Signal Amplification in NMR and MRI using hyperpolarised compounds
Lead Research Organisation:
University of York
Department Name: Chemistry
Abstract
The NMR Centre and the Neuroimaging Centre at the University of York have conducted a programme of work that has demonstrated that one of the fundamental limitations of conventional Nuclear Magnetic Resonance (NMR) and Magnetic Resonance Imaging (MRI) techniques can be dramatically overcome. NMR is the most popular method for performing analytical and structural chemistry and MRI is the technique of choice for carrying out non-invasive imaging in humans. Even though the global markets for these techniques exceeds 6billion annually, as identified in a recent US report to Congress, both technologies are limited in application due to poor sensitivity. A process termed hyperpolarisation, developed in York throughout the last decade, allows these limitations to be overcome. We have recently shown that 0.5 seconds worth of data collection equates to 58 days on the conventional device.In laymen's terms, both NMR and MRI deal with the probing of the magnetic behaviour of nuclei within molecules. These nuclei behave like bar magnets and therefore can either have a north or south seeking orientation. Parahydrogen is simply a reaction feedstock where rather than having a mixture of such orientations, we start with a pure magnetic form. We have established a new route to utilising this feedstock in MR studies. The parahydrogen simply acts like a radiator which when brought into contact with its surroundings warms the room. In this case, the result is a potential 31,000 increase in detected signal strength. The information obtained through MIR studies is well established as providing critical information related to diagnosis and treatment in the health field. The breakthrough in sensitivity enhancement offers opportunities for a step change in modern healthcare and in high resolution NMR markets. This is achieved without the chemical modification of a material and it can employ substances that are native to the body. We therefore expect that it will not suffer from the toxicological problems associated with gadolinium contrast agents and PET and hence be well received by the medical community and laymen alike.Please see Proposal Form for details
Planned Impact
Magnetic resonance imaging (MRI) is widely and powerfully used in front-line healthcare. The importance of MRI to modern medicine is such that any advances which increase its diagnostic availability will lead to major and lasting gains, with improvements in the selectivity and the sensitivity of MRI contrast agents particularly opening up major new healthcare possibilities. Given the multidisciplinary nature of MRI, future advances will rely on teams of scientists, biomedical scientists and clinicians working closely together in an interdisciplinary manner that come from companies and Universities. Here we seek to achieve this by applying a revolutionary new technology developed at the University of York. MRI works by detecting the radio frequency signals which result from nuclei undergoing a magnetic spin state alignment change. These signals, however, are very weak, severely limiting the information available from MRI. Information enhancement can be achieved by using a contrast agent. Indeed, over 1.4 million MRI scans were performed in the NHS in 2008 where almost one third required an injected contrast agent to provide useful clinical information. The contrast agents in current widespread use are based on gadolinium. These agents are relatively sensitive giving clinician's good anatomical information, but offer no biochemical selectivity. They also suffer from potential toxicity issues. There is therefore a widely recognised and urgent need for new contrast agents and, in particular, for new agents offering significant increases in sensitivity. Increases in sensitivity will lead to major benefits in front-line healthcare which include, for example, reductions of the size of MRI scanners which in itself would greatly expand the accessibility and availability of MRI. Advances in contrast agent selectivity and specificity would also give a step change in the quality of clinically useful information available from imaging. In this context, hyperpolarised contrast agents have the potential to revolutionise magnetic resonance methods such as MRI through unrivaled gains in contrast agent sensitivity. Already, hyperpolarised xenon is used medically in lung imaging. For example, while hardware developments such as increasing magnet size in high resolution NMR spectroscopy over the last 20 years have improved the strength of the detected signal by just over one order of magnitude, hyperpolarisation can increase sensitivity by five orders of magnitude in a single step with no changes in the detection hardware. Significantly, the ability to hyperpolarise molecules of biological interest opens up the possibility of major increases in not only sensitivity both also in selectivity. It is here where York has made significant breakthroughs by utilising parahydrogen to generate hyperpolarised contrast agents simply and easily. The advantage of York's new method is that it allows the rapid production of large amounts of hyperpolarised agents without changing their molecular structure (a significant advantage over other hyperpolarisation methods and dynamic nuclear polarisation techniques where the method of contrast agent generation is limited in either amount/speed of sample and/or range of materials that can be hyperpolarised). Using the York technology, the in vivo chemical functionality of the molecule will be retained which offers the potential to create highly sensitive and highly specific contrast agents reliably and inexpensively. The benefits of the hyperpolarisation approach for improving healthcare are not restricted to imaging. In its high resolution version it enables the detailed characterisation of molecules in solution, leading to direct applications for better drug discovery product screening, sample characterisation, stability studies, and enzyme structure determinations. The impact of this methods therefore spans many areas of science, but here we seek to primarily develop the MRI context.
