EMJ Innovations 7.1 2023

Editor’s Pick

A 3D-Printed Ultrasound Task Trainer for the Practice of Hip Joint Injections

Nassir Marrouche discusses innovation in cardiovascular medicine Interview

Editorial Board

Editor-in-Chief

Prof Mike Bewick iQ4U Consultants, UK

Editorial Board

Dr Olusola Michael Adeleke King's College London, UK

Prof Dolores Cahill University College Dublin, Ireland

Dr Nick Guldemond Erasmus University Rotterdam, the Netherlands

Prof Christian Jürgens BG Hospital Hamburg, Germany

Dr Vandita Kakkar University Institute of Pharmaceutical Sciences, India

Dr Kinan Muhammed University of Oxford, UK

Maj Dr Hannah Sophia Fujitsu Research of Europe, UK

Dr Noedir Stolf University of Sao Paulo Medical School, Brazil

Dr Axel Sylvan myrecovery.ai, UK

Dr Rachel Thomas Priory Hospital, UK

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EMJ is an online only, peer-reviewed, open access general journal, targeted towards readers in the medical sciences. We aim to make all our articles accessible to readers from any medical discipline.

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This Publication

ISSN 2513-8634

EMJ Innovations is published once a year. For subscription details please visit: www.emjreviews.com

All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. EMJ is completely independent of the review event (WHS 2022 and GIANT Health 2022) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever.

Front cover and contents photograph: Berlin,Germany, home of the WHS 2022 © Katja Xenikis / stock.adobe.com

Welcome letter

Editor

Evgenia Koutsouki

Editorial Manager

Anaya Malik

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Spencer Gore

Dear Readers,

Evgenia Koutsouki Editor

Welcome to the 2023 issue of EMJ Innovations, bringing you key highlights from technology in healthcare and covering congresses and key topics in the field. Despite 2022 being dominated by the emergence of the Omicron variant of severe acute respiratory syndrome coronavirus 2, the leaps of progress in healthcare have been nothing short of impressive. These range from the use of artificial intelligence for the grading and diagnosis of prostate cancer to the development of a deep learning model to predict the risk of developing lung cancer from a CT scan.

In December, the EMJ team attended the Global Innovation and New Technology (GIANT) Health Event 2022, which took place in London, UK, and brought together experts in health technology aiming to improve the health and wellbeing of people worldwide, through the support of health-tech entrepreneurs and the promotion of healthcare innovation. You will be able to get a taste of what was presented in our congress review section.

One of the highlights of this issue is our interview with Nassir Marrouche, whose research aims to optimise prediction, prevention, and outcomes for cardiovascular disease through digital health solutions. In addition, a feature on ways for addressing global cancer care inequities examines how using community-engaged research approaches can be used for this purpose. Finally, our Editor’s Pick discusses a novel approach to training clinicians for hip joint injections, by using a 3D-printed ultrasound task trainer.

I would like to take this opportunity to thank our authors, peer reviewers, and Editorial Board for their invaluable contributions to this issue. The EMJ team are looking ahead to 2023 as an exciting year full of potential for innovation and progress. Enjoy reading EMJ Innovations!

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Foreword

Dear Colleagues,

I have great pleasure in welcoming you to the current issue of EMJ Innovations. Following on from a highly successful World Health Summit, which took place in October 2022, and the Global Innovation and New Technology (GIANT) Health Event 2022 Future Hospital Show and UK National Integrated Care Systems (ICS) Congress 2022 in December, we present some exciting research and news from both gatherings, as well as the current submissions to the journal.

As healthcare becomes more and more challenging to deliver comprehensively, even in the developed world, innovation has never been so important. Recovering from a pandemic is proving to be a long road, with both predictable and unforeseen sequelae. Instability and system failures inevitably lead to some degree of ‘destructive innovation’, and offers opportunities to technologists, as well as clinicians, in service redesign. Never has this been more necessary than in the current challenging economic and political climate across the world.

Our contributors offer examples of hope in this discordant world. The discovery of incretin

systems reported in ‘Harnessing the Incretin System with Multi-Agonists’ gives us hope on developing biological treatments for metabolic disease and obesity. Rising to the economic challenge, it is heartening to read of both improved patient access and reduced costs in ‘CT Colonography Versus Optical Colonoscopy: Cost-Effectiveness in Colorectal Cancer Screening’.

