Research Outreach Issue 105

The outreach quarterly connecting science with society ISSN 2517-701X ISSUE 105

FEATURING RESEARCH FROM:

Russian Academy of Sciences; University of Texas Southwestern Medical Center; Medical College of Wisconsin; University of Kentucky College of Medicine; Kaunas University of Technology; Kanagawa Institute of Technology; New York University; Syntrix Pharmaceuticals; University of São Paulo; Nilupul Foundation; Indian Institute of Chemical Biology; Louisiana State University; Cylerus, Inc.; University College London; Aerospace Research Centre of the National Research Council Canada; University of California; Columbia University; Tohoku University; Solynta; Research Features 3 Royal Holloway, University of London; Children’s Hospital Oakland Research Institute; Polytechnic University of Turin; Technical University of Crete; University of the Witwatersrand; University of Bristol; BetaStem Therapeutics.

COLLABORATE DISSEMINATE ENGAGE

Research Publishing International offer a completely barrier-free publishing portal. We have a multi-media presence and readership, through both digital and physical print copies of Research Outreach magazine, and provide online hosting of research articles through feature webpages and downloadable PDF documents.

We abide by the Creative Commons (CC) license terms to ensure widespread, open-access dissemination of all the work featured across our various platforms.

An important factor in assisting research teams to maximise their exposure is the use of modern social media techniques. Combined with traditional digital and physical distribution of our publications, we engage heavily with the wider community through the use of various social media channels.

RPI has over 30 years of collective expertise in science communications. Our know-how ensures that we work efficiently and cost-effectively, boosting the impact of your research globally.

www.researchpublishinginternational.com Partnership enquiries contact: simon@researchoutreach.org Careers and guest contributions contact: emma@researchoutreach.org Facebook “f ” Logo

CMYK / .eps

Facebook “f ” Logo

CMYK / .eps

RESEARCH OUTREACH ISSUE 105

WELCOME

The outreach quarterly connecting science with society ISSN 2517-701X ISSUE 105

TO ISSUE 105

We’re also proud to publish under Creative Commons (CC) licensing. Building a genuinely open, transparent and international publishing community has become easier thanks to CC licences. Graham Steel (Publishing Consultant and Interim Representative for the United Kingdom to the CC Global Network Council) explains more.

The American Heart Association has been educating people on CPR, heart health, stroke and heart disease worldwide for nearly 100 years. Chief of Mission Aligned Businesses and Healthcare Solutions, John Meiners, tells us more about the Association’s key strategies including a focus on prevention.

We also have a review of the Society for Neuroscience’s annual meeting, Neuroscience 2018. Members of the Research Outreach team attended and were full of enthusiasm when they returned.

In this edition of Research Outreach, we cover Health & Medicine, Physical Sciences, Biology, Engineering & Technology, Education & Training and Behavioural Sciences – as diverse in topic as it is in geography, I hope you enjoy reading about this broad mix of research.

Editor Please feel free to comment or join the debate. Follow us on twitter @ResOutreach or find us on Facebook https://www.facebook.com/ ResearchOutreach/

FEATURING RESEARCH FROM: ISSN 2517-701X

This issue has a truly global feel with researchers featured from institutions around the world. Reflecting the international face of research is something we are particularly proud of and hope to expand on in future issues.

Russian Academy of Sciences; University of Texas Southwestern Medical Center; Medical College of Wisconsin; University of Kentucky College of Medicine; Kaunas University of Technology; Kanagawa Institute of Technology; New York University; Syntrix Pharmaceuticals; University of São Paulo; Nilupul Foundation; Indian Institute of Chemical Biology; Louisiana State University; Cylerus, Inc.; University College London; Aerospace Research Centre of the National Research Council Canada; University of California; Columbia University; Tohoku University; Solynta; Research Features 3 Royal Holloway, University of London; Children’s Hospital Oakland Research Institute; Polytechnic University of Turin; Technical University of Crete; University of the Witwatersrand; University of Bristol; BetaStem Therapeutics.

THIS ISSUE Published by: Research Outreach Founder: Simon Jones simon@researchoutreach.org Editorial Director: Emma Feloy emma@researchoutreach.org Operations Director: Alastair Cook audience@researchoutreach.org Editor: Hannah Fraser hannah@researchoutreach.org Designers: Craig Turl, Carlton Hibbert Global Project Director: Julian Barrett julian@researchoutreach.org Project Manager: Tobias Jones tobias@researchoutreach.org Contributors: Rachael Baker, Emma Green, Rebecca Ingle, Matt Jarvis, Gillian Livesey, Kate McAllister, Jessica Money, Rachel Perrin, Emily Porter, Kate Porter, Niall Taylor, Polly Wells, Cheryl Whiting, Stuart Wilson. /ResearchOutreach /ResOutreach

Copyright © and ™ 2018 Research Outreach

CC BY This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/ or send a letter to Creative Commons, PO Box 1866, Mountain View, CA 94042, USA.

www.researchoutreach.org

3

CONTENTS 6

LICENSE TO SHARE: How the Creative Commons licensing system encourages the remixing and reuse of published materials.

10

NEW 3D TECHNOLOGY TO HELP IN THE BATTLE AGAINST BRAIN TUMOURS Dr. Darin T. Okuda Novel methodology to visualise brain tumours in 3D.

14

CARCINOGENESIS: WHEN TRANSMISSION OF EPIGENETIC INFORMATION GOES AWRY Professor Patrick Riley Investigating the effect of epigenetic changes on carcinogenesis, the formation of cancer.

18

REDUCED PSA PROSTATE CANCER SCREENING: LIFE-THREATENING CONSEQUENCES? Dr Thomas E. Ahlering Demonstrating that high-risk prostate cancer results from USPSTF-enforced reduced prostate cancer screening.

22

LYMPH NODES TARGETED IN NOVEL CANCER THERAPY Professor Tetsuya Kodama Focusing on early diagnosis and treatment of lymph node metastasis, observed in most cancers, such as breast cancer and head and neck cancer.

30 4

www.researchoutreach.org

26

TIME FOR A NEW APPROACH TO SEVERE TRAUMATIC BRAIN INJURY AND STROKE Dr James Stone Developments in automated, real-time monitoring of brain stem function.

44

MOVING BEYOND DANGEROUS OPIOIDS FOR PAIN Dr John A. Zebala Syntrix Pharmaceuticals hope to tackle the opioid crisis by producing opiates with low lethality compared to schedule II opioids.

30

BICAMS: SHEDDING LIGHT ON COGNITION IN MULTIPLE SCLEROSIS Professor Dawn Langdon The Brief International Cognitive Assessment for MS (BICAMS), is a short, much-needed tool to assess cognitive function for people with Multiple Sclerosis.

48

ALCOHOL OVERUSE: CUTTING TO THE BONE Dr Martin Ronis Linking the damaging effects of alcohol consumption on bone in women of reproductive age with increased risk of osteoporosis.

52

LOCAL DRUG DELIVERY TO PROSTHETIC VASCULAR GRAFTS Dr Ronald Shebuski Preventing failure of prosthetic grafts in haemodialysis patients.

56

CLINICAL RELEVANCE AIMS TO UNCOVER NOVEL REGULATORS OF HUMAN CORONARY ARTERY FUNCTION The Human Vascular Research Group (HVRG) The HVRG studies the complex relationship and physiological effects of vascular stress response in health and disease.

60

MENDING BROKEN HEARTS: The American Heart Association and its life-saving treatment guidelines

64

STEM SUMMER PROGRAM Children’s Hospital Oakland Research Institute Aiming to increase the number of

36

40

FACTORS ASSOCIATED WITH YOUNG CHILDREN EXHIBITING PICKY EATING BEHAVIOUR Dr Pauline Emmett and Dr Caroline Taylor Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) to investigate factors associated with picky eating to determine whether the behaviour should be a source of concern for parents.

COULD STEM CELLS OFFER A VIABLE TREATMENT FOR RETINOPATHY? Dr Stephen Bartelmez BetaStem Therapeutics aims to treat diabetic retinopathy using a patient’s own stem cells.

I am very proud that the international Multiple Sclerosis community has come together to address and manage the cognitive aspects of MS. PROFESSOR DAWN LANGDON Page 30

68

44

104

students from underrepresented backgrounds pursuing and graduating with a STEM major.

68

72

IMPROVING MATHS PERFORMANCE IN SOUTH AFRICA’S PRIMARY SCHOOLS Professor Hamsa Venkat Improving primary maths teaching and learning.

CAREERS IN SCIENCE Professor Hollie Swanson Summer Training in Environmental and Pharmacological Sciences (STEPS) aims to enhance student learning and help prepare students from a variety of backgrounds, for successful science-related careers.

76 TECHNOLOGICAL

LEAPFROGGING THE GLOBAL ENERGY CRISIS Professor José Goldemberg Relieving the world’s crushing dependence on fossil fuels with a move to cleaner ethyl-alcohol based fuels.

80

84

OPINION DYNAMICS AND CONSENSUS IN SOCIAL NETWORKS Denis Fedyanin and Alexander Chkhartishvili Modelling opinion dynamics of social networks to analyse how individuals’ internal parameters affect their social power.

WHEN KINETIC THEORIES CLASH, MIND THE LATTICE STEP Professor Giorgio Kaniadakis and Professor Dionissios Hristopulos Investigating whether the Master

Health & Medicine

Education & Training

Equations or Fokker–Planck Equations are better for understanding how atoms move between lattice points within solid materials.

88

DYNAMIC VERSUS STATIC: EVOLVING MECHANICAL CHARACTERISATION Dr Meysam Rahmat Dynamic mechanical characterisation of materials, particularly nanocomposites.

92

PEERING INSIDE: 3D IMAGING IN MATERIALS Prof Dr Elena Jasiūnienė Investigating the properties of various materials, particularly self-compacting concrete, using X-ray computed tomography.

96

BLACK HOLE BINARIES AND GRAVITATIONAL WAVES Professor Zoltan Haiman Seeking evidence for the existence of massive black hole binaries.

100

against invading pathogenic microorganisms.

108

BETTER AND STRONGER POTATOES USING HYBRID BREEDING Dr.ir. Sjaak van Heusden Solynta has developed an innovative method for targeted breeding which will change the production and global distribution of potatoes.

112

GUINEA PIG AS A MODEL TO STUDY THE CAROTID BODY-MEDIATED CHRONIC INTERMITTENT HYPOXIA EFFECTS Dr Ángela Gómez-Niño Dr Asuncion Rocher Using the guinea pig as a model to explore the mechanisms that mediate long-term effects of exposure to low oxygen levels.

116 MINDFULNESS-BASED

INTERVENTION (MBI) PROVIDES POSITIVE OUTCOMES FOR THOSE IN LOWER SOCIOECONOMIC ENVIRONMENTS Ven Karma Jiga Assessing the feasibility of teaching mindfulness techniques to those in poverty to help improve their physical and mental well-being.

CREATING A BETTER OSCILLATOR Dr Koichi Narahara The physical phenomenon generated by travelling-wave field-effect transistors, such as electric pulses, shockwaves and solitons.

104 PATHOGENIC

MICROORGANISMS TARGETED BY COMPLEX CELLULAR COMMUNICATIONS Dr Malini Sen Deciphering the role of a protein called Wnt5a in defending

Physical Sciences

Engineering & Technology

120

NEW BRAIN RESEARCH SPARKS EXCITEMENT AT NEUROSCIENCE 2018

122

COMMUNICATION: SCIENCE IN BREWING

Biology

Behavioural Sciences

www.researchoutreach.org

5

Thought Leader

License to share:

How the Creative Commons licensing system encourages the remixing and reuse of published materials In a world where news, data and images are increasingly shared freely online, whether correctly or not, Creative Commons (CC) has stepped up to make allowing others to reuse and remix your research easy. By creating, maintaining and promoting all of the available CC licences, the organisation hopes to help an international community of scientists, educators and activists realise the benefits of the commons. In this interview with Graham Steel (Publishing Consultant and Interim Representative for the United Kingdom to the CC Global Network Council), we found out the real advantages of publishing under a CC licence.

C

reative Commons (CC) licences are free, international, easy-touse copyright licences that can be utilised by any authors or publishers.

They specifically allow research and data to be reused and remixed collaboratively.

The CC organisation, which created these licences in 2001, builds tools that

6

www.researchoutreach.org

make their licensing system discoverable and usable across the globe and across disciplines.

With goals such as opening up education for all, accelerating innovation in science and medicine through collaboration and inspiring works of art and culture,

the CC has its eyes set firmly on how CC licensing can shape a better future. Interim Representative for the United Kingdom to the CC Global Network Council, Graham Steel, told Research Outreach more about how the organisation came to be, how the licensing works and why it is so important.

The spectrum of rights

Copyright

Creative Commons Public Domain

Re-use requires the permission from the copyright owner.

Re-use is permitted without permission under the specifications shared in the licence.

All Rights Reserved

Some Rights Reserved

No Rights Reserved May be used without permission.

Making sense of The Spectrum Of Rights.

reuse of their works by offering them for use under generous, standardised terms; those who want to make creative uses of works; and those who want to benefit from this symbiosis. CC’s vision is to help others realise the full potential of the internet. CC has affiliates all over the world who help ensure CC’s licences work internationally.

Ryan Merkley, CEO of Creative Commons.

What is Creative Commons (CC), and what is Science Commons?

CC is a global non-profit organisation that was set up in 2001 by Lawrence Lessig, Hal Abelson and Eric Eldred (with the support of the Center for the Public Domain), that enables sharing and reuse of creativity and knowledge through the provision of free legal tools. The code layer of each licence was designed by the late Aaron Schwartz. CC’s legal tools help those who want to encourage

Science Commons was an initiative launched by CC in early 2005 which ran until 2009. Its primary focus was on building infrastructure for open science.

More broadly, CC has undertaken projects to build commons-based infrastructure for science through identifying and lowering unnecessary barriers to research, crafting policy guidelines and legal agreements and developing technology to make research, data and materials easier to find, share and use.

What does your role at CC involve?

After discovering Open Access (OA) academic papers in 2006, I became aware of CC-licensed works. I made direct contact with co-founder Lawrence Lessig and then released most of my musical works under CC licences, sent out at least 1500 t-shirts that related to CC works and spread the word about CC to family, friends, work colleagues and the general public. In 2016, CC migrated their

real-time communications to Slack which I joined and contribute to daily. Over the last few years, CC has been rebooting its global network structure, which resulted in the relaunch of the CC United Kingdom chapter. I was elected to serve as Interim Representative for the United Kingdom to the CC Global Network Council (GNC).

Why are licences important for scientific content?

Copyright, as we know it today, came along in 1710, so by default, publishers (not authors) owned the copyright to academic papers. This remained the norm until around 1991 with the formation of arXiv, an e-print service in the fields of physics, mathematics, computer science etc. OA publishing/ publishers started to emerge around the same as major players such as BioMed Central and The Public Library of Science in 1998 and 2000 respectively. Once CC had been established and launched a suite of CC licences, OA publishers started to publish research papers under CC. As of December 2017, the Directory of Open Access Journals listed 10,567 OA journals. In total 94.8% of these now have CC licences. The most used licence is the CC-BY licence (43.8%).

This licence lets others distribute, remix, tweak and build upon your work, even commercially, as long as they credit you

The number and choice of licences as they stand work extremely well and offer an option to suit everyone’s needs.

www.researchoutreach.org

7

CREATIVE COMMONS

LICENSES

COPY & PUBLISH

ATTRIBUTION REQUIRED

COMMERCIAL USE

MODIFY & ADAPT

CHANGE LICENSE

PUBLIC DOMAIN CC BY CC BY-SA CC BY-ND CC BY-NC CC BY-NC-SA CC BY-NC-ND

You can redistribute (copy, publish, display, communicate, etc.)

You have to attribute the original work

You can use the work commercially

You can modify and adapt the original work

You can choose license type for your adaptations of the work.

The Creative Commons licences explained.

for the original creation. This is the most accommodating of licences.

without using a CC licence, but this is in the minority.

Are there too many licences? Should CC BY be the default for text?

The CC licences have become widely adopted both within and beyond academia with over 48 million media files in the Wikimedia Commons alone.

They provide a range of options that give authors control over how their work can be reproduced and remixed.

CC has been and remains a pivotal element of OA. It has provided visionary thinking and evangelising about the benefits and possibilities of OA via conferences, networking with the main stakeholders within the OA movement, and calling upon the CC board of directors to give talks about CC and OA. CC hosted convenings, such as the 2006 Information Commons for Science Congress at the National Academies of Science in Washington, D.C., where renowned scientists and scholars from the United States and other countries gathered to discuss data-sharing strategies. In 2007, CC co-sponsored with the Committee on Data for Science and Technology (CODATA) the Workshop on Common Use Licensing of Scientific Data Products in Paris. This conference included representatives from the Global Biodiversity Information Facility, and leading legal scholars, scientists and CC International affiliates actively working on data sharing policies. It was through this collaborative

The number and choice of licences as they stand work extremely well and offer an option to suit everyone’s needs.

It is certainly refreshing to see alternatives to the norm in subscription-based publishing/publishers.

Should CC BY be the default for text?

With reference to the text of academic materials, yes I think it should be.

OA and CC – are they separable?

Can you expand on CC’s relationship and thoughts on OA? Can a journal be OA without using a CC licence?

Yes, a journal can be open access

8

www.researchoutreach.org

process that the Science Commons Data Protocol emerged as the best – and possibly only – solution to the challenges collectively identified at that time.

In the scientific and academic communities, the benefits that digital technologies offer in terms of facilitating the greater and more efficient dissemination of research and knowledge have not yet been fully harnessed – what are your thoughts on this?

There has been substantial movement over the years in this regard, but I agree there is certainly still much more that can and should be achieved. On the positive side, as of 2017, there are almost 1.5 billion CC-licensed works.

There also has been a substantial growth in the field of pre-prints and in a 2018 paper, Piwowar et al found that in 2015, 45% of the scholarly literature is OA. On the not so positive front, in 2011, George Monbiot released a sobering piece for The Guardian titled ‘Academic publishers make Murdoch look like a socialist’. Concerns have been also raised very recently with regards

Thought Leader

to Elsevier’s role in the European Union open science project.

Licence Conditions

The details of these licences depend on its version and comprise a selection of four conditions.

ATTRIBUTION (BY) You may copy, distribute, display and perform the work and make derivative works based on it only if they give the author or licenseor the credits in the manner specified by these.

CC has been established for more than 16 years now. What does the next five years hold? What are the strategic goals of the organisation?

CC has moved beyond simple licensing, towards making the commons more vibrant and usable, and enabling more collaboration and gratitude to help it flourish. They are focused on a variety of initiatives and products to make this happen. An example of this is CC Search, currently in prototype, which is being built as a ‘front door’ to the commons. CC Search not only surfaces CC-licensed content that is freely available to anyone, it also provides tools to make lists and attribute work with one click, and serves up a massive collection of images by utilising open media application program interfaces.

in making the world more open, and making culture more accessible and available to all.

Another example is the Creative Commons Certificate, an in-depth educational course about the ethos of openness, as well as CC licences and how they work. The course is

Can you provide some links to resources where researchers can learn more about CC licences?

If you are in the United Kingdom and interested in CC, please feel free to join

NO DERIVATIVE WORKS (ND) You may copy, distribute, display and perform only verbatim copies of the work, not derivative works based on it.

NON-COMMERCIAL (NC) You may copy, distribute, display and perform the work and make derivative works based on it only for noncommercial purposes.

SHARE ALIKE (SA) You may distribute derivative works only under a licence identical to the licence that governs the original work.

NOTE: A licence cannot feature both the Share Alike and No Derivative Works options.

The Share Alike requirement applies only to derivative works.

make Murdoch look like a socialist.

The Guardian 29 August 2011. www. theguardian.com/commentisfree/2011/ aug/29/academic-publishers-murdochsocialist (date last accessed 26 October 2018).

Moody G. Elsevier will monitor open science in EU using a measurement system that favours its own titles.

CC has moved beyond simple licensing, towards making the commons more vibrant and usable, and enabling more collaboration and gratitude. available to everyone and is geared towards empowering individuals and institutions to better advocate for openness and to help them be fully up to speed on how to interact with CC licences and CC-licensed works.

There’s also the Creative Commons Summit, an annual event. The summit is an opportunity for everyone interested in this work to get together in person with an international community of technologists, culture creators, academics and activists to share ideas and decide on the best ways to move the movement forward.

Finally, there’s the Creative Commons Global Network. This is a membership programme for organising, expanding and empowering the global community of people who are actively invested

the United Kingdom CC Slack channel (https://slack-signup.creativecommons. org/ and jump to CC UK).

You can also find more information via the following links: • Creative Commons • Creative Commons FAQ’s • Choosing a CC licence • How should I decide which licence to choose?

• Fact Sheet On Creative Commons an Open Science • Creative Commons Licensing Explained (video) • Building on the Past’ – An explanation of how Creative Commons works.

Winner of the Creative Commons Moving Image contest (video).

REFERENCES Monbiot G. Academic publishers

Techdirt 09 July 2018. www.techdirt. com/articles/20180706/09314440182/ elsevier-will-monitor-open-science-euusing-measurement-system-that-favorsown-titles.shtml (date last accessed 26 October 2018).

Pirwowar H, Priem J, Lariviere V, et al.

The state of OA: a large-scale analysis of the prevalence and impact of Open Access articles. Peer J 6:e4375.

Creative Commons licensing E: info@creativecommons.org W: https://creativecommons.org/ : @CreativeCommons

www.researchoutreach.org

9

Health and Medicine ︱ Dr. Darin T. Okuda

New 3D technology to help in the battle against brain tumours Dr. Darin T. Okuda is a clinician-scientist and professor of Neurology and Neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. Dr. Okuda strives to transform healthcare by developing new diagnostic tools that challenge current clinical practices.

His research group recently designed a novel method to visualise brain tumours in three-dimension (3D). This latest research aims to revolutionise the evaluation and management of patients with glioblastoma multiforme (GBM).

Dr. Okuda’s imaging techniques allow for greater tumour information.

G

lioblastoma multiforme (GBM) is a destructive and fast-growing brain cancer. It is the most common cancerous brain tumour in adults and with a five-year survival rate of just 5%, the outlook for patients with GBM is poor. Current treatments for GBM include surgery for tumour removal followed by chemotherapy and radiotherapy.

To monitor the effectiveness of these treatments, clinicians rely on imaging the tumour and observing changes over time.

HOLDING US BACK Studying the brain is notoriously difficult as access to the brain is very tricky – especially when trying to study the brains of living subjects. Different imaging techniques have been designed to help scientists peek inside the brain; one of these is 2D MRI. This technique is useful for imaging tumours like GBM. These 2D MR images are currently used to help healthcare providers monitor the effects of treatments on tumours.

Currently, the gold standard imaging technique is two-dimensional (2D) magnetic resonance imaging (MRI).

However, this 2D imaging method has many problems when managing patient treatment. With the available technology it is hard for healthcare professionals to know if the treatment needs changing, if the tumour is worsening or if the treatment is effective. Dr. Okuda’s laboratory designed a more advanced three-dimensional (3D) imaging technique enabling clinicians to observe tumours more clearly.

During MRI, a chemical called gadolinium is injected into the body to enhance and improve the visualisation and understanding of how leaky blood vessels are. Clinicians use these images to monitor GBM development. Currently it is accepted amongst healthcare professionals that an increase in the MRI contrast signal, known as a contrast enhancement, suggests tumour growth.

This sounds simple – when the contrast enhancement increases, the tumour is getting bigger. Unfortunately, it is not that easy to interpret what is going on in a 2D MRI; there are important limitations to take into account. Treatment for GBM, such as radiotherapy, can cause an increase in the contrast enhancement on the MRI. This phenomenon is known as pseudoprogression and it is often indistinguishable from tumour growth.

This makes it very difficult for clinicians to understand the true nature of the tumour and provide the best treatment for their patients.

In order to treat GBM patients effectively, it is vital that tumour growth be viewed accurately. These 2D forced perspective MRIs limit the understanding of tumour

10

www.researchoutreach.org

A

B

The contrast is clear between 2D MRI (left), the initial 3D image (centre) and data from the coverage analysis (far right). The patient in the top row exhibits 3D coverage data highly suggestive of tumour progression. Note how much more informative the 3D data are in comparison to that provided with 2D MRI.

growth and fail to reveal the complexity of the tumour, specifically the shape and texture. Dr. Okuda’s laboratory has developed novel software to help uncover the true characteristics of GBM tumours.

SEEING THINGS DIFFERENTLY Dr. Okuda’s research group was able to reveal 3D spatial, structural and surface features of GBM using a novel approach.

In a recent study, fifteen patients were recruited and divided into two groups: 1) clinically stable without new or worsening neurological symptoms and 2) patients with new or worsening neurological symptoms unattenuated by steroid treatment whose combined symptoms and MRI changes warranted a change in their established treatment plan. Each patient had MRI scans and the resulting 3D images were studied and the two groups compared. The researchers started by investigating the most active region of the tumour, the contrast enhanced region.

of the contrast enhanced region to reveal details about the tumours in a way that had never been seen before. The innovative software was not only able to effectively isolate the contrast enhanced portion of the tumour, but it was able to edit the acquired images in 3D, an aspect not previously available with other platforms. Three different approaches were used to study the acquired 3D files.

thickness of the contrast enhanced outer shell was different between clinical groups. In patients with stable tumours, the thickness of the shell was found to be more evenly spread compared to worsening tumours. The shells also tended to be thinner than in those patients with tumour growth.

Scientists are still trying to understand whether the width of the shell changes during tumour growth – more research would be needed to clarify this. Dr. Okuda’s research group suggests that monitoring individual patients over time may be more meaningful when looking at outer shell width during disease progression. This new technology could help healthcare providers understand more about how their patient’s tumour changes over time.

Dr. Okuda’s laboratory have designed a more advanced 3D imaging technique enabling clinicians to observe tumours more clearly.

The software that Dr. Okuda’s group developed allowed in-depth analysis

A technique known as ‘principle component analysis’ was used to understand more about the shape of the tumour. The outer shell of the tumour’s active region was analysed and the distance along three different axes was studied to reveal the tumour’s sphericity. The researchers predicted tumours which were getting worse would be more spherical in shape compared to stable tumours.

The researchers used ‘medial axis transformation’ to determine if the

‘Coverage analysis’ was used to identify the number of holes in the tumour’s contrast enhanced outer shell. The relationship between the inner and outer surfaces of the tumour were studied to understand the integrity of this region.

The researchers found that in patients with worsening tumours there were fewer holes in the outer shell compared to those

www.researchoutreach.org

11

Dr. Okuda examines a 3D printed model created from his team’s 3D data.

with stable tumours. The research group had expected to see this in a growing tumour because with nothing to prevent tumour growth, the cells migrate outwards resulting in a more spherical, fuller shape with less holes.

In combination, these three analysis techniques bring together a 3D picture of a tumour’s shape and texture. The 3D data was able to provide much more thorough information than the conventional 2D images. Furthermore, the researchers were able to show that the changes in 3D spatial, structural and surface features correlated with the clinical status of the tumour. This 3D morphological data provides a vital tool in monitoring tumour progression in patients in order to provide better treatment.

WHAT NEXT? This emerging 3D technology provides new hope for GBM patients. The 3D view of the tumour extends way beyond the traditional, constrained 2D images and provides more dynamic and comprehensive information about the tumour. This 3D technology will allow healthcare providers to gain new insights into tumour progression and gain a greater understanding of tumour

12

www.researchoutreach.org

This 3D morphological data provides a vital tool in monitoring tumour progression in patients in order to provide better treatment. advancement based on shape, texture and structural patterns. This will aid better management of patients and any changes in treatment to occur more efficiently.

For clinicians and patients, being able to distinguish between pseudoprogression and true tumour progression is key. The technology could also be used to monitor the effectiveness of various treatments such as immune-based therapeutic strategies which harness the immune system to fight cancerous tumours. While immunotherapy is well established for some cancers, it is still being evaluated for the treatment of GBM. It is possible that this 3D technology could play a part in evaluating the therapeutic effect of such treatments.

Not only is this 3D technology useful in monitoring tumours and treatment of the patient but it may also be a useful tool for patient education. These 3D computer

simulations of the tumour could be printed to create a 3D model. The patient could then see the exact size and shape of the tumour: this is much more tangible than viewing a series of 2D images. The acquired 3D files may also be used with augmented and virtual reality platforms.

Dr. Okuda’s research group is currently conducting studies using larger patient groups to confirm their findings and ultimately aim to measure the impact of their findings on patient care.

The group also hopes to use 3D data to identify disease progression before symptoms manifest in patients by leveraging machine and deep learning techniques. These efforts extend beyond the current routine disease surveillance measures and their methodology may one day be systematically applied to the management of all GBM patients in the near future.

Behind the Research Dr. Darin T. Okuda

E: Darin.Okuda@UTSouthwestern.edu T: + 1 214 645 8215 (office) W: https://profiles.utsouthwestern.edu/profile/146752/darin-t-okuda.html

Research Objectives

References

Dr. Darin T. Okuda and his team from UT Southwestern Medical Center in Dallas developed novel methodology to visualise brain tumours in 3D.

Hansen M, Pan E, Wilson A, McCreary M, Wang Y, Stanley T, Pinho M, Guo X, Okuda D. (2018). Post-gadolinium 3-dimensional spatial, surface, and structural characteristics of glioblastomas differentiate pseudoprogression from true tumor progression. Journal of Neuro-Oncology, 139(3), 731738

Detail Darin T. Okuda, M.D., M.S., F.A.A.N., F.A.N.A. Professor of Neurology & Neurotherapeutics Director, Neuroinnovation Program Director, Multiple Sclerosis & Neuroimmunology Imaging Program Director, Radiologically Isolated Syndrome Consortium Department of Neurology & Neurotherapeutics UT Southwestern Medical Center at Dallas 5959 Harry Hines Blvd.

Dallas, Texas 75390 USA Bio Dr. Okuda is a clinician-scientist and professor of neurology, specialising in neuroimmunology. His work aims to create next generation healthcare by developing innovative connections between patients and providers that transform medical management. He is involved in the implementation of extreme healthcare concepts focused on delivering care more accurately, efficiently, and intelligently.

Collaborators • Madison R. Hansen • Edward Pan • Andrew Wilson • Morgan McCreary • Yeqi Wang • Thomas Stanley • Marco C. Pinho • Xiaohu Guo

Newton B, Wright K, Winkler M, Bovis F, Takahashi M, Dimitrov I, Sormani M, Pinho M, Okuda D. (2017). ThreeDimensional Shape and Surface Features Distinguish Multiple Sclerosis Lesions from Nonspecific White Matter Disease.

Journal of Neuroimaging, 27(6), 613-619.

Okuda D. (2018). 2018 American Academy of Neurology Brainstorm. YouTube. Available at www.youtube.com/ watch?v=w_4aAVfyZq8&feature=youtu.be

Personal Response What difference will this make to brain tumour treatment from a patient perspective?

Our work allows for patients to be better educated on their condition as the acquired 3D images and models from tumours are immediately intuitive. This approach surpasses education that is provided with current 2D MRI views on a computer screen. These techniques, once confirmed in larger groups, will allow for the earlier recognition of tumour advancement as compared to treatment effects, the prevention of unnecessary neurosurgical procedures from being performed, and for treatment changes to occur more quickly. In addition, our 3D approach provides a more eloquent platform that may quickly inform on the value of new and novel GBM treatments for our patients.

www.researchoutreach.org

13

Health & Medicine ︱ Professor Patrick Riley

Carcinogenesis:

When transmission of epigenetic information goes awry Genes are blueprints that code for proteins and in turn, proteins drive most activities within our cells. But between genes and their protein products is the layer of epigenetics – genes may be expressed differently depending on the heritable, epigenetic features that switch them on and off.

Charting new territories in carcinogenesis, Professor Patrick Riley at University College London explores the idea that cancers arise when inheritance of epigenetic information goes awry.

A

lthough we all started as a single cell with a half-genome from each parent, that single cell quickly divided, new cells were created and became different from each other. This process of cell differentiation enables multicellular organisms to contain hundreds of different cell types, each capable of carrying out specialised functions. It was initially thought that these differences were the result of the loss of parts of genetic material from the fertilised egg. However, transplantation studies revealed that each cell expresses only a proportion of the genes in its total repertoire, and that the answer lies in the way that each cell deploys its genome.

Epigenetics is the process by which cells designate some genes for use and others for storage. In essence, epigenetic changes allow cells to regulate their gene expression without permanently changing the genes themselves.

Pushing the boundaries of our knowledge of the fascinating field of epigenetics is Patrick Riley, Emeritus Professor of Cell

14

www.researchoutreach.org

Pathology at University College London.

Professor Riley suggests that defects in the somatic inheritance of epigenetic information offer an explanation for the development and characteristics of cancer.

TURNING GENES ON AND OFF The process of differentiation involves gene silencing and relies on small, reversible changes to the DNA complex that makes up chromosomes; these include DNA methylation and histone modification. Within a cell, segments of DNA are tightly packed around proteins called histones to form nucleosomes. In turn, nucleosomes are strung together to create chromatin, the fibre from which chromosomes are made. This tightly packed coiling provides a way of strictly controlling gene activity (or gene expression).

To activate a gene, the portion of DNA containing the gene must be accessible. Histones control how tightly the DNA is packed, and thus

Duplication of the nucleosome

Newly synthesised histones

Recycled histones

p53 Methylated cytosine Quality control inspection of reassembled histones DNA

DNA polymerase

DNMT1

DNMT3a/3b

p53

Unmethylated cytosine

Highly schematised view of the stages in the duplication of the nucleosome organisation. The double-stranded DNA on the left is shown with the pattern of methylated cytosines (●) associated with a set of histones forming the initial nucleosome structure with associated proteins (in this case DNMT3a and 3b). The histones are removed and the two strands of DNA separated. Each of the single strands of DNA is copied by DNA polymerase, with the newly-synthesised complementary strands containing unmethylated cytosines (○). DNMT1 attaches to the hemi-methylated DNA and methylates sufficient of the unmethylated cytosines to enable the DNA to reassemble with the initial set of histones (some recycled and some newly synthesised as indicated by the arrows). With the proper nucleosome structure reformed, the associated DNMT3 enzyme complex completes any residual cytosine methylation reconstituting the initial nucleosomal pattern and ready for inspection by the p53 system. Possible sources of error are: (1) faulty methylation by DNMT1; (2) faulty reconstitution of nucleosome through faulty synthesis, modification or selection of histones; (3) failure to complete cytosine methylation due to absence of attachment or malfunction of DNMT3a/3b; (4) failure of the quality control system to detect nucleosomal abnormality.

how readable the genetic information is. Loosely packed nucleosomes (as in euchromatin) allow the DNA to be transcribed and the genes expressed.

In contrast, tightly packed nucleosomes (as in heterochromatin) prevent access of transcriptional machinery so that genes on these stretches of DNA are silenced.

The major way in which genes are silenced involves the attachment of methyl groups to specific cytosine bases of the DNA molecule.

This modification to part of the DNA determines the way that DNA associates with histones, consequently regulating which genes are able to be expressed. Epigenetic markers such as methyl groups keep cells on the straight and narrow – ensuring they divide in an orderly manner and remain true to their nature (e.g. that kidney cells remain kidney cells).

PRESERVING THE STATUS QUO In order to perpetuate the correct pattern of gene expression it is essential that at each cell division (when DNA is replicated), specific methylation patterns are replicated too. That is, DNA methylation has to be accurately copied to the newly made strands of duplicated DNA (i.e. correct transmission

during embryonic development) or failure of expression of previously active genes.

ERROR-PRONE EPIGENETIC INHERITANCE In a 2014 publication, Prof Riley proposed that carcinogenesis could be a result of a process involving defective transmission of epigenetic information, building on an idea first suggested in 1979 by Holliday1.

This concept is seen as a rational explanation for the main characteristics of cancer including the disturbances of chromosome structure and function, and the variable and abnormal patterns of gene expression resembling hypermutability.

Professor Riley suggests that defects in epigenetic inheritance offer an explanation for carcinogenesis. of essential epigenetic information).

Since the methylation pattern of DNA ultimately determines the chromosomal structure, any defective copying of DNA methylation could lead to altered chromosomal structure, resulting in inappropriate re-expression of previously silenced genes (such as those expressed

1 Holliday R. (1979) A new theory of carcinogenesis. Br J Cancer; 40:513–522.

www.researchoutreach.org

15

The crucial characteristic of malignant cells is abnormal migratory behaviour and as Prof Riley explains: “plants, whose cell walls preclude migration, do not get cancer. In animals, cell migration is an important feature of embryonic development but is strictly limited in the adult.” He noted that any defective expression of migratory behaviour normally associated with development would be catastrophic, particularly if it were a result of unscheduled expression of normal genes, as this would go unrecognised by the immune system.

Prof Riley also observes that cancer does not occur in non-dividing cells, suggesting that the crucial genetic errors arise only during DNA replication, as would be the case if they resulted from failure of fidelity of epigenetic copying.

CONFIRMATORY OBSERVATIONS Research by others is consistent with Prof Riley’s conjecture. All cancers display abnormal DNA methylation patterns, they show variable and abnormal gene expression, as well as chromosomal anomalies. In addition, it has been shown that the likelihood of malignant change

The key to carcinogenesis may lie, not in genetics, but in epigenetics.

POSSIBLE SOURCES OF ERRORPRONE EPIGENETIC TRANSMISSION Prof Riley’s current research has focused on unpicking the processes that may be responsible for defective epigenetic transmission, in particular the faulty methylation of DNA. The addition of methyl groups to DNA is controlled at several different levels, and is carried out by a family of enzymes called DNA methyltransferases (DNMTs). One particular enzyme, DNMT1, is of crucial importance because it recognises hemi-

Professor Riley suggests that an aberrant quality control system is an important factor in malignancy. occurring in a tissue is related to the number of stem cells and proportional to the rate of stem cell growth and proliferation.

Interestingly, there are differences between the majority of adult cancers and cancers of childhood (developmental malignancies). However, they both are explicable within the concept of an epigenetic origin. Developmental cancers appear to arise from the failure of differentiation. As Prof Riley explains: “childhood cancers arise from a lack of initial DNA methylation necessary to silence certain genes which impose restricted genetic patterns on the tissues of the developing organism. In these cases, the genesis of malignant behaviour appears to rest on the failure to initiate the proper epigenetic pattern rather than in the failure to perpetuate it.”

16

www.researchoutreach.org

methylated strands of DNA. During DNA replication in differentiated stem cells, the methylation pattern is maintained by a DNMT1 complex which methylates the newly-synthesised strand of DNA. Another important step involves the reassembly of nucleosomes and the incorporation of the correct histones.

These reconstituted structures determine the associated enzyme complexes that are important in the replication of the correct methylation pattern (as indicated in Scheme 1). Clearly there are several steps in this copying process that may be rendered defective by initiating mutations, such as, for example, by a mutation affecting the activity of DNMT1.

QUALITY-CONTROL MECHANISM A common defect in cancer cells involves inactivated p53. Acting as a ‘safety net,’ p53 prevents abnormal cells from

developing into tumours, and is the most common mutation detected in over 50% of cancers. Prof Riley puts forward the intriguing idea that the p53 system might be viewed as the ‘guardian of the epigenome,’ suggesting that one of its functions is to detect differences between the epigenomes of the division products of differentiated cells. Those that are detected as abnormal are earmarked for elimination by apoptosis (controlled cell death). In effect, p53 safeguards the accurate transfer of the epigenetic pattern, so that the differentiated pattern of gene expression and silencing is retained.

THE FUTURE: EPIGENETIC THERAPY? If the proposed model of carcinogenesis is correct, the initiating lesions consist of mutations affecting one or more components of the epigenetic copying mechanism, and it is probably unrealistic to be able to reverse the defective process; but it may be possible to devise an agent able to sensitively detect abnormal post-division methylation patterns and thus enable the development of uniquely targeted cytotoxic therapy.

However, in view of the apparent importance of the gatekeeper function of p53, there may be scope for preventive treatment by the introduction of extra copies of the gene, especially in highrisk individuals. There is evidence that the comparatively low cancer incidence in elephants is due to multiple copies of the p53 gene.

Behind the Research Professor Patrick Riley E: rebc900@ucl.ac.uk T: (+44) 20 8445 5687

Research Objectives

References

Professor Riley, University College London, investigates the effect of epigenetic changes on carcinogenesis, the formation of cancer.

Riley P A. (2014) Failure of fidelity of vertical transmission of epigenetic patterning as the basis for cancer. Melanoma Research, 24: 424-427.

Detail Professor Patrick Riley Totteridge Institute for Advanced Studies The Grange Grange Avenue London N20 8AB UK Bio Patrick Riley qualified in 1960 from UCHMS. He joined Claude Rimington’s Department of Pathological Chemistry in 1966 and worked on free radical mechanisms in pathology, including lysosomal damage and photosensitisation with Trevor Slater. He was successful in cultivating melanocytes in vitro and collaborated with Peter Sutton on culturing cancer cells. He spent much of his academic career studying melanocytes and melanoma, and developed experimental approaches to melanoma therapy involving metabolically targeted pro-drugs activated by tyrosinase.

Collaborators • Dr Mark Burkitt • Professor Roger Dean • Professor Charles Harding • Professor Ferdy Lejeune • Mr Brian Morgan • Professor John Vince

Riley P A. (1985) Pathological Migration: From Melanin to Malignancy. University College London.

Riley PA. (2018) Epimutation and Cancer: Carcinogenesis Viewed as Error-Prone Inheritance of Epigenetic Information.

J. Oncol. 1-4.

Riley P A. (1982) Is the establishment of a clone exhibiting defective DNA repair the initial stage of carcinogenesis? Med. Hypotheses, 9: 163-168.

Riley P A. (2017) The Epigenetic Theory of Carcinogenesis: p53 as the Guardian of the Epigenome. J. Oncol. Canc. Res., 1: 1-4.

Riley P A. (2018) Cancer Incidence in Relation to Species Size: The Peto Paradox in the Light of the Theory of Epigenetic Carcinogenesis. J. Med. Oncol., 1: 11-15.

Personal Response Pharmaceuticals that reverse epigenetic changes have exciting potential for a variety of cancers. How far are we from making this a realisation?