People |
ORCID iD |
S Duckett (Principal Investigator) | |
Gary Green (Co-Investigator) |
Publications
Ruddlesden AJ
(2015)
Catalytic Transfer of Magnetism using a Neutral Iridium Phenoxide Complex.
in Organometallics
Richards JE
(2018)
Using hyperpolarised NMR and DFT to rationalise the unexpected hydrogenation of quinazoline to 3,4-dihydroquinazoline.
in Chemical communications (Cambridge, England)
Mewis RE
(2015)
Deactivation of signal amplification by reversible exchange catalysis, progress towards in vivo application.
in Chemical communications (Cambridge, England)
Mewis RE
(2015)
Strategies for the hyperpolarization of acetonitrile and related ligands by SABRE.
in The journal of physical chemistry. B
Lloyd LS
(2012)
Utilization of SABRE-derived hyperpolarization to detect low-concentration analytes via 1D and 2D NMR methods.
in Journal of the American Chemical Society
Lloyd L
(2014)
Hyperpolarisation through reversible interactions with parahydrogen
in Catal. Sci. Technol.
Hövener JB
(2013)
A continuous-flow, high-throughput, high-pressure parahydrogen converter for hyperpolarization in a clinical setting.
in NMR in biomedicine
Holmes AJ
(2015)
The reaction of an iridium PNP complex with parahydrogen facilitates polarisation transfer without chemical change.
in Dalton transactions (Cambridge, England : 2003)
Green RA
(2012)
The theory and practice of hyperpolarization in magnetic resonance using parahydrogen.
in Progress in nuclear magnetic resonance spectroscopy
Fekete M
(2014)
Correction to Iridium(III) Hydrido N-Heterocyclic Carbene-Phosphine Complexes as Catalysts in Magnetization Transfer Reactions
in Inorganic Chemistry
Description | The work undertaken as part of this follow on fund bid allowed the ground work to be prepared to form the University spinout Hypernetics Imaging Ltd. The commerical case was developed through external consulation. We also worked towards to collection of in vivo data |
Exploitation Route | Our findings will be used by Hypernetics going forward. |
Sectors | Chemicals Manufacturing including Industrial Biotechology Other |
Description | The findings of this award formed the basis to allow the University to establish a spinout. Bruker as sell a parahydrogen generator and a range of flow probes developed in part during this award. |
First Year Of Impact | 2013 |
Sector | Healthcare |
Impact Types | Economic |
Description | GlaxoSmithKline (GSK) |
Amount | £65,000 (GBP) |
Organisation | GlaxoSmithKline (GSK) |
Sector | Private |
Country | Global |
Start | 09/2013 |
End | 09/2017 |
Description | GlaxoSmithKline (GSK) |
Amount | £65,000 (GBP) |
Funding ID | STU029361 |
Organisation | GlaxoSmithKline (GSK) |
Sector | Private |
Country | Global |
Start | 09/2010 |
End | 09/2013 |
Description | Wellcome Trust Capital Awards Scheme |
Amount | £4,360,000 (GBP) |
Funding ID | 092506/B/10/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2011 |
End | 11/2016 |
Description | Wellcome Trust Strategic Awards Scheme |
Amount | £3,500,000 (GBP) |
Funding ID | 098335/Z/12/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2012 |
End | 11/2017 |
Description | Bruker BioSpin |
Organisation | Bruker Corporation |
Department | Bruker BioSpin |
Country | Germany |
Sector | Private |
PI Contribution | We have worked with Bruker to produce a parahydrogen generator, a device for the preparation of hyperpolarised samples and a flow probe for the detection of hyperpolarised signals |
Collaborator Contribution | Bruker have provided access to equipment and engineering. They have provided legal support for patents |
Impact | Bruker now sell a parahydrogen generator. A beta test version of the polariser in on test with 5 international research groups. |
Start Year | 2009 |
Description | Using SABRE to aid in the study of biologically relevant molecules |
Organisation | AstraZeneca |
Country | United Kingdom |
Sector | Private |
PI Contribution | We have worked with AstraZeneca on the application of SABRE methods to aid in the characterisation and probing of small molecules of biological relevance |
Collaborator Contribution | Knowledge and materials |
Impact | Publications |
Start Year | 2009 |
Description | Using SABRE to aid molecular characterisation |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | GlaxoSmithKline has supported two studentships to drive forward the SABRE research. They are interested in using it to probe pharamaceutical products |