My Editor’s pick for this publication is ‘A 3D-Printed Ultrasound Task Trainer for the Practice of Hip Joint Injections’, a truly transformative tool in educating the clinicians of the future.

As we experience shortages of clinical personnel in our health systems, it is important that we see innovation in education, as well as in the delivery of healthcare. The international workforce ‘crisis’ in health and social care requires a paradigm shift in education, and streamlining rapid upskilling, as well as increasing the numbers of new entrants into our health systems.

I hope you enjoy the current issue of EMJ Innovations, and wish you a stimulating and innovative 2023.

Professor Mike Bewick Director and Founder of iQ4U Consultants, London, UK

WHS 2022

Insights from the World Health Summit (WHS) 2022

Location: Berlin, Germany, and online

Date: 16th–18th October 2022

Citation: EMJ Innov. 2023;7[1]:8-12. DOI/10.33590/emjinnov10302890. https://doi.org/10.33590/emjinnov/10302890.

FIRSTS were a theme at the annual World Health Summit (WHS) 2022 International Conference, which welcomed over 60,000 participants, attending both online and in-person in Berlin, Germany. For the very first time, the WHS was delivered in partnership with the World Health Organization (WHO), and the inaugural Virchow Prize for Global Health, an international award honouring outstanding achievements in addressing global health challenges, was awarded.

At over 775 years of age, Berlin is famous not only for historical landmarks such as the Brandenburg Gate, Berlin Wall, and several UNESCO World Heritage Sites, but also food, music, science, and a diverse culture. During the Summit’s opening ceremony, several speakers attested to the leadership that Germany has shown in research and in strengthening the global health architecture. Additionally, reflecting the musical background of the city, the opening ceremony also included a musical interlude by two musicians trained in Berlin and Hanover.

The conference took place across 3 days and saw over 400 speakers from 100 nations. The Summit was attended by a diverse group of key leaders and professionals across different sectors, who discussed the developments and challenges that 2022 held for global health, as well as how to take healthcare to the next level on a global scale.

The Summit was chaired by Axel Pries, President of the WHS and Dean of Charité – Universitätsmedizin Berlin, Germany, and Catharina Boehme, Chef de Cabinet at the WHO, Geneva, Switzerland, and moderated by Spring Gombe, Principal for Policy and Advocacy, Market Access Africa, Germany, and Kenya. Pries was proud to share the partnership with the WHO, stating that the initiative aimed “to bring together the eminent visibility, power, and relevance of the WHO with the dynamic team of the WHS.” Boehme reiterated Pries' sentiments, stating that the “WHO is honoured to be a co-organiser.” Boehme also discussed the challenge of the pandemic, but highlighted the lesson learned: “We can take on global threats, only together,”

“Pries was proud to share the partnership with the WHO, stating that the initiative aimed “to bring together the eminent visibility, power, and relevance of the WHO with the dynamic team of the WHS."”

and that partnership is essential in the face of several ongoing crises including war, disease, and climate change. Boehme also praised the host nation, stating: “Germany has shown outstanding leadership in its commitment to multilateralism, strengthening the global health architecture, and fostering a world that works together to solve pressing problems.” Boehme then introduced and welcomed Olaf Scholz, Federal Chancellor, Germany, to open the WHS 2022.

Scholz spoke of Germany’s history in research, highlighting the recent award of the 2022 Nobel Prize in Physiology or Medicine to Svante Pääbo for work regarding human evolution. The Federal Chancellor discussed how Pääbo has been engaged in research and education in Germany since the 1990s, reflecting the “quality of Germany as a research hub.” Scholz detailed the merits of basic science, stating that “basic research matters” and how, without this research, tackling global health problems would be far more challenging; highlighting the link between Pääbo’s work and the chromosome variant that increases the risk for severe COVID-19 infection, and how other basic science research has led to rapid development of vaccines during the COVID-19 pandemic. Scholz also discussed how Pääbo’s work shows the importance of co-operation across national boundaries and sectors, highlighting how the WHS is a forum for such collaboration, which will be necessary to help achieve earlier detection and prevention of future health crises alongside digital innovation.