Unfortunately, although epigenetic engineering has exciting potential in some areas, I do not see a significant future for it in cancer because (given that the proposed model is along the right lines) the fundamental mechanistic error will be repeated each time a cell from an affected clone divides – that is why the phenomenon is so devastating. Advances in genetic insertion might enable cancer to be eradicated by increasing the number of copies of p53 in the human genome, as suggested at the end of the article.

At present the most promising therapeutic advances seem to be in the field of immunology, and an interesting development might be to couple a powerful antigenic molecule to an agent capable of detecting anomalously methylated DNA, thus alerting the immune system to any epigenetically-defective cell.

www.researchoutreach.org

17

Health and Medicine ︱ Dr Thomas E. Ahlering

Reduced PSA Prostate Cancer Screening: Lifethreatening Consequences?

In 2012, the United States Preventive Services Task Force issued a grade D recommendation against PSAbased prostate cancer screening.

This is because early diagnosis of low-grade cancers can lead to unnecessary overtreatment and patient suffering. However, many epidemiologists are concerned that this could lead to severe unintended consequences. Dr Thomas E. Ahlering, from the University of California, has further explored these concerns and has shown in a ground-breaking study that reduced PSA-screening can lead to increased incidence of high-risk disease and increased mortality rate.

18

www.researchoutreach.org

P

rostate cancer is the second most common cancer worldwide and the sixth leading cause of cancerassociated death among men. In 2012, there were approximately 1.1 million cases and 307,000 deaths. Generally, prostate cancer affects men over the age of 50 years old (around 42% of cases) and the majority of patients are over 60 years of age. The prostate is a small gland in the pelvis that is only found in men.

The main function of the prostate is to produce seminal fluid that is then mixed with sperm made by the testicles. Often patients suffering from prostate cancer are asymptomatic until the prostate is large enough to affect the urethra and urination.

THE PROSTATE-SPECIFIC ANTIGEN BLOOD TEST Currently, there is no single test used to diagnose prostate cancer. A variety of different diagnostic tools can be used including MRI scans, blood tests, biopsies and digital rectal examinations

(a physical inspection of the prostate).

Another method used to detect prostate cancer is the ‘prostate-specific antigen’ (PSA) blood test introduced in 1988.

PSA is a protein produced by the prostate and prostate cancer cells. As men age and the prostate gland becomes larger the level of PSA naturally increases.

However, abnormally high levels of PSA can be a potential sign of cancer.

A major benefit of the PSA blood test is that it can be used to detect early-stage prostate cancer in asymptomatic men.

This has reduced the number of deaths from prostate cancer by at least 50%.

However, there are several limitations of the PSA blood test: i) in some cases men have a raised PSA level even if they do not have prostate cancer, ii) the PSA test can miss prostate cancer – around 15% of patients with a normal PSA level may actually have cancer, ii) the PSA test can diagnose a slow-growing prostate cancer which wouldn’t shorten the patient’s life and could, in fact, expose

Average Volume of Radical Prostatectomies per Year

63

2500

62.5 62

2000

Age (Years)

Number of Patients

Multi-institutional Trends in Demographics and Adverse Pathologic Features of Men Undergoing Radical Prostatectomy.

1500 1000

Average PSA of patients at time of surgery per year

60 59.5 2013

2014

2015

2016

2009-2012

5.60 5.40 5.20 5.00

2014

2015

2016

250

Number of patients

Number of patients

5.80

2013

Number of patients with LNI per year

250

6.00

61 60.5

0

Number of patients with pGS≥4+5 per year

6.20

61.5

500

2009-2012

Total PSA (ng/mL)

Average age of patients at time of surgery per year

3000

200 150 100 50

200 150 100 50

4.80 0

4.60 2009-2012

2013

2014

2015

2016

the patient to unnecessary suffering associated with overtreatment. Treatment for prostate cancer can have severe side effects impacting the patient’s quality of life including urinary, bowel and erection problems.

GRADE D RECOMMENDATION These limitations of the PSA blood test led to the United States Preventive Services Task Force (USPSTF) issuing a grade D recommendation in May 2012.

This means that PSA blood tests are no longer used as a diagnostic tool for prostate cancer screening. The task force argued that the benefits of the PSA blood test did not outweigh the costs.

0 2009

2010

2011

2012

2013

2014

2015

2016

2009

2010

2011

2012

2013

2014

2015

2016

Limitations of the PSA blood test led to the United States Preventive Services Task Force issuing a grade D recommendation. by this observation, Dr Ahlering and his team decided to perform a more in-depth study to investigate the effects of reduced PSA screening.

SHORTCOMINGS OF THE USPSTF STUDY The D grade recommendation was mainly based on two randomised trials – Prostate, Lung, Colorectal and Ovarian

(PLCO) and European Randomised Study for Screening of Prostate cancer (ERSPC).

The PLCO results revealed no significant mortality differences with PSA screening and the ERSPC showed that around 1400 patients needed to be screened in order to prevent one death. However, there are some significant flaws in these studies. The PLCO assigned men randomly to a PSA screening or usual

However, Dr Ahlering and other epidemiologists are concerned that a reduction in PSA screening could lead to several severe unintended consequences. These include: I) more men suffering from the effects of noncurative interventions such as radiation and hormonal therapy ii) physiological complications of recurrent prostate cancer iii) an increased incidence in high-risk disease and iv) a potential increase in prostate cancer-associated mortality.

Alarmingly, Dr Ahlering observed that the Task Force policy had a significant impact on his practice – there was a 2025% reduction in referrals 4 months postrecommendation. Dr Ahlering and his team also noticed that patients were older and had higher PSA levels indicating more advanced disease. Concerned

www.researchoutreach.org

19

care group. In-depth analysis revealed that there was a high contamination rate (52%) via PSA testing in the usual care group. Additionally, the ERSPC trial was insufficient. Typically, prostate-cancer associated mortality, from initial diagnosis, is 10-12 years. However, the follow-up time in this trial was only 7 years and a re-analysis revealed that the number of patients needed to be screened to prevent one death was 293.

THE STUDY In response to the grade D recommendation, Dr Ahlering and his colleagues performed a nationwide study, collecting data from an additional 8 high-volume surgeons throughout the United States. Overall, the team collated data from over 19,000 patients undergoing robot-assisted radical prostatectomy pre (October 2008 – September 2012) and post-policy (October 2012 – September 2016).

Population datasets take approximately 10-20 years to mature. However, instead of waiting for this long period of time, Dr Ahlering and his team used oncological metrics that are highly predictive of disease aggressiveness.

These methods include the pathologic Gleason grading system, whereby biopsy samples are used to diagnose patients,

20

www.researchoutreach.org

The one-year biochemical recurrence post-radical prostatectomy increased from 6.3% to 17.5%. seminal vesicle invasion and lymph node metastases.

The results confirmed that the proportion of low-grade prostate cancers dropped from 30.2% in the pre-policy era to 17.1% in the post-policy era. However, compared to the four-year average pre vs post policy there was a 22.6% reduction in surgeries performed, an increase in median PSA (from 5.1 to 5.8 ng/ml) and increase in mean age (from 60.8 to 62 years) and a doubling of high-grade Gleason cancers, meaning that the prostate cancers were much more aggressive post-policy.

Furthermore, the team found a 3.5fold increase in patients with advanced seminal vesicle involvement, a tripling of lymph node metastases and the oneyear biochemical recurrence post-radical prostatectomy increased from 6.3% to 17.5%. This is where PSA blood levels rise following treatment, which could indicate that the cancer has come back.

A major strength of this study was the use of propensity score matching

for age and PSA across both the prepolicy and post-policy screening eras.

The team show that there is a stepwise increase in high-risk disease each year after the policy was put in place.

FUTURE STUDIES Overall, Dr Ahlering and his team have highlighted the concerning effects of limited PSA screening. Although the recommendation has reduced surgical treatment for low-grade cancers, the study has shown that reduced screening can lead to an increased risk in aggressive forms of prostate cancer.

This affects the patient’s quality of life and significantly increases mortality rate.

Furthermore, the increase in biochemical recurrence after 12 months of surgery will lead to additional consequences associated with secondary treatment.

Clearly, it is of great importance that we find a compromise so that screening is effective and minimises overtreatment but preserves early diagnosis.

Behind the Research Dr Thomas E. Ahlering

E: tahlerin@uci.edu T: +1 714 456 7354 W: http://urology.uci.edu/prostate/

Research Objectives

References

Dr Thomas E. Ahlering from the University of California, shows that high-risk prostate cancer results from USPSTFenforced reduced prostate cancer screening.

Ahlering, T., Huynh, L.M., Kaler, K.S., Williams, S., Osann, K., Joseph, J., Lee, D., Davis, J.W., Abaza, R., Kaouk, J. and Patel, V. (2018). ‘Unintended consequences of decreased PSA-based prostate cancer screening’. World journal of urology, pp.1-8.

Detail

Harrison, P. (2018). ‘Prostate Cancer More Aggressive in PostUSPSTF Era’. Medscape. Available at: https://www.medscape. com/viewarticle/900073. [Accessed 11/11/2018].

School of Medicine University of California, Irvine 333 City Blvd West, Suite 2100, RT 81 Mail Code: 5395 Orange, CA 92868 USA Bio Dr Ahlering is a highly regarded surgeon in Urologic cancers. Since 2002, Dr Ahlering’s research efforts have concentrated on maximizing functional recovery and patient-reported outcomes following robot-assisted radical prostatectomy. His work continues to be highly regarded among the scientific community, with over 400 published abstracts and journal articles.

Collaborators • Linda My Huynh • Kamaljot S. Kaler • Stephen Williams • Kathryn Osann • Jean Joseph • David Lee • John W. Davis • Ronney Abaza • Jihad Kaouk • Vipul Patel • Isaac Yi Kim • James Porter • Jim C. Hu

Sadeghi-Gandomani, H., Yousefi, M., Rahimi, S., Yousefi, S., Karimi-Rozveh, A., Hosseini, S., Mahabadi, A.A., Abarqui, H.F., Borujeni, N.N. and Salehiniya, H. (2017). ‘The incidence, risk factors, and knowledge about prostate cancer through worldwide and Iran’. World Cancer Research Journal, 4(4), pp.1-8.

2018. Prostate Cancer. NHS. Available at: www.nhs.uk/ conditions/prostate-cancer/ [Accessed 11/11/2018].

2016. The PSA Test. Prostate Cancer UK. Available at prostatecanceruk.org/prostate-information/prostate-tests/psatest [Accessed 11/11/2018].

Personal Response How can we reduce overtreatment but ensure that prostate cancer is diagnosed early so it doesn’t develop into a high-risk disease?

To prevent (i.e. minimise) high-risk prostate cancers, the disease must be asymptomatic. Presently, organised PSA screening is the best means of identifying these men. The key to preventing overtreatment has two complementary paths. First, active surveillance/ watchful waiting with intent to pursue no treatment based on “expected” overall survival versus “estimated” cancer aggressiveness. In contrast, another path is to simultaneously improve treatment outcomes in order to reduce the treatment burden. In essence, liken a radical prostatectomy to an appendectomy: a low-risk procedure with minimal risk for complication. It is our assertion that overtreatment with minimal burden is superior to no burden at the cost of lives.

www.researchoutreach.org

21

Health and Medicine ︱ Professor Tetsuya Kodama

Lymph nodes targeted in novel cancer therapy

90% of global deaths caused by cancer are the result of its metastasis. Cancer can spread throughout the body through the blood system or the lymphatic system. With funding from JSPS KAKENHI, Professor Tetsuya Kodama at Tohoku University in Japan and his collaborators established a novel mouse model to study cancer metastasis through the lymphatic system. With this model, they identified lymph node metastasis as the starting point of metastatic disease.

Their research has focused on developing a new cancer therapy to target specifically lymph node metastasis and holds huge revolutionary potential for the treatment of metastatic cancer.

22

www.researchoutreach.org

C

ancer was estimated to have caused 9.6 million deaths globally in 2018. In 90% of cases, it is not the primary tumour that is lethal, but it’s metastasis. Metastasis is the spread of malignant (cancerous) cells around the body resulting in the growth of secondary, metastatic tumours. When a tumour metastasises, it can spread through the bloodstream (known as a hematogenous spread)

metastasise via the lymphatic system: these cancer cells travel to nearby lymph nodes (known as regional lymph nodes) where they develop, causing the lymph nodes to swell, and then circulate around the body to other ‘downstream’ lymph nodes. When cancer has reached the lymph nodes, it is also possible cancer will spread into the bloodstream in what has been termed ‘lymph nodemediated hematogenous metastasis’.

In 90% of cases, it is not the primary tumour that is lethal, but it’s metastasis. or through the lymphatic system (known as a lymphatic spread). The lymphatic system is comprised of lymphatic vessels that circulate lymph (fluid containing white blood cells, amongst other components), forming an important part of the body’s immune system. Cancers such as breast, head and neck cancer

This theory suggests that the first lymph node or group of nodes that cancer travels to (known as the sentinel lymph node/nodes) is the ‘start point’ of metastasis. Professor Tetsuya Kodama of Tohoku University, together with his colleagues have developed a new way to effectively treat metastatic cancer

by targeting these lymph nodes with chemotherapy directly introduced into the lymphatic system.

Staging of cancer is based on TNM classification. T category describes the primary tumour site. N category describes the regional lymph node involvement.

M category describes the presence or otherwise of distant metastatic spread.

In TNM classification, T0 is defined as no detection of a primary tumour, N0 is the absence of metastasis in the regional lymph nodes, and M0 is defined as no distant metastases. The factors of TNM classification other than T0, N0 or M0 are defined by the type of tumour. Classifying tumours according to the TNM system, however, has its limitations. One such limitation is the frequency at which lymph nodes are incorrectly described as ‘N0’.

If cancer has spread beyond the sentinel lymph node, but the downstream lymph nodes do not exhibit noticeable swelling, ‘false-negative’ results are obtained.

This makes the conventional treatments (surgical lymph node resection, radiotherapy and/or chemotherapy) for lymph node metastasis unsuitable to treat N0 false-negative metastatic cancer.

In addition, chemotherapy administered into the bloodstream through an I.V. injection or infusion (known as systemic administration) has been found to have limited success in treating cancer in the lymphatic system as the chemotherapy

Vein

Vein

Lymphatic Vessel

Lymph Node

Artery

Sentinel Lymph Node

Primary Tumour LYMPHATICS DRUG DELIVERY SYSTEM

A high dose of an anticancer drug into a metastatic lymph node (sentinel lymph node) and deliver the drug to downstream lymph nodes lymphatic network, thereby treating or preventing metastasis in the injected lymph node and downstream lymph nodes. The amount of drug used in the LDDS is extremely small compared to systemic chemotherapy, thus there are few side effects on the whole body.

drugs become diluted in the blood resulting in low concentrations of the drug reaching the lymph nodes.

Chemotherapy can also cause adverse side effects because it circulates in the body, rather than selectively treating the malignant target.

Research into improving the treatment of lymph node metastasis had been previously limited largely due to a lack of appropriate animal models of the disease. Kodama and his collaborators were able to establish a novel mouse model that contains lymph nodes of a similar size to that of humans (up to 10 mm), allowing lymph node metastasis to be studied in animals for the first time.

Lymphatic drug delivery systems were developed to allow direct administration of drugs to the lymphatic system through injections in lymph nodes (also known as intranodal injections). Using fluorescent dyes, Kodama and his team were able to visualise how fluid drains from the ‘upstream’ sentinel lymph node to ‘downstream’ lymph nodes in their novel mouse model. From these findings, lymphatic drug delivery systems were able to be developed to specifically target cancer in the lymphatic system.

When you go to the hospital feeling abnormality such as a lump, the palpation is performed first. Next, image diagnosis such as mammography, ultrasonography (echo) MRI and CT are conducted, finally biopsy is conducted to confirm the diagnostic results.

Using their mouse model, Kodama and his collaborators observed how cancer metastasises through the lymphatic system. Their research shows a decreased flow from the sentinel

www.researchoutreach.org

23

The lymphatic network consists of lymphatic vessels. Lymph nodes are organs, which are located in lymphatic vessels to remove foreign bodies. There are about total 600-800 lymph nodes spread out in the body.

lymph node to downstream lymph nodes when cancerous tumours develop in the vessels between them. Instead, the flow was orientated to the blood system.

This observation led the researchers to theorise that ‘lymph node-mediated hematogenous metastasis’ is the final stage in lymph node metastasis, and the sentinel lymph node should, therefore, be targeted as the ‘start point’ of cancer metastasis.

Cisplatin, a chemotherapy drug used to treat cancers such as breast cancer and head and neck cancer, injected into the sentinel lymph node of mice was found to stop the growth of tumours in false-negative metastatic lymph nodes. In addition, Kodama and his team observed fewer adverse side effects to cisplatin, such as kidney disease, when given as an intranodal injection than when given systemically through an I.V. By administering chemotherapy with lymphatic drug delivery systems, the concentration of the drug is much higher when it reaches the target lymph nodes, meaning dosage can be much lower and fewer doses would be needed.

Chemotherapy can be injected and

24

www.researchoutreach.org

This treatment has a huge potential to reduce cancer mortality by stopping cancer before it can spread beyond the lymphatic system. allowed to flow to downstream lymph nodes prior to surgical resection of the primary tumour and sentinel lymph node, dramatically reducing the risk of cancer recurrence. This treatment has a huge potential to reduce cancer mortality by stopping cancer before it can spread beyond the lymphatic system.

Kodama and his colleagues are currently researching factors that could limit the success of lymphatic drug delivery systems in treating false-negative lymph node metastasis. Their most recent paper describes an investigation into the impact of chemotherapy drug injection on the flow of the drug to downstream lymph nodes in mice. Their results show that factors such as injection pressure and the volume of the sentinel lymph node do not impact on the success of the treatment. They also identified an optimal range of injection rates to administer the

chemotherapy to ensure the drug flowed to downstream lymph nodes.

The group will design Phase I clinical trial to investigate the safety and effectiveness of lymphatic drug delivery system using chemotherapy within a few years, followed by Phase II clinical trials to confirm efficacy.

Kodama and his colleagues’ work has paved a new way in not only researching lymph node metastasis using mice and thinking about how cancer metastasis, but also in how cancer therapy can be targeted. Lymphatic drug delivery systems using chemotherapy could dramatically improve the survival rates across many types of cancer whilst decreasing the side effects of treatment.

The work briefly discussed here is likely to revolutionise cancer therapy.

Behind the Research Professor Tetsuya Kodama

E: kodama@tohoku.ac.jp T: +81 22 717 7583 W: www.ecei.tohoku.ac.jp/kodama/english/index.html

Research Objectives

References

Metastasis, a characteristic of many tumour types, is estimated to be responsible for the death of 90% of all patients with cancer. However, effective treatment of metastasis has not been established. In Professor Tetsuya Kodama’s laboratory, they focus on early diagnosis and treatment of lymph node metastasis, observed in most cancers, such as breast cancer and head and neck cancer.

Cancer Research UK (2017) TNM staging. [Online] Available at: https://www.cancerresearchuk.org/about-cancer/ breast-cancer/stages-types-grades/tnm-staging [Accessed 17/10/2018].

Detail Director of Biomedical Engineering Cancer Research Center Laboratory of Biomedical Engineering for Cancer Graduate School of Biomedical Engineering Tohoku University 4-1 Seiryo, Aoba, Sendai 980-8575, Japan Bio Dr Tetsuya Kodama is a Professor at Tohoku University. He is the Director of the Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering Tohoku University. He gained a PhD in engineering and a PhD in medicine from Tohoku University (Japan) in 1992 and 2011, respectively.

Funding JSPS KAKENHI Grant Number: 17K20077, 17H00865, 26242051, 24650286, 23300183, 21650124 Collaborators • Dr Shiro Mori, Tohoku University Hospital, Japan.

• Dr Maya Sakamoto, Tohoku University Hospital, Japan.

• Dr Naoko Mori, Tohoku University Hospital, Japan.

• Dr Koichi Ito, Tohoku University Graduate School of Information Sciences.

• Professor Kiyoto Shiga, Iwate Medical School, Japan.

Fujii, H., Horie, S., Takeda, K., Mori, S. and Kodama, T. (2018).

‘Optimal range of injection rates for a lymphatic drug delivery system’. Journal of biophotonics, [online] p.e201700401.

Available at: https://doi.org/10.1002/jbio.201700401 [Accessed 12/10/2018].

Kodama, T., Hatakeyama, Y., Kato, S. and Mori, S. (2015).

‘Visualization of fluid drainage pathways in lymphatic vessels and lymph nodes using a mouse model to test a lymphatic drug delivery system’. Biomedical optics express, [online] 6(1), pp.124-134. Available at: https://doi.org/10.1364/ BOE.6.000124 [Accessed 13/10/2018].

Kodama, T., Matsuki, D., Tada, A., Takeda, K. and Mori, S. (2016). ‘New concept for the prevention and treatment of metastatic lymph nodes using chemotherapy administered via the lymphatic network’. Scientific reports, [online] 6, p.32506.

Available at: https://doi.org/10.1038/srep32506 [Accessed 13/10/2018].

Tada, A., Horie, S., Mori, S. and Kodama, T. (2017).

‘Therapeutic effect of cisplatin given with a lymphatic drug delivery system on false negative metastatic lymph nodes’.

Cancer science, [online] 108(11), pp.2115-2121. Available at: https://doi.org/10.1111/cas.13387 [Accessed 13/10/2018].

Personal Response Cancer death rates are so high due to late diagnosis – how do you think targeting lymph node metastasis with lymphatic drug delivery systems could help reduce the mortality rates of cancer?

Although our method targets N0, lymphatic drug delivery systems are applicable to lymph nodes ³ N0, i.e, patients whose cancer has progressed into the lymphatic system to varying degrees. The method can also be applied to patients who are unsuitable for surgical resection of their lymph nodes, due to factors such as age or if the cancer has spread beyond the sentinel lymph node and outside the region of lymph node dissection. For patients such as these, our method can improve life prognosis greatly.

www.researchoutreach.org

25

Health and Medicine ︱ Dr James Stone

Time for a new approach to severe traumatic brain injury and stroke: Developments in automated, real-time monitoring of brain stem function Traumatic brain injury and stroke can lead to a potentially fatal condition known as transtentorial herniation (TTH).

Monitoring sedated patients for indications that TTH is developing presents many complications. Dr James Stone from New York University has developed a modified version of a test for brain activity in response to sound that shows promise in detecting early indications of TTH. This highly sensitive monitoring tool, Coma AlertTM could enable earlier intervention at the stage when further severe damage could be prevented and outcome quality improved.

T

he human brain is an electrophysiological marvel.

By the virtue of ionic chemical gradients creating minute electronic pulses, about 80 billion nerve cells have set up an electrical grid with 20 Watts of power. Although just enough to illuminate a small light bulb, the complexity of the brain is far and away unequalled by any man-made system and will likely remain so. Beginning with the first man-like creature, 4-5 million years of evolutionary shaping and adaptation has led the human brain to a complexity only partially mirrored on earth by our primate ancestors. The durability of the human brain to maintain high level, sophisticated functioning for a lifetime, under many manners of perturbation, speaks to a majestic beauty of design and architecture.

Invasive ICP monitors use a device placed inside the head of the patient.

26

www.researchoutreach.org

Brain malfunction due to head trauma or stroke (insufficient blood flow to the brain) resulting in death or disability is not an infrequent occurrence. Indeed, stroke is the world’s second most frequent cause of death (about 6.3 million deaths per year, World Health Organization, 2016).

When both mortality and permanent disability are factored in, Traumatic Brain Injury (TBI) is estimated to affect 50 million people each year. Although receiving more attention recently, TBI has been a major but largely neglected global problem. It is the leading cause of mortality in young adults, a major cause of disability across all ages, and believed to increase the risk of late-life dementia.

Financial consequences of TBI are estimated to cost the global economy $400 billion annually (Maas et al, Lancet Neurol 2017;16:987-1048).

CURRENT APPROACHES AND LIMITATIONS The key to improving outcome after severe TBI, deteriorated cases of moderate TBI, large volume stroke, or any large space-occupying brain condition with altered consciousness demands rapid diagnosis and timely treatment. Prompt airway intubation and adequate ventilation is required to reduce carbon dioxide levels – which lead to both engorgement of the blood vessels in the brain and increased intracranial pressure (ICP). Once intubated, the patient must be sedated. Under sedation, the usual clinical neurological indicators are lost other than the reactivity of the

pupils. A CT scan of the brain must be obtained as soon as possible to determine the presence of skull fractures, haemorrhage or contusion within the cerebral tissue, and haematomas (subdural or epidural) compressing the cerebral brain surface. Haematomas or swollen brain tissue may cause concerning midline shift and crowding at the base of the brain, resulting in herniation of the medial temporal lobe.

This displaces the midbrain and adjacent deep structures (vital to life) across the midline (known as uncal or transtentorial herniation, TTH).

Over the past 3–4 decades, critical care emphasis for severe TBI has been on placement of an invasive ICP monitor within the ventricles (fluid-filled cavities in the brain) or in the brain tissue itself.

Ventricular placement may provide a more accurate pressure and fluid drainage may help control ICP – but only if the ventricles are adequately open and communicate. ICP monitors are routinely placed on the side opposite the major damage, for fear of inciting further damage or deterioration in placement, and thus may underestimate the ICP level, or propensity for TTH.

In this setting TTH is a frequent cause of fatality or severe disability, as bruising and damage develops in the midbrain portion of the brainstem or adjacent regions. Onset of TTH is usually associated with changes in pupil size or reactivity and complicates severe TBI in about 30–40% of cases. Deterioration leading to TTH may also be seen in up to 20% with moderate TBI, large volume stroke, or other brain conditions.

Pupillary changes with TTH can occur within minutes or several hours or days after injury. Once present, TTH is not always fully reversible following urgent neurosurgical decompression. A noninvasive, real-time, automated and alarmed warning system is necessary to capture the earliest signs of TTH and allow adequate time for physicians and surgeons to intervene.

Because the brain is enclosed within the hard, rigid skull one may assume a measurement anywhere within the skull or brain will reveal a global pressure – much like the air pressure in an automobile tire. Unfortunately, this is not so. In fact, the brain tissue

not yet changed. At this desperate point, a surgical decompression or debulking of cerebral contusions or swelling (oedema) may be considered, but lacking a brain function monitor to guide us, timely opportunity often slips away.

It must be understood that the brain functions as an electrochemical organ and ICP measurement does not directly relate to any specific brain function: it remains a distinctly indirect measure of brain dysfunction. It should be appreciated that development of non-invasive, robust, continuous, neurophysiological recordings of basic brainstem (midbrain) conductivity/ viability is within our reach. It has been proved in controlled experiments in subhuman primates that a significantly earlier warning of TTH comes with such brainstem (midbrain) recordings from the scalp following auditory stimuli compared to ICP recordings.

A non-invasive, real-time, automated and alarmed warning system is necessary to capture the earliest signs of TTH – allowing adequate time for physicians and surgeons to intervene.

In many other cases haematoma size, brain swelling and midline shift are not deemed significant to warrant surgery, and the patient is observed in an intensive care unit (ICU). Once or twice per day the sedation can be temporarily withdrawn in a cursory and often unreliable effort to examine the patient’s ability to respond to pain stimuli and move extremities. Unfortunately, many patients under observation deteriorate several days later, and without apparent warning slip into various degrees of TTH. The culprit is often progressive brain swelling or consolidation of cerebral contusions, compounded by respiratory or fluid issues.

itself (about 70% of the contents of the skull) is predominately a viscoelastic (plastic) solid structure and not of liquid composition like the ventricular fluid.

Being highly non-compressible yet deformable, the brain substance is prone to develop pressure gradients especially within semi-closed compartments like the temporal and cerebellar cavities.

Close to the brainstem, these are not areas for ICP placement. The insidious onset of TTH may thus occur. A noninvasive monitoring device that can capture the early development of TTH, before pupillary changes occur, and lead to prompt medical and/or surgical treatments would greatly decrease the high mortality and very significant permanent disability in those who survive.

“Uncontrolled ICP” can be fatal. However, that situation is more often encountered where surgery was not initially required, but Neuro-ICU medical treatments begin to fail. It likely indicates some gradual degree of TTH herniation has begun, even if the pupil size and reactivity have

Dr Stone and his team feel the goal should be development of continuous neurophysiological monitoring for the earliest warning of TTH, when the patient’s functions may still be salvaged.

Over the past 30 years, general advances in Neuro-Intensive care including the adoption of ICP monitoring have shown clear improvements in the mortality of severe TBI, but significant improvement in the number of survivors with a favourable outcome has not been forthcoming. Recently, a study protocol treating severe TBI patients in the absence of ICP monitoring showed that frequent CT scans, especially when elevated ICP was suspected and treated, in addition to periodic sedation withdrawal clinical examinations, yielded outcomes not significantly different from those randomised to ICP monitorbased protocols. The authors warn that the above protocol warrants further study, but “the evidence suggests the absence of ICP monitoring does not preclude obtaining satisfactory recovery through aggressive management without such monitoring.” (Chestnut, et al J Neurotrauma 35:54-63. 2018).

www.researchoutreach.org

27

Dr Stone’s method of monitoring is non-invasive.

A BETTER WAY? Dr James Stone has been studying TBI function for over four decades. He has followed every milestone and progression in technology the field has seen. Stone recognised that as an electrical organ, the brain would benefit from more direct and sensitive measures of neural activity.

His early sub-human primate work established animal models of ICP and TTH progression and concurrent brain dysfunction monitored by sequential Evoked Potentials (EPs).

Whilst at the Cook Country Head Injury lab, Stone used an intracranial balloon within the temporal/parietal skull of monkeys to study increases in ICP and its effect on brain function up to the point of TTH. Vital signs, pupil size and reactivity and Evoked Potential (EP) responses were also recorded. EP responses are a type of neural activity evoked by a particular stimulus. Stone’s work primarily focused on somatosensory evoked potentials (SSEP) and brainstem auditory evoked potentials (BAEP) also known as the auditory brainstem response (ABR). In simple terms, the test for BAEP involves presenting patients with a sound, typically a ‘click’, at various loudness levels and monitoring the neural response from the midbrain portion of the vital brainstem.

A strong correlation was found between changes in BAEP, SSEP and increases in ICP as a balloon was inflated gradually over a four-hour period. BAEP gave the most sensitive warning before TTH, signalled by changes in the pupils, followed by the ICP and SSEP. A NEW STANDARD From this point onwards, Stone aimed to establish a more sensitive and earlier warning of TTH using the BAEP (Wave V and Vn amplitude and latency measures) examination. At the time, BAEP waves took approximately 7–8 minutes to record; Stone aimed to reduce this delay to 3–4 minutes. To achieve this, he developed modified BAEP (mBAEP) in animals and human volunteers by altering the auditory stimulus used by stimulating both ears simultaneously, increasing the rate of presentation (both build V and Vn amplitude) and utilising four diminishing loudness intensities.

Recording electrodes are placed on the forehead and neck. 75 normal hearing human volunteers established appropriate mBAEP testing modalities for study.

Next, about 150 patients with cerebral brain lesions were studied in order to test reliability of the mBAEP. A number of patients had concurrent measured ICP values. The standard BAEP at two

Recovery from brain trauma is a time game, where minutes really do matter.

Diagnosis within the first three hours can drastically improve patient outcome.

28

www.researchoutreach.org

different sound intensities, as well as the mBAEP was also performed in over 100 patients. In more recent studies, Stone used CT scans and MRI scans of the patients to document the size and locations of the lesions and improvement of mBAEP after surgical removal of the mass lesion. This allowed the use of multiple comparative measures to assess validity and sensitivity. Compared to the standard BAEP, Stone’s mBAEP produced more prominent V and Vn waves for latency and amplitude measurements.

This allowed greater and more robust statistical analyses. Importantly, this meant a faster and arguably more reliable measure of midbrain dysfunction than the standard snapshot BAEP techniques currently employed.

FUTURE DIRECTIONS As a collective, Stone’s work has sought to highlight the need for improved brain monitoring of severe TBI, large volume stroke, and other space occupying brain lesions and dysfunction at earlier stages than other popular approaches yielded.

The introduction and progression of the brainstem auditory evoked potentials (BAEP) continues to be a success in this direction. Across a number of studies, Stone has demonstrated the efficacy of mBAEP. Whilst their improvements over other measures are clear, limitations still exist.

These measurements at present are by no means automated, requiring a technician to take repeated measurements, as well as later interpretation of results. For Stone, there is a need to develop automated, nurse/staff friendly neurophysiological monitoring with alarms in the Neuro Intensive Care Units to best utilise these vital BAEP measurements (Stone et al 2017). He draws parallels with neurosurgical operating theatres where such monitoring already exists, implemented to alert staff when certain critical thresholds are reached. Such a system would achieve efficient, userfriendly monitoring of brain-trauma and other patients that is cost-efficient and staff-friendly with great potential to enhance both patient survival and outcome quality. His goal is partnership with industry to build a prototype of Coma AlertTM and begin implementation and studies in New York City where he presently resides.

Behind the Research Dr James Stone

E: jlstone4@gmail.com T: +1 312 806-0145 W: www.societyns.org/society/bio.aspx?MemberID=181

Detail

Research Objectives

James L Stone, MD, FACS Professor of Neurosurgery, New York University, Langone School of Medicine, NY, NY, and Chief of Neurosurgery Manhattan Veterans Hospital, NY, NY 440 E. 23rd St, Apt 3B New York, NY 10010 USA

Dr James Stone’s work focuses on real-time, nurse-friendly monitoring of vital brainstem function in brain trauma patients.

Bio Dr James L Stone, was born and raised in Chicago, IL USA, graduated from the University of Wisconsin in 1970 (BA), and from St. Louis University School of Medicine with honors in 1974 (MD). While a senior medical student in 1973 he rotated to Chicago’s Cook County Hospital (CCH) Trauma Unit – the USA’s first designated trauma centre.

There, Dr Stone was greatly influenced by the challenges of severe trauma care, and dynamic spirit of the Unit and its founding surgeons. His Surgical Internship was at CCH, followed by Neurological Surgery Residency at CCH and the adjacent University of Illinois Hospital at Chicago (UIC) completed in 1980. Neurology Residency and Clinical Neurophysiology Fellowship were also obtained at UIC. Dr Stone spent three decades treating and studying severe Traumatic Brain Injury (TBI) at CCH. Dr Stone’s major research effort has been the development of brainstem electrical recordings to be applied to the serious clinical problem of Transtentorial Herniation (TTH).

Funding Natus Medical/Neurology University of Illinois / Chicago Collaborators • John Fino • Kevin Kriegel Disclosure Dr Stone has Intellectual Property and a Corporation Remote Vital Monitoring, Inc. Both are in conjunction with his earlier work at the University of Illinois at Chicago (UIC), IL, USA.

References Stone J,L. et al.(2012) Modified brain stem auditory evoked responses in patients with intracranial mass lesions. Clinical EEG and Neuroscience. 43:291-302.

Stone J,L. et al.(2017) Brainstem monitoring in the Neurocritical care unit. A rationale for real-time, automated neurophysiological monitoring. Neurocrit Care 26:143-156.

Vinciguerra L, Bosel J. (2017)Noninvasive neuromonitoring: Current utility in subarachnoid hemorrhage, traumatic brain injury, and stroke. Neurocrit Care 27:122-140.

Remote Vital Monitoring Inc. (2018). Retrieved from https:// remotevitalmonitoring.net/.

Personal Response Is there any particular metric of success in this field of post brain-trauma monitoring which you think would be easy to frame for the general public?

Recognition and early capture of transtentorial herniation (TTH), offers the best chance to improve the outcome in severe TBI, large volume stroke and other brain conditions. A fellow researcher put this as follows: “Real-time assessment of global or regional brain dysfunction could help clinicians recognize early worsening, prompt specific management changes, monitor response to therapy…(and) …used as surrogate endpoints in clinical trials.” (Wijdicks EFM, Rabinstein AA. Critical care neurology: Five new things. Neurol Pract 2011;1:34-40). Additionally, such monitoring would augment our present treatments and be utilised in patients not ordinarily considered for invasive ICP monitoring – such as somnolent patients with moderate head injuries, stroke, and other brain lesions. (Stone JL, et al. Brainstem Monitoring in the Neurocriticalcare Unit: A Rationale for Real-Time, Automated Neurophysiological Monitoring.

Neurocritical Care 2017:26;143-156.)

Dr Stone is acting on behalf of UIC and the Corporation, not NYU Langone or Veterans Hospital.

www.researchoutreach.org

29

Health & Medicine ︱ Professor Dawn Langdon

BICAMS:

Shedding light on cognition in Multiple Sclerosis Multiple Sclerosis (MS) is a disease that attacks the central nervous system, leading to a variety of symptoms, across the physical and psychological domains. For many people with MS, symptoms can include difficulties with memory and thinking, which impacts on the quality of many aspects of their life. Dawn Langdon, Professor of Neuropsychology at Royal Holloway, University of London, has led an international project to develop BICAMS, an innovative battery of tests to revitalise our understanding of cognition in MS, with the aim that this aspect of the condition will be better understood and managed.

Cognitive difficulties can have a major impact on employment for people with MS.

M

ultiple Sclerosis (MS)1 affects more than 100, 000 people in the UK and millions more worldwide. It usually affects people between the ages of 20 and 50 years, and the average age of onset is approximately 34 years. MS is a neurological autoimmune condition, in which the body’s immune system attacks its own nerve cells 2.

or worse symptoms 4, which generally improve before another relapse occurs.

This is called relapsing-remitting MS 5.

Most relapsing-remitting patients enter the secondary progressive phase 5 sooner or later, when disability accumulates over time. Patients with primary progressive MS 5 do not have remission or relapse cycles; instead their symptoms gradually worsen over time from the outset.

MS attacks the myelin sheaths 3 that surround brain and spinal cord cells.

Myelin – a fatty substance that covers neurons – speeds up the transmission of electrical signals between cells allowing for efficient brain function. It is essential for normal motor, or movement, control and for other functions, including thinking and planning. In MS, the myelin sheath coating the nerves is damaged, leading to ineffective signalling between brain cells, and eventually cell death.

Some medications are available that reduce relapses and slow disability progression 6. Researchers are working to identify treatments that will halt the disease.

The majority of patients start experiencing relapsing remitting episodes, meaning that the symptoms of the condition come in waves of new

INVISIBLE SYMPTOMS MS is most known for its effects on motor control, leading some people to use wheelchairs eventually as the disease progresses. However, due to its widespread impact on the central nervous system, there are a constellation of other symptoms linked to the condition and a high range of variability between patients. Some of the lesser recognised effects of MS – sometimes referred to as the ‘invisible symptoms’ – can have a profound impact on quality of life. The invisible symptoms include fatigue, depression and pain. MS can also impact cognition.

Cognitive problems 7 – issues with memory, thinking and attention skills – are common in MS, affecting approximately half of patients living with the condition. Problems with thinking in MS are sometimes known as ‘cog fog’ 8 as patients describe being unable to think as clearly as they had done previously.

Cognitive impairment typically worsens as the disease progresses. As cognitive issues are not well known in MS, family and friends can find them hard to recognise and understand. Impairments in memory and concentration can

30

www.researchoutreach.org

affect daily tasks such as keeping up with conversations or managing household bills and can influence an individual’s ability to work 9.

An international team of experts led by Professor Dawn Langdon of Royal Holloway University of London are paving the way to better understanding of cognitive issues in MS. They have developed the Brief International Cognitive Assessment for MS (BICAMS) 10, a short, much-needed tool aimed at helping clinicians and researchers quickly and effectively understand the cognitive difficulties that affect more than half of patients.

DEVELOPING BICAMS Assessing cognitive impairment traditionally requires a lengthy neuropsychological testing – tests that reveal how brain function and aspects of cognition have been affected by disease or trauma, such as a stroke or accident.

Neuropsychological testing is conventionally carried out by trained psychologists using in-depth and lengthy pen and paper assessments.

Whilst this approach is comprehensive, it is also restrictive, limiting its use to specialist neuropsychologists, who are trained to use such assessments in scarce, well-resourced centres. As such, many people with MS who have cognitive impairment receive few valid tests of their cognitive function, meaning that their difficulties go misunderstood or even neglected, resulting in mismanagement 11.

BICAMS has been developed to provide non-specialists with the ability to assess the cognitive functioning of their MS patients, allowing many more centres to address cognition.

The availability of a brief, easy-to-use and standardised internationally recognised testing battery have also made it more likely that pharmaceutical trials are including assessments of cognition as part of their outcome measurements, meaning that cognitive impairment could

and validity. Reliability refers to the test’s robustness over repeated testing and between raters, whereas validity refers to the ability of the test to assess what it is intended to. A thorough evaluation of BICAMS revealed that it fulfilled all these markers of solid neuropsychological testing, making it a good measure.

Importantly, the battery has also been shown to be repeatable without marked learning effects, where participants do better on tests purely because they have done them previously.

Cognitive problems – issues with memory, thinking and attention skills – are common in MS, affecting approximately half of patients living with the condition. be better treated or managed in future12.

Cognitive impairment can be taken into consideration when potential drugs in the pharmaceutical pipeline are being assessed. Importantly, taking only 15 minutes to complete and requiring only pen and paper, BICAMS allows cognition to be tested inexpensively, maximising its potential use across centres and across countries.

PRINCIPLES OF NEUROPSYCHOLOGICAL TESTING In order to be an effective neuropsychological test, assessments must be shown to fulfil key criteria that measure robustness, including reliability

The BICAMS development process has had an international outlook13 from the outset, ensuring that the tests would be available to as many people as possible. This validation process has been carried out in eleven languages and in 16 different locations and cultures, again maximising its use across the world, which is key for its usefulness in clinical trials, which are increasingly carried out in multiple sites worldwide.

www.researchoutreach.org

31

BICAMS is now available for many people with MS around the world. Produced for triMS.online 2018 and reproduced with permission from Oxford Health Policy Forum; for further information contact: Info@trimsonlineconference.com.

BICAMS is a short, much-needed tool aimed at helping clinicians and researchers quickly and effectively understand the cognitive difficulties that affect more than half of patients.