Collaborator Contribution | They provide knowledge and materials. |
Impact | Publications |
Start Year | 2009 |
Description | Using parahydrogen to probe small molecules |
Organisation | Fera Science Limited |
Country | United Kingdom |
Sector | Public |
PI Contribution | We worked with FERA to develop methods to characterise trace amounts of organic materials that are relevant to food. |
Collaborator Contribution | Knowledge and Materials |
Impact | Publicatons |
Start Year | 2009 |
Title | Field cycling method for magnetic resonance |
Description | An NMR experiment on hyperpolarizable magnetic nuclei of substrate molecules in a living human or animal body, involves polarizing the substrate molecules by non-hydrogenating para-hydrogen induced polarization (=NH-PHIP) into a singlet/pseudo singlet state in low magnetic field and injecting the substrate molecules into the living body, the body or a part thereof being previously located inside a magnet at low magnetic field. The magnet is switched on to high magnetic field, and in at least part of the substrate molecules, the singlet state/pseudo singlet state is converted into observable magnetisation. An MRI or MRS measurement is carried out with the living body or the part thereof, collecting data from the substrate molecules. The NMR experiment is well applicable on hyperpolarized nuclei within a patient, with reduced losses of magnetization due to relaxation processes. |
IP Reference | US2014012129 |
Protection | Patent granted |
Year Protection Granted | 2014 |
Licensed | Yes |
Impact | We hope that this patent will be used by Bruker BioSpin. |
Title | HYPERPOLARITZATION OF COMPOUNDS FOR NMR, IN PARTICULAR BY MEANS OF PHIP |
Description | An NMR method is presented having enhanced sensitivity on a compound comprising hyperpolarizable nuclei, in particular applying enhanced PHIP. Polarization is thereby transferred from a prepared fluid, which is enriched with symmetric molecules of a particular spin state (e.g. para-hydrogen enriched), directly to the hyperpolarizable nuclei of a compound, without altering the chemical identity of the compound in this process. Spin transfer is achieved using a template having sites of ordered environment, and the fluid and the compound are brought together in the presence of the template. Polarization transfer to the hyperpolarizable nuclei of the compound is thereby easier to perform and can be applied to a broader scope of compounds. |
IP Reference | US2010219826 |
Protection | Patent granted |
Year Protection Granted | 2010 |
Licensed | Yes |
Impact | This product has been licensed to Bruker BioSpin |
Title | NMR MEASUREMENT APPARATUS WITH FLOW-THROUGH PROBEHEAD |
Description | The invention relates to a device (1, 21, 31, 41, 64) for the preparation and measurement of a nuclear spin reso nance (NMR) measurement sample (10), including-a flow-through NMR probehead (2), with a first tube (3) and a second tube (14) each for the supply and removal of a liquid NMR measurement sample (10),-at least one chamber (4, 22, 32) which is connected to one of the tubes (3, 14),-a sample inlet (5) for introducing the liquid measurement sample (10) into the device (1, 21, 31, 41, 64), wherein at least one chamber (4, 22, 32) has at least one connection for increasing (9, 24, 25, 42, 43, 46, 47) and releasing (8, 23, 27, 48a, 48b) the gas pressure, and in which at least one chamber (4, 22, 32) comprises means for mixing the liquid measurement sample (10) contained in the chamber (4, 22, 32) with a gas With the inventive device it is possible to reduce the measurement sample consumption when doing an NMR spectroscopic measurement on liquid measurement samples to which spin order can be catalytically transferred. |
IP Reference | US2011285396 |
Protection | Patent granted |
Year Protection Granted | 2011 |
Licensed | Yes |
Impact | This has been licensed to Bruker BioSpin |
Title | PULSE SEQUENCING WITH HYPERPOLARISABLE NUCLEI |
Description | There is described a method of selective observation of non-hydrogenative para- hydrogen induced polarisation (NH-PHIP) as enhanced magnetic resonance signals which comprises separating the thermal and longitudinal spin order states. There is also described a template comprising [Ir(COD)(NHC)(Py)]+, and analogues thereof, for use in a PHIP magnetic resonance technique and a method for its preparation. |