Looking towards the future, Scholz reflected on how we can impact change by drawing on conclusions from the past, and appealed for everyone to join in “drawing the right conclusions from the COVID-19 pandemic”: that preparedness matters. By acting on lessons learned, networking, collaboration, and dedicated research, it is hoped that improving preparation for future pandemics can be achieved. Scholz concluded by wishing everyone a “successful and insightful Health Summit 2022.”

Tedros Adhanom Ghebreyesus, Director-General of the WHO, spotlighted the theme of the conference in taking global health to a new level, detailing the three key requirements for this to be achieved: a global agreement based on a shared vision; a coherent and inclusive global architecture; and a fresh global approach that prioritises the promotion of health and prevention of disease. Ghebreyesus discussed that global health is under threat and must be defended, and shared how the conference provided an opportunity to forge the path ahead together, reinforcing the notion that co-operation, collaboration, and innovation will be needed to achieve this. Ghebreyesus concluded with the powerful statement that health is a “fundamental human right; it is not a luxury.”

Further adding to the themes of progression and preparedness, Ilona Kickbusch, Graduate Institute of International and Development Studies, Geneva, Switzerland, led a discussion with Inger Ashing, Chief Executive Officer of Save the Children International, London, UK, and Helga

"Scholz reflected on how we can impact change by drawing on conclusions from the past, and appealed for everyone to join in “drawing the right conclusions from the COVID-19 pandemic”: that preparedness matters."

Mutasingwa, Youth Representative and Medical Doctor, Global Youth Mobilization, Tanzania, Africa, on the topic of the future generation and taking global health to the next level. Ashing discussed how the impact of several crises, including the global pandemic, climate change, and cost of living crisis, has either halted or worsened decades of progress made in global child health. Ashing added that investment in early warning and anticipatory action to prevent crises before they happen is required, as well as investment in building resilient systems and supporting health and education systems. An impactful statement from children and young people involved with Save the Children International was delivered by Ashing, where these young people ask that policy makers look beyond national interest, work in partnerships, draw inspiration from innovation, take responsibility, and act with urgency. Mutasingwa added that the voices of young people need to be listened to and hopes that moving forward young people can be meaningfully engaged in healthcare systems.

Gombe discussed networks and collaboration in global health, and highlighted a quote from Macky Sall, President of Senegal and Chairperson of the African Union, calling for a new global health order that looks to “overcome the reluctance and deconstruct the narratives that persist

in confining Africa to the margins of decision-making circles.” In terms of taking global health to the next level, the needs and voices of all continents should be heard and considered in building a resilient and fit for purpose global health architecture. Sall reiterated several other leaders in their message, highlighting that the world must be better prepared for future health crises and work collaboratively to achieve the goals of improving global health.

Additionally, António Guterres, Secretary-General, United Nations (UN), New York City, New York, USA, highlighted how the pandemic set back efforts in implementing the 2030 sustainable development goals and revealed a lack of preparedness for managing global health crises. Guterres stated that, moving forward, recalibration of multilateralism and employment of global collaboration is needed.

With a focus on equity, Mark Suzman, Chief Executive Officer of the Bill & Melinda Gates Foundation, Seattle, Washington, USA, spoke passionately on the sustainable development goals. Suzman noted that to regain the progress lost to the COVID-19 pandemic, support for innovation and collaboration is necessary. Suzman further discussed polio eradication, which “remains a constant threat to children’s health” in endemic regions of Afghanistan and Pakistan. Suzman detailed the ongoing

work into polio eradication, the status of global polio infections, and announced the Bill & Melinda Gates Foundation pledge to the global polio eradication initiative. Suzman then introduced Bill Gates, Co-founder of the Bill & Melinda Gates Foundation, who appeared via video message. Gates gave thanks to Germany for their “strong support of polio eradication efforts” and highlighted that the threat can be ended if we work together. Gates commented that polio eradication was close, concluding with: “Now it’s up to all of us to get the job done.”

This year saw the inaugural Virchow Prize for Global Health, which was awarded in-person to John Nkengasong, U.S. Global AIDS Coordinator and Special Representative for Global Health Diplomacy, U.S. Department of State, USA, for their outstanding work on addressing complex global health challenges, on 15th October 2022. Initiator of the prize, Detlev Ganten, Virchow Foundation for Global Health, Berlin, Germany, spoke with the first laureate of the prize to understand what receipt of the award meant. Nkengasong commented that they were honoured, and felt that the history of Virchow speaks to how a multidimensional approach to solving global health problems should be undertaken. During their discussion, Nkengasong poignantly concluded that global health is about everyone, and the importance that all voices should be heard.