COMPONENTS OF BICAMS In deciding which items should be included in BICAMS, Professor Langdon and her team selected tests that would tap into the cognitive areas – or domains – already known to be affected in some people with MS. The tests included in BICAMS focus on how quickly people can process information, their ability to remember a verbal word list and their memory of abstract shapes shortly after they have seen them. The battery utilises the most relevant components of existing tests, including sections of the California Verbal Learning Test-II, the Brief Visuospatial Memory Test-Revised and the Symbol Digits Modalities Test.

32

www.researchoutreach.org

FINDINGS USING BICAMS Since the BICAMS was introduced it has been cited in a number of peerreviewed publications, going some way to filling the knowledge gap surrounding cognition in MS. A recent meta-analysis14

by Professor Langdon has shown that BICAMS testing has highlighted significantly reduced cognitive functioning compared to people living without MS across all of the domains tested, namely, information processing speed, immediate recall memory and immediate visual recall memory, in 14 countries.

Excitingly, the BICAMS has also been used in intervention studies, including one that demonstrated that six weeks of cognitive rehabilitation15 taking place on a computer at home can lead to improvements on some, but not all, aspects of cognition. The improvements were mirrored by a change in the activation of some areas

of the brain, assessed by functional MRI studies. Whilst it is not known how this change impacts on the quality of life of patients, it is a positive indication that some aspects of cognition can be rescued with the right management.

FUTURE STEPS Already the BICAMS has made great inroads into understanding the cognitive impairment that so affects the lives of those living with MS. It has recently been adopted and recommended by the American Academy of Neurology, further cementing its place as the go-to testing battery for this condition. An iPad version of the BICAMS is currently undergoing validation studies and, if successful, is only set to increase the amount it is used. Computerised testing reduces raters’ variability, making the measurement even more precise, and facilitates data collection to databases on servers. Feasible, effective and inexpensive means of assessing cognition are absolutely crucial to patient management, disease monitoring and assessing the effects of interventions.

The development of BICAMS has started a small but powerful revolution in bringing cognition to the forefront of MS management, shedding light on its effect on quality of life. People living with MS are only set to benefit from its increasing uptake by both clinicians and researchers.

QA &

Professor Dawn Langdon is Co-Chair of the BICAMS initiative and has led on the development of the iPad version of the cognitive assessment. She is passionate about raising awareness of the cognitive impact of MS and using international collaboration to create meaningful progress. We spoke to her about her motivations, the success of the BICAMS initiative and the reach she hopes it will have globally.

What inspired your work in this area?

I was working in a clinical job at the National Hospital for Neurology and Neurosurgery in London, on a rehabilitation unit where half of the people had multiple sclerosis (MS). It was very clear that many of them were struggling with cognitive

it hard to follow fast speech or pick up information against a distracting background. Memory is also often affected. However, everyday language functions are often pretty much OK. This means in casual conversations, nothing seems wrong. Because MS cognitive difficulties are not on the surface, they tend to get overlooked.

I have tried to foster a sense of being in the BICAMS family. I think a shared purpose and understanding across nationalities creates bonds, trust and energy. difficulties, but this aspect of the disease was not recognised or well managed by their families, friends, or even health professionals outside of specialist centres. I wanted to try to understand these difficulties better and improve health care services.

Why do you think the cognitive impact of MS has been almost overlooked in the past in favour of physical symptoms?

Partly I think it is because physical symptoms are immediately apparent to other people, for example using a walking stick or wheelchair. Also, cognitive difficulties can be hard to admit to and to talk about. The pattern of cognitive difficulties in multiple sclerosis is not clear in conversation or even clinic consultations. This is because information processing speed is often the most affected ability, which can be thought of as band width. It is a bit like your own personal internet slowing and freezing. This can make

Friends, families and workmates explain reduced participation and struggling at work as the impact of physical restrictions, but cognitive glitches may also be to blame.

How do you get an international community working together in such a successful manner?

I convened an international committee of 12 neurologists and neuropsychologists, who were all experts on MS cognition and represented all of the major language groups, and countries on both sides of the Atlantic.

BICAMS is a truly international initiative with input from researchers across the globe and from all major language groups.

Myself and my Co-Chair, Professor Ralph Benedict did our homework and worked to obtain a consensus.

We published two consensus papers.

In fact, from there the international MS community pretty much adopted BICAMS and set out to validate it in a proactive and committed way.

I did the usual academic things, writing papers and speaking at scientific conferences, but colleagues picked up the BICAMS torch and ran with it.

I was always ready to accept invitations to speak about BICAMS and do training sessions, but these were small contributions. I think that first, cognition was acknowledged to be an under recognised and poorly managed aspect of MS, which made life difficult for people with MS and their families.

Secondly, committed health care workers realised that a brief, feasible and psychometrically sound cognitive measure would be very useful in their practice. Unexpectedly, BICAMS has been utilised in many scientific papers about MS cognition, which was not part of our original planning and goals.

What advice would you give others about to embark on a similar project i.e. one that brings together an international community?

I think a broadly based, expert consensus group to back and author the project is essential. Encouraging engagement and offering support to centres as and how they need it is essential, so everyone can be involved at the level, and as independently, as they choose to be. Although everyone involved is a serious scientist and/or clinician, I have tried to foster a sense of being in the BICAMS family. I think a shared purpose and understanding across nationalities creates bonds, trust and energy.

BICAMS has received funding from multiple sources.

Does this bring any unique challenges and/or benefits?

I am very proud of the “patchwork” model of funding that BICAMS has created. We were very lucky to have funding for our committee’s work and meetings from Bayer at the outset.

Subsequently, validation and scientific

This range of funders means that BICAMS doesn’t belong to a single organisation or entity. It is truly owned by the international MS community, which is an enormous benefit. studies across the world using BICAMS have been funded by national pharma, neurology associations, national MS charities, or sometimes by colleagues who had a master’s student who needed a project. Novartis have kindly funded a UK first implementer study.

Several international pharma are using BICAMS in major international drug trials. This range of funders means that BICAMS doesn’t belong to a single organisation or entity. It is truly owned by the international MS community, which is an enormous benefit.

What are the next stages for rolling out BICAMS worldwide? What are your hopes for this tool?

We are currently working to identify clinics around the world who are

using BICAMS for routine clinical assessment. So far we know about 10,000 patients a year are being routinely assessed on BICAMS. We want to support and extend BICAMS’ use for routine clinical assessment. The AAN endorsement helps and we are involved in other groups producing guidelines for MS clinical assessment.

We are validating an iPAD BICAMS which we hope will make BICAMS even more feasible. Our vision is that every MS patient in the world will have access to routine cognitive assessment.

There is a very widely used measure of mainly physical disability in MS, the Expanded Disability Status Scale, or EDSS. It would be wonderful if BICAMS could become the cognitive EDSS. Already there are studies that compare and combine the two measures, so this may not be a far-fetched idea.

This tool could make a difference for people with MS around the world. How does it feel to be involved in work with such widespread impact?

I feel very humble as Co-Chair of BICAMS as I work alongside so many expert clinical researchers putting their time and effort into successfully developing the BICAMS story, and also seeing the data coming in from so many thousands of people with MS who have consented to participate in these studies.

It is all about teamwork and each study has only succeeded because of the commitment and partnership of health professionals and people with MS. I am very proud that the international MS community has come together in such an effective and influential way, to address and manage the cognitive aspects of MS.

34

www.researchoutreach.org

Behind the Research Professor Dawn Langdon E: d.langdon@rhul.ac.uk T: 01784 443956 W: www.BICAMS.net

Research Objectives The Brief International Cognitive Assessment for MS (BICAMS), is a short, much-needed tool to assess cognitive function for people with Multiple Sclerosis.

Detail Professor Dawn Langdon Royal Holloway University of London Egham Surrey TW20 0EX UK Bio Having trained at St Hilda’s College, Oxford and King’s College London, Dawn Langdon worked at Queen Square for 16 years as a clinical neuropsychologist, obtaining a PhD from the Institute of Neurology, London. She is now Professor of Neuropsychology at Royal Holloway, University of London, FBPS and BICAMS Co-Chair. She is a Trustee of the UK MS Trust.

Funding DL has participated in speaker bureau for Bayer, Merck, Almirall, Execemed, TEVA, Roche, Novartis, Biogen, Sanofi; has had consultancy from Novartis, Bayer, Merck, Biogen, TEVA, Sanofi; has had research grants from Bayer, Merck, Novartis, Biogen. All are paid into DL’s institution.

Collaborators •P rof Ralph Benedict, Co-chair BICAMS, University of Buffalo, New York, USA BICAMS committee: •P rof Maria Pia Amato, University of Florence, Italy •D r Jan Boringa, Meander Medisch Centrum, Amersfoort, Netherlands •P rof Bruno Brochet, Université Bordeaux-Segalen, France

References Langdon DW, Amato MP, Boringa J, Brochet B, Foley F, Fredrikson S, Hämäläinen P, Hartung HP, Krupp L, Penner IK, Reder AT, Benedict RH (2012) Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis. Multiple Sclerosis, 18(6), 891-8.

Benedict RH, Amato MP, Boringa J, Brochet B, Foley F, Fredrikson S, Hamalainen P, Hartung H, Krupp L, Penner I, Reder AT, Langdon D (2012) Brief International Cognitive Assessment for MS (BICAMS): international standards for validation. BMC Neurology, 16, 12:55.

Campbell J, Langdon D, Cercignani M, Rashid W. A Randomised Controlled Trial of Efficacy of Cognitive Rehabilitation in Multiple Sclerosis: A Cognitive, Behavioural, and MRI Study. Neural Plast.

2016;2016:4292585.

• Prof Fred Foley, Yeshiva University, Ferkauf Graduate School of Psychology, and Albert Einstein College of Medicine in Bronx, New York.

• Prof Sten Fredrikson, Karolinska Institute, Stockholm, Sweden • Dr Paivi Hamalainen, Masku Neurological Rehabilitation Centre, Finland • Prof Hans-Peter Hartung, HeinrichHeine-Universität Düsseldorf, Germany • Prof Lauren Krupp, Stony Brook University Medical Center, New York, USA • Prof Iris-Katharina Penner, University of Dusseldorf, Germany • Dr Anthony Reder, University of Chicago Medical School, Illinois, USA.

Personal Response How could findings from BICAMS influence how clinicians manage the care of people living with MS? Cognitive assessment offers a range of benefits. It is known that cognitive status at diagnosis predicts how fast the disease will progress and so clinics can monitor patients more closely. Positive lifestyle choices and regular mentally stretching activities can protect against cognitive decline and cognitive assessment can form the basis of coaching people with MS to adopt these helpful behaviours. People with MS who have cognitive impairment are less likely to manage their disease well, including medication, and once alerted to cognitive impairment, clinics can present information in a way that is easy to assimilate and monitor disease management. Cognitive impairment makes problems at work and unemployment more likely and clinics can refer for appropriate help. Cognitive impairment increases risks of falling and driving accidents, and clinics can act to reduce these risks.

www.researchoutreach.org

35

Health and Medicine ︱ Dr Pauline Emmett and Dr Caroline Taylor

Factors associated with young children exhibiting picky eating behaviour Picky eating in preschool children is a well-documented phase when children are reluctant to try new foods and/ or show very strong preferences for particular foods. This behaviour can create concern for parents, and this has created a whole market for advice and guidance, not all of which is evidence-based. Dr Pauline Emmett and Dr Caroline Taylor, from the Centre for Academic Child Health at the University of Bristol, explore factors associated with picky eating to determine whether this should be a source of worry for parents.

P

icky eating is usually classified as part of a spectrum of feeding difficulties observed in children.

Strong food preferences and suspicion of new foods in childhood may have had evolutionary benefits by reducing the risk of consuming toxins. However, in the modern world, these behaviours can provide a barrier to the acceptance of certain food items. This often causes concern amongst parents about nutrient intake and the risk of poor future health outcomes. Determining whether this behaviour is problematic is an important public health issue.

DEFINING AND MEASURING PICKY EATING There is no single widely accepted definition of picky eating, and therefore there is little consensus on how to measure it, resulting in a huge variety of prevalence estimates. Dr Pauline Emmett and Dr Caroline Taylor and their team investigated the range of methods used to assess picky eating as well as the different sources of data used to determine prevalence. Researchers reviewed the literature on picky eating between 1990 and 2015 and found that most studies on picky eating were cross-sectional, which means that they only look at behaviours and associated factors at one point in time. Such methods, therefore, do not allow for exploring the prevalence of picky eating over time or the potential health-related outcomes of the behaviour.

Emmett and Taylor found a wide range of tools used to assess picky eating, including the Children’s Eating Behaviour Questionnaire and the Child Feeding Questionnaire

as well as study-specific questions.

In addition, a variety of prevalence rates were found of picky eating, spanning from 6% to 50%. One of the few sources of longitudinal data, where participants are followed for an extended period of time, is the Avon Longitudinal Study of Parents and Children (ALSPAC). The prevalence of children being very picky eaters (based on a question about definite likes and dislikes) in ALSPAC varied with age from 10% to 15%, with the peak prevalence at 38 months.

PREDICTORS ASSOCIATED WITH PICKY EATING Researchers have also investigated factors which can predict picky eating in children. ALSPAC data was used to measure picky eating at age 3 years and then explore potential antecedents of this behaviour. It was found that feeding difficulties during complementary feeding and the late introduction of lumpy foods (after 9 months) were both associated with an increased likelihood of the child being a picky eater. A strong predictor was the child being choosy at 15 months, particularly if the mother was worried about this behaviour. At 15 months, the majority (56%) of children were considered to be choosy with food.

Of these children, 17% became very picky at age 3 years if the mother was not worried, in contrast to 50% if the mother was greatly worried about the choosy behaviour. Feeding ready-prepared food was also a predictive factor for later picky eating. Protective factors against picky eating were the mother providing fresh fruit and eating the same meal as her child.

In light of these results, Emmett and Taylor suggest that the likelihood of picky

HOW DOES EARLY CHOOSINESS RELATE TO LATER PICKY EATING? NOT CHOOSY 3130/44%

CHOOSY 4040/56%

AT 15 MONTHS GREATLY WORRIED 202/5%

NOT PICKY 34/17%

A BIT WORRIED 1097/27%

PICKY 100/50%

NOT PICKY 230/21%

SOMEWHAT PICKY

68/34%

NOT WORRIED 2741/68%

PICKY 333/30%

SOMEWHAT PICKY

534/49%

NOT PICKY 979/36%

NOT PICKY 1912/61%

PICKY 463/17%

SOMEWHAT PICKY

PICKY 211/7%

SOMEWHAT PICKY

1299/47%

1007/32%

AT 38 MONTHS eating can be reduced by providing foods that help the child to learn to chew from 6 months or earlier, supporting mothers through the second year of life when children have a natural tendency to be wary of new foods, providing fresh fruit for the child, the mother often eating the same meal as the child and feeding the child home-prepared fresh foods. They also emphasise that parents should be reassured that picky eating is normal and to continue to provide a variety of foods.

FACTORS ASSOCIATED WITH MATERNAL WORRY Factors associated with maternal worry were explored by Emmett and Taylor because maternal worry was associated with higher levels of picky eating behaviour in children. Researchers used ALSPAC data again to measure levels of worry amongst parents about choosy behaviour in their children at 15 months of age. They also investigated feeding behaviours and practices throughout the first 15 months to determine predictors of this worry.

It was found that half of the children (56%) were described as choosy at 15 months. Amongst these children, 27% had mothers who were a bit worried and 5% greatly worried. Mothers were more likely to be worried if their child was first born and/or difficult to feed or refused solids by 6 months of age.

Worried mothers were more likely to have introduced lumpy foods late

The figure shows the relationship between early choosiness, maternal worry about that choosiness and later picky eating behaviour.

A strong predictor of preschool-age picky eating was the child being choosy with food at 15 months, particularly if the mother was worried about this behaviour. (after 9 months). If mothers fed their child vegetables regularly by age 6 months, this was associated with a lower risk of being worried about choosy behaviour in their children. Researchers suggest that providing support and advice to parents when they begin complementary feeding could help to alleviate worries about eating behaviour.

DIETARY FIBRE INTAKE Picky eating has been suggested to be associated with an increased risk of constipation, as a result of a lower fibre intake. Emmett and Taylor used ALSPAC data to determine dietary fibre intake at 38 months and then to see whether this was predictive of stool hardness at 42 months. Picky eating at both these time points was also investigated. Researchers

found consistent evidence that children who are picky eaters consumed fewer fruits and vegetables than non-picky eaters, which contributed to a lower fibre intake. Picky eaters were also more likely to have hard stools than non-picky eaters, which was explained by the difference in fibre consumption. Researchers suggest that boosting fibre intake can be achieved through a number of different strategies.

These include encouraging parents to repeatedly offer their children small amounts of fruit and vegetables to overcome neophobia (fear of trying new foods), to provide an example for children by eating fruits and vegetables themselves and to adopt regular family mealtimes with the same meal being offered but not forced onto children.

% FIBRE FROM VEGETABLES (95% CI) Picky eaters

8.9 (8.2, 9.7)

Non-picky eaters

15.7 (15.5, 15.9)

p<0.001

Picky eaters obtain a smaller proportion of fibre from vegetables than non-picky eaters.

www.researchoutreach.org

37

Young children are often choosy about food and this is a natural part of their development.

MACRO- AND MICRONUTRIENT INTAKES Macro- and micronutrient intakes are another source of concern with picky eating. Emmett and Taylor used ALSPAC data to measure both picky eating and nutrient intakes when children were aged 3 and 7 years. It was found that picky eaters at age 3 years had lower mean carotene, iron, and zinc intakes than nonpicky eaters. This was also found at age 7 years. Iron and zinc were the nutrients most likely to have intakes in picky eaters below recommended amounts, with free sugars intake much higher than recommended for optimal health. There were no significant differences in energy intakes between the groups, and intakes were adequate for children’s estimated average requirements for energy.

The differences in nutrient intakes were explained by lower intakes of meat, fish, vegetables and fruits in picky eaters than non-picky eaters. Picky eaters also had higher intakes of sugary foods and drinks

‘Eat your greens’ – some vegetables have flavours that are difficult for children to learn to like. For tips on feeding vegetables see www.habeat.eu.

Protective factors against picky eating were the mother providing fresh fruit and eating the same meal as her child. than non-picky eaters at age 7 years.

Researchers suggest that alleviating parental concerns about picky eaters having inadequate nutrient intakes should be a key focus, along with encouraging parents to include more nutrient-rich foods and fewer nutrient-poor foods in their children’s diets.

GROWTH AND BODY COMPOSITION IN PICKY EATERS A further worry with picky eaters is the potential risk of being underweight or overweight. Emmett and Taylor investigated whether picky eaters were different in terms of height, weight and body composition from non-picky eaters using ALSPAC data. Children were measured on seven occasions between the ages of 7 and 17 years.

Usually hard stool, without fibre adjustment (OR (95% CI))

Usually hard stool, with fibre adjustment (OR (95% CI))

Not a picky

1.00 (ref)

1.00 (ref)

Picky eater

1.31 (1.07, 1.61)

0.65 (0.32, 1.35)

p=0.010

p=0.248

Multinomial models confirm that picky eaters are more likely to have hard stools than non-picky eaters and that this is mediated by fibre intake.

38

www.researchoutreach.org

Picky eaters were more likely to be slightly smaller and lighter than non-picky eaters but there were no significant differences between groups in terms of body fat.

The mean heights, weights and BMIs of picky eaters were consistently above the 50th centiles of reference growth charts which indicates that the majority were growing normally. More than two-thirds of picky eaters were not thin at any age point. However, almost one-fifth of the very picky eaters were thin at three or more age points compared with less than one-tenth of non-picky eaters. There was no evidence of an increased likelihood of being overweight or obese in either the very picky or somewhat picky children.

CONCLUSIONS Overall, findings from research by Emmett and Taylor suggest that picky eating in children is a normal part of growing up and parents need not be overly concerned about this behaviour.

However, there are a number of strategies that parents can employ to reduce the risk of picky eating. These include encouraging children to eat a varied diet, including fresh fruit and vegetables, as well as setting an example by eating a varied diet with their children.

Behind the Research Dr Pauline Emmett

Dr Caroline Taylor

E: p.m.emmett@bristol.ac.uk T: 44 (0)117 42 83096 W: www.bristol.ac.uk/social-community-medicine/people/pauline-m-emmett/ index.html W: https://research-information.bristol.ac.uk/en/persons/pauline-m-emmett(2e26d735-4184-4522-8163-7a986a7960eb). html W: https://www.habeat.eu/page0e89.html?a=parents W: www.bristol.ac.uk/alspac E: caroline.m.taylor@bristol.ac.uk T: 44 (0)117 42 83099 W: www.bristol.ac.uk/social-community-medicine/people/person/ @caroline1taylor caroline-m-taylor/overview.html

Research Objectives Dr Pauline Emmett and Dr Caroline Taylor from the Centre for Academic Child Health, Bristol Medical School, University of Bristol use data from the Avon Longitudinal Study of Parents and Children (ALSPAC), which is a long-term research project that enrolled more than 14,000 pregnant women in 1991 and 1992. It has followed the resulting offspring and their parents since recruitment using questionnaires and clinic visits. The research seeks to investigate factors associated with picky eating to determine whether the behaviour should be a source of concern for parents. These factors include fibre intake, macro- and micronutrient intakes, as well as child growth and body composition.

Detail

References

Centre for Academic Child Health Population Health Sciences Bristol Medical School University of Bristol 1-5 Whiteladies Road Clifton Bristol BS8 1NU, UK

Taylor, C. M., Wernimont, S. M., Northstone, K., & Emmett, P. M. (2015). ‘Picky/fussy eating in children: Review of definitions, assessment, prevalence and dietary intakes’. Appetite, 95, 349-359.

Bios Dr Pauline Emmett: Senior Research Fellow (semi-retired), Centre for Academic Child Health, Bristol Medical School, University of Bristol. Experienced research Nutritionist and Dietician. Oversaw Nutrition Research for the Avon Longitudinal Study of Parents and Children (ALSPAC) for 15 years. Interested in nutrition in pregnancy and childhood particularly early growth and development of children.

Taylor, C. M., Northstone, K., Wernimont, S. M., & Emmett, P. M. (2016). ‘Picky eating in preschool children: Associations with dietary fibre intakes and stool hardness’. Appetite, 100, 263-271.

Dr Caroline Taylor: Research Fellow, Centre for Academic Child Health, Bristol Medical School, University of Bristol. Caroline’s research interests are in nutrition in pregnancy and childhood, particularly in how diet and the environment in pregnancy affect the growth and development of the child.

Funding • The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. The research on picky eating is funded by Nestlé Nutrition.

• Dr Caroline Taylor is funded by a Wellcome Career Re-Entry Fellowship (Grant ref: 104077/Z/14/Z).

Taylor, C. M., Northstone, K., Wernimont, S. M., & Emmett, P. M. (2016). ‘Macro- and micronutrient intakes in picky eaters: a cause for concern?’. American Journal of Clinical Nutrition, 104(6), 1647-1656.

Emmett, P., Hays, N., & Taylor, C. (2018). ‘Factors associated with maternal worry about her young child exhibiting choosy feeding behaviour’. International Journal of Environmental Research and Public Health, 15(6), 1236.

Emmett, P. M., Hays, N. P., & Taylor, C. M. (2018).

‘Antecedents of picky eating behaviour in young children’.

Appetite, 130, 163-173.

Taylor, C. M., Steer, C. D., Hays, N. P., & Emmett, P. M. (2018).

‘Growth and body composition in children who are picky eaters: a longitudinal view’. European Journal of Clinical Nutrition, doi: 10.1038/s41430-018-0250-71.

Personal Response Are there other questions about picky eating that you both plan to investigate using the ALSPAC data?

We would be very interested to investigate long-term picky eaters, that is children who are picky eaters over many years, to assess if this has a greater effect on the diet and health than short-term picky eating. It would also be valuable to find out whether the differences we found in dietary intakes between picky and non-picky children at ages 3 and 7 years persist into the teenage years. Some children who are picky at young ages are not picky at later ages and it would be helpful to determine factors that predict this change, and which might provide an evidencebase for advice.

www.researchoutreach.org

39

Health & Medicine ︱ Dr Stephen Bartelmez

Could stem cells offer a viable treatment for retinopathy?

T Diabetes is a growing global epidemic, with over 400 million affected and cases expected to double in the next 10 years.

Retinopathy, or damage to the blood vessels in the retina, occurs in most patients with type 1 diabetes and 75 per cent of patients with type 2 diabetes, leading to vision loss for many.

BetaStem Therapeutics is a stem cell therapy company led by Dr Stephen Bartelmez. Their aim is to treat diabetic retinopathy by using the body’s own stem cells to repair the damage to retinal blood vessels caused by diabetes.

he macula is a part of the retina, located at the back of the eye.

Although very small (about 5mm in diameter), it is responsible for most aspects of our vision, including colour vision and the fine detail of what we see.

Diabetic macular oedema is a swelling of the retina as a result of fluid leakage from damaged blood vessels within the macula caused by the diabetes. In addition, macular ischemia (inadequate blood supply) can eventually result in diabetic retinopathy (DR), or damage to the blood vessels at the back of the eyes. DR is one of the leading causes of blindness in adults, and currently there is no effective treatment to repair cells and blood vessels damaged as a result of the disease.

Retinopathy can cause vision loss and even blindness.

40

www.researchoutreach.org

In healthy people, blood vessels are constantly regenerated by cells derived from circulating CD34+ stem cells.

These stem cells are generated in the bone marrow and released into the bloodstream and express the protein CD34+ on their surface. They divide and mature into all nine types of blood cells plus give rise to another cell type, endothelial cells, the building blocks of all blood vessels. The stem cells and endothelial cells migrate to lesions on blood vessels and facilitate repair.

However, during the course of diabetes, the patient’s CD34+ stem cells become dysfunctional: they can no longer give rise to endothelial cells or regulate repair of damaged blood vessels, both in the retina, and in the rest of the body.

Diabetic Retinopathy Superior Rectus Muscle

Aneurysm

Abnormal Blood Vessels

Sclera Retina

Lens

Hemorrhages

“Cotton Wool” Spots

Fovea Optic Disc Pupil Cornea

Optic nerve

Ciliary body

Central Retinal Vein and Artery

Inferior Rectus Muscle

Healthy Eye

Diabetic Eye

The difference between a healthy eye and the eye of a diabetic patient suffering from retinopathy. The damage to the retina eventually causes loss of vision.

STEM CELLS AND TRANSFORMING GROWTH FACTOR BETA 1 All blood cells are derived from haematopoietic stem cells in a process known as haematopoiesis. This takes place in the bone marrow, and in a healthy adult, approximately 50 to 70 billion new blood cells of nine different types are produced each day. To generate all these cells requires a complex series of events involving many positive and negative signals from the surrounding tissue as well as within the stem cells themselves.

Transforming Growth Factor beta 1 (TGF-β1) is a small protein secreted by many cells in the body. Classified as a cytokine (a type of small protein important in cell signalling in blood and immune cells), Dr Bartelmez and colleagues found that TGF-β1 is a major regulator of haematopoiesis. TGF-β1 finely inhibits cellular divisions at major cellular checkpoints. Their work has helped elucidate the key roles of TGF-β1 in stem cells in human blood and bone marrow.

TGF-β1 CONTROLS ALL STAGES OF HAEMATOPOIESIS Using blood samples taken from mice as well as humans, the scientists were able to separate CD34+ stem cells from other blood cells present and grow them in the lab. Next, by treating the cells ex vivo with an antisense phosphorodiamidate morpholino oligomer (PMO) the scientists could inhibit TGF-β1 for a short period of time in the stem cells. A PMO is a small DNA analogue which temporarily blocks

The team found that TGF-β1 regulates mouse and human blood stem cells in the lab and in the body in a number of ways. the stem cells from making a targeted protein. The scientists studied different techniques to deliver PMO into cells which included syringe loading, micro injection, and by combining the PMO with fat molecules containing a positive charge, known as cationic lipids.

However, the best method for uptake of TGF-β1-PMO into stem cells was found to be unassisted entry. Thus CD43+ stem cells were incubated with the PMOs overnight at 37 degrees Celsius during which time the TGF-β1-PMO was

taken up by endosomes on the surface of the stem cells. The temperature of the incubation as well as the concentration of the PMO was found to be important.

This technique actually transiently inhibits the TGF-β1 in the CD34+ stem cells.

It acts as a switch to first inhibit the TGF-β1 then the stem cell reacts to this inhibition by upregulating the TGF-β1 gene mRNA -TGF-β1. Next, the PMO is effluxed from the stem cell causing a burst of TGF-β1 protein production.

Stem cells in the process of dividing.

www.researchoutreach.org

41

The protein was found to have many functions. These include the ability to: stimulate or prevent cells from dividing; promote cells to self-destruct or differentiate (change to another cell type); or prevent these molecular pathways from occurring. One key finding was that transient TGF-β1 inhibition induces a balance between CD34+ cell growth, division, maturation, and periods of cell inactivity.

In humans, Dr Bartelmez identified three markers of enhanced stem cell activity that increase after PMO treatment of stem cells: 1) increased levels of CXCR4, a protein necessary for stem cell homing and adhesion; 2) increased Nitric oxide production, which is required for cell mobility; and 3) increased ability of CD34+ cells to migrate and repair vascular lesions.

The group also studied how long-term CD34+ haematopoietic stem cells were able to regenerate and repopulate the bone marrow in mice after inhibition of TGF-β1. They found that after lethal irradiation, they were able to use as few as sixty of these cells to rescue mice from death (>20,000 untreated stem cells were required to achieve the same result). In addition, they found that when the retina of mice was injured due to insufficient blood flow, and the TGF-β1-PMO treated CD34+ stem cells were introduced into the eye, the recruitment of diabetic CD34+ cells to injured retinal capillaries dramatically increased when compared to non-treated stem cells.

Image of a retina showing signs of diabetic retinopathy.

TGF-β1 helps to maintain the balance between CD34+ cell growth, division, maturation, and periods of cell inactivity.

DIABETIC RETINOPATHY: MOVING TOWARDS A CURE The goal of BetaStem Therapeutics is to use the diabetic patient’s own CD34+ to treat their retinopathy. They aim to do this by first isolating the CD34+ stem cells from the patient’s blood and then correcting the dysfunctions in the CD34+ stem cell ions by temporarily inhibiting the patient’s TGF-β1 by incubating the CD34+ cells for 16 hours ex vivo with PMO. This process rehabilitates the CD34+ stem cells which are then introduced back into the patient’s eye.

Here, the CD34+ stem cells specifically bind and repair the damaged blood

Diabetes is a risk factor for retinopathy but it can be caused by other conditions such as long-term elevated blood pressure.

42

www.researchoutreach.org

vessels in the retina. The use of PMO is a feasible approach due to its ability to enter haematopoietic stem cells and transiently inhibit TGF-β1 signalling.

PMOs do not “touch” the TGF-β1 gene itself: they merely bind to the TGF-β1mRNA and block it from translation to the protein. The half-life of the PMO is short and the stem cell rapidly effluxes the PMO-mRNA complexes. The molecules also have an excellent safety profile.

Transient, or brief, inhibition of TGF-β1 may lead to the treatment of other vascular complications and could potentially improve current bone marrow transplantation processes used in the treatment of blood cancers. The treatment poses a very low risk of adverse events.

However, challenges remain, particularly when it comes to the selection of animal models that can help predict the human response to this treatment.

BetaStem Therapeutics is now preparing to test TGF-β1 inhibition in diabetic patients for the first time in a clinical trial.

The next goal for the company will be the development of methods in the lab to further study TGF-β1 in haematopoietic stem cells. Moving forward they will develop culture conditions in which cell division of latent stem cells is stimulated while their maturation and ageing is prevented, in the presence of either TGFβ1-PMO or TGF-β1-inhibiting antibodies.

Behind the Research Dr Stephen Bartelmez E: sbartelmez@betastemtherapy.com T: +1-206-427-0350

Research Objectives

References

BetaStem Therapeutics aims to treat diabetic retinopathy using a patient’s own stem cells.

Sitnicka E, Ruscetti FW, Priestley GV, Wolf NS, Bartelmez SH. (1996) Transforming growth factor beta 1 directly and reversibly inhibits the initial cell divisions of long-term repopulating hematopoietic stem cells. Blood. Jul 1;88(1):828. PubMed PMID: 8704205. b.

Detail Dr Stephen Bartelmez 2 Lower Crescent Ave Suite 2 Sausalito CA 94965 USA Bio Stephen Bartelmez, PhD, is the founder of BetaStem Therapeutics. He completed his immunology training at UC Berkeley & University of Glasgow and his stem cell training at Einstein College of Medicine, NYC. Following this, he sailed to Australia to work with Ray Bradley PhD, the father of modern blood stem cell research. Dr Bartelmez is a former member of faculty at Hutchinson Cancer Research Center, U. of Washington, ViaCell Inc. He founded BetaStem Therapeutics Inc. in 2006.

Funding National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Heart, Lung, and Blood Institute (NHLBI), National Eye Institute (NEI) USA, and Stephen and Elizabeth Bartelmez Collaborators • Frank Ruscetti PhD • Pat Iversen PhD • Charlie Garcia MD • Ewa Sitnicka PhD • Carl Storey

Ruscetti FW, Bartelmez SH. (2001) Transforming growth factor beta, pleiotropic regulator of hematopoietic stem cells: potential physiological and clinical relevance. Int J Hematol.

2001 Jul;74(1):18-25. PubMed PMID: 11530800 c.

Ruscetti FW, Akel S, Bartelmez SH. (2005) Autocrine transforming growth factor-beta regulation of hematopoiesis: many outcomes that depend on the context. Oncogene. 2005 Aug 29;24(37):5751-63. PubMed PMID: 16123808. d.

Bhatwadekar AD, Guerin EP, Jarajapu YP, Caballero S, Sheridan C, Kent D, Kennedy L, Lansang MC, Ruscetti FW, Pepine CJ, Higgins PJ, Bartelmez SH, Grant MB (2010) Transient inhibition of transforming growth factor-beta1 in human diabetic CD34+ cells enhances vascular reparative functions. Diabetes. Aug;59(8):2010-9. PubMed PMID: 20460428 PMID: 24223881; PubMed Central PMCID: PMC2911069 Bartelmez, S., Storey, C., Iversen, P., Ruscetti, F. (2016) Transient inhibition of endogenous transforming growth factor ß1 in hematopoietic stem cells accelerates engraftment and enhances multi-lineage repopulation efficiency. J Stem Cell Res Ther 1::00045 D01 f.

Patrick L. Iversen, Francis W. Ruscetti, Charles Garcia and Stephen H. Bartelmez (2018). Functional Activation of Autologous Human Diabetic Stem Cells for Cell Therapy, Gene Therapy, Dr Houria Bachtarzi (Ed.), Publisher: InTech, in press

Personal Response What are your aspirations for BetaStem Therapeutics as a company over the next five years?

We previously have had a “pre-IND” meeting with the US-FDA in preparation to complete our IND to proceed with our first patient studies. With sufficient funding, our goal to test the safety and efficacy in diabetic patients with retinopathy looks realistic. Dr Charlie Garcia (Ophthalmologist in Houston, Tx) has been working with us for over four years and is helping design a clinical trial. He has been working with patients with diabetic retinopathy for more than 40 years. Currently, there are no effective treatments, making this an important unmet need. So far, the stem cells look promising.

www.researchoutreach.org

43

Health and Medicine ︱ Dr John A. Zebala

Moving beyond dangerous opioids for pain: Syntrix creates new drug for safer pain relief Opioids are currently the mainstay treatment for the 25 million people suffering from daily pain in the United States. Prescription opioids have led to lethal overdoses and contributed in part to the five-fold increase in opioidrelated deaths from 1999 to 2016. Investigators at Syntrix Pharmaceuticals (Auburn, Washington State) have developed desmetramadol, a new and improved lowlethality opioid to help tackle the opioid crisis.

I

n the United States 25 million people suffer from daily pain. Currently, opioids are the mainstay treatment for these patients. But opioids are highly addictive, and can lead to misuse and lethal overdose. There are an estimated 20,500 deaths involving prescription opioids per year due to overdose in the United States. If illicit opioids are included, like heroin and fentanyl, deaths due to any opioid rise to about 40,000 per year in the United States.

The American situation has reached a crisis point with the cost and scale of the crisis growing across the country. With their new low lethality pain drug, Syntrix Pharmaceuticals hopes to provide one needed component in a broad effort to tackle the opioid crisis.

CRISIS POINT The number of opioid-related overdoses continues to rise with deaths doubling in the past ten years and quadrupling over

Prescription opioids can provide relief from daily pain.

44

www.researchoutreach.org

the past sixteen years, the Centers for Disease Control and Prevention (CDC) found in a recent report. In 2016, the economic cost of the opioid epidemic in Washington State was calculated at over $9.19 billion, with three-quarters of the cost, or $7.18 billion attributed to fatalities. The economic and social impacts of the crisis demand immediate action. Replacing the supply of available prescription opioids with a low-lethality alternative would be predicted to have a significant impact on fatalities, which is the major economic and social impact driver of the crisis.

THE PROBLEM WITH OPIOIDS Opioids are a group of drugs used to treat pain. Some are derived from molecules obtained from the poppy plant, and others like fentanyl are obtained purely by chemical synthesis.

They bind to receptors in the body called opioid receptors. These are found in the brain and spinal cord, and when bound by opioids help to suppress pain.

When used for pain relief, many people will develop a tolerance to opioids: they gradually need to take more in order to achieve the same pain-relieving effect. The problem with opioids is that the same receptor that controls pain transmission also controls the drive to breathe. In an overdose, the opioid drug binds to a specific type of opioid receptor (the mu-opioid receptor) in the medulla of the brain that causes slow and ineffective breathing or ‘respiratory depression’. Untreated respiratory depression can in turn lead to death.

Opioids are so potentially dangerous that the United States lists certain of them under the Controlled Substances Act. There are five categories, schedule I – V, schedule I having the most severe

potential for abuse, through to schedule V with the lowest. Schedule I drugs are further distinguished from schedule II to V drugs as having no currently accepted medical use (e.g., heroin, LSD). There are currently 170 million prescriptions for schedule II opioids per year in the United States. Each of these prescriptions has a high potential to be abused, and it is believed millions of people are at risk of or already suffering from opioid addiction and abuse.

The US government desperately wants to reduce the costs associated with opioid-related fatalities. This year the United States Congress identified research and development as an integral part of the response to this crisis. They recognised that the complexity of this evolving situation requires new discoveries and improvements to existing approaches, from the biology of addiction to overdose prevention and on a bipartisan basis quickly passed the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment, or SUPPORT Act. The SUPPORT Act was signed into law by President Trump on October 24, 2018.

The CDC has recommended reducing the dose of schedule II opioids in patients to reduce opioid-related overdosing and fatalities – but patients still require effective pain relief.

Other than the dangerous schedule II opioids, there are very few safer and less abuse-prone options for doctors to prescribe. Syntrix Pharmaceuticals

Desmetramadol technology replicates ideal CYP2D6 metabolism of tramadol without CYP2D6.

has been working on a solution. They have a strategy to reduce fatalities associated with prescription opioids whilst providing effective pain relief for patients. The inspiration for their new drug came from tramadol.

TRAMADOL: THE PROS AND CONS OF A POPULAR PAIN DRUG Tramadol is an opioid approved in the United States for the treatment of moderate to moderately severe pain.

It is classified as a schedule IV drug, so it is less prone to abuse than schedule II opioids and is safer. It is also more difficult to overdose on tramadol than schedule II opioids. A lethal overdose of tramadol is in excess of 5 grams, or 100 tablets of tramadol in its typical 50 mg tablet strength. Compare this to fentanyl, a schedule II opioid, for which a lethal dose is 0.002 grams, an amount

so small it appears no bigger than half a sesame seed. In other words, the lethal dose of fentanyl is 2,500 times less that of tramadol. Overdoses on tramadol alone are a rarity and therefore it has become popular with physicians as a safer pain medication. In the United States, it is the second most commonly prescribed pain relief with 41 million prescriptions dispensed in 2017.

Tramadol sounds like a superhero amid the opioid crisis, but like any superhero it has its shortcomings.

Tramadol is a complex drug. It must be broken down in the body into a metabolite called M1 and it is this metabolite that provides pain relief for the patient. Tramadol is broken down into M1 by an enzyme in the body called CYP2D6. The amount of this enzyme activity can vary from patient to patient,

There are an estimated 20,500 prescription opioid deaths per year due to overdose in the United States.

www.researchoutreach.org

45

Comparison of the relative amount of each substance required for a lethal overdose. Tramadol must be taken in much higher quantities before it is lethal.

ranging from too much to too little.

And here lies the problem. If a patient has lots of the enzyme CYP2D6 they are known as an ultra-metaboliser: they make lots of M1, potentially reaching dangerous levels in the body.

On the other hand, some patients are metabolically deficient because they have too little CYP2D6 enzyme activity, either because they are taking another drug that inhibits the CYP2D6 enzyme, or because they were born lacking some or all of the CYP2D6 genes. Pain syndromes are often accompanied by depression, and such patients are treated with antidepressants that are also powerful CYP2D6 inhibitors.

Tramadol has little benefit in patients who are metabolically deficient due to either their genetics or a co-prescribed CYP2D6 inhibitor, because they fail to make sufficient M1 for pain relief. An estimated third of patients are either ultra-metabolisers or are metabolically deficient. These liabilities in tramadol’s metabolism make it difficult for clinicians to use it broadly as a substitute to the dangerous schedule II opioids.

It seems like tramadol isn’t a perfect low-lethality opioid solution to the opioid crisis, but it has provided an excellent starting point for Syntrix Pharmaceuticals. Learning lessons from tramadol, Syntrix has developed a new medication to tackle the opioid crisis, desmetramadol, that is predicted to

46

www.researchoutreach.org

Syntrix Pharmaceuticals hopes to introduce a new low lethality drug to help tackle the opioid crisis. have the safety features of tramadol without its metabolic liabilities.

MOVE OVER TRAMADOL: SYNTRIX DEVELOPS DESMETRAMADOL With generous grant support from the National Institute on Drug Abuse, Syntrix developed desmetramadol.

Desmetramadol delivers tramadol’s active metabolite M1, but unlike tramadol, it doesn’t have to be broken down in the body. Syntrix hopes that desmetramadol will be the first opioid with the low-lethality safety profile of tramadol but without its metabolic liabilities. Stuart Kahn, MD, Syntrix Medical Director, stated, “Due to the metabolic limitations of tramadol, large numbers of pain patients have not been receiving adequate relief on tramadol. Often, they find relief only from dangerous schedule II opiates.

