The Netherlands; ¶Section of Notifiable and Exotic Viral Diseases, Central Institute for Animal Disease Control, P.O. Box 147, 8200 AC, Lelystad, The Netherlands; and ʈCenter for Infectious Disease Epidemiology and Diagnostic Laboratory for Infectious Diseases and Perinatal Screening, National Institute of Public Health and the Environment, Antonie van Leeuwenhoeklaan 9, 3720 BA, Bilthoven, The Netherlands Communicated by Peter Palese, Mount Sinai School of Medicine, New York, NY, December 16, 2003 (received for review November 28, 2003) Highly pathogenic avian influenza A viruses of subtypes H5 and H7 (1, 2). Because of the recent increase in awareness of AIV are the causative agents of fowl plague in poultry. Influenza A zoonoses and the increase in the intensity of surveillance studies, viruses of subtype H5N1 also caused severe respiratory disease in sporadic zoonotic infections with H9N2 AIV in China have been humans in Hong Kong in 1997 and 2003, including at least seven detected also (16). The transmission of AIV from birds to fatal cases, posing a serious human pandemic threat. Between the humans, therefore, continues to be a threat to public health.
    [Show full text]
  • WHO- AUDIO Emergencies C Oronavirus Press Conf Erence COVID19 Origi Ns Mission 30MAR20 21 (1) Virtual Press Conference 30 March 2021
    WHO- AUDIO_Emergencies_C oronavirus_Press_Conf erence_COVID19_Origi ns_Mission_30MAR20 21 (1) Virtual Press conference 30 March 2021 Speaker key: TJ Tarik Jasarevic PBE Dr Peter Ben Embarek TF Professor Dr Thea Fisher JW Professor John Watson MK Professor Dr Marion Koopmans DD Professor Dr Dominic Dwyer VD Vladimir Dedkov HNV Dr Hung Nguyen-Viet FL PD. Dr. med vet. Fabian Leendertz PD Dr Peter Daszak FAL Dr Farag El Moubasher KM Professor Dr Ken Maeda IS Isabel Sacco JL Jérémie Lanche DY Du Yang SN Sarah Newey KS Kier Simmons SH Shoko Koyama KV Karen Weintraub JZ John Zarocostas AN Anjalee Khemlani CO Christiane Oelrich RM Robin Millard SJ Sara Jerving 00:00:03 TJ Hello, good evening, good afternoon or good morning to everyone. My name is Tarik Jasarevic, and I’m welcoming you to our press conference regarding the publication of the report that was looking into origin of SARS- COV2 virus. The report itself has just been published on our website. We have sent the link to the webpage where the report is placed, as well as the press release and opening remarks by Dr Tedros at today’s meeting with member states where the report was presented. The report, as I said, describes the findings of the Wuhan field visit that took place from January 14th to February 10th, and that was conducted by a group of international scientists and Chinese scientists, as mandated by the World Health Assembly Resolution that was adopted in May last year. So, here today, we are to present those findings to the members of the media.
    [Show full text]
  • VEO Kick-Off Meeting Report 04-05 June 2020
    Versatile Emerging infectious disease Observatory Forecasting, nowcasting and tracking in a changing world VEO Kick-off Meeting Report 04-05 June 2020 1 Versatile Emerging infectious disease Observatory Forecasting, nowcasting and tracking in a changing world Contents 04 June 2020, The VEO Project and COVID-19 ............................................................................................. 3 Evelyn Depoortere, EC Scientific Officer ................................................................................................... 3 Marion Koopmans, EMC, VEO – the project ............................................................................................. 3 VEO & COVID: Unravelling the infodemic ..................................................................................................... 5 Marcel Salathé, EPFL, Digital epi and COVID ............................................................................................ 5 Daniel Remondini, UNIBO, Network Analysis of social media data .......................................................... 6 VEO & COVID: Forecasting, nowcasting and tracking ................................................................................... 7 Luisa Barzon, UNIPD, The COVID epidemic in northern Italy ................................................................... 7 Simon Cauchemez, IP, Estimating epidemic size and trajectories: the challenges .................................. 8 Bas Oude Munnink, EMC, Precision public health, real-time sequencing to track and support
    [Show full text]
  • Detection of New SARS-Cov-2 Variants Related to Mink 12 November 2020
    RAPID RISK ASSESSMENT Detection of new SARS-CoV-2 variants related to mink 12 November 2020 Summary Since April 2020, when the first SARS-CoV-2 infection was reported in the Netherlands in a mink and subsequently in a mink farm worker, it has been established that human-to-mink and mink-to-human transmission can occur [1]. Since then, infections in mink have been reported in Denmark, Italy, Spain, Sweden and the United States [2]. On 5 November 2020, Denmark reported 214 human COVID-19 cases infected with SARS-CoV-2 virus variants related to mink, as well as infected mink at more than 200 mink farms. Most human and animal cases reported since June 2020 have been in the North Jutland Region. The SARS-CoV-2 variants detected in these cases were part of at least five closely-related clusters; each cluster was characterised by a specific mink-related variant, identified in humans and animals from infected mink farms. Denmark has implemented robust response measures to control the outbreaks in mink and decrease the spill-over between the human and the animal reservoir. One of the clusters (Cluster 5), which was reported as circulating in August and September 2020, is related to a variant with four genetic changes, three substitutions and one deletion, in the spike (S) protein. Since the S protein contains the receptor-binding domain, and is a major target for immune response, such mutations could, in theory, have implications for viral fitness (ability to infect humans and animals), transmissibility, and antigenicity. As a consequence, the evolution of viruses with increasing changes in functional domains of the S protein could affect treatment, certain diagnostic tests and virus antigenicity.
    [Show full text]
  • Tick-Borne Diseases:Opening Pandora’S Tick-Borne Box
    TICK-BORNE DISEASES:OPENING PANDORA’S BOX TICK-BORNE PANDORA’S DISEASES:OPENING TICK-BORNE DISEASES: OPENING PANDORA’S BOX Seta Jahfari Seta Seta Jahfari jahf_cover.indd 3 30-8-2017 13:59:03 TICK-BORNE DISEASES: OPENING PANDORA’S BOX SETA JAHFARI Tick-borne Diseases: Opening Pandora’s Box Teken-overdraagbare ziekten: het openen van de doos van Pandora Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof. dr. H.A.P. Pols en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op vrijdag 3 november 2017 om 11:30 door Setareh Jahfari geboren te Teheran, Iran Tick-borne Diseases: Opening Pandora’s Box ISBN 978-94-6295-728-2 Dissertation Erasmus University Rotterdam, Rotterdam, the Netherlands. The research presented here was performed at the Dutch National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. Cover design & Lay-out: Remco Wetzels | www.remcowetzels.nl Printed by: ProefschriftMaken | www.proefschriftmaken.nl Copyright 2017 Setareh Jahfari. All right reserved. No parts of this thesis may be reproduced, stored or transmitted in any form or by any means without the prior permission of the author or publishers of the included scientific papers. Promotiecommissie: Promotoren: Prof. dr. M.P.G. Koopmans Prof. dr. J.W. Hovius Overige leden: Prof. dr. P.H.M. Savelkoul Prof. dr. ir. W. Takken Prof. dr. A. Verbon Copromotor: Dr. H. Sprong Dedicated to my caring mother, and my loving Shahin CONTENT
    [Show full text]