Core topics covered over the course of the Summit were architecture for pandemic preparedness, climate change and planetary health, digital transformation for health, food systems and health, global health for peace, health systems resilience and equity, and investment for health and wellbeing. The first day of the conference saw a multitude of panel discussions, workshops, and global health insight sessions covering a variety of topics from Europe’s Beating Cancer Plan, outsmarting pandemics, and planetary health to global efforts to end HIV and AIDS, and the European Global Health and One Health Strategy. The second day saw a focus on pandemic preparedness, global health architecture, equity, and sustainability; and the final day featured sessions on technology and digital innovation, antimicrobial resistance, and food security.

Next year’s WHS will take place in Berlin, Germany, from 15th–17th October 2023. Until then, please enjoy our feature articles from this year’s conference, which focus on the innovative topics of achieving a global health data space and using digital tools to transform disease prevention, which will be key in ensuring global health is taken to a new level by promoting the paradigm shift to disease prevention and health promotion needed, as highlighted by Ghebreyesus.

WHS 2022

The Digital Transformation of Prevention

Authors: Anaya Malik, Editorial Manager

Citation: EMJ Innov. 2023;7[1]:13-15. DOI/10.33590/emjinnov/10308488. https://doi.org/ 10.33590/emjinnov/10308488.

RAPID digital transformation as a result of the COVID-19 pandemic has led to the increased use of telehealth, although it has been long-established, dating back to the use of television and radio for patient care delivery. More recently, healthcare institutions have been compelled to advance greatly in digital interactions, using them for improved digital engagement with patients and communities and for monitoring patient health. Many patient-facing digital health products assist patients to improve outcomes through behaviour and lifestyle changes, either on their own or in conjunction with existing treatments. In a session titled ‘The Digital Transformation of Prevention’ at the World Health Summit 2022, which was opened in Berlin, Germany, held both in person and virtually, experts in digital health and innovation came together to discuss the shift of powerful digital transformation towards improving prevention and supporting wellbeing. This means using digital tools not only for monitoring patient health but also for predictive purposes.

The meeting was chaired by Heyo Kroemer, CEO of Charité –Universitätsmedizin Berlin, Germany, who endorsed the combination of prevention and digital health to strengthen prevention and support wellbeing, support population-level disease prevention, and improve broader preventative health and lifestyle change efforts. The speakers discussed how to make prevention more effective using digital tools and how such change can be initiated. Kroemer suggested the need for a trust architecture, a framework that enables trusted data to flow through a service-oriented system, so that patient data is held safely and securely.

The Why and How of Digital Prevention

Molly Biwer, Chair of Brand Strategy at the Mayo Clinic, Rochester, Minnesota, USA, presented ‘Bold. Forward.’, which is a new venture from the Mayo

Clinic that underscores how “the field should spark revolutionary advances in our ability to cure, connect, and transform healthcare.” Biwer described how the Mayo Clinic continues to transform healthcare by leveraging data technology and artificial innovation expertise to change how care is provided. The purpose of their work is to “create a world where the best possible care, which isn’t always in the hospital, is available to everyone, everywhere.” The Mayo Clinic Platform is another technology venture from the institution with the aim to gather medical records from everybody in the world to start to predict diseases and conditions before they occur and enable the work of clinicians to cure diseases.

Shobana Kamineni, Executive Vice Chairperson of Apollo Hospitals Enterprise Ltd., New Delhi, India, joined the session virtually, attributing this to the benefits of digital access. She began by addressing the shortage of healthcare workers, which is one of the biggest

challenges faced by those working in healthcare, whether it is in the curative or preventative field. There is a projected global shortage of 18 million healthcare workers by 2030,1 a staggering statistic emphasising the opportunity for digital healthcare to optimise processes and to help make individuals more productive. Kamineni’s secondary reasoning for the benefits of digital prevention includes remote access to healthcare, which has already removed many of the boundaries impacting patient access to healthcare. In many ways, COVID-19 has accelerated or exacerbated the way healthcare is accessed. In some countries across the world, we are seeing a K-shaped recovery of people who cannot afford proper healthcare, for example, the 40 million people in India who live below the poverty line. Kamineni explained the need to combine digital care with prevention as we are otherwise at risk of facing an increase in mortality and morbidity from noncommunicable diseases. The World Economic Forum has stated that we will be spending almost 47 trillion USD on prevention of chronic diseases in the next 20 years, leading Kamineni to urge big organisations with large data to join forces in a case for digital prevention for the world.