The side effects and risks those patients face include dependency and death.

Desmetramadol has the potential to provide effective pain relief to these patients with greater safety.”

In a recently completed clinical trial, Syntrix hopes to show that desmetramadol provides the safety and pain relief of tramadol without its

metabolic issues. Sixty participants were recruited for the study and they were all administered a CYP2D6 inhibitor.

Subjects were then randomly allocated to receive desmetramadol, tramadol and placebo, with each treatment separated by two weeks. The researchers hypothesise that tramadol will lose its pain relief and act like a placebo, whereas desmetramadol will provide pain relief superior to tramadol. The outcome cannot be predicted in advance since the behaviour of tramadol in the human body is complex. If successful, Syntrix believes that desmetramadol could generally replace tramadol globally, and that many of the 170 million schedule II prescriptions in the United States that contribute to the opioid crisis could be replaced by desmetramadol.

John Zebala, MD, PhD, President and CEO said, “With desmetramadol broadly increasing the utility of tramadol and enhancing its safety, we expect to further accelerate the shift away from schedule II opioids.” The final stage of clinical trials is planned for desmetramadol in 2019 to 2020, and it is hoped that Food and Drug Administration approval will be obtained in 2020 to 2021.

Behind the Research Dr John A. Zebala

E: jzebala@syntrixbio.com W: www.syntrixbio.com

Research Objectives

References

Syntrix Pharmaceuticals aims to tackle the opioid crisis by producing opiates with low lethality compared to schedule II opioids.

Senator Patty Murray. Senate Committee on Health, Education, Labor, and Pensions. The Economic Cost of the Opioid Epidemic in Washington State. Available at: https:// www.murray.senate.gov/public/index.cfm/2018/4/opioidcrisis-senator-murray-unveils-new-analysis-showing-opioidcrisis-costs-washington-state-billions. Accessed November 29, 2018.

Detail Dr John A. Zebala Syntrix Pharmaceuticals 215 Clay Street NW Suite B5 Auburn, WA 98001 USA Bio Dr Zebala is the Syntrix President and CEO. During his 10+ year tenure with the company, Dr Zebala established company direction and brought company drug assets from discovery through Phase 1 and Phase 2 clinical trials. Dr Zebala is the Principal Investigator on over $20 million in NIH grants to the company. He is an inventor on over 20 issued US patents, and author to more than 25 peer-reviewed scientific articles. Dr Zebala received his MD and PhD from Cornell Medical School. Dr Zebala has served as an invited reviewer on NIH study sections and review groups concerning drug development and therapeutics.

Funding National Institute on Drug Abuse Collaborators • John A. Zebala* • Shawn L. Searle† • Lynn R. Webster† • Matt S. Johnson‡ • Aaron D. Schuler* • Dean Y. Maeda* • Stuart J. Kahn* *Syntrix Pharmaceuticals, Auburn, Washington. †PRA Health Sciences, Salt Lake City, Utah. ‡DF/Net Research, Seattle, Washington.

Executive Office of the President of the United States. Heath Research and Development to Stem the Opioid Crisis: A Federal Roadmap. A report by the Fast-Track Action Committee (FTAC) on Health Science and Technology Response to the Opioid Crisis convened under the National Science & Technology Council of the Committee on Science.

October 2018.

SBIR Phase 2b Research Proposal – Syntrix research proposal to National Institute on Drug Abuse grant DA027304.

Personal Response Do you think pain relief without opioids will ever be possible?

I certainly hope so. The most ideal pain medicine would presumably be one that was safe and free of any abuse potential. However, large pharmaceutical companies have been looking for non-opioid pain medicines for the last halfcentury with many failures. They have yet to find anything more effective for pain than the opioids. Opioids have a well-established mechanistic role in pain and so developing a low-lethality variant made sense to us as a strategy to address the opioid crisis with a safer medicine that would have a high likelihood of being highly effective in treating pain.

What first inspired you to work in this area?

When I was a young MD-PhD student in New York in the early 1990s, I had just started a clinical rotation at the Memorial Sloan-Kettering Cancer Center and was taking care of a patient with terminal breast cancer. She was in severe pain due to metastases to her bones. Her opioid prescription was so large it would have instantly killed a normal person. The pharmacy at Sloan-Kettering was the only pharmacy in the city that could fill it. It was at that time that I decided I was going to pursue a career developing new therapeutics to broadly help many patients, rather than become a practising physician seeing one patient at a time.

It probably also explains why Syntrix’s current drug pipeline is focused on drugs that treat pain and cancer. Pain is still the #1 reason people see a doctor. Finding better ways to treat it is critical.

www.researchoutreach.org

47

Health and Medicine ︱ Dr Martin Ronis

Alcohol overuse: cutting to the bone Building on several decades of research, Dr Martin Ronis, a Professor at the Louisiana State University Health Sciences Center-New Orleans explores the effects of alcohol on bone turnover. His current research aims to better understand the molecular basis for the toxic effects of alcohol, particularly in women, with a view to uncovering vital therapeutic targets to prevent bone loss. As alcohol-induced bone loss shares many features in common with bone loss during menopause and ageing, his work provides fundamental insights into common pathways underlying the regulation of bone growth and turnover.

O

ur bones are living tissues that continue to undergo change and replacement (bone remodelling), even into adulthood. As we grow in childhood, our bone mass increases until it reaches ‘peak bone mass’ (PBM).

Defined as the greatest amount of bone an individual can attain, PBM is reached in late teens and early 20s. Individuals with a higher PBM have a reduced risk of osteoporosis (a bone disease that occurs when the body loses too much bone, makes too little bone, or both), a leading cause of morbidity and mortality in older post-menopausal women.

ALCOHOL AND BONE HEALTH Although the majority of people drink within safe limits, many consume alcohol at levels proven to be harmful to their health. In the USA, approximately 20% of women aged between 18-30 years (4.4 million) binge drink. Drinking more alcohol than the safe limit can affect bone health, and long-term alcohol consumption can interfere with bone

BETTER BONES This is where the research of Dr Martin Ronis, Professor in the Department of Pharmacology and Experimental Therapeutics at the Louisiana State University Health Sciences Center – New Orleans comes in. His research explores the effects of alcohol on bone turnover. He is particularly interested in the relationship between inhibition of bone formation and stimulated bone resorption associated with alcohol abuse in young women and the increased risk of osteoporosis – resulting from a failure to attain PBM. His research involves multidisciplinary basic sciences, including whole animal physiology, nutrition and endocrinology, pathology and molecular biological techniques. Ultimately, Prof Ronis aims to better understand the molecular basis for the toxic actions of alcohol, which might uncover new therapeutic targets to prevent bone loss.

Prof Ronis’ current work builds on a long history of alcohol research with

Osteoporosis is a leading cause of morbidity and mortality in older postmenopausal women. growth and remodelling. The resulting reduction in PBM predisposes women to osteoporosis in later life. Clinical studies show that alcohol abuse is correlated with osteoporosis, a decreased bone mass and the risk of fractures, and can delay fracture healing. Although it is well known that women are more susceptible to the toxic effects of alcohol (i.e. ethanol) than men, much less is known about the mechanisms underlying the toxic effects of alcohol overuse in women with respect to their bone health.

48

www.researchoutreach.org

collaborators at the Department of Pediatrics UAMS/Arkansas Children’s Hospital. The researchers explored the effect of chronic ethanol exposure in a rat model that mimics blood alcohol patterns found in binge drinkers.

They found that bone density, cortical area, and mature bone strength were negatively affected by alcohol, and showed for the first time that chronic ethanol inhibits rapid bone formation during limb lengthening.

They also demonstrated that certain pro-inflammatory molecules – called

cytokines – play an important role in the process of ethanol-related skeletal pathology. Excitingly, the team were able to protect fracture healing using inhibitory antibodies against these cytokines in the same rat models.

This early work combined with the fact that alcoholism is a known risk factor for osteoporosis led Prof Ronis to think about ways in which reduced bone mass (osteopenia) occurs after chronic alcohol consumption, leading to increased risk of osteoporosis in ageing. Since osteoporosis is predominantly a disease that affects women, Prof Ronis decided to focus his research efforts on females and on unique physiological states (including cycling, pregnancy and postlactation), dovetailing with another area of his research into alcohol-nutritional interactions in pregnancy, funded by the National Institute on Alcohol Abuse and Alcoholism.

ETHANOL EFFECTS IN PREGNANCY In a study published in 2006, Prof Ronis directly tested the effect of ethanol in pregnancy and cycling rats. The team measured the effect of alcohol on skeletal parameters including tibial bone mineral density (TBMD), bone mineral content and bone mineral area (BMA). A dose-dependent skeletal toxicity following alcohol exposure was observed, demonstrated by decreases in TBMD and BMC. Their data suggested that ethanol-induced bone loss in pregnant rats is mainly due to inhibited bone formation. In striking contrast, bone loss in non-pregnant rats was higher than in that observed in pregnant rats and occurred through a different mechanism, concomitant with additional increases in bone resorption and a decrease in circulating estradiol levels.

PROTECTIVE ESTRADIOL LEVELS Exploring the pregnancy-protective effect of alcohol further, Prof Ronis and his team demonstrated the role of osteoclastogenesis – the process whereby osteoclast cells are developed.

Osteoclasts are the cells responsible for breaking down bone, resulting in bone resorption. Prof Ronis showed that estradiol levels block alcohol-stimulated

ETHANOL EFFECTS ON BONE TURNOVER Ethanol

ADIPOCYTE TNFα

FORMATION STEM CELL

eg. Vit D3

Wnt

Pregnancy/ Post-Weaning

STEM CELL IL-6

Ethanol

IGF-1, IGF-BPs Cycling Female/Male

RANKL

Osteoblast Osteocyte Ethanol

E2

HORMONES

ROS

Cycling Female/Male

RESORPTION

Ethanol

ROS E2/NAC

Osteocalcin

REDUCED NEW BONE FORMATION

EtOH

RANK Osteoclast TRAP

INCREASED BONE LOSS AND RELEASE OF MINERALS

Overview of pathways underlying ethanol effects on bone turnover. ROS – reactive oxygen species; TNFα – tumor necrosis factor α; Wnt – Wingless/Integrated signalling pathway; IGF-1 – insulinlike growth factor 1; IGF-BPs – insulin-like growth factor binding proteins; E2 – estradiol; NAC – N-acetylcysteine; RANK – receptor activator of nuclear factor κβ; RANKL – receptor activator of nuclear factor κβ ligand; IL-6 – interleukin 6; TRAP – tartarate resistant acid phosphatase.

Prof Ronis’ current work aims to unpick in fine detail, the ROS signalling mechanisms in bone after excess ethanol consumption. oxidative stress, which in turn promotes RANKL (receptor activator of nuclear factor κβ ligand, a substance needed for osteoclast formation) – inducing osteoclastogenesis. This finding has significant implications for the use of contraceptive pills containing oestrogens for protecting against alcoholic osteopenia (weak bones) in individuals who drink excessively. Notably, the team also showed that anabolic bone rebuilding is completely blocked by alcohol in post-lactation female rats.

This has important implications for postlactating women who resume drinking after stopping breast feeding, suggesting

that they may be at increased risk of osteoporosis with age.

THE ROLE OF OXIDATIVE STRESS Intrigued by the differences in bone remodelling during specific physiologic states (pregnancy, lactation and menopause), Prof Ronis went on to explore the underlying molecular mechanisms further. In an elegant series of experiments, the team showed that ethanol inhibits bone formation via a shift in the differentiation of bone marrow mesenchymal stem cells. Rather than forming osteoblasts (bone cell forming cells), these stem cells instead

Micro-computerized tomography images of mouse tibial trabecular bone demonstrating loss of bone volume after ethanol (EtOH) consumption is greater in animals where the enzyme NOX4 (NADPHoxidase 4) is knocked out relative to bone loss in wild-type (WT) mice as a result of reduced stem cell numbers in the knockout mice.

www.researchoutreach.org

49

differentiate into fat cells or adipocytes.

They demonstrated that oxidative stress was an important mechanism for this.

The team then went on to show that the production of excess reactive oxygen species (ROS) production by NADPH oxidase (NOX) enzymes was responsible for the effects of ethanol on bone turnover. Experiments of bone loss in female rats and mice fed ethanol was blocked by dietary antioxidants including N-acetylcysteine (NAC), vitamin E and also DPI an inhibitor of NADPH oxidase (NOX) enzymes.

Interestingly, Prof Ronis found that the effects of ethanol to inhibit osteoblastogenesis (the production of osteoblast cells that form bone) and stimulate bone marrow adipose cell formation were not blocked in experimental genetic mice that lacked an active form of NOX1/2 enzymes. Since a major component of ethanol pathology in bone is the generation of excess ROS, this led the team to hypothesise that another source of ROS mediates this effect. The researchers subsequently explored the contribution of ROS-generating NADPH oxidase-4 (NOX4) and mitochondrialderived ROS in driving ethanol-induced suppression of bone formation.

Control

NAC

H&E stained images of decalcified tibial bone from post-lactating female rats at the growth plate.

Pink staining – mineralised bone, outside – cortical bone, inside – columns of trabecular bone. White circles – adipocytes (fat cells) in the bone marrow. Loss of bone after ethanol (EtOH) consumption is accompanied by increased marrow adiposity (B) and this is reversed by co-treatment with the dietary antioxidant N-acetylcysteine (NAC).

CURRENT RESEARCH Using a new mouse model of excess alcohol consumption, Prof Ronis’ current work aims to unpick in fine detail the ROS signalling in bone after excess ethanol. Excitingly, recent data also

EtOH

NAC/EtOH

Immunohistochemical staining for nitrotyrosine protein adducts (brown) in female mouse tibial bone following consumption of ethanol (EtOH) with or without co-treatment with the dietary antioxidant N-acetylcysteine (NAC). Increased staining after EtOH indicates oxidative stress accompanies loss of bone (purple) and increased marrow adiposity (white circles) which is blocked by NAC.

50

www.researchoutreach.org

suggests that a certain level of ROS signalling is necessary for normal stem cell self-renewal and bone development during ageing. To test whether NOX4 is responsible for mediating the effects of ethanol on bone formation, ex-vivo (experiments on tissue removed from the body) bone marrow cultures from genetic mice that lack NOX 4 in selected bone cell types (osteoblast precursors, osteocytes, osteoclasts) will drill down on the mechanisms involved.

The teams’ recent findings suggest that dietary antioxidants prevent alcoholinduced osteopenia as a result of blocking excess hydrogen peroxide.

Hydrogen peroxide is a form of ROS produced as the result of the activation of NADPH oxidase enzymes following the metabolism (breakdown) of ethanol.

Importantly, since alcohol-induced bone loss shares many features in common with bone loss during menopause and ageing, molecular studies of alcohol actions on hydrogen peroxide downstream effects in bone may well provide fundamental insights into common molecular pathways underlying the regulation of normal bone growth and turnover.

Behind the Research Dr Martin Ronis

E: mronis@lsuhsc.edu T: +1 504 568 4514 W: www.researchgate.net/profile/Martin_Ronis W: www.medschool.lsuhsc.edu/pharmacology/ronis_home.aspx

References

Research Objectives

Brown EC., Perrien DS., et al. (2002). ‘Skeletal Toxicity Associated with Chronic Ethanol Exposure in a Rat Model Using Total Enteral Nutrition’. J Pharm and Exp Therapy, 301;3 1132-8.

The goal of Dr Ronis’ research is to better understand the molecular basis for the toxic actions of alcohol, particularly in women, with a view to uncovering therapeutic targets. In particular, the results from research aim to link the deleterious effects of alcohol consumption on bone in women of reproductive age with increased risk of osteoporosis, a major cause of morbidity and mortality in post-menopausal women.

Perrien, DS., Wahl, EC., et al. (2004). ‘IL-1 and TNF Antagonists Prevent Inhibition of Fracture Healing by Ethanol in Rats’.

Toxicological Sciences, 82, 656-660.

Shankar K, et al. (2006). ‘Physiologic and genomic analyses of nutrition-ethanol interactions during gestation: implications for fetal ethanol toxicity’. Exp Biol Med, 231:1379-1397.

Shankar K, et al. (2006). ‘Different molecular mechanisms underlie ethanol-induced bone loss in cycling and pregnant rats’.

Endocrinology, 147(1):166-178.

Shankar K, Ronis, MJJ, Badger TM. (2007). ‘Effects of Pregnancy and Nutritional Status on Alcohol Metabolism’. Alcohol Res, 30; 1:55-59.

Chen J-R, et al. (2008). ‘Protective Effects of Estradiol on EthanolInduced Bone Loss Involve Inhibition of Reactive Oxygen Species Generation in Osteoblasts and Downstream Activation of the Extracellular Signal-Regulated Kinase/Signal Transducer and Activator of Transcription 3/Receptor Activator of Nuclear FactorkB Ligand Signaling Cascade.’ J Pharmacol. Exp Therap, 324, No. 1:50-9.

Chen, J-R, et al. (2010). ‘A role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through inhibition of Wnt/beta catenin signaling’. J. Bone Min Res, 25: 1117-1127.

Mercer KE, et al. (2014). ‘Loss of functional NADPH oxidase 2 protects against alcohol-induced bone resorption in female p47phox-/- mice chronically fed ethanol’. Alc. Clin. Exp. Res., 38: 672-682.

Chen J-R, et al. (2015). ‘Deficient Nox2-dependent ROS signaling accelerates skeletal ageing in mice’. J. Biol. Chem, 290: 1469214704.

Alund, A, et al. (2016). ‘Reactive oxygen species differentially regulate bone turnover in an age-specific manner in catalase transgenic female mice’. J. Pharmacol. Exp. Ther, 358: 50-60, 2016. Journal Cover.

Alund, A.W., Mercer, K.E., Pulliam, C.F., Suva, L.J., Chen, J-R., Badger, T.M. and Ronis M.J.J. (2017). ‘Protection by dietary antioxidants against ethanol-induced osteopenia and changes in bone morphology in female mice’. Alc. Clin. Exp. Res, 41: 46-56.

Watt, J., Alund, A.W., Pulliam, C.F., Mercer, K.E., Suva, L.S., Chen, J-R. and Ronis M.J.J. (2018). ‘NOX4 deletion in mice exacerbates the effect of ethanol on trabecular bone loss and osteoblast colony formation’. J. Pharmacol. Exp. Ther., 366: 46-57.

Detail Dr Martin Ronis, LSU Health Sciences Center – New Orleans, 1901 Perdido Str. New Orleans LA 70112, USA. Bio Martin Ronis B.A., M.A. Nat. Sci. Cantab., PhD is a tenured full Professor in the Department of Pharmacology & Experimental Therapeutics at the Louisiana State University Health Sciences Center – New Orleans. He is a current National Institute on Alcohol Abuse and Alcoholism (NIAAA) MERIT awardee.

Funding NIH (NIAAA): R01 AA012928, R01 AA012819, R01 AA018282, R37 AA018282 Ronis Lab: Drs Mats Hidestrand, Kartik Shankar, Jin-Ran Chen, Kelly Mercer, Alex Alund, the University of Arkansas for Medical Sciences and Drs James Watt, Kim Pedersen, Louisiana State University Health Sciences Center – New Orleans.

Collaborators: Drs Thomas Badger, Charles K. Lumpkin, James Aronson, the University of Arkansas for Medical Sciences and Dr Larry Suva, Texas A&M University.

Personal Response Your contribution to the field of alcohol toxicology is immense. What’s next for your research?

In addition to my current work on alcohol and skeletal toxicity, I have spent many years working on alcoholic and non-alcoholic fatty liver disease.

Recently, we have focused on the role of nutrition in the progression of liver pathology to liver cancer.

Interestingly, we find that both alcohol and saturated fats are liver tumour promoters. Changing dietary fat to mono-unsaturated fats like olive oil and dietary protein from dairy to soy protein can protect. Protection appears linked to changes in gut microbiota. We are currently studying these links between diet, gut bacteria and liver cancer. In addition, we are expanding our studies on skeletal toxicity beyond alcohol to look at the effects of environmental pollutants such as polychlorinated biphenyls.

www.researchoutreach.org

51

Health and Medicine ︱ Dr Ronald Shebuski

Local drug delivery to prosthetic vascular grafts: Preventing failure of prosthetic grafts in haemodialysis patients Dr Ronald J. Shebuski, President and CEO of Cylerus, Inc., wants to revolutionise the way vascular grafts work. His company, Cylerus, has an innovative way to deliver an antiproliferative drug, sirolimus, in a consistent and controlled manner. This method of drug delivery, via a porous graft material called ePTFE, has the potential to reduce failure of arteriovenous access grafts crucial for haemodialysis and to, therefore, improve outcomes for patients with chronic kidney disease.

C

ylerus, Inc. was formed by Dr Stephen Hanson in 2007 to develop new drug delivery approaches for preserving the lifespan of synthetic vascular grafts. Dr Ronald Shebuski was appointed as President of Cylerus in 2010, bringing a wealth of experience in biotechnology development. Also, part of the team is Drs Prabir Roy-Chaudhury, Diego Celdran, and Heidi Mansour (U AZ-Tucson) and Dr Sandra Rugonyi (OHSU, Portland, OR). The vision of the company is to have a positive impact in the haemodialysis graft access market within a short time frame once their novel drug delivery device is commercialised.

VASCULAR GRAFTS Prosthetic vascular grafts will often become blocked due to obstruction (stenosis). Stenosis is frequently caused by a proliferation of cells in the vessel, including smooth muscle cells and cells called fibroblasts. Graft failure is the

Cylerus’ local drug delivery system comprising an ePTFE graft (white), silicone rubber drugeluting cuff (DEC) and reservoir around the graft, connecting tubing, and a drug-filled osmotic mini pump (an Alzet in this image).

52

www.researchoutreach.org

Electron micrograph of ePTFE graft material demonstrating internodal pores (30 uM). The Cylerus technology takes advantage of these pores to deliver drug through the graft wall to the inner lumen of the graft in a continuous and circumferential manner..

result of the formation of excessive scar tissue which obstructs blood flow within the graft, as well as in the blood vessels connected to the graft.

There are two main types of blood conduits; those created from the patient’s vein, or those made from expanded polytetrafluoroethylene (ePTFE), also known as synthetic or prosthetic grafts. These prosthetic grafts are most commonly used to form arterio-venous (AV) access grafts for haemodialysis patients, which join an artery and vein to provide an access site for needle insertion to hemodialyze, or to bypass an obstructed artery in peripheral vascular disease. However, a high percentage of these grafts fail. For example, prosthetic AV access grafts fail in around 50% of cases, 3 months after placement.

The primary aim of the Cylerus DrugEluting Cuff (DEC) graft is to prolong the functionality of ePTFE AV grafts in end-stage renal disease patients who require chronic haemodialysis. There is also a pre-emptive focus, rather than a reactionary one, meaning that possibility of stenosis is accounted for in advance, rather than dealt with if it occurs.

WHY IS A NEW PRODUCT NEEDED? In the US, there are approximately 125,000 haemodialysis patients with ePTFE grafts. These grafts require an average of 1.6 interventions per year to maintain the functionality of the graft (around 200,000 interventions per year) and to make sure it is possible to connect the patient to the dialysis machine.

Stenosis is the most common cause of graft failure which requires intervention.

Analysis of the distribution of blood flow velocities in the ePTFE graft model utilised in humans for AV access. The prosthetic graft material is sewn end-to-side between an artery and vein (called an anastomosis) to establish vascular access. Blood flow velocities in the conduit are lowest at the wall of the conduit and fastest in the centre of the bloodstream which concentrates drug (sirolimus) near the inner wall where it is required to prevent obstruction of the graft conduit.

The major problem area of these conduits is downstream of the venous anastomosis (iliac vein in the figure) which becomes obstructed with proliferating cellular material.

Unresolved, this can lead to thrombosis (clotting) in the connection between the ePTFE graft and the patient’s vein.

This provides strong support for the notion that there is both a medical and an economic need to extend the length of time that prosthetic grafts are viable.

Currently, fistulas are the preferred method for vascular access during haemodialysis, 56% compared to a 32% use of grafts in 2011. This is thought to be due to a campaign by the ‘Fistula First’ program in 2003 and the fact that fistulas have good durability and are low cost with a low risk of complications. However, it is expected that as graft design and graft construction materials continue to advance, and therefore improve the durability and longevity of prosthetic grafts, the preference for grafts over fistulas will increase. If managed correctly, prosthetic grafts can be as effective, if not more so, than fistulas.

THE TECHNOLOGY The product designed by Drs Hanson and Shebuski and the team at Cylerus consist of a sirolimus filled pump, which is attached to a catheter leading to a drug delivery cuff. Sirolimus is an antiproliferative drug, meaning

By 2020, it is estimated that over 100,000 patients will be undergoing dialysis 2-3 times a week in the US. that it prevents overgrowth of cells which may lead to stenosis of the graft. The Drug-Eluting Cuff (DEC) is placed around the ePTFE graft close to the graft anastomosis (the point where the patient’s vein and the graft are joined together). Due to the porous nature of the ePTFE graft, the drug is able to move through the walls of the graft into the bloodstream. The drug is then carried by the blood flow to the site of anastomosis, where it is able to prevent the proliferation of cells, meaning the graft does not become blocked and no secondary intervention is needed to correct the graft.

As sirolimus is locally concentrated along the ePTFE graft and peripheral vessel wall, hyperplasia, or cell proliferation, is effectively prevented, whilst still maintaining safe circulating drug levels in the rest of the body. Furthermore, using low doses of sirolimus means that the drug infusion could last up to 90 days before the pump needs to be replaced

or refilled; this prolongs graft functionality, whilst avoiding drug effects elsewhere.

Drug delivery can also be stopped at any time if any adverse effects arise.

As the drug is derived from a source external to the graft, and then diffuses through the walls of the graft, the flow of blood through the graft itself is not modified. Altering the surface of the graft, e.g. coating it with a drug, runs the risk of invoking adverse healing responses or thrombosis.

Indirectly competitive technologies, such as drug-eluting balloons, are also reported to be under development.

However, the approach used by Cylerus has several advantages over these.

For example, the balloons deliver the drug intermittently, so the effects may only be transient. In comparison, Cylerus’ approach allows for constant, prolonged drug delivery, directly through the walls of the graft so that a concentrate, uniform amount of the drug is released

www.researchoutreach.org

53

Primary Patency

in a continuous, circumferential and intraluminal manner.

Directly competitive drug-eluting grafts are also under development. However, these may show limitations which Cylerus’ product does not, and have not reported the same decrease in thickening of vessel walls that Cylerus’ studies demonstrated.

These limitations include the amount of drug that can be delivered, how it is delivered and damage to the graft itself during implantation.

PROOF OF PRINCIPAL Cylerus received a Phase I grant from the National Institute of Health in 2012, and since then have been able to demonstrate the effectiveness of their product in preclinical trials.

These studies included trials in baboons and pigs. The trial carried out in baboons showed that sirolimus infusion in baboons with implanted ePTFE grafts resulted in a 79% reduction in the amount that the vessel wall thickened. An important note from this is that sirolimus showed an outstanding local antiproliferative effect but did not suppress the immune system in the rest of the body.

Flow dynamic modelling of a baboon ePTFE model showed a continuous flow of a predicted amount of drug through the blood vessel. This study also demonstrated that Cylerus’ product is able to provide sirolimus at a concentration which is high enough to inhibit hyperplasia, not only at the graft anastomoses but within the surrounding blood vessels associated with the graft too.

The company has a current NIH-funded SBIR project examining the safety and efficacy of this novel drug delivery technology in pigs, a species which is often used as a model for humans due to the similarity of size and anatomy of the cardiovascular systems. In addition to the DEC graft, the drug-filled pump may

60% Primary patency is defined as the time from placement of the access to the next procedure of any type on that access

45% 30% 15% 0%

3 Months

6 Months

www.researchoutreach.org

18 Months

24 Months

Incidence of prosthetic graft failure in human AV access. Primary patency is defined as the time from placement of the access to the next procedure of any type on that access. Note already at 3 months that almost half of the implanted prosthetic grafts require intervention to maintain function and ability to dialyze. Pflederer et. al. 2008. Semin Dial 21(4):357-363.

Concentration Boundary Layer

Infusate

Graft - Vessel anastomosis

Trans-graft Drug Delivery: The delivery of a therapeutic agent (drug, gene, cell or chemical) through the porous ePTFE graft will result in extremely high concentrations of the drug at the graft-blood interface where the flow velocity by definition is zero (Hagen–Poiseuille equation). The delivered agent will also be preferentially pushed along the graft-blood interface in the direction of flow such that it will bathe the graft-vein anastomosis and the distal (proximal) vein.

contain any drug or therapeutic, not just the body-temperature stable sirolimus formation used in this example, opening the door for many more applications of this technology. Certainly, this may form the basis for some of Cylerus’ future products.

WHAT NEXT? The goal of the Cylerus’ drug delivery technology is to extend the amount of time that prosthetic vascular access grafts can be successfully used for haemodialysis.

By 2020, it is estimated that over 100,000

The goal of Cylerus is to extend the amount of time that prosthetic (ePTFE) vascular access grafts can be used successfully for haemodialysis.

54

12 Months

patients will be undergoing dialysis 2-3 times a week in the US. With their latest preclinical studies due to finish in 2019, Cylerus, Inc. hope that they will soon be able to file the required regulatory paperwork to allow them to progress with the clinical investigational use of their product. Filing these documents will also allow the Company to make the jump from a start-up research and development entity, to a fully-fledged commercial entity.

Providing a drug-eluting device, such as is proposed here, may have a major impact for patients with end-stage kidney disease, as it will decrease the morbidity associated with synthetic graft maintenance, hence vastly improving quality of life, as well as significantly reducing healthcare costs.

Behind the Research Dr Ronald Shebuski

E: rshebuski@gmail.com T: +1 321 421 7065 W: www.cylerus.com

Research Objectives Dr Ronald Shebuski, President and CEO of Cylerus, Inc., wants to revolutionise the way vascular grafts work.

Cylerus promotes the use of prosthetic vascular grafts with the aim to improve AV access for patients undergoing haemodialysis.

Detail Dr Ronald Shebuski 733 Lake George Drive Melbourne, FL 32940 USA Bio Dr Shebuski has 30 years’ experience in the pharmaceutical industry (Merck, SKF, PNU) and currently is President & CEO of Cylerus developing novel drug delivery technology to prolong the function of prosthetic vascular grafts, particularly for patients requiring chronic haemodialysis. The Cylerus technology was licensed from OHSU in Portland, OR. Funding National Institute of Aging (a Division of NIH) has funded a Phase I/II Fast-Track SBIR awarded to Cylerus on 8/15/17 (PIs Drs Ronald J Shebuski and Prabir Roy-Chaudhury).

Collaborators The University of Arizona-Tucson and Drs Prabir RoyChaudhury (co-PI), Diego Celdran, Heidi Mansour. Also Dr Sandra Rugonyi (OHSU, Portland, OR).

References Cylerus, Inc. Executive Summary and Commercialisation Plan, provided by Ronald J. Shebuski, 2018.

Cylerus, Inc., Vascular Drug Delivery. Available at: https://www. cylerus.com [Accessed 21 October 2018].

Shebuski, R.J. & Ray-Chaudhury, P. (2017). ‘Localized Delivery of Sirolimus to Hemodialysis Vascular Access Grafts’. Available at: http://grantome.com/grant/NIH/R44-AG059279-01A1 [Accessed 21 October 2018].

Personal Response How do you see Cylerus, Inc. developing over the next 10 years?

Following the successful completion of Phase II of the current SBIR Fast Track Grant awarded Cylerus by the National Institute of Aging (NIA), the company will move into clinical development. The Phase II SBIR will fund FDA-required preclinical safety work at the University of Arizona-Tucson, which is a key collaborator to Cylerus on this project.

www.researchoutreach.org

55

Health and Medicine ︱ The Human Vascular Research Group (HVRG)

Clinical relevance aims to uncover novel regulators of human coronary artery function Charting new territories in vascular disease research, The Human Vascular Research Group (HVRG) at the Medical College of Wisconsin uses fresh human tissues to address important questions in vascular biology.

Focusing on the microcirculation, the smallest of blood vessels inside our bodies, their aim is to better understand coronary artery disease (CAD) and other clinical problems associated with microvascular defects. Heart disease is the leading cause of death worldwide and new approaches to treatment and prevention are vital.

T

he microcirculation is made up of a network of blood vessels, including small arterioles, capillaries, and venules. Its primary function is to supply oxygen and nutrients to tissues and remove metabolic waste.

The microcirculation is responsible for orchestrating adjustments of blood vessels to match local blood supply with oxygen demand of tissues – both in normal resting conditions and in response to external stimuli (e.g., increased heart rate) that require increased amounts of oxygen and nutrients.

THE MICROCIRCULATION AND CORONARY ARTERY DISEASE Heart disease is the leading cause of death worldwide and a significant portion of heart-related deaths are directly linked to blood vessel dysfunction. Changes in the microcirculation are a well-known early indicator for coronary artery disease (CAD). While age and onset of CAD are associated with changes in the regulation of dilation of human

HVRG – Team Science: Back row (left-right): Dr Karima Ait-Aissa, Matthew Rappelt, Dr David D. Gutterman. Middle back row (left-right): Dr Andreas M. Beyer, Dr Matt Durand. Middle front row (left-right): Todd Le, Dr Andrew Kadlec, Dawid Chabowski. Front row (left-right): Dana Murphy, Kelsey Walters, Dr Julie K. Freed, Dr Natasha Zinkevich, Dr Laura Norwood Toro.

56

www.researchoutreach.org

coronary and adipose microvessels, the factors that regulate these changes are poorly understood. Although animal models provide some insight into blood vessel regulation in health and disease, they often do not translate directly into humans.

As microvascular function is extremely challenging to measure directly in the human heart, alternative ways to interrogate blood vessel function are needed to further our understanding of pathological changes observed in human subjects. Taking a unique approach, the Human Vascular Research Group (HVRG), consisting of Drs Julie Freed, David Gutterman, Matt Durand and Andreas Beyer, is set to increase our mechanistic understanding of changes observed with onset of disease. The group uses isolated microvessels from surgically discarded tissue to explore why microvascular dysfunction is a powerful predictor of cardiovascular disease.

Their aim is to identify clinically relevant pathways and investigate these in more detail using animal models and cell culture models in support of the findings obtained from human microvessels. Their hope is to uncover novel targets for treatment and prevention of human heart conditions.

ASSESSING MICROVASCULAR FUNCTION The team has a wealth of expertise in studying microcirculatory function in intact human tissue samples, an approach that provides obvious clinical relevance. Their specialised method employs direct videomicroscopy of cannulated, pressurized arterioles to assess microvascular function in vitro (outside the body). Through this, the HVRG team has unearthed several signalling pathways that play a key role in the regulation of vascular tone during normal conditions, acute stress, and chronic disease that impact the

CHANGE IN MEDIATORS OF FMD THROUGHOUT LIFE 100 80 60

A

Age 0-18

0

*

*

C

*

K+

AA

COX

CYP450 (EET)

K+

BK ADP

D

Age >55

Physiological Stimulus

*

* * * * *

*

* * *

-20

*

NO *

PGI2

* *

MnSOD

60 40

NO

*

* * * * *

20 0

H2O2

*

**

20

40

60

80

100 0

20

Ca++

I-Arg

NOS

40

60

80

100

AC cAMP

Ca++ EDHF

EDHF

NO

NO

K+

Ca

dilation

cGMP GC

GTP

Vascular Smooth Muscle

Lumen

Flow gradient (cmH2O)

Ca

PGI 2

H2O2

*

*

-20 0

PGI 2

O2

ACh

CAD

80

Shear

% Max. Diameter

20

*

* PGI2 * * *

MECHANISMS OF ENDOTHELIUM-DEPENDENT DILATION

Age 18-55

*

40

100

B

Endothelium

Mediator of flow-mediated dilation is changed throughout life and with the onset of disease. Left Flow-mediated dilation (FMD) in isolated atrial microvessels from: A children age 0–18, B younger adults age 18–55, C older adults age >55 and D subjects with clinically diagnosed coronary artery disease (CAD) independent of age. The mediator of FMD changed from mostly PGI2 (indomethacin inhibitable) with minor contributions of NO (L-NAME inhibitable) in children to predominantly NO and a minor contribution of PGI2 in younger adults. In older adults, a small reduction in dilator capacity is observed due to loss of PGI2 mediated dilation while with the onset of CAD NO-mediated dilation is lost with a compensatory increase in H2O2 (peg-Catalase inhibitable) production to flow stimulus.

understanding and treatment of a variety of cardiovascular disorders.

A NOVEL APPROACH The human microcirculation not only plays a role in regulating tissue perfusion but has been recognised as a modulator of the local tissue environment. The team believes that this provides an explanation for the multitude of dilator and constrictor factors released from the endothelium (the cells lining the blood vessel walls) that also influence vessels further downstream and the function of surrounding tissues.

The HVRG team proposes a novel idea: that communication between microvessels and their surrounding tissues is multimodal. That is, the release of nitric oxide (NO, which causes vessel dilation) preserves normal tissue function by blocking inflammation. Conversely, in disease states or stress conditions, the release of other substances from the endothelium leads to cellular dysfunction, thrombosis, and fibrosis.

Their theory neatly explains why microvascular dysfunction is such a powerful predictor of cardiovascular injury.

Cardiovascular stress and disease expose the dynamic nature of the mediators of microvasculature dilation, which can be changed either acutely (e.g. by changes in pressure within the vessel or pharmacological interventions) or by chronic diseases such as CAD. The HVRG team and collaborators explore changes in the dilator pathways, hoping to shed light on ways that microcirculation-

The team has a wealth of expertise in studying microcirculatory function in intact human tissue samples, an approach that provides obvious clinical relevance. provoked dysfunction leads to clinical implications (e.g. atherosclerosis).

THE STRESS-INDUCED SHIFT IN MEDIATOR OF VASODILATION In human coronary arterioles from patients with CAD, loss of nitric oxide-mediated dilation to shear stress (flow-mediated dilation, FMD) is compensated by the release of hydrogen peroxide (H2O2) from mitochondria in the endothelial cells. Interestingly, both hydrogen peroxide and nitric oxide are vasodilators, yet they have opposing effects on the health of the microvasculature and surrounding tissue – nitric oxide promotes latency, whereas H2O2 promotes inflammation and atherosclerosis. The HVRG is exploring the mechanisms that switch the mediator released from the endothelium, believing it to be pivotal in reducing tissue stress from inflammation.

The researchers are investigating adaptive autophagy (the regulated mechanism that disassembles unnecessary cellular components), which is shown to be necessary for the endothelial shearinduced production of nitric oxide. Their hypothesis is that by blocking autophagic flux, NO is reduced, and inflammation increased, leading to a change from NO production to H2O2 as the mediator of FMD in CAD patients.

A PIVOTAL ROLE OF ENDOTHELIAL MITOCHONDRIAL FUNCTION Two pathways involving the production of ceramide and a reduction in telomerase activity are critical in the shift from NO to H2O2. Both ceramide and reduced telomerase activity are known to suppress mitochondrial function and promote mitochondrial free radical production such as H2O2. The traditional role of telomerase is to protect the nuclear genome from shortening during cell division by adding a repeat sequence to telomeres (regions of repetitive DNA sequences at the end of chromosomes); thus telomerase protects the end of chromosomes from damage. Under conditions of acute stress, TERT, the catalytic subunit of telomerase is translocated to the mitochondria where it has been shown to bind to mitochondrial DNA (mtDNA). The exact role of TERT in the mitochondria is somewhat puzzling as mtDNA is circular and does not have telomeres to protect. Ceramide, a prototypical sphingolipid product of sphingomyelinase, is produced in endothelial cells, found in human plasma, and is a risk factor for atherosclerosis.

Ceramide is a known inhibitor of telomerase activity in the cancer literature, which makes ceramide and telomerase both active targets of investigation for the treatment of various cancers,

www.researchoutreach.org

57

however, to date unsuccessful. One of the reasons why ceramide or anti-telomerase activity has not paid off as a viable anticancer treatment may be the general toxicity of such drugs that manifests as cardiovascular toxicity. On the other hand, however, targeting ceramide and telomerase or their associated pathways may be a novel therapeutic strategy for the treatment of coronary artery disease as well as cancer if risk versus benefit analysis is carefully evaluated.

As mitochondrial function appears to be critical for physiological vasodilator capacity in the human heart, the HVRG is investigating underlying mitochondrial damage as the causative link between these pathways. Both activation of telomerase or inhibition of ceramide production contributes to the prevention of mtDNA damage. The team has already demonstrated that TERT re-activation and translocation to the mitochondria, as well as decreasing levels of ceramide, can restore the “normal” mechanism of flowinduced endothelium-dependent dilation from H2O2 to NO (thus moving away from a CAD phenotype). Their central tenet is that mtDNA damage is one of the underlying causes that leads to an increase in ROS production. Mitochondrial ROS has been shown to promote the development of arteriolosclerosis and endothelial dysfunction, predisposing individuals to vascular complications.

At the same time, NO has a well-known

Dr Julie K. Freed (right) and Mary Schultz (left) discussing vascular responses during an experiment.

Their theory neatly explains why microvascular dysfunction is such a powerful predictor of cardiovascular injury. inhibitory effect on the generation of mitochondrial ROS and is known to increase telomerase activity.

The relevance of these findings extends itself beyond the laboratory. Dr Durand, in collaboration with Dr Allison Hyngstrom at Marquette University, were the first investigators to quantify the hyperemic blood flow response to muscle contractions in the legs of stroke survivors.

They discovered that reduced blood flow to the paretic leg (impaired function as a result of a stroke) during muscle contraction was strongly correlated with reduced leg strength and poor motor control. Their studies led to the finding

REGULATION OF THE MECHANISM OF FLOW INDUCED DILATION IN THE HUMAN MICROCIRCULATION

(Flow)

High Pressure CAD Chemo/Radiation

Exercise Healthy Diet

LPP3

TERT NO

(Autophagy)

(Health)

Ceramide LPA

H2O2 (Disease)

In healthy adult subjects (left), arteriolar endothelium produces NO which support a quiescent nonproliferative/anti- atherosclerotic state. With onset of disease (CAD) or exposure to acute stress (increased intraluminal pressure), flow through the microvasculature releases hydrogen peroxide, creating a proinflammatory environment throughout the organ, potentially leading to hypertrophy, fibrosis, and atherosclerosis. LPP3, Autophagy, TERT, Ceramide and LPA among others have been identified to play important parts in regulating this switch in dilator mechanism.