IP Reference | WO2010067076 |
Protection | Patent application published |
Year Protection Granted | 2010 |
Licensed | Yes |
Impact | We are working with Bruker BipSpin on the application. |
Title | Parahydrogen Generator |
Description | We worked with Bruker BioSpin to produce a device to make parahydrogen |
Type Of Technology | New/Improved Technique/Technology |
Year Produced | 2013 |
Impact | The device is being used by a number of researchers to help support hyperpolarisation studies aligned to clinical MRI. |
URL | http://www.bruker.com/products/mr/nmr/accessories/hyperpolarization/parahydrogen-generator/overview.... |
Company Name | Hypernetics Imaging Limited |
Description | |
Year Established | 2013 |
Impact | Currently seeking investment |
Description | 5th Australian Organometallics Meeting (Sydney) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | 70 academics, postdocs and research students attended a research presentation, which sparked questions and discssion afterwards Subsequent joint ARC grant with B Messerle (Sydney) |
Year(s) Of Engagement Activity | 2010 |
Description | 7th Conference on Field Cycling NMR Relaxometry |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | People attended a presentation which sparked questions and discussion afterwards Other researchers now use our methods |
Year(s) Of Engagement Activity | 2011 |
URL | http://www.ffcrelax.com/ffcrelax/ffc2011/mainpage.php?folder=program&page=index.php |
Description | BioNMR workshop Weizmann Institute. |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | Over 50 people attended a presentation which sparked questions and discussion afterwards Over 15 research groups worldwide have adopted our methods |
Year(s) Of Engagement Activity | 2013 |
URL | http://www.weizmann.ac.il/weizsites/bionmr/ |
Description | Chemistry Meets Imaging: Molecular Routes to Enhance Contrast |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation at international meeting at Duke, USA |
Year(s) Of Engagement Activity | 2015 |
URL | http://cmbi.duke.edu/conferences/ |
Description | Euromar, Florence, Italy. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Over 100 people attended a presentation which sparked questions and discussion afterwards Over 15 research groups worldwide have adopted our methods |
Year(s) Of Engagement Activity | 2010 |
URL | http://www.euromar.org/about.html |
Description | Experimental Nuclear Magnetic Resonance Conference (ENC), Daytona Beach USA. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Over 100 people attended a presentation which sparked questions and discussion afterwards Over 15 research groups worldwide have adopted our methods |
Year(s) Of Engagement Activity | 2010 |
URL | http://www.enc-conference.org/ |
Description | German-UK MR Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited key-note talk at international meeting. |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.chemie.tu-darmstadt.de/gdch-fgmr2015/fgmr_2015/index.en.jsp |
Description | Gordon Conference, In Vivo Magnetic Resonance |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Over 100 people attended a presentation which sparked questions and discussion afterwards Over 15 research groups worldwide have adopted our methods |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.grc.org/programs.aspx?year=2014&program=invivo |
Description | Huddersfield Hyperpolarisation Meeting |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Series of presentations detailing aspects of hyperpolarisation |
Year(s) Of Engagement Activity | 2016 |
Description | Imaging in 2020 VII, Bridging Molecular Imaging and Therapy, Jackson Hole USA. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | people attended a presentation which sparked questions and discussion afterwards 15 research groups worldwide have adopted our methods |
Year(s) Of Engagement Activity | 2011 |
Description | Intermediary Metabolism in Cancer meeting, Dallas USA. |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Over 100 people attended a presentation which sparked questions and discussion afterwards Over 15 research groups worldwide have adopted our methods. This includes groups at Johns Hopkins, UT Southwestern Medical Centre, and the University Medical Center Freiburg |
Year(s) Of Engagement Activity | 2010 |
URL | http://www.utsouthwestern.edu/edumedia/edufiles/departments_centers/airc/annual-symposium-202010.pdf |