58

www.researchoutreach.org

that the peripheral microcirculation (leg) is significantly impaired after a stroke and that improvements in microvascular function contribute to the improvement of motor function in this population.

Further, the Durand lab is exploring simple non-invasive means to improve microvascular function. Application of a technique called ischemic conditioning (short, intermittent bouts of limb ischemia using a blood pressure cuff) is sufficient to improve paretic leg strength and hyperemic blood flow by approximately 15%. This improvement in strength is also accompanied by an acute improvement in arterial flow-mediated dilation.

Currently, Drs. Durand and Freed from the HVRG are jointly conducting a clinical trial which will examine the effects of ischemic conditioning on peripheral vascular function and frailty in pre-surgical, elderly colon cancer patients who traditionally have poor surgical outcomes.

Together these findings underline the growing recognition that dysfunction of the microcirculation contributes to the development of cardiovascular and other chronic diseases in humans.

Ongoing research from the HVRG connects known functions of the microvasculature that neatly explains its intimate link to disease development in human subjects. Applying clinically relevant data from human tissues, the HVRG team hopes to provide a detailed mechanistic understanding of disease with the goal to develop novel therapeutics that can translate into the clinic.

Behind the Research Andreas M. Beyer David D. Gutterman Matthew J. Durand

Julie K. Freed

E: abeyer@mcw.edu T: +1 414 955 7514 W: www.mcw.edu/Cardiovascular-Center/Research-Labs/Cardiovascular-Center-FacultyLabs/Andreas-Beyer-Lab.htm W: www.mcw.edu/Cardiovascular-Center/Research-Labs/Julie-Freed-MD-PhD-Lab.htm W: www.mcw.edu/departments/pharmacology-and-toxicology/faculty/david-gutterman-md W: https://fcd.mcw.edu/?module=faculty&func=view&name=Matt_Durand_Phd&id=6476

Research Objectives

References

The HVRG studies the complex relationship and physiological effects of vascular stress response in health and disease. The main focus of these labs is to understand how the mechanisms of vasodilation change from nitric oxide (healthy individuals) to mitochondrialderived hydrogen peroxide (individuals with CAD). Several interconnected signalling pathways including ceramide, extra-nuclear telomerase, PGC1α, LPA, and others have been identified to regulate mitochondrial function in the human microcirculation.

Gutterman D, Chabowski S, Kadlec A, Durand M, Freed J, Ait-Aissa K, Beyer A. (2016). ‘The Human Microcirculation’.

Regulation of Flow and Beyond. Circ Res. 118:157-172.

Detail Cardiovascular Research Center Medical College of Wisconsin Milwaukee, WI 53226 MEB 4825, USA Bio The HVRG consists of several investigators with diverse backgrounds. Dr David Gutterman is a cardiologist with a prolonged interest in understanding the human microcirculation; Dr Andreas Beyer is a trained geneticist and physiologist with a background in vascular function and hypertension research. Dr Julie Freed is a cardiac anesthesiologist with a focus on lipid signalling and vascular function. Dr Matt Durand is a cardiovascular physiologist who studies the effect of a non-invasive intervention, called ischemic conditioning, on motor, neural, and vascular function in chronic stroke survivors.

Funding NIH/NHLBI, WE-Care Foundation, Advancing Healthier Wisconsin, American Heart Association Collaborators • Andreas M. Beyer • David D. Gutterman • Julie K. Freed • Matthew J. Durand

Freed, J.K., et al. (2014). ‘Ceramide changes the mediator of flow-induced vasodilation from nitric oxide to hydrogen peroxide in the human microcirculation’. Circ Res, 115(5): p. 525-32.

Beyer, A.M., et al. (2014). ‘An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles’. Am J Physiol Heart Circ Physiol, 307(11): p. H1587-93.

Beyer AM, Freed JK, Durand MJ, Riedel M, Ait-Aissa K, Green P, Hockenberry JC, Morgan RG, Donato AJ, Peleg R, Gasparri M, Rokkas CK, Santos JH, Priel E, Gutterman DD. (2016). ‘Critical role for telomerase in the mechanisms of flow-mediated dilation in the human microcirculation. Circ Res, 118(5):856-66.

Durand, M.J., et al. (2015). ‘Impaired hyperemic response to exercise post stroke’. PloS one, 10(12): p. e0144023.

Personal Response In your research, you make elegant use of human vessels.

Can you explain some of the advantages of your methods over animal models?

The human coronary microcirculation exhibits several unique characteristics that have been identified through in vitro studies. Interestingly, dilator responses in commonly used model systems such as rodents, dogs, or pigs do not always correlate with findings in human tissue, making studies in human microvessels of critical need. Abnormal microvascular function typically precedes and predicts the development of conduit artery atherosclerosis and its risk factors. This indicates that it may be possible to reverse the negative effects of microvascular defects before vascular disease progresses to the development of large vessel atherosclerosis, plaque formation, and eventual cardiac events.

www.researchoutreach.org

59

Thought Leader

Mending broken hearts: The American Heart Association and its life-saving treatment guidelines

When someone suffers a cardiac arrest, the first few minutes that follow the attack are crucial and can decide if someone lives or dies. The effective administration of cardiopulmonary resuscitation (CPR) can greatly improve people’s chances.

The American Heart Association have been educating people on CPR, heart health, stroke and heart disease worldwide for nearly 100 years and their latest mission is not just to save and treat patients, but to prevent heart conditions occurring in the first place.

T

he American Heart Association’s official guidelines on cardiopulmonary resuscitation and emergency cardiovascular care are some of the most respected around the world, not just in the United States. Their mission to save lives and prevent heart disease and stroke begins with up-to-date and reliable research and ends with hands-on education on an international scale. Tools, services and training are made available by the Association to healthcare workers, patients and the public alike because saving lives is everyone’s problem.

60

www.researchoutreach.org

In this interview with Research Outreach, American Heart Association’s Chief of Mission Aligned Businesses and Healthcare Solutions, John Meiners, tells us more about the Association’s key strategies and how they aim to carry these out.

Can you tell us more about the American Heart Association (AHA) in terms of its background, history and core mission?

The American Heart Association’s mission is to be a relentless force for a

world of longer, healthier lives. For nearly 100 years, we have been fighting heart disease and stroke, striving to save and improve lives. The Association was started in 1924 by six cardiologists as a professional society for doctors and has evolved to unite more than 33 million volunteers and supporters as well as our 3,400 employees.

Can you tell us more about your role and responsibilities at AHA? I oversee several revenue-generating mission delivery departments at the

association, including Emergency Cardiovascular Care (ECC), Workplace Health, International Programs and Patient Quality Systems

guidelines into clinical processes that take patient population characteristics into account. We help healthcare providers and patients achieve improved health with evidence-based information and tools for heart failure, stroke, blood pressure and cholesterol management through quality improvement initiatives and certification programmes.

The Workplace Health department offers a suite of science-based,

Can you tell us what your global lifesaving programmes are and how the AHA works with many partners, across many countries to address the issue of non-communicable diseases and help save more lives?

About 8 years ago, the organisation began to increase its effort to address cardiovascular disease around the world, offering technical support, scientific exchange and training to governments, health care providers, hospital

The American Heart Association’s mission is to be a relentless force for a world of longer, healthier lives.

Improvement. The Emergency Cardiovascular Care business is comprised of more than 4,000 training centres and 450,000 instructors who last year trained 22 million people in over 100 countries.

evidence-informed tools and services to help build and maximise an effective workplace culture of health, which can increase productivity, reduce absenteeism and control healthcare costs.

Our Patient Quality Systems Improvement team works to improve outcomes for patients by putting knowledge into practice. We do this by converting scientific research into treatment guidelines, then translating

Our International team collaborates with governments and nongovernmental organisations to adapt successful solutions from the United States to extend the quality and lives of communities elsewhere.

and pre-hospital systems, workplaces and communities.

The American Heart Association system of care approach – in coordination with local cardiovascular societies, heart and brain health advocates, business and government leaders – now drives global heart and brain health at all levels of society around the world.

In support of a country’s health priorities, we provide our technical expertise and

www.researchoutreach.org

61

experience in developing both patient and public programmes to improve the quality and length of people’s lives.

With our partners, we share the best in science with people around the world through our annual Scientific Sessions, International Stroke Conference and ten speciality conferences, and by supporting joint science sessions with other countries’ cardiology societies at their local meetings.

We create educational programmes and tools that help people improve their

John strives to identify unmet needs and connect the dots to find inspiration and innovative solutions.

62

www.researchoutreach.org

health, such as Go Red For Women®, which educates women about their greatest health risk, cardiovascular disease, and is now promoted in more than 40 countries. We help improve hospital systems of care with programmes like Get with the Guidelines and Saving Children’s Lives in Botswana, Tanzania and India, an initiative designed to empower community health workers with skills to reduce under-fives mortality in low to middle-income areas.

We train 22 million people around the world annually – from advanced healthcare providers and corporate employees to new parents – in first aid, cardiopulmonary resuscitation (CPR) and advanced life support. And, we advocate for stronger public health policies that support improved nutrition availability, obesity reduction initiatives and improved hospital treatment and systems of care.

The Association is a strategic partner with the World Heart Federation and celebrates World Heart Day on 29th September – can you tell us about this collaboration, what this World Heart day consists of and its global impact?

The American Heart Association is a founding partner of the World Heart Federation and an enthusiastic supporter

of the commitment to reduce premature deaths from non-communicable diseases by 25% by 2025. World Heart Day was started in 2000 and aims to increase awareness of heart disease and stroke.

The campaign for World Heart Day is about what you can do to get and keep your heart healthy. This year’s campaign – My Heart, Your Heart – was about creating a sense of commitment around the common cause of heart health. World Heart Day resonates around the world and plays a key role in spreading awareness of cardiovascular disease and the simple steps we can all take to reduce our risk.

The American Heart Association encourages everyone to learn how to perform CPR. Can you tell us why this is so important?

It is estimated that more than six million sudden cardiac deaths occur worldwide each year. Globally, the incidence of out-of-hospital cardiac arrest ranges from 20 to 140 per 100,000 people, and survival ranges from 2% to 11%.

Statistics prove that if more people knew CPR, more lives could be saved. When a person has a cardiac arrest, survival depends on immediately receiving CPR from someone nearby. CPR, especially if performed immediately,

Thought Leader can double or triple a cardiac arrest victim’s chance of survival. It is also a fact that most cardiac arrests happen at home so if you need to give CPR in an emergency, you will most likely be trying to save the life of someone you love: a child, a spouse, a parent or a friend.

The American Heart Association is the leader in resuscitation science, education and training, and publisher of the official AHA Guidelines for CPR and ECC. How are the Association’s guidelines helping save lives around the world?

Healthcare professionals use CPR/basic life support/advanced cardiac life support/ paediatric advanced life support to save lives because that is the right thing to do.

At the time they are using one of these skills, they know they only have a very few minutes to save a life. Many healthcare providers know that the American Heart Association does a tremendous job in evaluating research behind recommendations and that you can

Association is a catalyst to achieving maximum impact in equitable health and well-being.

For more than 90 years, we have focused on treating cardiovascular disease. Over the last decade, we have turned our

at saving lives of cardiac arrest patients in the hospital.

Developed through our strategic relationship with Laerdal, and launched in February 2015, the Resuscitation Quality Improvement programme develops high-

This system of care approach drives global heart and brain health at all levels of society around the world. trust what the Association says as being cutting edge and reliable. We has been writing these guidelines for a long time so we are a trusted organisation.

When international training centres open, they know that they will be teaching reliable, proven techniques/ skills/medications to their students.

When a health minister in China comes to us asking if we can teach resuscitation to 10% of their population, it is because they have done their homework and recognise that the Association guidelines are developed in a rigorous way, and our business processes are uncompromising with the patients survival and full recovery as the critical outcome.

What are the plans for the American Heart Association next year?

As part of our mission to be a relentless force for a world of longer, healthier lives, we recently revised our Strategic Impact Statement, which guides how we go about our work: the American Heart

attention to preventing cardiovascular events. That effort requires improving health factors and risks that contribute to not just cardiovascular disease but many others including cancer and diabetes, so we find ourselves focusing increasingly on total health.

Over the next decade, we will address overall health and well-being, anchored in cardiovascular and brain health, as well as health equity across all populations.

Additionally, we are seeking a paradigm shift in hospital resuscitation practice.

Poor quality CPR is a preventable harm, and timely delivery of high-quality CPR is the greatest determinant of survival from cardiac arrest. Unfortunately, even with trained professionals, poor quality CPR is common. Advances in technology and evidence now show that low-dose, high-frequency psycho-motor training is significantly more effective at increasing and maintaining CPR competency, and that resuscitation quality improvement initiatives are both necessary and effective

quality resuscitation skills through lowdose, high-frequency CPR skills practice and high-fidelity coaching. Validated by early evidence on actual patient care and survival, more lives are being saved.

To find out more about the American Heart Association, visit www.heart.org/en/.

Contact: Tracie G. Bertaut APR 7272 Greenville Avenue Dallas, TX 75231 USA E: Tracie.Bertaut@heart.org T: +1 504 722 1695 W: www.heart.org

www.researchoutreach.org

63

Education & Training ︱ Children’s Hospital Oakland Research Institute

STEM Summer Program: Inspiring the next generation of scientists More students in the United States are studying STEM (Science, Technology, Engineering, and Mathematics) majors at university. However, there is a notable discrepancy in underrepresented students choosing STEM, including racial minorities and those first in their family to attend college. Research internships, such as the CHORI Summer Student Research Program, provide the much-needed boost in scientific research knowledge and confidence for underrepresented students to study and pursue careers in STEM. Co-directors of the program, Drs Bertram Lubin and Ellen Fung, firmly believe programs such as these can change the statistics behind underrepresented students pursuing STEM futures and bring greater diversity to science.

High school junior, Chima Ezeh, in his first basic laboratory experience, studied the colonisation of Neisseria Meningitidis in the laboratory of Dr Gregory Moe at CHORI.

64

www.researchoutreach.org

T

he number of students enrolling to study STEM (Science, Technology, Engineering, and Mathematics) subjects at university in the United States has progressively increased over the last few decades.

However, more than half of students that enrol in a STEM subject will change their major during their time at university. The decrease in STEM enrolment and graduation is most notable in ‘underrepresented’ students.

Underrepresented students include ethnic and racial minorities and women.

They constitute 68% of all university students in the States but remain underrepresented in STEM careers.

Providing encouragement for students to consider STEM careers before and during university can change these statistics and increase diversity in STEM fields.

A student’s self-confidence and motivation are some of the greatest factors that influence their pursuit of a subject through university into a career. Research experience, “active learning” (problem-solving), and being

part of a community of students with shared interests have all been shown to increase students’ persistence with STEM subjects. Summer internships, such as the Children’s Hospital Oakland Research Institute (CHORI) Summer Student Research Program (SSRP), offer effective interventions within a student’s academic trajectory to develop their confidence in STEM through one-onone mentorship and broadening their scientific community.

The CHORI SSRP was initiated in 1981, the brain child of Dr Bertram Lubin, now an internationally recognised paediatric haematologist. He was first in his family to attend college and therefore fully aware of the challenges present when negotiating the university system with minimal support. Almost 40 years later, Dr Lubin continues to Co-Direct the program along with Associate Scientist, Dr Ellen Fung. In a highly competitive selection process, CHORI SSRP selects underrepresented students from both high schools and universities. Real world research experiences are provided with practising medical and scientific professionals. CHORI SSRP interns develop their confidence in science, inspiring them to pursue futures in STEM subjects, and encouraging greater diversity in STEM fields.

CHORI is the renowned biomedical research institute of the University of California San Francisco (UCSF) Benioff Children’s Hospital Oakland. Students participating in the CHORI summer program have access to clinical research in close to 35 sub-specialty areas including but not limited to, haematology, oncology, endocrinology and orthopaedics. Over 200 basic scientists, post-doctoral fellows, and laboratory staff guide students interested in basic science in stem cell therapies, immunobiology, infectious disease prevention, nutrition and genomics. With funding from a variety of foundations and government

sources, including the NIH (National Institutes of Health), the CHORI summer program offers in-depth research opportunities in any of these fields. “I have the privilege to work directly with these incredibly gifted young students.

They are the future face of science, and they inspire me,” says Co-Director, Dr Ellen Fung.

CHORI SUMMER STUDENT RESEARCH PROGRAM Over nine weeks, CHORI summer students: are paired with a mentor who educates and empowers them in a medical research field; attend weekly seminars and discussion forums to learn about contemporary scientific research; design, carry out, and present their own research project; join a community of likeminded peers and CHORI alumni. Some summer students have presented their work at national scientific conferences, and even co-authored published papers with their CHORI SSRP mentors.

Studies have shown that summer research programs increase the likelihood of underrepresented students pursuing careers in STEM. Furthermore, programs that include mentorship increase the likelihood of these students pursuing postgraduate education. Compared to 2014 US census data, CHORI summer program alumni are: 3.5 times more likely to pursue postgraduate studies than the US average for Asian or Pacific Islander students; over 6 times more likely than average for Hispanic/Latino students; and almost 9 times more likely than average for Black/African American students.

The CHORI Summer Student Research Program provides students not only with skills and knowledge to make them attractive candidates for future research work as a professional, but with the confidence needed to pursue a STEM career. Furthermore, the CHORI Summer Program aims to provide students from disadvantaged backgrounds, racial and ethnic minorities, and students with disabilities, the opportunity to engage with and be inspired by STEM research.

Greater diversity within STEM gives rise to greater creativity and innovation – key characteristics needed to solve today’s challenging scientific problems.

Bonny Alvarenga, Chloe Ghent (fore), Nicolas Nido and Lara Ramirez (background) discuss the challenges and occasional surprises in medical ethics during a weekly lecture.

The program strives for diversity and is committed to changing the statics behind underrepresented students studying STEM. TESTIMONIALS FROM CHORI ALUMNI Student testimonials speak volumes about the CHORI Summer Student Research

individuals. It is about making new, valuable connections with my fellow CIRM [California Institute for Regenerative Medicine] friends, my mentors, and other students and scientists involved in the program. It is about getting inspired by the talks given by prominent scientific figures and the touching stories

CHORI summer program alumni are … more likely to pursue postgraduate education than the US average.

Program. Julia Nguyen, who took part in the program in the summer of 2017, says: “…this internship is about more than just lab work. It is about joining a community of curious, intelligent, and like-minded

of bone marrow transplant pen pals.

And it is about learning the true ways of science and getting the opportunity to contribute to humanity’s growing pool of knowledge.”

Percentage of CHORI SSRP Alumni who pursue graduate education* 76.0%

80.7%

72.7%

US CENSUS CHORI Alumni

28.5%

21.4% 8.2% Asian or Pacific Islander

Black/ African American

13.5% 4.7% Hispanic/ Latino

White/ Caucasian

*Of those respondents who have completed a minimum of undergraduate education.

www.researchoutreach.org

65

Catherine Campusano, a high school junior, spent her summer in the laboratory of Dr Dario Boffelli gaining a deeper understanding of the erythroid differentiation pathway.

The CHORI Summer Student Research Program has been training underrepresented students in STEM for nearly 40 years.

These feelings are echoed by other students, including the 2018 CHORI Summer Program participant, Chima Ezeh: “During this program, I have been fortunate to integrate myself into such a diverse community of students who share an ever-growing passion to further the field of science and medicine.”

Students from the 2016 cohort are excited about the future opportunities available to them after the CHORI program: “…I am happy to say that this summer full of discovery has been of large growth to me, and has brought to light unforgettable opportunities I thought were once far from my grasp. May this be the beginning of many adventures to come!” says Anna Victoria Serbin.

“Working next to highly educated scientists who are passionate about their research has allowed me to imagine myself in their shoes. It has led me to ask myself questions like “Can I do this

in the future?”, “Would I enjoy waking up every day to know I will be working in a lab?”, “Can I imagine myself eventually publishing a scientific paper?”,

The program strives for diversity within STEM and is committed to changing the statics behind underrepresented students studying science.

“How rewarding will it actually be to pursue a PhD?”” says Raymundo Sanchez.

“Entering college with the experience and knowledge I have gained from this internship will undoubtedly prepare me for my coursework and allow me to earn even more prestigious opportunities. I feel extremely well equipped for the future in science and medicine that I want to pursue.

My experience as a CIRM SPARK [Summer

Educational Background of Parents of Students Served

Social & Economic Background of Students Served

Did not graduate from high school 10%

Did not graduate from college 58%

Did not attend college 32%

Includes data from recent CHORI student interns: 2012-2018.

66

www.researchoutreach.org

Program to Accelerate Regenerative Medicine Knowledge] Award intern has given me the confidence that I could not only do research like this, but excel

Disabled 13%

Low Income* 12%

Socially or Economically disadvantage 75%

*In 2018, low income defined as family of 4 with income <$44,000

in research like this. From here, I see no other direction for me to go but up,” says Ava Daniel.

And whilst all the students developed confidence and knowledge in scientific research, some students also learned a sense of humour is often needed.

Recounting his summer spent performing qPCRs (quantitative Polymerase Chain Reactions), 2018 CHORI Program participant Jonathon Luo says: “It is often said that baking is a science, but you rarely hear anyone saying science is like baking… Day after day, I laboured to pipette drop after drop into their appropriate wells, bent over and fatigued… the strain of pipetting started to set in, reminding me that my right thumb was still getting a pretty hardcore workout… I’ve learned countless new skills, gained a great amount of knowledge in the field of molecular biology, and of course, had lots of fun…

But perhaps most importantly, I will leave this experience with extreme respect for laboratory scientists all over the world, who inarguably have the strongest thumbs on the planet.”

Behind the Research Dr Bertram Lubin

Dr Ellen Fung

E: ssrp@chori.org T: +1 510-450-7604 W: www.chori.org/ssrp

www.facebook.com/CHORISummerResearch/

Research Objectives

References

The Children’s Hospital Oakland Research Institute (CHORI) Summer Student Research Program aims to increase the number of students from underrepresented backgrounds pursuing and graduating with a STEM major.

Carpi, A., Ronan, D.M., Falconer, H.M. and Lents, N.H., (2017). Cultivating minority scientists: Undergraduate research increases self efficacy and career ambitions for underrepresented students in STEM. Journal of Research in Science Teaching, 54(2), pp.169-194.

Detail

Pender, M., Marcotte, D.E., Domingo, M.R.S. and Maton, K.I., (2010). The STEM pipeline: The role of summer research experience in minority students’ Ph.D. aspirations. Education Policy Analysis Archives, 18(30), p.1

CHORI (Children’s Hospital Oakland Research Institute) Summer Student Research Program 5700 Martin Luther King Jr Way Oakland CA 94609, USA Bio Bertram Lubin MD, Internationally recognised Haematologist and Associate Dean Children’s Health at UCSF, and Ellen Fung, PhD Associate Scientist at CHORI, Co-Direct the Summer Student Research Program. With the same focus for nearly four decades, the SSRP has trained well over 1000 underserved students interested in STEM, many of whom are now practising physicians and basic scientists.

Funding • NIH (National Institutes of Health) • DDCF (Doris Duke Charitable Foundation) • CIRM (California Institute for Regenerative Medicine) • ACHPP (Alameda County Health Pathway Partnership)

en de r • scient

ific

•a

c

ad em i

cul tu

nic • g

TY

c

VERSI

eth

DI

l•

CHORI CELEBRATING OUR

CHORI (2018) Summer Student Research Program. [online] Available at: www.chori.org/Education/Summer_Internship_ Program/program_description.html [Accessed 23/10/2018] CHORI (2018) Blogs from CIRM High School Trainees. [online] Available at: www.chori.org/Education/Summer_Internship_ Program/CIRM_Blog.html [Accessed 24/10/2018]

Personal Response

Collaborators • Biology Scholars Program at UC Berkeley • CHAMPS (Community Health & Adolescent Mentoring Program for Success) at UCSF Benioff Children’s Hospital Oakland • Students Rising Above, Achieve Scholars, Biotech Partners

ra

Graham, M. J., Frederick, J., Byars-Winston, A., Hunter, A. B., Handelsman, J. (2013) Increasing Persistence of College Students in STEM. Science, [online] 341 (6153), 1455-1456.

Available at: https://www.doi.org/10.1126/science.1240487 [Accessed 25/10/2018]

DIVERSITY

What do you think student’s benefit from most by taking part in something like CHORI Summer Student Research Program?

Dr Ellen Fung: As many of our students come from households with little to no science background and minimal experience with US secondary education, what our students gain from just nine weeks in the SSRP is often immeasurable. In addition to practical laboratory and clinical skill development, experience with hypothesis and protocol generation, statistical analysis and presentation practice: CHORI SSRP students broaden their scientific network. Their new scientific community is invaluable to opening doors and improving opportunity for acceptance into university, graduate school and future participation in other highly competitive internships.

www.researchoutreach.org

67

Education & Training ︱ Professor Hamsa Venkat

Improving Maths performance in South Africa’s primary schools Professor Hamsa Venkat holds the SARCHi Research and Development Chair in Primary Maths Education at the University of the Witwatersrand in Johannesburg.

She leads the Wits Maths Connect project. The project team works with ten partner primary schools serving disadvantaged student populations, and develops and researches interventions to help teachers improve their students’ maths performance. Intervention models and materials with evidence of success are being taken up in provincial and national pilots in South Africa, leading to improvements in both the classroom and teacher education.

S

outh Africa faces a range of social issues including high levels of unemployment, inequality and widespread poverty. The schooling system is dominated by low performing schools with large classes and few resources serving the poor. The schools, teachers and children face substantial poverty-related impediments.

Internationally, there is limited research on mathematics teaching and learning among poor and hungry children.

Professor Venkat seeks to redress this bias, providing a sense of these on-theground realities that have to be taken into account to design substantively useful and pragmatic intervention models.

WITS MATHS CONNECT PROJECT Professor Hamsa Venkat holds a Research and Development Chair in Primary Maths Education at the University of the

Witwatersrand in Johannesburg. She leads the Wits Maths Connect project, which is now in its second five-year phase. The project team works with ten partner primary schools serving disadvantaged students, devising and trialling interventions aimed at improving primary maths performance through a focus on supporting coherent and connected classroom teaching.

Intervention models and materials with evidence of success are being taken up in provincial and national pilots in South Africa and beyond, and feed into improvements in both the classroom and teacher education.

PHASE ONE During the first five years of the project (2011–2015), the researchers worked with the partner schools supporting the development of primary mathematics teaching and learning. One focus was building number sense through working with both teachers and learners in the Lesson Starters Project. The second was the I Hate Maths project aimed at building communities of primary teachers and the public with an interest in talking about mathematics. A 20-day Primary Mathematics for Teaching course was developed, with multiple trials showing robust improvements in primary teachers’ mathematical knowledge.

PHASE TWO The 20-day course and the I Hate Math workshops are continuing through the second phase of the project (2016–2020).

Building on the models of the Lesson Starters Project, an additional focus of the second phase is the Seeing Number Structure project which includes workshops and in-class coaching to assist

68

www.researchoutreach.org

These on-the-ground realities have to be taken into account to design substantively useful and pragmatic intervention models. teachers to focus their pupils’ attention on number relationships and properties, encouraging them to employ strategic thinking with number, rather than relying on counting to solve problems. Another key element in phase two is expanding work on multiplicative reasoning.

quality of primary maths teaching when working from an evidence base of gaps in teacher knowledge. It aims to address this gap in mathematical knowledge and improve the teaching and learning of multiplication and division across the primary grades.

THE MULTIPLICATIVE REASONING PROJECT Research into the educational quality of South African primary teachers’ mathematical content knowledge revealed particular weaknesses relating to multiplicative reasoning. Multiplicative reasoning is the understanding and ability to solve mathematical problems involving a multiplicative structure. This includes mutliplication and division problems, but extends to fractions, ratio and proportion situations, and is a fundamental part of mathematical learning.

DEVELOPING THE MODEL At this level of learning, there is evidence that short sequences of well-structured lessons can have a positive effect. A short-term intervention, comprising four lessons, carefully designed to take into account levels of learning and classroom culture was developed. The pedagogic approach, together with the structure and content of the lessons, are based on the ‘Big Books of Word Problems’ by Professor Mike Askew, a member of the project team.

The Multiplicative Reasoning project builds on the project team’s experience of developing interventions to improve the

The pilot model was designed so that students would be tested before and after the four-lesson sequence in order to provide pre-intervention and post-

intervention data on learner performance and their approaches to solving the problems. Weekly training workshops and supported teaching were also provided.

Encouraging results from a series of postgraduate students leading the teaching with single classes led to a scaled-up project with the members of the project team acting as teachers in nine classes of one of the partner schools. A test-teach-test sequence took place with weekly planning meetings with the teachers and research team and also revealed promising results.

A further scaling, to involve classroom teachers in all ten partner schools was then designed.

LESSON STRUCTURE Based on these positive results, a fourlesson model was designed. Each lesson was made up of the following four sections: 1. Revision of multiplication and division facts.

2. Students work in pairs followed by a whole class discussion of three initial problems led by the teacher.

3. Students work independently on six problems.

4. Multiplication and division number sentence examples for independent practice.

www.researchoutreach.org

69

The test was made up of 14 multiplicative reasoning problems with five additive reasoning problems, to see how students differentiated between the two.

APPLICATION The project was then rolled out for all ten partner schools across the Intermediate Phase Grades 4–6. Two grade 7 maths teachers, one from a government fee-paying suburban school and one from a government no-fee township school, also offered to take part in the program. Although both schools serve disadvantaged populations, the suburban school benefited from smaller class sizes and less crowded classrooms. The teachers attended afternoon workshops, led by members of the project team, prior to leading the intervention lessons.

The pre- and post- tests were administered by members of the project team before the intervention commenced and repeated six weeks later. Students were told to answer the questions, choosing the most efficient approach and showing working out where they felt it was required.

RESULTS The township school started with a lower performance profile than the suburban school. The post-intervention results showed an overall improvement in multiplicative reasoning performance across both schools, with larger improvements in the township school, and prompted a detailed analysis of the learning outcomes of the intervention with these Grade 7 classes. This centred on matching students’ pre- and posttests and analysing the differences in the students’ performance on the multiplicative reasoning problems and examining the observed changes in the students’ approaches to solving the problems.

The test results reported in a recent paper

by Hamsa Venkat and Corin Mathews have shown substantial improvements in the students’ ability to use appropriate methods to calculate answers. Students

Multiplicative reasoning is the understanding and ability to solve mathematical problems involving a multiplicative structure.

appear to be more able to make sense of the problems through a ‘key models and connections’ approach.

These results indicate that well-structured short-term intervention models are useful, practical tools for teachers to implement in order to improve their students’ performance in multiplicative reasoning tasks. They work without disrupting broader curriculum coverage.

The next step is to investigate if the model can work with less input from the project team. A roll-out involving provincial subject advisers working with the intervention material and trialling the model with just one initial workshop for teachers is planned.

WITS MATHS CONNECT RESEARCH AND DEVELOPMENT ACTIVITIES The Wits Maths Connect project team are involved in a number of other current research and development projects.

Provincial initiatives include the Coaching 4 Development course for primary maths subject advisors. This is a 16-day course split across University-based days and lesson observation days. It aims to

Intervention models are useful, practical tools for teachers to implement in order to improve their students’ performance.

70

www.researchoutreach.org

connect and deepen the subject advisers’ mathematical knowledge together with their willingness and ability to have constructive mathematically-focused conversations with primary teachers in order to support teaching development of mathematics.

National initiatives include the Foundation Phase Grade 3 Diagnostic Assessment. This is a three-week testteach-test diagnostic assessment model with interim teaching activities focused on key mental mathematics skill areas.

It aims to use assessment to develop number fluencies and strategies. The project team are working in partnership with the Rhodes Numeracy Chair and the Department of Basic Education on national trials of these assessment tools and teaching activities.

The team members teach and supervise across B Ed, Hons, Masters and doctoral programmes at Wits. They are also involved as partners in the Department of Higher Education and Training Primary Teacher Education (PrimTEd) project which focuses on pre-service primary mathematics teacher knowledge and practice development as well as working with the Department of Basic Education on the development and trialling of national diagnostic assessments for the early grades

Behind the Research

Professor Hamsa Venkat and team E: hamsa.venkatakrishnan@wits.ac.za T: +27 (0)117173742 W: https://www.wits.ac.za/staff/academic-a-z-listing/v/ hamsavenkatakrishnanwitsacza/ W: http://tiny.cc/WMCP

Research Objectives

References

Professor Hamsa Venkat from the University of the Witwatersrand in Johannesburg focuses on improving primary maths teaching and learning.

Venkat, H. & Mathews, C. (2018). Improving multiplicative reasoning in a context of low performance. ZDM Mathematics Education. Available at: https://link.springer. com/article/10.1007%2Fs11858-018-0969-6 [Accessed 12 November 2018].

Detail Professor Hamsa Venkat Wits Maths Connect Corridor Marang Block Wits School of Education St Andrews Road Parktown Johannesburg South Africa Bio Professor Hamsa Venkat holds the NRF/FRF SARCHi Research and Development Chair in Primary Maths Education at the University of the Witwatersrand in Johannesburg. Her current work focuses on primary mathematics teaching and learning development.

Previously, she was a mathematics teacher in London, before obtaining a BERA-award winning PhD from King’s College London and moving into teacher education at the Institute of Education.

Funding The multiplicative reasoning study and the broader work of the Wits Maths Connect – Primary project are generously supported by the FirstRand Foundation (with the RMB), Anglo American Chairman’s fund, the Department of Science and Technology and the National Research Foundation.

Research Team The research and development work of the Wits Maths Connect – Primary project are supported by a team of staff and postgraduate students: co-Project Managers, Dr Samantha Morrison & Corin Mathews, Wits Distinguished Scholar, Prof Mike Askew, and team members: Dr Lawan Abdulhamid, Herman Tshesane, Marie Weitz, Sameera Hansa, Thulelah Takane, Dr Lynn Bowie and Lincoln Lavans.

Venkat, H. & Askew, M. (2018). Mediating primary mathematics: theory, concepts and a framework for studying practice. Educational Studies in Mathematics. https://link. springer.com/content/pdf/10.1007%2Fs10649-017-9776-1. pdf Venkat, H. & Spaull, N. (2015). What do we know about primary teachers’ mathematical content knowledge in South Africa? An analysis of SACMEQ 2007. International Journal of Educational Development, 41, 121–130. https://doi. org/10.1016/j.ijedudev.2015.02.002 Askew, M. (2005). Beam’s Big Book of Word Problems Year 3 and 4 (New edition). London: BEAM Education.

Askew, M. (2005). Beam’s Big Book of Word Problems Year 5 and 6 (New edition). London: BEAM Education.

Personal Response What are your plans for future research in developing primary maths performance?

Promising results have led to provincial, national and international interest in the intervention modes and materials that have been developed in the Wits Maths Connect – Primary project. We are currently building a longitudinal analysis of improvement in the sophistication of children’s approaches to solving number problems in the context of our development work. The linked research and development activity has been powerful for producing evidence-based models and materials that policy-makers and researchers can take up and trial. Over time, we feed into better understandings of how to address and improve primary mathematics learning outcomes for children in contexts of disadvantage.

www.researchoutreach.org

71

Education and Training ︱ Professor Hollie Swanson

Careers in Science:

Summer Training in Environmental and Pharmacological Sciences (STEPS) The future of scientific research depends on a talented, diverse and inclusive workforce with high scientific proficiency.

Undergraduate research experiences have been shown to play a key role in encouraging students, especially those from historically underrepresented groups, to pursue careers in science and healthcare professions. In response to these needs, Professor Hollie Swanson, from the University of Kentucky has developed the Summer Undergraduate Research Fellowship (STEPS), which offers individualised research experiences in different areas of pharmacology and environmental health sciences to undergraduate students from a variety of backgrounds.

Professor Swanson and participants of the STEPS program pose at the end-of-program reception celebration.

72

www.researchoutreach.org

T

he genesis of the STEPS project arose from Professor Hollie Swanson’s reflections about her own career goals whereby she sought to align her passion for research with the needs of the scientific community.

Swanson’s expertise in research pertains to problems relating to environmental health sciences whereas her teaching activities focus on delivering pharmacology related concepts to undergraduate, graduate and professional students. Through her work, Swanson aims to use both her expertise and teaching experience to encourage students from all backgrounds to pursue careers in science and research.

Swanson was keen to develop a program which could offer individualised research experiences to undergraduate students.

Funding from the American Society of Pharmacology and Experimental Therapeutics provided initial support

the STEPS project, whereby five undergraduate students were enrolled in a 10-week summer program.

Subsequently, Swanson received a second source of funding from the National Institutes for Environmental Health Sciences, which provided support for an additional 12 undergraduate students as well as 12 peer mentors who offered career advice to students. The program is designed to introduce students to the highly interdisciplinary and collaborative nature of environmental health science research, which is focused on solving key global health problems. An additional focus is on preparing underprivileged and under-represented students for successful careers in relevant fields.

RECRUITING STUDENTS Swanson carefully considered the target audience of the STEPS program.

She sought to include students from

Participants engaging in the improvisation workshop.

her local area of Kentucky because of the large numbers from socioeconomically disadvantaged backgrounds whom she wanted to encourage and support.

A particularly effective way to recruit onto the program was through obtaining recommendations from other academic staff members. Swanson has developed connections with a number of universities including Eastern Kentucky University and Morehead State University. Both institutions were actively looking for research opportunities for students so were keen to become involved.

Swanson realised that beginning recruiting early was essential in getting sufficient students on board and now begins the recruitment before the students leave for their Christmas break. The University of Kentucky also produced a video to help with recruiting students onto the STEPS project. In addition, as the program has become more established, word of mouth has become a useful way of encouraging more students to apply.

discussing ethics, lab books as well as the importance of communication in a way that is enjoyable for students. This enables them to get to know both the university campus and each other better. The strong group dynamics developed also help students to optimise their experience of the project.

The students participating in the program spend the majority of their time in their faculty mentor’s laboratories. Due to the multidisciplinary nature of environmental health sciences and pharmacology, this includes a wide variety of departments and colleges. Throughout the summer, the students also work on developing

sustainable farming. Students discussed the use of outreach and the importance of using culturally appropriate ways to reach an audience. In addition, on one week students worked with an agriculture extension agent to check stream health by collecting insects and measuring water quality. They discussed runoff and the range of substances that can end up in the water supply.

Careers are a key concern of the students participating so the program also involved lunches where researchers visited and discussed their research and career paths.

Students are able to interact with these professionals to become aware of the wide variety of career options available to them. Shadowing opportunities were also organised for students where they could establish networks to help them progress towards their chosen career. These activities allow students to see how science is used in their local community whilst also having exposure to different potential career paths.

Students are able to interact with these professionals to become aware of the wide variety of careers options available to them.

PROGRAM ACTIVITIES In order to prepare students for the program, they participate in several days of orientation activities. This includes

soft skills, such as interview and oral communication skills.

Weekly activities are organised throughout the program, such as hiking. On one week of the program, a hike at Red River Gorge was arranged through an outdoor centre. Another week, students received a visit from rapper Farmer Brown, who raps about nutrition and

At the end of the program, the students prepare a poster that describes their research projects and presents them to the faculty and staff of the involved departments. An event with around 50

www.researchoutreach.org

73

Student participants presenting their research findings at the end-of-program poster session.

attendees is organised where students can receive feedback on their work from graduate students. This also provides the opportunity for graduate students to gain experience in providing constructive advice. Participating students are also provided with a token as a reminder of their experience in the program. They receive either a pestle and mortar or a globe, depending on whether they have been engaged in pharmacology or environmental health sciencerelated research.

These tokens are engraved with the word STEPS and the year of their fellowship.

to discuss scientific concepts. Receiving this feedback from students has been hugely rewarding for Swanson, who has altered her view of professional success.

Through experiencing their talent, zest for learning and continued curiosity, she now feels more confident about the future of society. Particularly significant for Swanson is the feedback from students that she

involved in training a new student for the project. Discussions have also started to take place about what phase two of the program may look like. Swanson is considering partnering with other institutions to provide students with different types of research experiences.

For example, areas of particular interest would be those focusing on the relationship between climate change and environmental health. Another area of interest would be a partnership that would provide the students with insights pertaining to the global nature of science and research. The possibilities for the future are working with non-profit organisations like the Alan Alda Centre for Communicating Science or COMPASS. These are cross-disciplinary organisations which aim to help scientists learn to communicate more effectively with the public. Swanson would also like students to have the opportunity to participate in improvisation activities to allow them to become more confident in their communication skills.

Through experiencing their talent, zest for learning and continued curiosity, she now feels more confident about the future of society.

FEEDBACK FROM STUDENTS Feedback is obtained from students by administering pre and post program surveys about their expectations and experiences of participating. Preliminary results from these surveys indicate that through participating students gain confidence, a greater understanding of the nature of scientific research, how to formulate a research question, how to work independently and how

74

www.researchoutreach.org

has changed their lives and subsequently interacting with them in medical and graduate school classes, taking steps closer towards their future career in scientific research.

THE FUTURE OF THE PROGRAM Many of the students from the first year of the program stayed in the lab and continued to work on their scientific research. Swanson has been impressed with their continual motivation in their studies. One of the students from the first year of the program has also been

Behind the Research Professor Hollie Swanson

E: hollie.swanson@uky.edu T: +1 859 323 1463 W: https://med.uky.edu/users/hswan W: https://surfsures.blogspot.com/ www.linkedin.com/in/hollie-swanson-522821a/

Research Objectives Professor Swanson’s Summer Training in Environmental and Pharmacological Sciences (STEPS) aims to enhance student learning and help prepare students from a variety of backgrounds, for successful science-related careers.

Detail Dept. of Pharmacology and Nutritional Sciences, MS 305, University of Kentucky College of Medicine, 800 Rose Street, Lexington, Kentucky 40536, USA Bio The director of the Summer Undergraduate Program in Environmental Health Sciences and Pharmacology, Professor Hollie Swanson received her PhD degree from Purdue University and completed postdoctoral training Michigan State and Northwestern Universities.

She is currently Professor of Nutritional Sciences and Pharmacology and directs the Women’s Executive Leadership Development program.

Funding • National Institutes of Environmental Health Sciences (NIEHS) • American Society of Pharmacology and Experimental Therapeutics (ASPET)

Personal Response Have you experienced any challenges whilst working on the STEPS project?

The biggest challenge has been overcoming my own personal characteristics. I love coming up with new ideas and flying by the seat of my pants. In addition, and like many introverts, I spend most of my life inside my own head.

These attributes can translate into poor execution and poor communication. This program involves 50-75 faculty, staff and students during the short 10-week program. This means I need to plan ahead, be specific, align everyone’s expectations, get the most out of them and make sure it all runs smoothly. Fortunately, I have a very supportive departmental chair and outstanding staff that I can rely on.

It has taken some trial and error, but we now function well as a team developing timetables and effective administrative processes to ensure that the students have the best summer experience possible.

What are your future plans for research in this area?

Future plans for research in this area include: 1) Understanding the needs of the students with respect to their career progression in STEM. 2) understanding how these needs differ amongst different groups (i.e., gender, socio-economic, racial, first generation, etc.).

3) Identifying how undergraduate research experiences (like the STEPS program) can be modified to better meet the needs of all the participating students.

www.researchoutreach.org

75

Physical Sciences ︱ Professor José Goldemberg

Technological leapfrogging the global energy crisis:

How can changing the role of science in developing countries help with an oncoming climate catastrophe?

In 1975, the Brazilian government launched the National Alcohol Program (NAP) with the sole aim of relieving the country’s crushing dependence on fossil fuels with a move to cleaner ethyl-alcohol based fuels – and, thanks to researchers like Professor José Goldemberg, of the University of São Paulo, the program was an overwhelming success.

Combining the country’s own natural resources with technological leapfrogging – and skipping over the less suitable technologies used by industrialised nations – means that, today, ethanol replaces 50% of the gasoline that would otherwise be in use in Brazil.

Professor José Goldemberg argues that it’s time to take the approach globally.

T

he impact that human beings have had on the environment is immeasurable – from the vast areas of rainforest that disappear every single day, to the country-sized island of plastic floating in the Pacific Ocean.

Air pollution. Oil spills. Mass extinction.

Politicians who claim they don’t believe in monsters, when a titanic monster sits right outside our collective door, waiting. It seems that every day we draw closer to blindly falling prey to its trap: a climate catastrophe is just around the corner. In recent years, climate change and the renewable energy sector have received a lot of media attention – and you’d be forgiven for thinking that the issues are controversial but, in fact, over 95% of practising climate scientists agree that human beings are the main driving force behind global warming.

It’s easy, perhaps even comforting, to blame the generations that came before us: to say that their carelessness and greed is what led us to this point – led the monster to our door – but that only tells part of the story. In fact, much like the uneven global distribution of wealth, the majority of global energy is consumed by a minority of people.

Approximately 70% of the world’s

commercial energy is consumed by the 25% of the world population who live in industrialised countries, with the remaining 30% being rationed out to the 75% of people living in developing nations.

This situation is not a sustainable one and it would be naive to expect the balance to stay the same. If we look at the data, what we see is that the energy use of industrialised nations has actually stabilised in recent years, while that of developing countries continues to grow.

What happens when the scales begin to tip and developing countries consume more and more energy? particularly energy from polluting fossil fuels?

Professor José Goldemberg has spent his entire career looking at problems such as these and, if man-made environmental degradation in general and climate change is are going to be the bitterest pill our generation has to swallow, perhaps we can take a leaf out of his work to sweeten the taste with sugar.

SUGARCANE AS A SUSTAINABLE FUEL It might seem like a starry-eyed idea from one of Isaac Asimov’s novels but, in reality, Brazil has been using sugarcane to fuel its cars for almost half a century. The idea started in 1975 when, in response to an international oil crisis,

the government launched the National Alcohol Program (NAP) with the aim of alleviating some of the country’s dependence on fossil fuels. Back then, Professor Goldemberg was interested in how crops, already in production in Brazil, could be used to create ethanol and other ethyl-alcohol fuels.

In a 1978 paper, published in Science, he looked specifically at the energy cost and expenditure of several different crops: sugarcane, cassava and sweet sorghum. He focused on these specific crops because they are essentially a form of non-polluting solar energy: the sun’s rays provide the crops with the energy they need to grow – and a little extra; that extra energy is stored by the plants – quite literally saved away for a rainy day – and can be extracted in the form of ethyl-alcohol at a later date.

Professor Goldemberg’s work demonstrated that sugarcane was the most efficient crop to use when converting this solar energy into a chemical fuel and it paved the way for the Brazilian energy-boom that followed. Today, an estimated 50% of the gasoline that would be in use for fuelling cars in Brazil has been replaced with ethanol from sugarcane, a renewable fuel.

An achievement that was made possible, in part, by what Professor Goldemberg calls technological leapfrogging.

that was doomed to fail from the start due to the fundamental requirement to shield pilots from the masses of radiation produced using extremely heavy materials. Heavy materials and

on political pressures more than what is actually needed. In developing countries, funding is often directly related to the research being undertaken in developed nations. As Professor Goldemberg

Scientific research is motivated not only by curiosity of love for science, but also by fashions and the perception that some areas of research are more rewarding than others. aircraft go together like chalk and cheese and the aircraft program would eventually be replaced with the submarines that we have today. History is littered with similar examples of ill thought out scientific endeavours.

In science, funding is often provided by organisations who lack experience in front-line science. Government bodies who look for buzz-words in funding applications and dole out money based

explains, ‘Scientific research is motivated not only by curiosity of love for science but also by fashions and the perception that some areas of research are more rewarding than others’. This often leads to politicians pouring money into projects that are failed from the start because the underlying infrastructure that makes something successful in one country is missing in another. But is there a better way?

ENHANCING THE ROLE OF SCIENCE IN DEVELOPING COUNTRIES At the height of the Cold War, when nuclear was everything, the US Air Force was pouring millions of dollars into developing the Convair NB-36H nuclear-powered plane. A project

www.researchoutreach.org

77

Professor Goldemberg believes that developing nations can – and should – leapfrog over the technologies that are unsuitable for their specific situations.

Converting sugarcane to a fuel is one specific example of how this can work well, but the approach can be generalised to many technologies around the globe.

Take the issue of supplying lighting to isolated villages around Africa, for instance. The majority of the country lacks the electrical grid system that developed nations use and, while this could be implemented at great cost, professor Goldemberg argues that it is unnecessary in most cases.

SUSTAINABLE DEVELOPMENT OF ENERGY AROUND THE WORLD Typically, lighting in isolated villages is currently supplied by kerosene lamps, batteries or candles and replacing these with standard incandescent light bulbs would be a better solution.

However, imagine skipping over this old technology and going straight to Compact Fluorescent Lightbulbs (CFL), which are four times as efficient. This has the knock-on effect that it is now feasible to power the system using Photovoltaic (PV) solar cells, leapfrogging over less efficient technologies, like the inefficient electricity grid and the expensive power station that supplies electricity to it. ‘A PVCFL system is some 100 times as efficient as kerosene and a half-million times more efficient than candles’ says Professor Goldemberg. ‘The PV-CFL solution leapfrogs over its alternative: a large,

78

www.researchoutreach.org

Expanding the Brazilian ethanol program by a factor of 10 would supply enough ethanol to replace more than 20% of the gasoline used [around] the world. expensive electric generating station, sending power over miles of transmission and distribution lines, supplying a bulb that ultimately converts less than 1% of the original fuel energy to light’.

If a similar technological leapfrogging approach was adopted around the world in our fight against climate change, the energy crisis we are currently facing could be avoided. ‘A simple calculation shows that expanding the Brazilian ethanol program by a factor of 10 would supply enough ethanol to replace more than 20% of the gasoline used [around] the world’ explains Professor Goldemberg. The approach isn’t limited to ethanol fuel or village lighting, though – it can be applied to a whole swathe of technologies around the world and help fight the oncoming energy crisis we are currently facing.

On describing his vision and achievements in 1675, the worldrenowned scientist, Sir Isaac Newton, famously said ‘If I have seen further [than others] it is by standing on the shoulders of Giants’. Serving as a source of inspiration for scientists, this adage has been repeated around the world, time and time again, when advanced

technological breakthroughs have been reached. But, when focused so intensely on what has come before, it’s easy to lose perspective on where we’re going. At some point, during the years that have passed, some areas in science and technology have resorted to blindly following in the footsteps of predecessors, without considering how useful their approach might be.

Vision and perspective are important.

The work of Professor José Goldemberg, of the University of São Paulo, Brazil, resonates over more than 200 years with those wise words from Isaac Newton.

He reminds us that using what others have achieved previously can solve problems in often unexpected ways – but that it is important to consider the approach used in tackling a problem.

Technological leapfrogging provides a route for scientists to skip over the potential stumbling blocks of using unsuitable technologies and, in Brazil, it has been used to alleviate one of the biggest problems we face today: the global energy crisis and global warming.

Expanding the approach globally could shape the energy-climate for future generations around the globe.

Behind the Research Professor José Goldemberg

E: goldemb@iee.usp.br T: 5511 3091 5053 W: www.iee.usp.br/ W: http://www.iiasa.ac.at/web/home/about/achievements/awards/ Zayed-Lifetime-Achievement---Goldemberg.en.html W: www.af-info.or.jp/en/blueplanet/doc/list/2008essay-goldemberg.pdf

Research Objectives Professor José Goldemberg, of the University of São Paulo, research aims to relieve the world’s crushing dependence on fossil fuels with a move to cleaner ethyl-alcohol based fuels.

Detail Institute of Energy and Environment- University of São Paulo Av. Professor Luciano Gualberto, 1289 São Paulo/SP Brazil 05508010 Bio Professor Goldemberg received his PhD in Physical Sciences from the University de São Paulo in 1954. Presently, Professor Emeritus he was the Rector of the University from 1986 to 1990 and Minister of Science and Technology and Minister of the Environment of Brazil. In 2000, he was awarded the VOLVO Environment Prize.In 2008, he was awarded the Blue Planet Prize and in 2013 the “Lifetime Achievement Award” from the Zayed Future Energy Prize.

Collaborators • Dr José Roberto Moreira • Amulya K.N. Reddy • Robert H. Williams • Thomas B. Johansson

References Goldemberg, J. et al (1978).’Energy Balance for Ethyl Alcohol Production from Crops’. Science, Vol. 201 (4359), pp. 903-906.

Goldemberg, J. (1998). ‘Leapfrog energy technologies’. Energy policy, Vol. 26 (10), pp. 729-741.

Goldemberg J. Johansson T. B., Reddy A. K. N. and Williams R. H. (1985). ‘Basic Needs and Much More With One Kilowatt Per Capita’. AMBIO, Vol. 14 (4-5): pp. 190-200.

Goldemberg J. (1998). ‘What is the Role of Science in Developing Countries?’. Science, Vol 279 (5354), pp. 11401141.

Personal Response Having worked within the energy field for such a long time, you must have witnessed a lot of technologies come and go. Are there any technologies whose success – or failure – you have found surprising?

Successful examples: • Wind-generated electricity, which was a curiosity 50 year ago and today represents 4.4% of the world’s electricity production mostly in developing countries • Cooking with LPG (liquid petroleum gas) replacing inefficient wood cooking stoves • Cellular telephones eliminating fixed telephones grids Unsuccessful examples: • Supersonic commercial flights • Production of gasoline and diesel oil from shale sands in Canada • Large-scale storage of electricity in batteries.

www.researchoutreach.org

79

Physical Sciences ︱ Denis Fedyanin and Alexander Chkhartishvili

Opinion dynamics and consensus in social networks Denis Fedyanin and Alexander Chkhartishvili are researchers at the V.A. Trapeznikov Institute of Control Sciences of the Russian Academy of Sciences in Moscow. They use statistical modelling of social network structures to simulate opinion dynamics and decision making.

Their recent work focuses on a consensus analysis of complex social network structures.

T

he development of online social networks together with their influence on the social, economic and political aspects of modern society, has triggered an escalation in interest in social network structures. Social networks, however, have been around much longer than the internet. Where people interact with each other, whether they are acquaintances, friends or adversaries, information is exchanged, opinions are influenced and social networks exist.

OPINION DYNAMICS How specific individuals influence the formation of another individual’s opinion is of particular interest to Denis Fedyanin and Alexander Chkhartishvili and their research at the V.A. Trapeznikov Institute of Control Sciences, Russian Academy of Sciences, Moscow. They are using statistical modelling of the network structures to simulate opinion dynamics and decision making. Their recent work focuses on how a group of people, a social network, can reach a general agreement, or consensus of opinion.

THE DEGROOT MODEL The researchers have chosen to use the DeGroot model to analytically describe opinion dynamics. This is a network interaction model known for its computational efficiency. The DeGroot model simulates the spread of information and the forming of opinions within a social network. This allows the researcher to understand how the network’s structure influences the transmission of information and

80

www.researchoutreach.org

the formation of opinion. It also provides a description of how individual members of a group can reach a consensus.

The DeGroot model is based on a Markov chain, a random process where the probability of any future event depends only on its current state, not on its past behaviour; so the future is independent of the past. In this model, an agent is characterised by his or her opinion. Each opinion is allocated by an arbitrary real number; not necessarily a probability as it would be with a Markov chain.

The model pools the opinions of each agent into a network model, which gives a prediction on the final opinions of all persons. These opinions coincide if network consensus takes place.

The model can also be used to determine how central an individual agent is within a network’s decision making.

MODELLING OPINION DYNAMICS AND CONSENSUS Each agent can be depicted as a node in a network. Initially, each agent has a specific opinion about an issue which is given a numerical value between 0 and 1 that can be a probability or have other interpretations. Opinions are updated over time. All opinions evolve in accordance with an iterative and linear process whereby each agent’s opinion is updating using a weighted average of the other agents’ opinions. These weights are based on influence and confidence. The level of confidence that agent A has in agent B is the same as the level of influence that agent B has over agent A. The total confidence level of any agent is 1.

Agents communicate by exchanging opinions. At each subsequent step,

each agent’s opinion is the weighted sum of the opinions of the agents that he or she trusts, where the weights are the levels of confidence. A consensus arises if opinions converge to a single value that is the overall opinion of the network. This is always the case when each person has non-zero confidence and there are no autonomous clusters in the network.

The contribution of each agent to the collective overall opinion can be determined using linear algebra.

REAL LIFE OPINIONS Let us consider a group of friends that form a social network. We have information on their initial opinions regarding a particular issue and we construct a model where each person’s new opinion is a combination of their last opinion and the opinions of their friends.

Given this model, we can measure the influence of each person in the group.

It is unlikely that each person just constructs their new opinion based on their previous opinion and the opinions of other people in the social group. It is more likely there are some hidden advisors that can also affect opinion.

COMPOUND NODES Fedyanin and Chkhartishvili have modified the initial model to include the influence of these advisors in the formation of an individual’s opinion.

Where previously each person, or node, in the network was represented by a single agent, each person is now represented by a compound node

The development of online social networks has triggered an escalation in interest in social network structures. comprising two agents, external and internal, that interact with each other.

CONSENSUS IN NETWORKS OF COMPOUND NODES Communication between a given node and other network nodes is carried out by the external agent. The internal agent can only interact directly with the external agent in the same node, and can be considered as taking the role of a personal advisor.

The researchers have found that given a measure of the influence of each

person in the initial network, they can calculate the new influences in a revised model by including a simple formula incorporating information of how much a person respects his or her values and how their values could be changed by a person’s behaviour.

If there is a consensus in the original model, then repetition of the iterative process over a sufficient period of time leads to convergence in the modified model and results in the formation of the collective overall opinion or consensus of all people in the group.

www.researchoutreach.org

81

Ann’s advisors

MODELLING TWO COMPOUND NODES The researchers have also studied the interaction of two compound nodes and found that under certain conditions a node’s level of influence can have a stronger dependence on the internal parameter.

Bob’s advisors

No Yes Ann

APPLICATION The process can be applied to the following situation. Ann and Bob have to make a decision. Let us consider two scenarios: 1: The decision is not very important, so Ann and Bob do not involve their advisors.

2: The decision is very important, so Ann and Bob involve their advisors.

Someone’s opinion is determined by how much he or she wants to agree or answer ‘yes’ to a particular question.

These opinions are shown as colours in the diagram: • Green represents 100% agreement with ‘yes’.

• Red represents 0% agreement with ‘yes’ Arrows depict influences. The larger the arrow from A to B, the larger influence of A on B. Bob’s influence on his advisors is large but so is their influence on him.

Ann’s influence on her advisors is small but so is their influence on her.

Bob

Social Network with Advisors

Ann

Bob

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

1

2

3

They have established a model that includes the overall influence of internal factors like confidence in personal advisors.

Can we derive the consensus opinion in a setting if we know the opinions in another one? Fedyanin and Chkhartishvili have found a solution and stated it using a simple formula.

Example 1

4

5

6

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Ann

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Ann’s advisors

Bob

Ann’s advisors

Bob

Example 3 Bob’s advisors

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Ann

Ann’s advisors

Bob

Bob’s advisors

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31

The horizontal axis represents time and the vertical axis represents a measure of attitude to “Yes” where 1 means 100% “Yes”, and 0 means 100% “No”.

82

www.researchoutreach.org

CONCLUSIONS The DeGroot model is a powerful tool for studying matters relating to the spread of information and beliefs. It provides an explicit basis for measuring centrality within a social network and identifying which individuals have the most influence over the opinions of a group.

Bob’s advisors

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31

Example 2 Ann

Yes

A social network is an example of application.

Basic Story Bob

No

Social Network with NO Advisors

Opinion dynamics Ann

?

Fedyanin and Chkhartishvili have extended the DeGroot model to enable consensus analysis of complex network structures where each node comprises two mutually interacting agents. They have established a model that includes the overall influence of internal factors on their initial opinions, without any restrictions on the number of members in the social network or the number of interactions between them.

The researchers have identified further research involving the examination of the communication processes of nodes with more complicated internal structure, i.e. nodes where more than two agents interact, as well as further complex models of opinion dynamics.

Behind the Research Denis Fedyanin

Alexander Chkhartishvili

E: dfedyanin@inbox.ru T: +7 (926) 177 17 46 T: +7(465) 334 89 10

Research Objectives

References

Denis Fedyanin and Alexander Chkhartishvili from the Russian Academy of Sciences model opinion dynamics of social networks to analyse how individuals’ internal parameters affect their social power.

Fedyanin D.N., Chkhartishvili A.G. (2018). ‘Consensus in Social Networks of Compound Nodes’. Automation and Remote Control, Vol 79 (6), pp.1117-1124.

Detail Denis Fedyanin / V. A. Trapeznikov Institute of Control Sciences of Russian Academy of Sciences, 65 Profsoyuznaya street, Moscow 117997, Russia Bio Denis Fedyanin received his Master’s Degree in Applied Mathematics and Physics from the Moscow Institute of Physics and Technology. He is a researcher with both the Active Systems Laboratory at the V.A. Trapeznikov Institute of Control Sciences, Russian Academy of Sciences, Moscow and the International Laboratory for Logic, Linguistics and Formal Philosophy at the Higher School of Economics.

Dr Alexander Chkhartishvili has graduated from the Faculty of Computational Mathematics and Cybernetics of Lomonosov Moscow State University. He is a Doctor of Science in Mathematics. Dr Chkhartishvili is the head of the Complex Networks laboratory at V.A. Trapeznikov Institute of Control Sciences, Russian Academy of Sciences, Moscow. He previously worked at the Faculty of Public Administration at Lomonosov Moscow State University.

Funding V.A. Trapeznikov Institute of Control Sciences Social power, Compound nodes, DeGroot model.

Fedyanin D.N., Chkhartishvili A.G. (2013). ‘A model of informational control in active network structures in case of an incomplete awareness of the principal’. Automation and Remote Control, Vol 74 (12), pp.2155-2162.

Fedyanin D.N., Chkhartishvili A.G. (2011). ‘On a model of informational control in social networks’. Automation and Remote Control, Vol 72 (10), pp.2181-2187.

Fedyanin D.N., Zuev A.S. (2012). ‘Models of opinion control for agents in social networks.’ Automation and Remote Control, Vol 73 (10), pp.1753-1764.

DeGroot, M.H. (1974). ‘Reaching a Consensus’. Journal of the American Statistical Association, Vol 69 (345), pp.18-121.

Personal Response What motivated your interest in researching opinion dynamics and consensus?

Opinions play an important role in our life. People easily change their opinions and these opinions lead to decisions and make important changes in the world – such as decisions on global warming, acceptable lines between freedom and security, standards etc. These decisions could have an economic dimension too since they influence the production and sales of goods and, this knowledge could be converted to economic benefits in a simple way. All this reasoning means that prediction of opinions deserves one’s interest.

Collaborators • Burkov V.N. • Novikov D.A. • Giliazova A.A. • Gubanov D.A. • Kozitsin I.V.

www.researchoutreach.org

83

Physical Sciences ︱ Professor Giorgio Kaniadakis and Professor Dionissios Hristopulos

When kinetic theories clash, mind the lattice step: A statistical physics approach to the motion of atoms within materials What happens when the method used to search out an answer appears to have an effect on the answer itself? In the field of Statistical Physics, two different approaches have been used to describe the particle kinetics: the so-called Master Equations; and their counterpart, the Fokker– Planck Equations. But which is better and why does the approach used have an effect on the result? Professor Giorgio Kaniadakis, of the Polytechnic University of Turin, and Professor Dionissios Hristopulos, from the Technical University of Crete, are using a statistical approach to try and find the solution.

A

t first glance, our entire universe appears to be continuous: an endless sea of space and time, stretching out in every direction. It’s not – but it’s not obvious. It isn’t at all obvious, for example, that, when watching a beautiful summer sun set on the horizon, you are actually looking at the sun through a sea of billions of tiny particles of gas – and that the signature orangered haze in the sky is a by-product of the fact that those gas particles are made up of discrete atoms and obey the rules of Quantum Mechanics. We know this now, but we didn’t always. Until recently, everything in science was assumed to be continuous – the discovery of Quantum Mechanics changed that.

World leading scientists, such as Albert Einstein and Max Planck, set out to find the rules that would allow us to make sense of this new universe. A universe made up of discrete particles of matter and energy. The theories they developed at the turn of the century changed the world forever.

Just as we can imagine a liquid (or gas) as a sea of atoms, so too can we imagine a solid material. In the case of a solid, however, the atoms don’t move around as freely: they are held in place by stronger chemical bonds than their counterparts and end up arranged in a well-structured manner.

Scientists call this array of atoms the crystal lattice – an imaginary construct that positions the atoms relative to one another. As you can imagine, the crystal lattice can take on different shapes, depending on the chemical properties of the atoms that occupy it, with the simple cubic lattice being one of the easiest to understand. Imagine building

84

www.researchoutreach.org

a fort out of cardboard boxes. If you use boxes which are cube shaped – with each one the same size – then when you build your fort up, the boxes will fit squarely on top – and side by side – of one another. You could even build another, much larger cube out of the boxes. Now imagine that an atom sits at every corner of a box. This is what happens in a simple cubic lattice structure.

Particles can – and do – move around in solid materials. Electricity, the flow of electrons through conductive materials, is a notable example but entire atoms can also move around between lattice points. And, just like energy and matter are quantised in Quantum Mechanics, this motion of atoms takes place in discrete jumps, from lattice point to lattice point, and can be described in physics in a number of ways. The Kinetic Interaction Principle (KIP) expresses the transition probability of a particle moving from one lattice point to another. This motion of particles can be described by two different sets of equations: the Master Equations and the Fokker–Planck Equations.

THE DISCRETISATION PROBLEM When using mathematics to solve real physical problems, the first step is often to discretise the problem.

This means that we break the problem up into smaller, more manageable chunks so that the rules of mathematics are easier to apply. To achieve this so-called discretisation, a number of different methods have been developed, each with their own sets of assumptions and intricacies that need to be considered when such methods are applied.

π (t , x i −1 →x i )

The Kinetic Interaction Principle:

π (t , x i →x j ) = w ij α (f i ) b (f j ) Atoms can move between lattice points (the green dots).

This diagram shows the transfer of probability to the central point (in red) and from the centre point (in blue).

xi

x i −1

π (t , x i →x i −1 )

In their recent paper, Nonlinear Kinetics on Lattices Based on the Kinetic Interaction Principle, Professor Giorgio Kaniadakis (Polytechnic University of Turin) and Professor Dionissios Hristopulos (Technical University of Crete) investigate whether the Master Equations or Fokker–Planck Equations are better for understanding how atoms move between lattice points within solid materials. Their paper presents some interesting points.

The Master Equations are discrete in nature by construction, but the FokkerPlanck Equations are not. ‘The motion of particles in lattices involves discrete jumps between the lattice sites,’ says Professor Kaniadakis. ‘Master equations are the mathematical tool used to describe the dynamic evolution of physical processes on lattices [and] their solutions determine the probability of finding a particle at any time at a specific lattice site’. On the other hand, the Fokker–Planck Equations assume that space is continuous. However, space and time must be discretised in order to achieve a mathematical solution of these equations on electronic computers. An interesting result is that the method used to discretise the Fokker-Planck Equations has an effect on their final outcome.

π (t , x i +1 →x i ) x i +1

π (t , x i →x i +1 )

Master equations are the mathematical tool used to describe the dynamic evolution of physical processes on lattices.

WHEN THE APPROACH AFFECTS THE OUTCOME Science is often described as the pursuit of knowledge. While this idea isn’t entirely false, it isn’t entirely true either: it places too much emphasis on the ultimate goal, i.e., knowledge itself. In science, the pursuit is also important.

When the road followed in the pursuit has an effect on the outcome, something interesting is going on. In the case of the Fokker–Planck Equations for specific discrete systems different discretisation approaches produce different end results, obscuring the one, true solution.

In order to overcome this ambiguity, Professors Kaniadakis and Hristopulos used a Statistical Physics approach, which encompasses particles that behave as fermions, bosons or anyons,

to tackle the problem. Starting with a simplified version of a well-known Master Equation, and applying it to a theoretical one-dimensional gas, they show that it can be used to derive the Kinetic Interaction Principle (KIP) for that system. Studying the KIP, and generalising it into 3D space, allows the researchers to make some physical predictions about realistic lattice systems. The approach is then further refined by introducing a new quantity into the KIP: the Discrete Fokker– Planck Current. This allows Professors Kaniadakis and Hristopulos to close the loop by arriving at a continuum FokkerPlanck equation starting from a discretised Master equation.

The results show that the Master Equations can be used to produce a set of Fokker-Planck Equations which

www.researchoutreach.org

85

can then be solved numerically for a real physical problem. ‘This approach resolves the ambiguity that results from different numerical discretisation schemes of the Fokker–Planck equation,’ they explain in their recent paper. ‘The proposed discretisation scheme based on the master equation is physically motivated and follows from the KIP that describes microscopic nonlinear dynamics’. This means that the solutions are based on the physical system itself and are therefore a better starting point for describing the motion of atoms within a lattice than any previous approach.

THE MATTHEW EFFECT For whosoever hath, to him shall be given, and he shall have more abundance: but whosoever hath not, from him shall be taken away even that he hath.

Matthew 25:29 You don’t have to be a religious person to recognise that the above statement holds true in certain economic situations: the idea that ‘the rich get richer while the poor get poorer’ has been around for a very long time. Surprisingly, Professors Kaniadakis and Hristopulos have shown that it is an idea that applies equally well to the exchange of mass between interacting grains of matter.

Their new approach incorporates a system with a particular form of KIP that can have two equilibrium states: a democratic state, where the mass is distributed equally amongst the grains; and an elitist state, where grains that were initially large increase in size over time, at the expense of grains that were initially small.

A model of a crystal lattice.

86

www.researchoutreach.org

KIP and the Matthew Effect DEMOCRATIC REGIME

EXTREME MATTHEW EFFECT

The Matthew effect describes how an unbalanced system can have two equilbrium states - democratic, where mass is distributed equally or elitist, where the large get larger and small get smaller.

Using master equations as the starting point, the researchers show how to discretise the Fokker-Planck equations in agreement with the physical reality.

‘Perhaps one could view the massexchange grain system as a crude paradigm of social dynamics that represents the exchange of wealth between individuals,’ jokes Professor Hristopulos. An idea that might not be as far-fetched as it sounds – statistical physics has found its way into many other

fields, from psychology to traffic control and even economics.

Professor Giorgio Kaniadakis, of the Polytechnic University of Turin, and Professor Dionissios Hristopulos, from the Technical University of Crete, took an advanced Statistical physics approach to describe how atoms move around on a crystal lattice. They show that, by using a set of well-known Master Equations as a starting point, they can solve the Fokker-Planck Equations that describe the system without any of the ambiguities associated with other approaches. Their solutions are based on the physical state of the system itself and are, therefore, a much better starting point than any previously reported approach. Their results have interesting implications in a number of fields – from Condensed Matter Physics to Solid State and Chemical Physics – and will help us to understand our world in a more robust way than was previously possible.

Behind the Research Professor Giorgio Kaniadakis

Professor Dionissios Hristopulos

E: giorgio.kaniadakis@polito.it E: dionisi@mred.tuc.gr T: +30-28210-37688 W: www.geostatistics.tuc.gr/index.php?id=4907 W: www.linkedin.com/in/dthchania/ W: www.researchgate.net/profile/Dionissios_Hristopulos

Research Objectives

References

Professor Giorgio Kaniadakis (Polytechnic University of Turin) and Professor Dionissios Hristopulos (Technical University of Crete) investigate whether the Master Equations or Fokker–Planck Equations are better for understanding how atoms move between lattice points within solid materials.

Kaniadakis, G & Hristopulos, D T. (2018). Nonlinear Kinetics on Lattices Based on the Kinetic Interaction Principle.

Entropy, [online] 20(6), 426. Available at: www.mdpi. com/1099-4300/20/6/426 [Accessed 13 November 2018].

Detail

Hristopulos, D T & Muradova, A. (2016). Kinetic model of mass exchange with dynamic Arrhenius transition rates.

Physica A, 444(2016), 95-109.

Giorgio Kaniadakis Politecnico di Torino Department of Applied Science and Technology Corso Duca degli Abruzzi 24, 10129 Torino, Italy Dionissios Hristopulos School of Mineral Resources Engineering Technical University of Crete Chania 73100 Greece Bio Giorgio Kaniadakis is a theoretical statistical physicist, author of more than 120 articles (h-index=29). He serves as Editor of several journals of physics and has edited 18 Special Issues of journals quoted in the Web of Science.

He has been involved in the organisation of more than 20 conferences and is the founder of the SigmaPhi International Conferences on Statistical Physics.

Dionissios Hristopulos studied physics at Princeton University. After two years in the Greek military, he worked as postdoc and then as research Assistant Professor in Environmental Sciences and Engineering at the University of North Carolina (Chapel Hill). In 2000 he moved to the Pulp and Paper Research Institute of Canada and in 2002 to the Technical University of Crete, where he currently works as a Professor in Geostatistics.

Kaniadakis, G. (2001). Non-linear kinetics underlying generalized statistics. Physica A, 296(2001), 405-425.

Personal Response On working on such a high-level mathematics based problem, do you think there have been any particular challenges or benefits to running a collaborative project from completely different countries? Collaborations always appear to work best when each member of the team brings a specific skill, or approach, that complements with another team member’s skill, or approach. How do you think your individual skills and experience have complemented each other?

Geographical distance is not an obstacle for scientific collaboration these days. While it is nice to be able to meet face to face and discuss ideas in front of a blackboard, it is equally important to work with people who share research interests and have compatible methods of work, from the planning of the research to the writing up of the results. Our skills are complementary in the sense that both of us have formal training in physics; one of us (GK) focuses on fundamental aspects of statistical mechanics, while the other (DH) emphasises applications of statistical mechanics in other fields (e.g., data analysis). This research is the result of an ongoing collaboration between the two groups, and provides a natural springboard for continuing the collaboration into the future.

www.researchoutreach.org

87

Physical Sciences ︱ Dr Meysam Rahmat

Dynamic versus static: Evolving mechanical characterisation Materials used for aerospace applications have to be incredibly robust. For commercial airlines, the materials used to build the aircraft need to be capable of withstanding temperatures from -45 to 45 °C and windspeeds of over 400 kilometres per hour. All materials must undergo stringent testing, designed to replicate the real dynamic conditions encountered during use. Dr Meysam Rahmat, in his research at the Aerospace Research Centre of the National Research Council Canada, works on designing new tests to more accurately measure and test the types of dynamic forces such materials experience during use to better understand their behaviour and properties.

A

erospace materials are some of the most stringently tested materials on earth. They have to be capable of withstanding a wide range of environmental conditions, such as temperature and pressure, while retaining their desired properties. While durability of such materials is mandatory, it is even more important that failures of the material are easily, and sufficiently early, identified. The ultimate objective is to prevent accidents such as the China Airlines Flight 611 crash, where metal fatigue led to the deaths of 225 people.

Being able to detect impending failure of materials requires a comprehensive knowledge of the material’s behaviour.

To do so, these materials are studied using a variety of lab-based testing techniques, alongside numerical simulations, in an effort to predict how the material behaves close to the failure point.

For such testing and modelling to be useful for aerospace materials, they must effectively mimic the types of forces the material would experience when in use. For example, the metals used for aeroplane wings are tested in the lab once they are made into wings by bending them and applying stress and strain to the materials on a variety of testing rigs. Through repeated testing and modelling, a comprehensive understanding of the metal behaviour can be achieved to identify what early warning signs can be used for in-situ testing once the aeroplane is in use.

Many of the existing tests look at applying static forces to the material. This is where the load applied to the material is essentially constant over a given time and would be a good way of modelling, for example, the constant force that the weight of the seats has on the plane’s structure. However, static stress tests cannot provide a good model for many of the rapidly changing forces that aeroplanes experience while in use.

To investigate how a material reacts when a force is suddenly applied, dynamic testing is used instead. Dr Meysam

Foam compression with DIC

Aluminum foam compression test.

88

www.researchoutreach.org

High speed compression of polymer

Tensile tests on nanomaterials.

Rahmat at the Aerospace Research Centre of the National Research Council Canada has been pioneering new testing methods that focus on the effects of dynamical stress on aerospace materials, which has revealed very different results to static, or quasi-static (where the force is applied over a longer period of time than it would be for a dynamic test), with important implications for aircraft safety.

STRESSFUL MEASUREMENTS To perform the dynamic strain tests, Dr Rahmat uses a servo-hydraulic load frame. Such frames can be customised for different types and magnitudes of load. For Dr Rahmat’s dynamic tests, he uses a load frame specifically designed to achieve high speeds. The frame can reach speeds of up to eight metres per second as it suddenly applies load to the stationary sample, resulting in the sudden transfer of force. A series of sensors measure local deformation in different locations on the sample to obtain ‘stress’ (a measure of force acting on the sample that can lead to deformation) and ‘strain’ (a measure of deformation in the material due to the force that can lead to cracking).

DIC setup for tensile test.

Exclusively using static tests cannot provide a good model for many of the rapidly changing forces that aeroplanes experience while in use.

One common issue with these types of dynamic stress measurements is that the values measured by the load cell oscillate during the measurement, making it difficult to extract the true stress-strain values experienced by the sample.

Some preventive actions, such as using lightweight clamps and optimising the mounting position of the gauges, can be carried out to minimise these oscillations.

Part of Dr Rahmat’s work has been to carefully investigate how changing testing parameters such as sample geometry affects the final values obtained for the material properties to ensure their

accuracy and whether these corrections to minimise the oscillations are applicable to different materials.

STRESS FRACTURES One of the first materials Dr Rahmat has investigated using his approach is an aluminium dogbone structure, named for its resemblance to the shape of a dog bone. This is a typical shape for a tensile test sample as the narrow section in the middle is subject to the majority of the deformation. This is important for ease of testing: if the stresses were concentrated near the sides of the sample, where it

www.researchoutreach.org

89

FE model of puncture test.

Puncture test on composites.

Punctured aluminum.

Puncture test on polymer.

is clamped to the testing machine, this would lead to artificial readings as the clamping of the sample would interfere with the measurement. This is also beneficial for measuring elongation, as it means the measured change in length of the material comes exclusively from the material, not also from changes in the clamps.

type of fractures the material experienced, depending on whether it had received the force very suddenly or gradually over a longer period. While small changes in the surface structure of the metal that can only be observed by a microscope might

nanoscale materials and have not been well-studied using dynamic strain methods. By testing a nanocomposite formed of a common epoxy, with and without boron nitride nanotubes, Dr Rahmat and his team were able to see how the inclusion of the nanotubes added greater elasticity and tensile strength to the sample but had little influence on the shear properties of the epoxy.

The information obtained from such tests is highly valuable not just for understanding material behaviour but also from a design perspective.

During these dynamic measurements, what Dr Rahmat found was that for this wellstudied aluminium sample, there was a large deviation for the ultimate strength and the elongation at failure between the values measured dynamically versus quasi-static measurement.

This is important for not just making sure the testing of materials is realistic for what it will ultimately experience in the field, but also refining the modelling of the responses of such materials to the anticipated stress and strain.

Optical microscope images of the tested material also showed differences in the

90

www.researchoutreach.org

seem trivial, this indicates differences in the amount of energy absorption by the aluminium depending on the speed of the force, showing the material would have different resistances to different types of loading conditions.

METALS TO NANOCOMPOSITES All of this testing and model refinement has ultimately enhanced our understanding of very well-studied materials, but Dr Rahmat has been expanding this to nanocomposites as well. Nanocomposites are novel and complex materials composed of different

The information obtained from such tests is highly valuable not just for understanding material behaviour but also from a design perspective, as it becomes possible to determine which mixtures have the most desirable properties.

The methods Dr Rahmat has been developing are also very generalisable to a wide range of substances, which he will continue to explore in his future work.

Behind the Research Dr Meysam Rahmat

E: meysam.rahmat@nrc-cnrc.gc.ca T: +1 (613) 991 5360 W: www.nrc-cnrc.gc.ca/eng/

Research Objectives Dr Meysam Rahmat’s work focuses on dynamic mechanical characterisation of materials, particularly nanocomposites.

Detail Aerospace Research Centre National Research Council Canada 1200 Montreal Road Ottawa, ON K1A 0R6 Canada Bio Dr Rahmat received his PhD in mechanical engineering from McGill University in 2011, and started working at the National Research Council Canada (NRC) the following year.

His main focus is on composite materials, nanocomposites, and dynamic mechanical characterisation of materials.

Funding National Research Council Canada through Security Materials Technology Program, Project A1-006934 Collaborators • Richard Desnoyers • Behnam Ashrafi • Alex Naftel • David Backman • Gang Li • Michael B. Jakubinek • Yadienka Martinez-Rubi • Benoit Simard: National Research Council Canada

References Meysam Rahmat, “Dynamic Mechanical Characterization of Aluminum: Analysis of Strain-Rate Dependent Behavior”, Mechanics of Time-Dependent Materials, 2018, In Press, https://doi.org/10.1007/s11043-018-9393-0.

Meysam Rahmat , Alex Naftel, Behnam Ashrafi, Michael B. Jakubinek, Yadienka Martinez-Rubi, Benoit Simard, “Dynamic Mechanical Characterization of Boron Nitride Nanotube— Epoxy Nanocomposites”, Polymer Composites, 2018, In Press, https://doi.org/10.1002/pc.24995.

Personal Response What types of material do you want to explore next with this testing method?

Any type of homogeneous (including metals, polymers and ceramics) and non-homogeneous material (including composite materials) can be characterised using this method. Also, different types of material architectures such as closed cell foams are currently being tested to evaluate their energy absorption capabilities under impact.

What is the most satisfying aspect of your work in this field?

Mechanical characterisation is an essential step in the iterative process of structural design; whether through proof of concept or screening tests in the earlier stages of the process, or during full scale final evaluation of the structure for certification purposes. The main objective of these tests is to ensure that during its service life, the structure will not experience any catastrophic failure after going through all those harsh experiments in the lab. When an aircraft retires after many years of service with no major problem, it just shows that every critical element of its complex and multi-disciplinary system worked to its best and served its function. That’s when an engineer’s effort is paid off.

Also, there is no denying that crashing and breaking lab specimens at high velocity is fun!

www.researchoutreach.org

91

Physical Sciences ︱ Prof Dr Elena Jasiūnienė

Peering inside: 3D imaging in materials New strong materials are in demand in many sectors, leading to the development of different hybrid structures. These can be made from dissimilar light materials such as aluminium alloys, which are joined by incorporating reinforcing fillers into the weld, or self-compacting fibre-reinforced concrete, which is reinforced using fibres.

However, creating new materials is not without its problems.

The process parameters can be imperfect or are affected by different variables or unforeseen circumstances. The quality of the structure can be affected and the performance of the loaded structure could be unexpected.

To see how these different reinforcements influence the properties of materials, Prof Dr Elena Jasiūnienė, Ultrasound Research Institute, Kaunas University of Technology, uses X-ray computed tomography to allow her to peer inside the structures of materials and reconstruct them in three dimensions.

92

www.researchoutreach.org

T

he idea of X-ray vision may have come from science fiction, but the ability to see into solid objects and take images of what is inside them is now very much a reality. One of the simplest forms of X-ray imaging is used in hospitals, to allow medical professionals to image bones and other dense tissues inside the patient. This produces a flat image where the densest areas are highlighted in white as they absorb the greatest amount of the incoming X-ray radiation.

Now, using more modern X-ray imaging methods, it is possible to image not just two-dimensional images of the inside of an object, but reconstruct

The bulkhead and nosecone of the Orion spacecraft are joined using friction stir welding.

its contents in full three-dimensional detail. The ability is unique to X-ray computed tomography, an X-ray imaging technique that can be used on a wide variety of materials, including metals, biological structures and many complex materials, including hybrid structures such as concrete combined with steel or dissimilar metal joints with nanoparticle fillers.

The versatility and non-destructive nature of this approach is why Prof Dr Elena Jasiūnienė, Ultrasound Research Institute, Kaunas University of Technology, Lithuania has been taking advantage of the unique abilities of X-ray computed tomography to examine

different ways of strengthening concrete and other lightweight, yet structurally strong, materials. X-ray computed tomography allows her to see how different kinds of processing to create these materials affect the structure and location and size of defects. All of this can be used to refine production methods and inspire approaches for the design of customised materials for specific applications.