Description | Invited Speaker, Euromar, Dublin, Eire. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Over 100 people attended a presentation which sparked questions and discussion afterwards Over 15 research groups worldwide have adopted our methods |
Year(s) Of Engagement Activity | 2012 |
Description | MRC Hyperpolarised MRI workshop |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Workshop to consider progress in hyperpolarisation that will lead to clinical use |
Year(s) Of Engagement Activity | 2015 |
Description | New national centre to transform medical imaging |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Detail new funding stream A new £6.8 million research centre based across two Yorkshire universities will aim to transform diagnosis and treatment of patients suffering from cancer, heart disease and musculoskeletal diseases with the help of new medical imaging facilities to be created at Leeds Teaching Hospitals and the University of York. |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.york.ac.uk/news-and-events/news/2014/medical-imaging-centre/ |
Description | New scanning technology aims to achieve quicker diagnosis of disease |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | New scanning technology aims to achieve quicker diagnosis of disease. Groundbreaking research taking place at the University of York could lead to Alzheimer's disease being diagnosed in minutes using a simple brain scan. Scientists are working on new technology that could revolutionise the way in which Magnetic Resonance Imaging (MRI) scans are used to view the molecular events behind diseases like Alzheimer's, without invasive procedure, by increasing the sensitivity of an average hospital scanner by 200,000 times. The technology underpinning this project, SABRE (Signal Amplification by Reversible Exchange), has received a £3.6m Strategic Award from the Wellcome Trust to fund a team of seven post-doctoral researchers from this month. on-going |
Year(s) Of Engagement Activity | 2012 |
URL | http://www.york.ac.uk/chym/news/2012/scanning/ |
Description | Opening National Centre of Hyperpolarised MRI |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Scientific talk on developments in SABRE hyperpolarisation. |
Year(s) Of Engagement Activity | 2016 |
Description | Rank Prize Symposium |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I contributed to a workshop aimed at driving forward change in chemical detection Over 15 research groups worldwide have adopted our methods |
Year(s) Of Engagement Activity | 2011 |
URL | http://www.rankprize.org/index.php/symposia/general |
Description | Talk, ISMAR, Rio de Janerio, Brazil |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | people attended a presentation which sparked questions and discussion afterwards Over 15 research groups worldwide have adopted our methods |
Year(s) Of Engagement Activity | 2013 |
Description | Using SABRE to improve NMR and MRI |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk given in Paris |
Year(s) Of Engagement Activity | 2016 |
Description | Wellcome Trust Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | To inform on progress towards the clinical uptake of SABRE |
Year(s) Of Engagement Activity | 2016 |
Description | Wellcome Trust, Next Generation Brain Imaging Technologies, London, UK. |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | people attended a presentation which sparked questions and discussion afterwards Funding awarded to take methods forward. |
Year(s) Of Engagement Activity | 2011 |
Description | York Hyperpolarisation Symposium (2 Day) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Series of 20 talks over 2 days |
Year(s) Of Engagement Activity | 2016 |
Description | press release |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Information shared with public Research progresses towards clinical use |
Year(s) Of Engagement Activity | 2010 |
URL | http://www.york.ac.uk/news-and-events/news/2010/research/hyperpolarisation/ |
Description | press release |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | A press release written to share a research success Over 30 reports in the national and international media picked up this press release. Interviews resulted on local radio. |
Year(s) Of Engagement Activity | 2009 |
URL | http://www.york.ac.uk/news-and-events/news/2009/medical-diagnosis/ |