LIGHTWEIGHT AND STRONG Part of the increasing demand for strong materials that are still lightweight is motivated by attempts to decrease energy consumption. Lighter materials have several benefits as less energy is required to transport them and, if they are being used to make transport vehicles, it reduces their fuel demands too. A common way of achieving high strength while reducing weight is to make alloys, mixtures of two or more different materials. Aluminium alloys are very popular for this purpose but can be very hard to handle during construction as they are difficult to weld into structures using conventional welding techniques.

Some of this difficulty in the welding process results in inconsistencies and imperfections in the final weld on a microscopic scale. To identify such deficiencies, Prof Dr Jasiūnienė and her team used a combination of X-ray computed tomography and acoustic microscopy to investigate the invisible defects inside welds between different alloys. From the reconstructions of the three dimensional images of the inside of the welds, they could pinpoint exactly where the defects in the weld zones formed. The 3D capabilities of 3D tomography mean all of this can be done in real space and it is possible to resolve defects that would overlap with each other in more standard 2D imaging.

The small size of the nanoparticles, and the defects they can cause, make them very difficult to identify with other

Defects formed in the inner structure of the samples friction stir welded by incorporating reinforcing fillers into the weld with different welding parameters: from top to bottom – after 1 pass, after 2 passes in the same direction, after 3 passes in the same direction; after 2 passes in opposite directions.

non-destructive imaging techniques.

The non-destructive nature of the technique also means it is suitable for use on manufactured pieces that require checking and could potentially be done routinely to assess fatigue or accumulating damage.

SELF-COMPACTING CONCRETE Concrete is a mixture of cement and a binder that is usually liquified with water.

After the mixture is made, it remains in a gel-type form so it can be poured

It is possible to image not just 2D images of the insides of objects, but reconstruct their contents in full 3D detail.

into moulds and manipulated until it sets as a solid. While it is being poured, the concrete needs to be compacted so that all the air bubbles and voids in the structure are removed to ensure that there are no inhomogeneities in the structure of the concrete and it is as strong as required. This is achieved by using a steel probe to act as a continuous source of vibration while the concrete is being poured.

Self-compacting concrete eliminates the need for continuous vibration and typically has a higher strength for a given water, cement and binder ratio than the traditional form. One way of making self-compacting concrete is to include superplasticisers that help

www.researchoutreach.org

93

A

B

C

Image A shows a photo of the concrete cylinder sample, which was investigated. Image B shows a slice of 3D CT data in the middle of the sample. Image C reveals the 3D distribution of steel fibres within the self-compacting concrete.

it to be more elastic and flexible than normal concrete. By removing the need for vibration or tamping after pouring and as it also flows very well, self-compacting concrete is much less labour intensive to lay and can be used in areas where it is not possible to compact normal concrete or to create more complex shapes that would not otherwise be achievable.

One type of self-compacting concrete uses steel fibres, much as traditional concrete uses steel bars, to help reinforce the structure. However, it is difficult to know exactly how all of the fibres are aligned after the pouring process, even though the orientation of the fibres is critical in the amount

Understanding the inner structure of concrete is essential to understanding its strength.

94

www.researchoutreach.org

3D images of the inner structure allows quality evaluation of the different structures non-destructively – making the invisible visible. of reinforcement strength the steel fibres will provide along different axes.

Visualising the orientation of such fibres, given their small size, is the perfect problem for X-ray computed tomography as it can capture the full size, shape and relative orientation in 3D of the fibres in the concrete.

Prof Dr Jasiūnienė has been applying her expertise in X-ray computed

tomography to see how the flowproperties of the concrete influence the eventual orientation of the fibres.

Her work has demonstrated that low viscosity concretes show the greatest amount of inhomogeneity in the steel fibre distribution after being poured but also that steel fibres orientate parallel to casting direction after some distance.

Meanwhile in high viscosity concrete, fibres are distributed all over the beam more evenly, but they don’t orientate parallel to casting direction as in low viscosity concrete.

LOOK INTO THE FUTURE X-ray imaging tomography is a highly versatile, non-destructive technique that is widely used in engineering for its ability to recreate 3D images of the insides of many kinds of material. Prof Dr Jasiūnienė has been successfully able to use this to better understand the microscopic structure of metal alloys and concretes to help guide manufacturing decisions and reproducibility of the desired mechanical properties of such materials. In the future, she will continue to develop and apply tomography and related methods for the study of not just commonplace concrete, but also for materials used in space engineering and nuclear power plants.

Behind the Research Prof Dr Elena Jasiūnienė

E: elena.jasiuniene@ktu.lt T: +370 698 00899 W: https://lt.linkedin.com/in/elena-jasiuniene-6a60082a W: https://ultrasound.ktu.edu/ct/

Research Objectives

References

Prof Dr Jasiūnienė investigates the properties of various materials, particularly self-compacting concrete, using X-ray computed tomography both alone and in conjunction with other methods.

Jasiūnienė, E., Žukauskas , E., Dragatogiannis, D.A., Koumoulos, E.P., Charitidis, E.A. (2017) Investigation of dissimilar metal joints with nanoparticlefillers. NDT and E International, 92, 122-129. Available at: https://doi. org/10.1016/j.ndteint.2017.08.005

Detail Prof. Dr. Elena Jasiūnienė Baršausko 59- A423 LT-51423 Kaunas Lithuania Bio Elena Jasiūnienė received an Applied Electronics Masters degree and a PhD in Technological sciences, Measurements engineering, from Kaunas University of Technology. She later worked at the Federal Institute for Materials Research and Testing, Berlin, Germany. Currently she is Senior researcher at Prof. K. Baršauskas Ultrasound Research Institute and Professor at Department of Electronics Engineering, Faculty of Electrical and Electronics Engineering, Kaunas University of Technology.

Funding • FP7 Collaborative project “SAFEJOINT”. The abbreviation “SAFEJOINT” stands for “Enhancing structural efficiency through novel dissimilar material joining techniques” (Grant agreement no.: 310498) • Kaunas University of Technology under grant agreement Nr.MTEPI-P-15010, project BeReTyr “Determination of Dispersive Reinforcement and Structural Defects in New Generation Concretes Using X-ray Micro Tomography“

Jasiūnienė, E., Cicėnas, V., Grigalinūas, P., Rudžionis, Navickas, A.R., (2018) Influence of the rheological properties on the steel fibre distribution and orientation in self-compacting concrete.

Materials and Structures, [online] 51(103), Available at: https:// link.springer.com/article/10.1617%2Fs11527-018-1231-y [accessed 16 Nov 2018]

Personal Response What other material and systems have you been investigating with X-ray imaging tomography?

Investigations of very different types of materials/ structures have been performed: investigation of the structure of 3D scaffolds for bone tissue regeneration; investigation of titanium pin array structure produced using additive manufacturing technology; human teeth for investigation of root canal transportation and centring ability of rotary endodontics instruments; visualisation of inner structure of microchips; investigation of the integrity of concrete in order to assess the harmful consequences of alkali-silica reaction on the composition of the material; investigation of glider longeron, made from CFRP to determine porosity.

Collaborators • Dr Vaidotas Cicėnas, (Prof. K. Baršauskas Ultrasound Research Institute, Kaunas University of Technology) • D.A. Dragatogiannis, E.P. Koumoulos, C.A. Charitidis (Research Unit of Advanced, Composite, Nano Materials & Nanotechnology, School of Chemical Engineering, National Technical University of Athens, Athens, Greece) • Žymantas Rudžionis, Paulius Grigaliūnas (Faculty of civil engineering and architecture, Kaunas University of Technology)

www.researchoutreach.org

95

Physical Sciences ︱ Professor Zoltan Haiman

Black hole binaries and gravitational waves: Unlocking the secrets of our universe in unexpected ways When Albert Einstein predicted the existence of gravitational waves over one hundred years ago, nobody could foresee what the implications could possibly be – but, as they make the move from predicted theory to proven fact, researchers like Professor Zoltan Haiman, of Columbia University, are devising ways of using them to study binary systems of colliding black holes and the very early universe in completely new ways.

A

s far back as we’ve been able to crane our necks, our civilisation has been looking to the stars with a sense of wonder and awe. Our earliest ancestors worshipped the skies with a fierce superstition – and on the darkest of nights in the quiet of the countryside, away from the light pollution that plagues our towns and cities, it’s easy to see why: our heavens hold a beauty that is unparalleled anywhere else in the natural world.

It wasn’t long before our ancestors started applying the rigour of mathematics to the

sky – astronomy is, in fact, the oldest of the natural sciences, dating back to prehistoric times. The sun went down and everyone was at it: the Babylonians, the ancient Chinese, the Greek philosophers, the Egyptian Pharaohs – every civilisation that was advanced enough to record what they were doing: all standing on the shore of an endless ocean of light, underneath dark skies with bright and starry eyes, meticulously studying the mechanics of celestial bodies far beyond their comprehension; watching with a sense of wonder as points of light danced above them in the night.

Photo Credit: CC BY 4.0

Today, our knowledge of the Universe has surpassed the wildest hopes and dreams of those who came before us. We know that some of those points of light are actually giant nuclear fusion reactors called stars, just like our own sun; and some of them are galaxies so far away that our eyes reduce them – a collection of billions of stars – to one single point.

We know how stars are born – and how they die – and that if a star is big enough when that time comes, it will collapse in on itself to form a singularity: an object so dense that not even light can escape its gravitational pull. We call these objects black holes. We know that at the centre of almost every galaxy lies a supermassive black hole and that galaxies often collide with each other (see image to the left) to form even larger galaxies. One thing we’re not entirely clear on, however, is what happens when the black holes from two colliding galaxies meet and form binary systems.

An image of two galaxies colliding taken by the Hubble Space Telescope.

96

www.researchoutreach.org

THE GRAVITATIONAL WAVES DISCOVERY SWEEPING THROUGH ASTRONOMY For most of our history, astronomers have viewed the stars through the lens

Photo Credit: CC BY 4.0

In the recently formed NGC 6240 galaxy, there are two supermassive black holes spiralling closer and closer to one another.

of Newtonian physics. Einstein’s theory of relativity changed that: time and space were no longer different entities but two sides of the same coin, interlinked in a system that is almost impossible for us to comprehend (the fact that Einstein did is why he is so famous). It replaces the force of gravity, proposed by Isaac Newton, with a seemingly abstract idea: space and time are a medium in which everything exists. Heavy objects, like planets, warp this medium and change its shape and that’s what we experience as a force pulling us towards the Earth (gravity). Space-time is a difficult idea to grasp but the beauty of Einstein’s theory is that it explains so much of the universe so fully that it is impossible to ignore. That and the mathematics stack up: scientists have been trying – and failing – to prove him wrong for over a hundred years.

An interesting prediction that comes out of Einstein’s theories is the existence of gravitational waves – ripples in the fabric of space-time itself. Until recently, a prediction was all that they were but since 2016, scientists have been able to measure them and, as our technology advances, they will be able to further exploit gravitational waves to investigate what happens when two galaxies collide.

We know that black hole binary systems play a fundamental role in shaping the galaxies they belong to – and that their collision would likely be the most

Such massive black hole binaries are expected to play a fundamental role in sculpting their host galaxies, and their eventual mergers would be the most energetic phenomena in the universe. energetic phenomena in the known universe – but much like gravitational waves, direct evidence of black hole binary systems has so far been lacking.

This is because the black holes are too close to each other to tell apart using our current telescopes (see above image).

That could be about to change.

LISA In 2034, the European Space Agency (ESA) plans to launch LISA, a Laser Interferometer Space Antenna, which will be able to detect the gravitational waves resulting from the interaction between two colliding black holes (see image overleaf). This will provide astronomers with a shiny, new set of tools to probe the farthest reaches of our universe.

Until then, researchers like Professor Zoltan Haiman continue to study such binary black hole systems using theoretical calculations and advanced computational simulations.

AN ASTRONOMICAL FINGERPRINT FOR BINARY BLACK HOLE SYSTEMS In a recent paper, released earlier this

year, Professor Haiman predicted what happens when two black holes collide as their host galaxies merge. As the black holes become close to one another, they begin to orbit around a common centre of mass – a point somewhere in space analogous to the pivot-point on a seesaw, around which the masses at either end rotate. They move slowly at first and, if the energy contained within their orbit was to remain the same, the system could continue like this forever, with the black holes caught in a neverending dance. But energy is sucked from the orbit in the form of gravitational waves. They cause the orbit to shrink in size, and the black holes to spiral inward, colliding to form a single black hole.

The process takes an extremely long time to complete and, in the last few years of the merger, the gravitational waves become extremely strong. It is at this point that LISA will be able to detect them. Unfortunately, though, LISA will not be able to detect the galaxy in which the tango took place. The gravitational waves will be released as periodic undulations,

www.researchoutreach.org

97

As both phenomena are caused by the same orbital motion, they should occur together and help astronomers pin down the location of the merger. As Professor Haiman explains: ‘This tell-tale “X-ray chirp”, accompanying the gravitational wave chirp, should allow astronomers to uniquely identify the host galaxy of the merging black hole pair – since there will be only one galaxy with such X-ray pulsation, matching the gravitational waves’. In other words, black hole binary systems should have their own unique astronomical fingerprint that can be traced to a well-localised point on the sky.

The presence of strong X-ray pulsations, in tandem with the gravitational waves being detected by LISA, was also seen in detailed hydrodynamical simulations, computing the response of the circumbinary plasma to the “propeller” motion of the black holes, by Professor Haiman and his collaborators Professor Andrew MacFadyen and graduate student Yike Tang (at New York University) [Ref 3].

ACCESSING INFORMATION FROM THE BEGINNING OF TIME Using this new approach, astronomers will be able to unlock a whole host of new information about black hole binary systems and, by extension, our entire universe. Determining the exact location of a handful of such black hole binary systems will allow astronomers to connect black holes with their host galaxies. They will also be able to map the accelerating

98

www.researchoutreach.org

Photo Credit: Nasa, Public Domain

following the binary’s orbital motion -what Professor Haiman calls gravitational wave pulsars – and, in the last few months of the merger, the system will be rotating at extremely high speeds (about 10% of the speed of light, or around 30 thousand kilometres per second). Professor Haiman’s research suggests that as a result, the binary should release similar periodic pulsations every few minutes or so. Professor Haiman, with his graduate student Daniel D’Orazio and colleague Professor David Schiminovich at Columbia University, has earlier suggested that the sinusoidal pulsations seen in optical and ultraviolet bands of a known bright distant quasar is due to the same phenomenon: for a pair of more widely separated, and less rapidly moving black holes, these lower-energy pulsations would be expected and appear consistent with the observed data [Ref 2].

When black holes move closer to each other, reaching distances not much larger than our solar system, they distort space time and emit gravitational waves. The LISA spacecraft (consisting of three separate satellites connected with laser interferometer links, indicated by the red triangle) will be able to see these gravitational waves.

Comparing the distance to the galaxy with its apparent recession speed will map the expansion rate of the universe over cosmic time, back to early epochs which are beyond the reach of [current methods]. universe back to the very beginning of time. ‘Comparing the distance to the galaxy with its apparent recession speed will map the expansion rate of the universe over cosmic time, back to early epochs which are beyond the reach of the similar, Nobel-prize winning exercise done with supernovae,’ explains Professor Haiman. It will also allow astronomers to test whether X-rays and gravitational waves propagate at the same speed – as Einstein’s theory predicts – and if they don’t, then perhaps Professor Haiman’s proposed method will be the one that finally proves that Einstein’s theory of relativity is not the full story.

Over one hundred years ago, Albert Einstein changed how we viewed the universe and, almost as a by-product of his theory, predicted the existence of gravitational waves. It has only been in the past few years that astronomers are beginning to prove that he was

right – with the experimental verification of gravitational waves in 2016. A proof which is providing astronomers with a new lens through which to view our expanding universe and unlock mysteries that our ancestors could only dream about.

Although astronomy is the oldest of the natural sciences, it is also the one which holds the most potential for new discovery. This is even more true now – the research by Professor Haiman, and similar work done by others, have shown that unexpected new breakthroughs can be enabled by combining gravitational waves with data obtained with traditional telescopes. It seems like hardly a day goes by without there being a new discovery, or announcement, thanks to the advancement of technologies and theories by researchers such as Professor Haiman. Throughout all of that, though, one thing in astronomy has remained the same: we still look to the skies with a sense of wonder and awe.

Behind the Research Professor Zoltan Haiman

E: zoltan@astro.columbia.edu T: +1 212 854 6822 W: http://user.astro.columbia.edu/~zoltan/

Research Objectives

References

Professor Zoltan Haiman’s work at Columbia University aims to find evidence for the existence of massive black hole binaries.

1: Haiman, Z (2017). The electromagnetic chirp of a compact binary black hole: a phase template for the gravitational wave inspiral. Physical Review, D96 (2), 023004.

Detail Professor Zoltan Haiman Department of Astronomy, Columbia University 500 West 120th Street, MC 5246 New York, NY 10027, USA Bio After completing high school in Budapest, Hungary, Zoltan Haiman completed his undergraduate studies in Physics at MIT and a post-graduate certificate in Chemistry at Cambridge University, UK. A PhD in Astronomy from Harvard University was next, followed by a postdoctoral fellowship at the Astrophysics theory group at Fermilab, Batavia IL and a Hubble Fellowship at Princeton University.

He has been a member of the faculty in Columbia University’s Astronomy Department since 2003.

Funding NASA, NSF Collaborators Former graduate student and Professor Andrew MacFadyen, co-authors of the related simulation work (both at New York University), and former graduate student Daniel D’Orazio and Professor David Schiminovich, co-authors of the study interpreting the optical/ultraviolet pulsation of a known quasar (both at Columbia University).

2: D’Orazio, D.J., Haiman, Z. and Schiminovich, D. (2015).

Relativistic boost as the cause of periodicity in a massive black-hole binary candidate. Nature, 525 (7569), 351-353.

3: Tang, Y., MacFadyen, A., and Haiman, Z. (2018). The late inspiral of supermassive black hole binaries with circumbinary gas discs in the LISA band. Monthly Notices of the Royal Astronomical Society, 476 (2), 2249–2257.

Personal Response What is it that motivates you to work in astronomy and cosmology?

It is a privilege to be removed from the constraints of day-to-day business here on Earth, and to be thinking instead about the unsolved mysteries of the universe.

And it is highly rewarding to contribute, even a tiny bit, to our understanding of how things work in it.

Engineering and Technology ︱ Dr Koichi Narahara

Creating a better oscillator:

Dissipative solitons and travelling-wave field‑effect transistors The key to improving the performance of high-speed electronic circuits is the generation of short electrical pulses with reduced phase noise. Dr Koichi Narahara of the Department of Electrical and Electronic Engineering at Kanagawa Institute of Technology studies electric pulses generated by travellingwave field-effect transistors.

He found that the devices possess unique properties that could provide increased operating frequencies and decreased phase noise when compared to traditional oscillators, rendering them invaluable to modern electronics.

A

travelling-wave field-effect transistor (TWFET) is a special type of field-effect transistor (FET) with electrodes employed as transmission lines in addition to its electrical contacts.

An FET is a semiconductor device used to amplify or switch electrical signals and power, which has three terminals; the source terminal, where the electrons enter, the drain, through which they leave the channel, and the gate. By applying voltage to the gate, one can control the electrons that travel from the source towards the drain. When a voltage difference is generated between the body and the gate, an electric field is created, which increases the conductivity between the drain and source terminals. A TWFET consists of two transmission lines: one or the other is periodically loaded with current flowing from the gate and drain of a small grounded FET, respectively.

Since they were discovered in 1965, TWFETs have been studied for their use in broadband amplification. However, owing to the electromagnetic couplings between transmission lines, no efficient design method has been established for short-channel TWFETs. For limiting small signals, the output of any device is assumed to be linearly dependent on the input, meaning that the strength and shape of the electromagnetic wave which is produced will be unchanged. However, this assumption doesn’t hold for many devices, where properties such as resistance, capacitance and inductance are not constant. These devices are known as ‘nonlinear’ devices. Until now the nonlinear properties of TWFETs have been generally neglected.

100

www.researchoutreach.org

Dr Narahara studies a method of amplifying short electrical pulses using TWFETs with electromagnetic couplings (where an electromagnetic field in one set of electrical wiring or circuit leads to an electric charge in another) and has devised a way to use their nonlinearity for shaping electromagnetic waves or pulses. These couplings induce two different propagation modes (ways in which pulses travel) in TWFET. He succeeded in confining all the pulse energy into one of the modes and amplified the pulses carried by that mode.

As long as a pulse travels in a unique mode, it is free from the distortions caused by the difference between modes.

Usually, short-wavelength waves travel slower than long-wavelength waves in TWFET, which causes dispersive distortions to the short and baseband pulses. By introducing nonlinearity, this dispersion can be compensated for. Moreover, a TWFET succeeds in balancing the dissipation and gain.

As a result, it supports dissipative solitons.

A soliton is a type of wave that maintains its shape as it moves at a constant velocity. In this way, Dr Narahara designed a TWFET that supports short electrical pulses without significant distortions.

The interaction of dissipative solitons has the potential to produce a technological break-through in the phase-noise performance of oscillators.

Oscillators are devices that change the direct current obtained from a power supply to alternating current. They are found in many common electrical devices but typically produce high levels of phase noise which can interfere with their functioning. By considering a closed topology, Dr Narahara has created what

Schematic of TWFET.

Synchronization of dissipative solitons.

Schematic of TWFET. Gate line

SCHEMATIC OF TWFET

SYNCHRONISATION OF DISSIPATIVE SOLITONS. initial independent rotation

Drain line Gate line

ΔT Drain line

L1

Source

Source

L1

L2

time [0.5 µs/div]

Drain line

rotating DSs eventually synchronized

Drain line

L2

L1

Gate line

Gate lineoscillator using is essentially a pulse TWFETs, which could someday render a valuable scheme for reducing phase noise.

In addition to the development of dissipative solitons, the nonlinearity in TWFETs induces several other wave phenomena usable for generation of highfrequency continuous or pulsed signals.

Without nonlinearity, waves are carried by superposed sinusoidal propagation modes, and exponential modes cannot contribute to their propagation.

In contrast, a hybridisation of sinusoidal and exponential modes becomes possible in the presence of nonlinearity.

Dr Narahara found that the hybrid-mode supports quasi-stable propagation of incident pulses and significantly compresses their widths.

In addition, he found that shockwaves can be excited in TWFETs, which are special in that they can reflect any incoming waves, resulting in an increase of the frequency. In addition, the shockwave in a cavity exhibits interesting self-organisation. By the proper design of the structure and applied voltage, the shockwave reaches the far end and is reflected backwards toward the input. The edge is again reflected at the input to become a stable shock front. Through the repetition of this process, the shock front oscillates in a TWFET cavity. When the input amplitude is increased, two or more oscillating fronts develop autonomously and are mutually synchronised.

These phenomena can be combined with the dynamics of dissipative solitons, leading to sophisticated methods for

ΔT

ΔT vanished.

L2

time [0.5 µs/div]

The shock front operates as an approaching wall to the counter-moving waves, the frequency of reflected wave becomes greater than the incident one through the Doppler effect. either multiphase, (de)multiplexed, or phase-locked ultrashort pulse streams.

each collision, and so the amplitude of the colliding pulses decrease over time. While an anticlockwise pulse has DISSIPATIVE SOLITONS a slightly smaller amplitude than the A dissipative soliton generally possesses clockwise pulse before a collision, the a uniquely defined amplitude and velocity amplitude discrepancy increases after and is able to interact with other solitons the collision; specifically, the amplitude as well as other types of waves. Repeated of the anticlockwise pulse decreases head-on collisions of 2 dissipative solitons whereas that of the clockwise pulse either generate a series of small pulses. The increases or remains the same. After Experimentally colliding pulses donate a fraction ofobserved their several subsequent head-on collisions, Doppler effect energy to the generated pulses within TWFET.the anticlockwise pulse disappears,

EXPERIMENTALLY OBSERVED DOPPLER EFFECT IN TWFET Five-period sinusoidal wave (incident)

Shock front

0 1 time [ μs] Reflected wave with increased frequency

space [cell] 40 160

www.researchoutreach.org

101

Pulse shortening by TWFET.

When two TWFETs are connected to another one via a resistor, a dissipative soliton that rotates on one of them attractively interacts with the dissipative soliton that rotates on the other TWFET. Therefore, the two dissipative solitons in these coupled TWFETs are phasesynchronised in such a manner that they simultaneously pass the connecting cells.

Using this property, a closed-TWFET system can be used to generate phasecontrolled pulse trains. Using the twopoint connections of the closed TWFETs, the two dissipative solitons can be designed to rotate in either the common or mutually reversed directions. Similar synchronised dissipative solitons can develop even in three or more TWFETs. Such a scale extension can lead to various schemes of phase control, including generation of multiphase pulse trains.

In particular, the connection of the two TWFETs where the size of one is set to an integer multiple of the other generates two or more dissipative solitons in the larger one. Dr Narahara found that the two dissipative solitons interact repulsively in a closed TWFET. Hence, a stabilised dissipative soliton in a closed TWFET can position the antipode of its paired dissipative soliton. This interaction contributes to a reduction in inter-pulse spacing fluctuation, which results in the reduction in the phase noise present in the pulse train output.

SHOCKWAVES One of the nonlinear effects in distributed systems is the development of shockwaves. A shockwave is a type of propagating wave that carries energy like an ordinary wave but is characterised by an abrupt, nearly discontinuous, change in pressure, temperature and density of the medium. Shockwaves have been observed in transmission lines that are loaded along their length with either the voltage-dependent capacitors known as varactors.

PULSE SHORTENING BY TWFET 1st pulse 2nd 3rd

input

500 mV

n=20 n=40 n=60 n=80

space

and the clockwise pulse uniquely survives and rotates on the closed TWFET.

n=100 n=120 n=140 0

time [µs]

Dr Narahara derived the condition for the shockwave formation on a TWFET and experimentally showed that the TWFET successfully exhibited shockwave formation. In addition, he showed that the shockwave accompanied the drain current such that it reflected the waves originating ahead. When a shock front is formed at the drain, it comes in contact with counter-moving waves and in doing so its frequency becomes greater than the counter-moving waves due to a mechanism called the Doppler effect. Essentially, says Dr Narahara: “The shock front operates as an approaching wall to the counter-moving waves, the frequency of reflected wave becomes greater than the incident one through the Doppler effect.”

The Doppler effect is the change in wavelength of a wave in relation to an observer who is moving relative to the wave source. As the observer moves closer to the waves, each wave takes slightly less time to reach the observer than the previous wave leading to a decrease in the time between the arrival of waves at the location of the observer.

This causes an increase in frequency.

In addition, by properly designing the transmission line size and voltage levels

Through the combined dynamics between dissipative solitons and shocks, TWFET networks can lead to a new systematic scheme of designing oscillators.

102

www.researchoutreach.org

30

of the applied pulses, when the shock front reaches the far end it is reflected back towards the input. The edge is again reflected at the input to become a stable shock front. The process is repeated continuously to establish edge oscillation. A similar oscillation develops in a transmission line periodically loaded with tunnel diodes and is shown to be a kind of limit cycle that can be synchronised with external oscillation or possibly coexisting edge oscillations.

Moreover, the number of oscillating edges increases with the amplitude of the signal input to the gate line. Each edge can be synchronised with the other edges. Double and quadruple oscillating edges were successfully detected by time-domain measurements performed

by Dr Narahara.

THE FUTURE OF TWFETS Dr Narahara is optimistic that TWFETs could someday replace oscillators in modern devices as electronics evolved to require ever-smaller and higher speed circuits. “Through the combined dynamics between dissipative solitons and shocks, TWFET networks can lead to a new systematic scheme of designing oscillators,” said Dr Narahara. Much is still not known about the nature of dissipative solitons and the knowledge imparted by Dr Narahara’s research has shown that the TWFET is a valuable tool for the study of these fascinating waveforms, which have the potential to advance the field of waveform physics as well as contribute enormously to future electronic technological breakthroughs.

Behind the Research Dr Koichi Narahara

E: narahara@ele.kanagawa-it.ac.jp T: +81 46 291 3085 W: www.ele.kanagawa-it.ac.jp/~narahara/

Research Objectives

References

Dr Koichi Narahara studies the physical phenomenon generated by travelling-wave field-effect transistors, such≈as electric pulses, shockwaves and solitons.

Narahara, K. (2018). ‘Synchronization of dissipative solitons in a system of closed traveling-wave field-effect transistors’.

Nonlinear Dyn, 94:711-721 DOI 10.1007/s11071-018-4388-6.

Detail Dr Koichi Narahara 1030 Shimoogino Atsugi Kanagawa 243-0292 Japan Bio Dr Koichi Narahara studied at the University of Tokyo and then worked at Nippon Telegraph and Telephone Corporation and Yamagata University.

He moved to Kanagawa Institute of Technology in 2014 and is now a Professor in the Department of Electrical and Electronic Engineering.

Narahara, K. (2012). ‘Development of Shockwaves in travelingwave field effect transistors’. J. Appl. Phys. 112 , 084914 ; DOI: 10.1063/1.4762011.

Narahara, K. (2018). ‘Dynamics of dissipative solitons developed in a closed traveling-wave field-effect transistor’.

Int J Circ Theor Appl, DOI: 10.1002cta.2509.

Narahara, K. (2013). ‘Characterization of edge oscillation in a traveling-wave field-effect transistor’. Physical Review E 88, 012907, DOI: 10.1103/PhysRevE.88.012907.

Narahara, K. (2011). ‘Characterization of Short-Pulse Generation Using Traveling-Wave Field-Effect Transistors’.

Jpn.J.Appl.Phys, 50, 014104. DOI: 10.1143/JJAP.50.014104.

Personal Response Can you tell us your future plans for research in this field?

The synchronised dissipative solitons must be verified experimentally in the near future. After the elaboration of the device structure for pulse compression and shock/ soliton generation, compound utilisation of TWFETs will become highly valued. In general, wave phenomena are realised through synergistic contributions by dispersion, dissipation, gain, electromagnetic couplings, and nonlinearity. TWFETs contain sources of all these elements so that they have significant potential to develop any natural wave phenomena on a semiconductor wafer. I keep studying what is possible in TWFETs without considering technological values too much.

www.researchoutreach.org

103

Biology ︱ Dr Malini Sen

Pathogenic microorganisms targeted by complex cellular communications When the human body is challenged by infection, the defences of the immune system are called into action.

Dr Malini Sen of the Indian Institute of Chemical Biology is leading research into the role of a protein called Wnt5a in defending against invading pathogenic microorganisms.

Wnt5a is found in macrophages, large white blood cells that form one of the first lines of defence against infection. Dr Sen and her team have shown that Wnt5a signalling plays a key role in helping macrophages to engulf and destroy invading microorganisms.

W

hen an infection enters the human body, it triggers a sophisticated, complex and targeted immune response. The invaders can take many forms – bacteria, viruses, parasites – but whatever the challenge, the forces of the immune system have a response. As part of the first line of defence, macrophages (a name that comes from the Greek term for “big eaters”) are a vital component of the immune response. In a process called phagocytosis, these large white blood cells locate, engulf and destroy threats to the body. These threats can include pathogenic bacteria and other invading microorganisms, foreign substances, cancer cells and cellular debris.

Extensive research has shown that phagocytosis involves a complex yet highly coordinated cascade of events. A variety of different proteins and lipids on the macrophage cell surface work together to capture a bacterium and draw it into the cell. Within the macrophage, numerous organelles and proteinlipid interactions result in pathogenic bacterial clearance in a process called xenophagy.

Xenophagy, an innate component of the immune system, makes use of the cell’s

104

www.researchoutreach.org

own autophagy (literally, “self-eating”) machinery to break down the proteins and organelles of the invading microorganism.

EVADING THE MACROPHAGE Sometimes, however, a microorganism gets the better of a macrophage, leaving the body without one of its most important defenders. When this happens, people can develop chronic illnesses that fail to respond to treatment. For example, patients with diseases such as Chronic Obstructive Pulmonary Disease (COPD) can develop sepsis as a result of infection by drug-resistant bacteria like Streptococcus pneumoniae or Pseudomonas aeruginosa. Sepsis is a lifethreatening condition that can cause multiple organ failure, and is triggered by the body’s own overwhelming immune response to an infection. Sepsis remains difficult to treat and is considered to be a global health concern.

To better understand how some pathogens are able to evade the body’s immune defences, Dr Sen and her team investigate the ways in which the immune system is maintained.

Macrophages need to be primed and maintained in a constant state of readiness if they are to be effective. Key to this process is a protein called Wnt5a.

THE ROLE OF WNT5A IN THE IMMUNE RESPONSE The protein Wnt5a belongs to a family of secreted glycoproteins that are involved in transmitting cellular signals. Wnt5a binds to two proteins that transverse the cell membrane: either the protein Frizzled (Fz), or a type of cell-surface receptor protein called ROR, or both. In the early stages of mammalian development, Wnt5a is involved in cell growth and differentiation.

During this time, Wnt5a plays a vital part in cell migration and cytoskeletal reorganisation (arranging and supporting the internal structure of the cell). Dr Sen and her colleagues decided to investigate whether Wnt5a might contribute to the process of phagocytosis in a similar way.

In 2012, Dr Sen and her team published the results of a study with a non-pathogenic lab strain of bacteria that showed that signalling between Wnt5a and Fz plays an important part in the phagocytosis of bacteria where bacteria are “eaten” by the macrophage while being broken down and thus rendered harmless. The team demonstrated this by creating two models: one where Wnt5a production was inhibited and one where the Wnt5a receptor Fz5 was blocked.

In both cases, uptake of bacteria into the macrophage was inhibited. In a follow up study, published recently, Dr Sen and her team demonstrated the effect of Wnt5a-Fz5 signalling on phagocytosis and bacterial clearance (xenophagy) of pathogenic bacteria.

THE IMPORTANCE OF SIGNALLING It was important for Dr Sen and her team to investigate the mechanisms by which macrophages are primed to tackle infection. This immune homeostasis, whereby immune cells are maintained in a steady state of surveillance for infection is essential if macrophages are to swiftly and effectively tackle infection.

Dr Sen and her colleagues established that basal (i.e. constant, low-level) Wnt5a signalling both keeps macrophages prepared to perform their innate immune functions and supports their survival.

The team found that the recognition and internalisation of bacteria and viruses is partly dependent on a homeostatic Wnt5a-based signalling system.

Wnt5a-Fz5 Signalling in macrophages promotes clearance of bacterial pathogens through complex interactions among its signalling intermediates.

Wnt5a plays a vital part in cell migration and cytoskeletal reorganisation.

WNT5A AND LEISHMANIASIS While establishing the crucial role of Wnt5a in tackling pathogenic bacteria the team decided to broaden the scope of their research. In 2017, Dr Sen and her colleagues published their findings on the role of Wnt5a signalling in infection by the parasite Leishmania donovani. L. donovani causes the most severe form

of the disease leishmaniasis, known as visceral leishmaniasis or “black fever.” This condition is the second-largest parasitic killer in the world (after malaria) and causes symptoms including fever, anaemia and swelling of the liver and spleen.

Leishmania donovani is a cunning parasite, able to not only evade the host’s

Wnt5a gene encodes Wnt5a protein

Wnt5a gene location in chromosome 3 (human).

www.researchoutreach.org

105

immune defences but to actually use those defences to survive. When a macrophage engulfs L. donovani, the parasite creates a protective space, or niche, for itself. These safe spaces are termed parasitophorous vacuoles (PV). Sequestered in its parasite niche, L. donovani is safe from the digestive mechanisms that would normally destroy microorganisms within the macrophage.

However, exactly how L. donovani and other parasitic infections form and sustain PV and avoid destruction remains unclear.

The key to the puzzle may be found in the cytoskeleton, the structure that provides mechanical support and maintains internal organisation of the cell. There is an established link between bacterial pathogenesis (the way in which bacteria cause disease) and the cytoskeletal dynamics of the host cell. The protein Wnt5a is also known to have an important relationship with the cytoskeleton. Dr Sen and her team, therefore, theorised that Wnt5a signalling could influence the formation of PV by L. donovani.

Dr Sen and her colleagues observed a decrease in Wnt5a in macrophages infected by L. donovani. The parasite likely achieves this by suppressing Wnt5a signalling in the host cell and/or through the use of its proteases, enzymes that can break down host proteins.

The consequent reduction in Wnt5a protein could cause alterations to the macrophage cytoskeleton and disrupt immune homeostasis. L. donovani would then be able to take advantage of the abnormal changes to build a protective niche within the macrophage.

Wnt5a mediated bacterial killing as depicted by confocal microscopy; (a) Red dots indicate Propidium Iodide stained bacteria (less in Wnt5a than PBS), (b) Green dots indicate LC3B punctae (more in Wnt5a than PBS), which represent xenophagy (bacterial killing). PBS is vehicle control for Wnt5a.

Basal Wnt5a signalling both keeps macrophages prepared to perform their innate immune functions and supports their survival.

THE FUTURE During their research, Dr Sen and her team also discovered that bolstering Wnt5a signalling within a macrophage reduces parasite survival, probably because Wnt5a triggers fusion of lysosomes (small organelles containing

Macrophages interact with pathogens to initiate immune response.

106

www.researchoutreach.org

destructive enzymes) with PV. This finding is potentially hugely significant in tackling infections by L. donovani and other parasites that are able to evade the host immune response. While L. donovani thrives by inhibiting Wnt5a signalling in the host cell, boosting Wnt5a function could potentially form the basis of a new treatment route for leishmaniasis.

Dr Sen and her colleagues hope that the knowledge gained from their research will help to increase understanding of both the strategies invading microorganisms use to evade their host’s defences, and the ways in which immune responses strive to resist and repel these attacks. One day, this knowledge could be used to develop protocols to support and enhance the function of macrophages and other immune cells in patients with weakened immune systems, thus preventing the spread of deadly pathogens.

Behind the Research Dr Malini Sen

E: msen@iicb.res.in E: msen648@gmail.com T: 91 332 499 5730 W: https://doi.org/10.4049/ jimmunol.1302817 W: https://doi.org/10.1073/pnas.1207789109 W: https://doi.org/10.4049/ jimmunol.1601927 W: https://doi:10.3389/fimmu.2018.00679

Research Objectives

References

Dr Sen’s research looks at deciphering the role of mesenchymal stem cell factors such as Wnts in various aspects of immune homeostasis, immune response to infection and inflammation.

Chakraborty, A, Kurati, SP, Mahata, SK, Sundar, S, Roy, S and Sen, M. (2017). ‘Wnt5a Signaling Promotes Host Defense against Leishmania donovani Infection’. Journal of Immunology, 199, 992-1002.

Detail Division of Cancer Biology & Inflammatory Disorder Indian Institute of Chemical Biology (IICB) 4 Raja SC Mullick Road Kolkata 700032 India Bio Dr Sen earned her Bachelor’s degree from Calcutta University, India and her PhD from Albert Einstein College of Medicine, NY. She was an Arthritis Investigator at the Dept. of Medicine, UCSD and became a faculty member in the Indian Institute of Chemical Biology, a unit of CSIR, India in 2007.

Funding Department of Biotechnology & Council of Scientific and Industrial Research (CSIR), India.

Collaborators • Suborno Jati, Research Scholar, IICB, India • Arijit Chakraborty, Research Scholar, IICB, India • Sushil Mahata, Professor, VA Medical School, UCSD, USA • Syamal Roy, Professor, NIPER, India • Victor Nizet, Professor, UCSD, USA

Maiti, G, Naskar, D and Sen, M. (2012). ‘The Wingless homolog Wnt5a stimulates phagocytosis but not bacterial killing’. PNAS, 109 (41), 16600-16605.

Naskar, D, Maiti, G, Chakraborty, A, Roy, A, Chattopadhyay, D and Sen, M. (2014). ‘Wnt5a-Rac1-NF-kB Homeostatic Circuitry Sustains Innate Immune Functions in Macrophages’.

Journal of Immunology, 192, 4386-4397.

Jati S, Kundu S, Chakraborty A, Mahata SK, Nizet V and Sen M (2018). ‘Wnt5a Signaling Promotes Defense Against Bacterial Pathogens by Activating a Host Autophagy Circuit’. Frontiers in Immunology, 9: 679. doi: 10.3389/fimmu.2018.00679.

Personal Response What are the next steps in investigating the role of cytoskeletal dynamics in the immune response?

We are trying to dig deep into the molecular details of how Wnt5a signalling intermediates in host macrophages are intertwined with the cytoskeletal dynamics during the immune response to different microbial pathogens. In this regard, we are focusing on the influence of Wnt5a signalling on cytoskeletal actin binding and nucleating proteins, which come into play when a functional cytoskeleton reacts to pathogen assaults. Through different experimental procedures, we hope to figure out how Wnt5a signalling utilises the cytoskeletal dynamics to distinguish pathogens from non-pathogens during the arbitration of the host autophagy circuit for pathogen clearance, thereby resisting infection.

What are your future plans for research in this area?

We would like to conduct experiments aimed at a detailed evaluation of the significance of Wnt signalling in the context of sepsis, which is associated with an impaired immune system.

www.researchoutreach.org

107

Biology ︱ Dr.ir. Sjaak van Heusden

Better and stronger potatoes using hybrid breeding Potato is a hugely important crop worldwide, being eaten across the world and across cultures. Increased crop productivity and strength will help cater for the increasing global population, and also serve to reduce famine in challenging and impoverished environments. The potato breeding company Solynta in The Netherlands has successfully produced a hybrid breeding program for potatoes which will allow the rapid selection and turnover of favourable traits, traits which could help feed millions of people worldwide.

P

otato breeding techniques are lagging far behind those of other popular crops such as rice, maize, and wheat. This is because potato breeding suffers hinderances through its genetic complexity, resulting in slow progress. The cultivated potato Solanum tuberosum is tetraploid, meaning it has four sets of chromosomes – in this situation, it is easy for unfavourable alleles to make their way unseen into the next generation, and introducing new, favourable traits can be very tricky.

At Solynta, a potato seed breeding company based in Wageningen, Holland, an innovative method for targeted breeding has been developed which will change the production and global distribution of potatoes. This method allows for the combination of beneficial traits from different potato varieties to make ‘elite’ progenies which have a higher yield, disease resistance, and of course, better taste. Furthermore, this method allows for vastly improved transportation which will be done at the seed stage, rather than fully grown potato tubers.

Potatoes are also a much more nutritious source of food than other top crops such as rice, soy and wheat. They contain high levels of vitamins and

108

www.researchoutreach.org

relatively few calories, yet potatoes can be processed and cooked into many different forms – potentially providing varieties that grow where not much else can grow.

With the help of the Solynta breeding technology, each of these traits can be harnessed, genetically selected for, and reproduced.

A HYBRID BREEDING PROCESS Historically, selection of better potato varieties took a very long time. Firstly, it was simply trial and error to breed a suitably stronger crop, after this the selected plant underwent a lengthy multiplication process. The best potato would be selected and planted in the ground to multiply the number of tubers, this process takes a year. This must be repeated year upon year, until after around seven years a commercially viable number is produced. To make matters worse, with time, these potatoes can become increasingly susceptible to diseases, such as potato blight Phytophthora infestans.

This new targeted breeding process relies on a few important principles which counteract these historical problems.

The first is that the breeding process is completed using diploid potatoes rather than tetraploid. This is achieved by diploidisation and using S. chacoense diploid potatoes. The resulting organism is a diploid hybrid potato plant, with just two sets of chromosomes.

Normally, diploid potato plants are selfincompatible but some S. chacoense plants contain a gene called Sli, which overcomes self-incompatibility.

A flowering diploid potato plant.

This diploid ‘germplasm’ contains a high level of heterozygosity but then is repeatedly selfed (bred with itself).

Selfing gradually dilutes the level of heterozygosity of the progeny until they are, after about 6 generations, almost completely homozygous. These parental plants could be the first selfcompatible, diploid potato plants ever made. Homozygous parents are needed for the creation of hybrids.

Due to inbreeding depression, the first generations were in general weaker.

However, due to the selection of only the most vigorous (strong) potato plants, the parent lines quickly became stronger and more homozygous. Strong parental plants can be hybridized to make F1 hybrid seeds. The resulting hybrid potato plants were generally better and stronger than the inbred parent lines (heterosis).

THE BENEFIT OF SEEDS The potato seeds can be harvested when the hybrid plant forms berries.

These seeds (true potato seeds) have an incredible benefit over the previous method with tubers (tubers are also named seed potatoes). The weight of 100 potatoes is equal to the weight of 16 million seeds, as it’s possible to fit 2500 seeds in just one gram. This magnitude of difference will

Berry development after crossing. The yellow bag prevents the berries to fall off and to get mixed with berries from other crosses.

drastically reduce transportation cost and difficulty.

The seeds are also pathogen free whereas tubers mostly have a low level of disease-causing pathogens. True potato seeds also withstand changes in temperature and humidity. Ultimately the reduction in transport will also reduce carbon footprint.

DISCOVERING TRAITS, IMPROVING POTATOES Now that a steady flow of strong, diploid

One huge application of Solynta’s potatoes will be to help farmers and feed people, in previously difficult or challenging locations.

potato plants is present, Solynta could then focus on isolating and selecting for beneficial potato traits. During this whole process, the traits needed for strong potatoes were identified and then genetically targeted and selected for.

This was done using a process called QTL (Quantitative Trait Locus) mapping.

Each phenotypic trait (observed in the potato) is described by one or, normally more than one, gene. In order to understand which genes control the outcome of a potato, the team looked at SNPs (Single Nucleotide Polymorphisms). Simply put, this is when one nucleotide differs on a particular individual’s genome. By using sequencing and statistics, it’s possible to determine when this is linked to a particular phenotypic trait. Plants with

www.researchoutreach.org

109

Extracted and cleaned seeds (on white filter paper), two halves of a berry and some potato tubers.

Potato tubers of one of the founder lines of Solynta.

Potato seeds after cleaning.

those detected genome alterations are then selected for breeding.

In order to further enhance this process, the parental lines could then be ‘backcrossed’ to add new ‘hybrid traits’ to one of the parent lines. This strengthened the parent lines, which were then hybridized to make an even stronger hybrid potato. Each time a stronger, tastier, or larger potato was grown. This process is so rapid in Solynta because of the speed of growth from seed, and genetic selection of traits.

Collection of berries which developed after self-pollinations of a diploid parent.

110

www.researchoutreach.org

These parental plants could be the first self-compatible, diploid potato plants ever made. Homozygous parents are needed for the creation of hybrids.

FEEDING GLOBAL POPULATIONS One huge application of Solynta’s potatoes will be to help farmers and feed people, in previously difficult or challenging locations. The benefits of these potatoes are going to be large in the high-income countries,

but even larger in low to middleincome countries.

The Solynta hybrid diploid potato seeds were transported and tested in East Africa, specifically the mountains of DR Congo. The results were extremely optimistic, with a much higher yield of potato than under normal East African conditions.

Furthermore, the seeds were extremely easy to transport and were free of pathogens which are so common in the tropical African climate and can decimate farmers’ stocks between seasons. It’s also very possible to adapt the diploidisation and genetic hybridization techniques from Solynta’s technology to African potato varieties, increasing the breadth of choice in these areas. It seems only a matter of time before these farming methods are being used worldwide in order to catch up with the global demand for food production alongside our ever-expanding human population.

Behind the Research Dr.ir. Sjaak van Heusden

E: sjaak.vanheusden@solynta.com T: +31 620 843 929 W: https://solynta.com/

Research Objectives

References

Solynta has developed an innovative method for targeted breeding which will change the production and global distribution of potatoes

De Vries M, ter Maat M, Lindhout P. (2016). ‘The potential of hybrid potato for East-Africa’. Open Agriculture, Vol 1: pp.

151-156.

Detail

Lindhout P, de Vries M, ter Maat M, Ying S, Viquez-Zamora M, van Heusden S. (2018). ’Hybrid potato breeding for improved varieties’. Achieving sustainable cultivation of potatoes, Vol 1, pp. 99-122.

Dr.ir. Sjaak van Heusden Solynta Dreijenlaan 2 6703HA WAGENINGEN The Netherlands Bio Sjaak van Heusden fields of expertise are tomato and diploid potato pre-breeding with emphasis on marker technology. Besides research, he is involved in international teaching and cooperation. In the last five years, he has been mainly employed as a geneticist at the potato breeding company Solynta.

Funding Solynta Collaborators • Wageningen University and Research

Lindhout P, Meijer D, Schotte T, Hutten R, Visser R, van Eck H. (2011). ‘Towards F1 Hybrid Seed Potato Breeding’. Potato Research, Vol 54 (4), pp301-312.

D. Meijer; M. Viquez-Zamora; H. J. van Eck; R. C. B. Hutten; Y. Su; R. Rothengatter; R. G. F. Visser; W. H. Lindhout; A. W. van Heusden (2018). ‘QTL mapping in diploid potato by using selfed progenies of the cross S. tuberosum × S. chacoense’.

Euphytica, 214:121

Personal Response If already successful in other crops, what has stopped this process being achieved before in potatoes?

Making diploid potatoes has already been tried for decades but was never successful. A better use of new technologies to overcome self-incompatibility and to follow the level of homozygosity in selected plants, make it now possible to make the transition of tetraploid potatoes to diploid potatoes. Over time, as we transition to diploid potato breeding, we will be able to undo previous dogmas, such as a high yield is only possible with tetraploid potatoes.

What are your future plans for research in this area?

Solynta wants to introduce successful varieties in Africa.

To do this large numbers of clean seeds of plants with enhanced levels of resistance are needed. Later, other markets will be targeted.

Biology︱ Dr Ángela Gómez-Niño and Dr Asuncion Rocher

Guinea pig as a model to study the carotid body-mediated chronic intermittent hypoxia effects The ability to sense and respond to changes in oxygen is essential for survival. Dr Ángela GómezNiño and Dr Asuncion Rocher along with their research team at Valladolid University aim to better understand the physiology and pathophysiology of oxygen sensitivity. In particular, the team employ the use of the guinea pig as a model to explore the mechanisms that mediate longterm effects of exposure to low oxygen levels. With its unique oxygen-sensing systems, the guinea pig promises to be an invaluable tool to study and understand the pathological effects occurring in sleep apnoea disorder.

Hartley guinea pig.

112

www.researchoutreach.org

H

ypoxia is the reduction of oxygen supply to tissues to below normal, physiological levels. Hypoxia can be produced, for example, by exposure to high altitudes. Mammals have developed different oxygen-sensing mechanisms to maintain the oxygen supply within cells in response to hypoxia. When the body senses a decrease in oxygen, its strategy is to increase breathing depth and rate (hyperventilation), in addition, the heart beats faster. These strategies are controlled through feedback mechanisms triggered by sensory receptors called chemoreceptors. One of the main chemoreceptors responsible for oxygen-sensing is the carotid body (CB), which monitors and responds to changes in the partial pressure of oxygen and carbon dioxide in arterial blood.

CAROTID BODY CHEMORECEPTORS ARE STIMULATED BY HYPOXIA The CB is found in carotid arteries – the main arteries that run along both sides of the throat – and is sensitive to the levels of blood gases. The CB has a high density of blood vessels and is made up of a cluster of specialised cells, called type I cells, that are connected by nerve endings from the carotid sinus nerve, a branch of the ninth cranial pair nerve.

Upon detecting a drop in blood oxygen levels (or excessive carbon dioxide in the blood, known as hypercapnia), type I cells release specialised signals (known as neurotransmitters, for example, catecholamines, ATP and acetylcholine) that stimulate the carotid sinus nerve, carrying chemoreceptor information to the brainstem to initiate reflex responses. In this way, the CB reflex response, triggered by hypoxia, restores oxygen blood concentration to its normal level. Information from the CB is thus transmitted to the brainstem, which increases breathing frequency (hyperventilation) as well as stimulating the nervous system (sympathetic activation), thereby counteracting the effects of hypoxia.

A research team at the University of Valladolid, led by Dr Ángela GómezNiño, Professor at the Department of Cell Biology, and Dr Asuncion Rocher, Professor of Physiology, explores the mechanisms involved in oxygen sensing and transduction in CB arterial chemoreceptors. Their research has implications for hypoxia-related pathologies, particularly sleep apnoea disorder. One exciting focus of their work

B

N

125

*** ***

CIH

A

*** ***

fR (breath/min)

100 75 50 25 0

21% O2

10% O2

employs the use of the guinea pig. The guinea pig represents an exciting model to help better understand the underlying mechanisms mediating the long-term effects of hypoxia exposure. Specifically, their newly proposed model has important implications for understanding the role of the CB in mediating the pathological effects observed in sleep apnoea disease.

OBSTRUCTIVE SLEEP APNOEA Sleep apnoea is a serious sleep disorder that occurs when a person’s breathing is interrupted during sleep; loud snoring and episodes of breathing interruption during sleep are classic symptoms. In sleep apnoea disorders, breath can become very shallow or may even stop briefly during the sleep.

In severe cases, the condition causes breathing to repeatedly stop and start during sleep meaning that the brain, and the rest of the body, does not get enough oxygen. Chronic intermittent hypoxia (CIH) is thought to be one of the main causes of arterial high blood pressure observed in obstructive sleep apnoea syndrome. It is believed that repeated episodes of hypoxia/ re-oxygenation produce oxidative stress, inflammation and sympathetic hyperactivity, generating dysfunction of the blood vessel lining (endothelium) and high blood pressure. Indeed, recent evidence suggests a positive correlation between CIH, increased CB responsiveness and high blood pressure

7% O2

5% O2

(hypertension), and an increased risk of heart disease.

CHRONIC INTERMITTENT HYPOXIA Animal models exposed to recurrent hypoxia and re-oxygenation episodes in CIH show increased CB sensitisation, which in turn increases the secretory response and chemoreceptor input to the brainstem, exaggerating the resulting nervous reflex (sympathetic reflex). Experiments have shown that if the CB is removed, these effects can be reduced in response to intermittent hypoxia. The majority of hypertension research is conducted on rodents, due

Plethysmography recording of respiratory parameters measured in normoxic (N) or breathing air and intermittent hypoxia (CIH) exposed guinea pigs. A. Image of awake and freely moving guinea pigs during whole body plethysmography recordings. B. Respiratory frequency (or breaths per minute; fR) response to air (21% oxygen), acute hypoxia (5 min) (breathing 10 or 7% oxygen) and hypercapnia (5% CO2) tests. Only intense hypoxia (7% O2) and hypercapnia increased ventilation. No diferences between control (N) and chronic intermittent hypoxia treated (CIH) guinea pigs were observed.

(Data are expressed as mean ± SEM (n=8) Twoway ANOVA; ***p<0.001 vs. 21%. O2)

to similarities between rodent and human blood pressure control and cardiovascular responses. In contrast, experiments using guinea pigs, originally from the Andes, showed a different response in early studies led by Dr Gómez-Niño. Her work demonstrated that guinea pigs show a poor or no ventilatory response to hypoxia compared to other mammals.

Dr Gómez-Niño’s intriguing research demonstrates that unlike other rodents, the poor ventilatory response to hypoxia in guinea pigs is due to low levels of functional CB. The team measured

The team are exploring the guinea pig as a model to better understand the mechanisms that mediate long-term effects of exposure to low oxygen levels.

Cardiovascular responses to hypoxia. Continuous recording of arterial blood pressure from a CIH guinea pig breathing air (21% O2) or hypoxia (10% O2). To measure arterial pressure, guinea pigs were anaesthetized (ketamine plus diazepam; 100 y 5mg/Kg, respectively; ip). After a incision in the neck, they were tracheostomized and ventilated with room air (CL Palmer) or with the gas mixture (10% O2 and 90% N2). Once the right common carotid artery was located, it was cannulated with a catheter connected to a pressure transducer (Transpac IV; ICU Medical, San Clemente, CA) and signals were sent and stored (BIOPAC Systems, Inc. MP 150, Goleta, CA; Acknowledge 3.9.1) for later analysis.

www.researchoutreach.org

113

INTERMITTENT HYPOXIA

CENTRAL NERVOUS SYSTEM (Brainstem neurons)

CC CSN CB

CSN

The picture shows the dissection of the bifurcation of the common carotid artery and the carotid body with the attached carotid sinus nerve. The decrease of oxygen in blood (hypoxia) is detected by chemoreceptor or type I cells (CC) of the carotid body that by releasing neurotransmitters increase the frequency of action potentials or discharges in the carotid sinus nerve (CSN). This information reaches the brainstem generating systemic responses (hyperventilation and increase of sympathetic activation that can produce hypertension). CC= chemoreceptor cell of the carotid body; CSN= carotid sinus nerve).

This is what happens in humans and other animal models but not in guinea pigs.

The team showed an absence of the hypoxia-driven CB reflex in the guinea pig. the guinea pig CB response to hypoxia and compared it to the well-known rat hypoxic response. Their research, published in Frontiers in Physiology, demonstrated for the first time the absence of the hypoxia-driven CB reflex in the guinea pig. This lack of guinea pig CB response to hypoxia would suppress the chemo-reflex sensitisation, reducing or eliminating the respiratory and nervous reflex (sympathetic reflex) effects of intermittent hypoxia exposure. The lack of response to hypoxia showed that CIH does not modify the excitability of the CB. Their research did show, however, that intermittent hypoxia-induced sympathetic hyperactivity and promoted cardiovascular responses by increasing heart rate and arterial blood pressure and that this is independent of CB stimulation.

INVESTIGATING THE LACK OF RESPONSE TO HYPOXIA Dr Gómez-Niño went on to test the idea that this lack of CB hypoxia response in guinea pig would suppress chemoreflex sensitisation, thereby attenuating or eliminating respiratory, sympathetic and cardiovascular effects of CIH treatment. The research team set out to explore whether the guinea pig CB can be overactivated by CIH; their aim was to correlate the CIH effects on CB

114

www.researchoutreach.org

chemoreceptors with cardiovascular and respiratory responses to hypoxia.

To mimic the situation of an obstructive sleep apnoea patient, the team exposed male guinea pigs to acute hypoxia (30day exposure to CIH). They measured CB secretory activity, ventilatory parameters, systemic arterial pressure and sympathetic activity. Their results showed that guinea pigs exposed to CIH lack activity (as measured by release of catecholamine. Only severe hypoxia (7% O2) resulted in an increased ventilatory response and oxygen consumption to the CIH animals. In other words, CIH exposure blunted hyperventilation to hypoxia normalised to oxygen consumption. However, the team found that catecholamine levels were increased in the blood, suggesting that CIH induced nerve activity. The team concluded that CIH does not sensitise the CB chemoreceptor response to hypoxia but promotes cardiovascular adjustments, albeit not via the CB activation.

A MODEL TO INVESTIGATE CHRONIC INTERMITTENT HYPOXIA Dr Gómez-Niño and Dr Rocher postulate that the absence of the hypoxia-driven CB reflex in the guinea pig is could

SYSTEMIC RESPONSE (cardiorespiratory response)

SYMPATHETIC STIMULATION

RESPIRATORY RESPONSE

HYPERTENSION

HYPERVENTILATION

be similar to that seen in neonatal mammals (In Olea et al., 2018, the team showed that it is not the case).

Neonatal mammals have an immature CB chemoreflex and respond to hypoxia through another pathway – via the direct effect of hypoxia on, the adrenal medulla. (It could be through the hypoxic stimulation of specific areas in the central nervous system).

Excitingly, the researchers at the University of Valladolid believe that the guinea pig represents a useful tool for examining the mechanisms underlying the long-term effects of CIH exposure – in particular, the brainstem sensitivity to hypoxia and cardiovascular responses generated by intermittent hypoxia. The team’s hope is that this model will also provide evidence for the role of the CB mediating pathological effects in sleep apnoea diseases. Dr Gómez-Niño and Dr Rocher’s next steps are to examine the missing mechanisms that underlie the lack of effects of intermittent hypoxia on the guinea pig CB to provide evidence for its role in mediating hypertension observed in sleep apnoea disorder.

Behind the Research Dr Ángela Gómez-Niño

Dr Asuncion Rocher

E: angela@biocel.uva.es E: rocher@ibgm.uva.es T: +34 983 423086 T: +34 983 423000 ext 4122

Research Objectives

References

Dr Ángela Gómez-Niño and Dr Asuncion Rocher along with their research team at Valladolid University aim to better understand the physiology and pathophysiology of oxygen sensitivity. In particular, the team employ the use of the guinea pig as a model to explore the mechanisms that mediate long-term effects of exposure to low oxygen levels.

Docio I. Olea, E, LLoret J-P, Gallego-Martin T, Obeso A, Gomez-Niño A, Rocher A. (2018). ‘Guinea Pig as a Model to Study the Carotid Body Mediated Chronic Intermittent Hypoxia Effects’. Front. Physiol. 9:694. doi: 10.3389/ fphys.2018.00694.

Detail Dr Ángela Gómez-Niño The University of Valladolid UC/Plaza de Santa Cruz, 8, 47002 Valladolid, Spain Bio Dr Ángela Gómez-Niño is associated professor teaching cell biology and her research is focused on the mechanisms involved in oxygen detection and transduction in the carotid body arterial chemoreceptors and the hypoxia-related pathologies, mainly those associated to sleep apnoea disorders.

Dr Asuncion Rocher is Professor of Physiology at the Medical School of the Valladolid University where she teaches graduate and postgraduate courses in physiology and biomedicine. Her research is focused on arterial chemoreception, oxygen sensing and hypoxia-related pathologies.

Funding MINECO/FEDER, UE BFU2015-70616R, ISCiii CIBER CB06/06/0050 and FUNGE UVa PIP-063_166091.

Gonzalez-Obeso, E., Docio, I., Olea, E., Cogolludo, A., Obeso, A., Rocher, A., and Gomez-Niño A. (2017). ‘Guinea pig oxygen-sensing and carotid body functional properties’. Front.

Physiol, 8:285. doi: 10.3389/fphys.2017.00285.

Olea, E., Gonzalez-Obeso, E., Agapito, T., Obeso, A., Rigual, R., Rocher, A., and Gomez-Niño A. (2018). ‘Adrenal medulla chemo sensitivity does not compensate for the lack of hypoxia-driven carotid body chemoreflex in guinea pigs’. Adv. Exp. Med. Biol, 1071: 167-174.

Personal Response What first drew you both to the guinea pig as a potential model organism to use in your research?

Our previous experience working on mammal arterial chemoreceptors was based mainly on rats. We have used the rat as a model to mimic chronic intermittent hypoxia, the hallmark of sleep apnea disorder symptoms that appear in patients. The literature showed that guinea pigs did not hyperventilate in hypoxic environments what led us to characterize the guinea pig carotid body. We demonstrated that guinea pigs have a hypo-functional carotid body, without adaptation to chronic hypoxia. Based in our hypothesis of the carotid body as the origin of sleep apnea symptoms, we decided to use guinea pigs as a model to study the effects of intermittent hypoxia exposure.

Collaborators • Elvira Gonzalez-Obeso • Inmaculada Docio • Elena Olea • Ana Obeso • Jesus Prieto-LLoret • Teresa Gallego-Martin • Ana Gordillo

www.researchoutreach.org

115

Behavioural Sciences ︱ Ven Karma Jiga

Mindfulness-Based Intervention (MBI) provides positive outcomes for those in lower socioeconomic environments The western world today demands a great deal from its inhabitants, both physically and mentally. The prevalence of mental health problems is high, and none more so than those in low socioeconomic status, with financial hardship recognised as a root cause for life stress and anxiety. Although trained in both eastern and western based mindfulness techniques, Karma Jiga applies the western secular approach to reach this population. Using an adapted Mindfulness-Based Intervention (MBI), he delivers mindfulness techniques to those in poverty to help improve their physical and mental well-being, without charge. The potential benefits to the individual and wider community could prove significant in a world where mental health issues seriously affect 1 in 3 people.

I

t is no surprise to find that those living in lower socioeconomic environments are more prone to suffer from several stress-induced physical and mental disorders. Financial stress is often cited as one of their leading causes, particularly in westernised cultures. It is now well documented that extended periods of stress, regardless of source, can increase susceptibility to a myriad of illnesses and disease, both physical and psychological.

Most, if not all of us, can relate to experiencing stress at some point in our lives, but unfortunately for some, this can be a near lifelong affliction.

BRIEF HISTORY OF TREATMENT APPROACHES The treatment of stress is now at the forefront of medical and psychological sciences, both striving towards developing the most effective treatments for those who need them. Until relatively recently, the most prevalent approach was pharmacological. However, both pharmacological and nonpharmacological approaches have their merits and demerits. The pharmacological approach can require dealing with both side effects and ongoing costs of drugs, whereas the psychological approach can have high initial costs and a reliance on the will and confidence of the participant to approach their difficulties from a different standpoint. However, for those participating in MBI’s from within low socioeconomic environments, it is not uncommon for both approaches to be in play at the same time.

KARMA JIGA AND MINDFULNESSBASED INTERVENTION (MBI) Many practitioners and ordinary people are now switching their focus towards treatments rooted in more Eastern ideals.

The words meditation and mindfulness are becoming more common. What may have once seemed like a more ‘far out’ activity

is now arguably considered more normal for Westerners. Mindfulness, although it may mean different things to different groups of people, has been defined as the awareness and acceptance of what arises in and around you as it happens ; however, this requires developing an ability to let go of, and become less involved with our thoughts, feelings and emotions as they come to mind.

Typical mindfulness-based interventions, such as Mindfulness-Based Stress Reduction (MSBR) and MindfulnessBased Cognitive Therapy (MBCT) consist of a 6-8-week programme delivered by trained practitioners. These combine basic Buddhist based meditation practices with a more science-based understanding of stress and wellbeing. The idea is to allow thoughts to come and go and let go of the desire to judge or focus on them. By becoming less attached to these thoughts, the negative impact on a person’s current mental state is lessened. Reports have yielded signs that these approaches can positively influence physical and neurophysiological processes which are harmed by stress such as blood pressure and cortisol levels.

Karma Jiga is trained in both eastern and western mindfulness schools of thought and techniques. He has developed a mindfulness training course aimed at those in low socioeconomic areas called Headroom, and is currently based in Dundee, Scotland. Headroom is a ninesession mindfulness-based intervention (MBI), based on the training in MBSR and MBCT he received at Bangor University.

He aims to develop mindfulness techniques specific to the problems more commonly faced by those in low socioeconomic environments, whilst establishing their feasibility. Headroom is free and open to anyone earning less than the real living wage. The potential benefits

to the community are now becoming known, with participation increasing as the word spreads! Participants who have completed the course have said that they feel more like their old selves and less stressed when dealing with circumstances without their control.

THE SCIENCE – DOES IT WORK? An important measure for any type of treatment plan or psychoeducation course is whether it works and can be verified empirically. Early research investigating the efficacy of MBIs was promising with significant increases in several well-being measures found across twenty studies (Grossman et al, 2004), and whilst some review studies have reported only moderate reductions in anxiety and stress levels (Goyal et al. 2014), the overall trend is positive. The variety of circumstances

Mindfulness has been shown to reverse neurophysiological changes caused by prolonged stress. and mental health issues encountered by those in low socioeconomic environments influences the interpretation of results and makes for a complicated area of study, let alone the fact that genetics may play a significant role in the occurrence of anxiety, stress and depression. Whilst the validity and results of some studies in the mindfulness field have been called in to question, the effects of mindfulness on those in poverty is a unique area of research which needs to be developed.

A primary concern for any MBI programme, especially with low SE populations is attrition, i.e. the rate

of course completion by individuals.

Knowing that high dropout rates were a common problem which could affect the ability to produce a viable study, Karma Jiga developed a recruitment protocol that would determine the programmes initial feasibility. This protocol was effective in that it improved accessibility by providing for participants needs while taking into account participants individual circumstances. Ongoing course evaluation provided information regarding programme feasibility.

Participants were 107 referred or selfreferred members of the public living on

ROBUST IMPROVEMENTS IN WELL-BEING B

WHO-5

WELLBEING

70 60 50 40 30 20

The Training & Control groups – before & after – all measures.

GENERAL WELL-BEING 5 4 Scores

90 80

Scores

WELLBEING

A

3 2 1

10 0

0

C

Post-training

Pre-training D

MENTAL WELL-BEING

MINDFULNESS

4 Scores

WELLBEING

5

3 2 1

Post-training

MAAS 5 4 Scores

Pre-training

3 2 1 0

0 Pre-training

Post-training

Pre-training Training group

Post-training

Control group

www.researchoutreach.org

117

CHANGE IN OUTLOOK A

B

T1 THEMES

Having needs met

T1 THEMES

Healthy choices

Taking action

Taking part, moving forward

Making connections

Confidence, self esteem, contentment

Feeling positive

Developing resilience

Not feeling ill health Managing difficulty

Managing difficulty 0

5

10

15

Coding references (frequency)

5

0

10

Coding references (frequency)

NEGATIVE

15

20

POSITIVE

Move from ‘day to day” reactive decision making, to longer term responsive planning. low incomes in the most deprived areas of Dundee. However, with post-orientation dropouts, mid-course dropouts and other considerations, the final research group total numbered 40 (20 experimental conditions, 20 control). Participants were guided through a series of exercises and meditations to improve their sense of awareness and physical and mental wellbeing throughout the 8-week course.

These were assessed through the World Health Organisation (WHO) Well-being Index and Mindfulness Attention and Awareness Scale (MAAS), both widely used and verified in the field. In layman’s terms, this part of the study was gauging whether this adapted MBI course led to an increase in awareness and wellbeing, whilst assessing attrition rates to establish the feasibility of the programmes further use.

comparing mean scores between the control and experimental groups were conducted. There were notable significant differences in scores between the experimental group completers and control group completers, with experimental/training course completers having significantly higher scores on the WHO-5. The MAAS measures, however, showed no significant change and requires further investigation. Further to this, the experimental or training group showed significant positive differences between pre and post training in the qualitative analysis, which also gave rise to free expression through the addition of two open-ended questions. Thus, positive correlations between the changes in WHO-5 scores and General Wellbeing Scores collectively imply the Headroom MBI typically led to improvements across well-being measures.

In addition, a thematic and more personal and unique pre and post-course qualitative analysis were carried out to assess how mindfulness practice had affected participants and how they viewed their states of wellbeing before and after the course. Both forms of analysis introduced self-report measures incorporating 5-point Likert scales. Quantitative measures

PERSISTING PROBLEMS OF ATTRITION The persistent problem of attrition remains, with the majority of dropouts in Karma Jiga’s and others work in this area due to reasons beyond the control of the course provider, or the service user. According to Karma Jiga’s work, a frequent barrier to course attendance were medication

There is a strong positive correlation between debt and poor physical and mental health.

118

www.researchoutreach.org

side effects and the time of day – the latter being an issue he is currently attempting to address and will monitor as the research progresses.

FOOD FOR THOUGHT AND FUTURE DIRECTIONS Karma Jiga is still providing this incredibly valuable approach to the residents of Dundee and hopefully, this will continue to gain momentum and support from other local authorities. Any ambiguity in the research surrounding mindfulness highlights the need to give this and future research the due attention and opportunity to address any anomalies that arise, as the benefits of mindfulness can be profound. They compare favourably with the effects of pharmaceuticals but with little or no negative side effects or ongoing expense. Positive outcomes from mindfulness may not be limited solely to the individual, rather, they have the potential to positively impact the wider community, and in turn the nation.

Karma Jiga and his colleagues at Nilupul plan to develop a framework that would allow this programme to be rolled out to other cities, reaching anyone who would benefit. Furthermore, he is looking into how Headroom can be developed into a teaching programme within the further education system to enable peer to peer delivery of the programme within socioeconomically deprived communities.

Behind the Research Karma Jiga

E: karmajiga@nilupul.org T: +044 1382 872020 W: www.nilupul.org W: www.mindfulnessdundee.co.uk W: www.headroom.nilupul.org www.facebook.com/nilupulfoundation

Research Objectives Karma Jiga and his colleagues at Nilupul Foundation’s research is aimed at establishing the feasibility of holding the courses in areas of socioeconomic depression, lowering high levels of attrition by those suffering from the effects of poverty, and developing mindfulness techniques specific to problems more commonly faced by those in these environments.

Detail Nilupul Centre, 51 Reform St, Dundee, DD1 1SL Scotland Bio Karma Jiga is trained in the Tibetan Buddhist Tradition and modern-day mindfulness. He is a former engineer, award-winning musician, composer, author, artisan, project manager and current CEO of Nilupul Foundation. His present-day research focus is to provide mental health solutions for those suffering the effects of poverty.

Funding • Scottish Government & Big Lottery Fund • Peoples Health Trust

References Grossman, P., Niemann, L., Schmidt, S., & Walach, H. (2004).

‘Mindfulness-based stress reduction and health benefits’.

A metaanalysis. Journal of Psychosomatic Research, 57(1), 35–43. https://doi.org/10.1016/S0022-3999(03)00573-7.

Goyal, M., Singh, S., Sibinga, E., Gould, N., RowlandSeymour, A., Sharma, R., et al. (2014). ‘Meditation programs for psychological stress and well-being: a systematic review and meta-analysis’. JAMA Internal Medicine, 29(6), 997–1003. https://doi.org/10.1016/j.biotechadv.2011.08.021.

Personal Response What is the main barrier to attendance and completion of mindfulness courses and do you have any ideas of how to get around them?

At present, the main barrier is cost for the less well off. Mindfulness is more the domain of the middle and more educated class. Even among those who complete a mindfulness course, the number who apply themselves and engage meaningfully in the practices between sessions is difficult to assess. Not everyone is willing to disclose how much or even if they have applied themselves, despite the importance of personal responsibility for individual mental health and wellbeing being emphasised within the course sessions. So reduced cost and inspirational delivery seem to me to be the way forward.

Collaborators • Dundee City Council • Dundee Community Health Team • Community Support Workers • Health & Social Care Integration specialists.

• General Practitioners (GP’s)

www.researchoutreach.org

119

COMMUNICATION

New brain research sparks excitement at Neuroscience 2018 Neuroscience 2018, the annual meeting of the Society for Neuroscience (SfN), is the world’s largest source of emerging news about brain science and health. SfN welcomed over 30,000 scientists from across the globe to deliberate, debate and discuss new research. The Research Outreach team share their impressions of the conference.

I

nside the conference centre in San Diego the air was full of excitement and curiosity. Rigorous questioning, new ideas, debating around every corner.

Over 30,000 scientists from across the world, all different ages and stages of their careers, met with one common interest: their dedication to understanding the brain and the nervous system. The annual meeting for the Society for Neuroscience, Neuroscience 2018, was underway.

The conference was vast, spanning five days in November in one of the largest conference centres in the world. Scientists discussed all sorts of brain-related issues

most diseases. It works by hijacking a virus to carry genes into cells where it gets to work altering genes to treat or prevent a disease. The unhealthy gene might be replaced with a healthy copy of the gene, it may be turned off or a new gene may be added to help fight a disease. New findings presented here show the potential of gene therapy for treating incurable neurological disorders including Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s disease.

Patients with ALS have a poor prognosis.

It is a terminal disease leading to paralysis and eventually death. One of the most

was also on the agenda at Neuroscience 2018. Sleep disruptions are associated with many different disorders including anxiety, dementia and traumatic brain injury. These disruptions are sometimes seen as a side effect of brain disorders but new research presented here suggests sleep disruption can make brain disorders worse.

New research shows that sleep disruption could worsen Alzheimer’s disease.

The biological clock is controlled by a set of genes called clock genes. If the clock genes are not working correctly then this disrupts sleep. But fascinatingly

Over 30,000 scientists from across the world, met with one common interest: their dedication to understanding the brain and the nervous system. from diseases and disorders to healthy brain function and its impact on society to the ethics of neuroscience.

After immersing ourselves in five days of neuroscience we were buzzing at some of the new research. Check out what we discovered at Neuroscience 2018.

GENE THERAPY Let’s start off in the exhibition hall.

It was teeming with excitement as thousands of researchers presented posters and discussed their findings.

Gene therapy is particularly intriguing – it essentially allows researchers to edit genes. It is a relatively new concept that is still in the experimental phase for

120

www.researchoutreach.org

well understood causes of ALS is a mutation in the SOD1 gene. Scientists have used gene therapy to carry a small molecule into cells to prevent SOD1 from being made. Using just a single injection in the most severe ALS mouse model, the researchers were able to show it was safe and effective at reducing SOD1.

These animal studies are essential for insuring their safety and efficacy in ALS patients. This research is really exciting as it presents brand new steps towards being able to prevent and treat disorders that currently have no cure.

SLEEP Getting a good night’s sleep was essential for five days of neuroscience. And sleep

these genes also have a role to play in Alzheimer’s. Researchers have shown that disruption of the clock genes can cause increased damage to neurons and increased amyloid plaques, misfolded proteins, adding to the progression of Alzheimer’s disease. Another research group showed that anxiety is increased in sleep deprived people and that deep slow-wave sleep is needed to calm overactive brain regions. This new work highlights that sleep is a priority!

PROSTHETICS And then there’s the areas of research where sci-fi becomes reality! Researchers at Neuroscience 2018 explained how artificially connecting neurons can be

References

©Society for Neuroscience. All rights reserved. Photo by Joe Shymanski.

Neuroscience 2018 website: www.sfn.org/Meetings/ Neuroscience-2018

The bustling conference hall at Neuroscience 2018.

used to physically control the body incredibly useful research for people with disabilities and prosthetics.

Current prosthetics are limiting for amputees as they have no sense of touch or control over the prosthesis. To address this problem scientists developed a new prosthetic hand that communicates to the nervous system through implanted electrodes. It restores a sense of touch by stimulating sensory neurons in the residual limb with fine wires implanted inside the neurons. Sensors in the prosthetic hand deliver stimulation pulses to the sensory neurons.

The Neural Enabled Prosthetic Hand (NEPH) provides amputees with sensations and better control of the prosthesis. The research announced at Neuroscience 2018 marks the first time a person has been fitted with a NEPH outside the laboratory. This provides researchers with a much greater understanding of how the brain translates

intentions into actions, enhancing the possibilities of brain–machine interactions.

Research into new technologies such as new prosthetics often sparks conversation around social implications.

One research group was looking into how media coverage on visual prostheses affects visually impaired individuals’ feelings on prosthetics. A common theme from the research was the potential risks of the treatment and whether it fully restores vision. These conversations are vital to help inform the next stages of their project.

This is just a snapshot of the incredible range of research presented at Neuroscience 2018. The size and scale of the conference demonstrates just how many people are dedicated to understanding the brain. It’s an exciting time for neuroscience with evolving technologies allowing innovative and potentially game-changing advances to be made in the field.

Abstracts from SfN website: www.sfn.org • R. Jung, S. S. Kuntaegowdanahalli, A. K. Thota, A. E. Pena, K. W. Horch, J. Patrick, J. J. Abbas Neural-enabled prosthetic hand system to restore sensation in upper-limb amputees. Program No. 404.10. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online • B. V. Lananna, C. J. Nadarajah, C. A. Mckee, M. R. Cedeno, P. Griffin, J. Dimitry, E. S. Musiek The astrocytic circadian clock gates neuroinflammation and neuronal health through regulation of Alzheimer’s disease biomarker Chi3l1 (YKL-40). Program No. 267.11. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

• J. L. Lanciego, A. J. Rico, I. G. Dopeso-Reyes, D. Marin-Ramos, E. Roda, A. I. Rodriguez-Perez, J. L. Labandeira-Garcia, D. Sucunza Glucocerebrosidase gene therapy induces alpha-synuclein clearance and stops disease progression. Program No. 292.01. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018.

Online.

• J. Patel, E. Hildt, K. L. Laas The ethical implications of media coverage on visual prostheses in the words of visually impaired individuals. Program No. 028.02SU. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

• E. B. Simon, M. P. Walker Under slept and Overanxious: The neural correlates of sleep-loss induced anxiety in the human brain. Program No. 192.11. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018.

Online • G. M. Thomsen, S. B. Likhite, S. Corcoran, A. Kaspar, K. Foust, L. Braun, K. C. Meyer, B. K. Kaspar Intrathecal AAV9-SOD1-shRNA administration for amyotrophic lateral sclerosis. Program No. 208.16. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

www.researchoutreach.org

121

COMMUNICATION

Science in brewing People have been brewing beer for thousands of years; taking advantage of the metabolism of a tiny fungus (yeast) to create that ever-popular social lubricant from grains and fruits. Today, it’s estimated that the world consumes a staggering 100 billion litres of beer each year. Here, we take a closer look at some intoxicating facts behind the amazing science of those sweet amber suds.

G

rains, water, hops and yeast are the four essential ingredients needed to make beer. Grains provide the all-important sugars for the fermentation process. Hops – containing acids, tannins and oils – are added for aroma and bitterness, and also help to preserve the beer. The largest ingredient is water (making up 85–95% of even the strongest beers) and affects the flavour, making a beer ‘local’.

A SOBERING THOUGHT Without yeast, there’s no beer. The yeast is where the magic happens. French chemist Louis Pasteur was the first to demonstrate that fermented beverages result from the action of living yeast transforming

alcohol as lager, giving its distinctive sweet and fruity flavour.

BREWING SCIENCE The four basic steps of brewing are malting, mashing, boiling and fermenting.

Malt is a grain prepared for brewing by malting (unsurprisingly). Malted barley is most commonly used, but wheat, corn, fruit and even rice are good alternatives.

It’s the malt that provides the yeast with the sugar for the fermentation process and thus determines how strong the beer is.

MASHING AND BOILING The brewing then kicks off, by soaking then heating the grains. A process called mashing. The grains absorb

Yeast transforms sugars into alcohol ... from the yeast’s point of view, alcohol is a waste product. glucose into ethanol. Realising that this occurs in the absence of oxygen, he called it ‘respiration without air.’

ALE VERSUS LAGER Two types of yeast produce different drinks: ales and lagers. The yeast used to brew lager is Saccharomyces carlsbergensis (isolated at Copenhagen’s Carlsberg brewery). Ales use Saccharomyces cerevisiae (‘sugar fungus ale’). But there are other differences. The name lager (from the German lagern: to store) hints as to its method of brewing.

Lagers ferment slowly, from the bottom up and at low temperatures, giving them their crisp flavour. Ales ferment quickly from the top down and are brewed in a warm environment. This type of yeast doesn’t turn quite so many sugars into

122

www.researchoutreach.org

water. Soluble sugars and starches are released. Important enzymes also get to work during this stage - converting the starches into smaller, fermentable sugars.

Temperatures are carefully controlled to optimise enzyme activity. After mashing, comes rinsing (or sparging), to extract the sugars. Grains are separated from the water by pouring through a sieve.

The grains are then discarded, and sugars boiled. As the water evaporates, the sugar concentration increases. Next, hops are added. They’re a bit like the spice of beer, giving that characteristic flavour.

FANTASTIC FERMENTATION Once cooled (high temperatures

will kill any yeast), the mixture is now ready to start fermenting. The chemical process of fermentation is where the yeast converts the unfermented beer (called wort) into beer. It transforms the sugars into alcohol. From the yeast’s point of view, alcohol is a waste product.

Un-‘beer’ -lievable? As yeast continues to grow and metabolise sugar, the accumulation of alcohol becomes toxic and eventually kills the cells. Most yeasts can tolerate an alcohol concentration of 10–15%, hence the alcohol content of beers (and wines) is typically in this concentration range. To get the higher alcohol concentrations associated with spirits, distillation is required. Yeast also produces carbon dioxide, giving that lovely fizz. Fermentation lasts from a few days to a week. For stronger beers or lagers, it’s longer, up to months. Finally, it’s ready to be bottled, kegged or served!

Now that we’re not so new to brew, let’s raise a glass and salute this fabulous brewing science that leaves us feeling tipsy. Cheers!

Rachel Perrin, PhD, is a science communication writer based in Bristol, UK.

Social Media for Scientists RSM was born out of multiple conversations with researchers who see a real benefit in connecting with a broad audience over an ongoing basis. Social Media can now be considered one of the most prominent and important engagement tools of the modern era. We help you get the ball rolling and can even provide long term Social Media Management support.

Start your Social Media journey now: www.researchsocialmedia.com

Partnership enquiries: simon@researchoutreach.org Careers and guest contributions: emma@researchoutreach.org www.researchoutreach.org