“The field should spark revolutionary advances in our ability to cure, connect, and transform healthcare.”

Tim Ferris, the inaugural National Director of Transformation at NHS England, London, UK, was the next speaker to be introduced. Kroemer commended NHS England for implementing efficient systems of information and surveying during the pandemic, which other European countries tried to emulate in the midst of the crisis. Ferris explained that the infrastructure put in place is a lasting benefit from COVID-19 because the data flow within the NHS is significantly better than before the pandemic. COVID-19 also demonstrated that when we deploy digital solutions to providers, they can be deployed at pace, and the opportunity to use adaptive design techniques has allowed for practices to be fixed after trialling. COVID-19 has taught that digital delivery solutions can speed up dissemination of information but also have the potential to increase health inequalities due to the disparate uptake by some populations. Digital transformation may be the solution to the challenge, since information collection enables you to build more targeted and more specific solutions for populations that are not getting the benefit of a new programme or roll-out. During the pandemic, Ferris explained, this was an important learning point for the NHS as the organisation constantly had to hyper-segment different populations that were not getting adequate vaccination coverage with personalised approaches. Ferris vouched that digitalisation of prevention is key in tackling health inequalities, and a personalised, adaptive approach is the optimal strategy for disease prevention.

Ran Balicer, Chief Innovation Officer at Clalit Health Services, Tel Aviv, Israel, was invited to introduce the digital health infrastructure in Israel. Israel has a health system comprising four large integrated care providers that usually take lifelong responsibility over the patients and rely on national capitation budgets. Years of investment in digital health infrastructure and harnessing digital innovation for proactive population health visibly paid off during the pandemic. This type of universal system makes longterm prevention a priority not only clinically for the individual but financially for the payers. This has been a key driver for the system’s involvement in preventative health and in using digital transformation to drive preventative medicine. The country has over 20 years of individual level integrated data health, which enables innovative approaches of population health and proactive prevention. Balicer gave an example of how Clalit Health Services made predictions on individuals they did not have data for during the pandemic. Israeli healthcare services wanted to introduce a predictive, proactive approach to highest risk patients for severe COVID-19 at a time when there were no cases of COVID-19. They took an old model for predicting influenza complications and data that came from China and Italy on the relative mortality between different age groups. The model was statistically ‘nudged’ to fit to the new and rising situation. Based on this, they approached a significant number of individuals, advising that new data suggest they would be at highest risk for COVID-19 and to stay at home and receive online care. This model was

References

1. World Health Organisation (WHO). Addressing the 18 million health

assessed later and was found to be accurate within 7% of the population.

Elisabeth Staudinger, a Member of the Managing Board at Siemens Healthineers AG, Erlangen, Germany, shared the mission of the organisation; they are a company that enables care and that wants to reach patients regardless of where they are. They work to leverage possibilities to pioneer breakthroughs in healthcare and maintain a strong focus on diagnostics. Digitalisation of prevention is an ideal approach to healthcare if it means an individual never becomes ill, and healthcare providers are effective in managing the health of a population. Companies such as Siemens Healthineers are vital in picking things up as early as possible, playing to their key strengths in diagnostics, and optimising their vast collection of data to centre information around the individual.

"Digitalisation of prevention is key in tackling health inequalities."

The opportunities for digital transformation to be a central enabler for prevention are vast and have the support of key influencers in healthcare. Prevention as a way to reduce the incidence of disease within the population is key, and discussions such as these allow us to consider whether the combination of prevention and digital transformation is the key approach to solving some crises many of our healthcare systems are facing. ●

worker shortfall - 35 concrete actions and 6 key messages. Available at: https://www.who. int/news/item/28-05-2019-

addressing-the-18-million-healthworker-shortfall-35-concreteactions-and-6-key-messages. Last accessed: 19 January 2023.

World Health Summit 2022: How to Achieve a Global Health Data Space

Authors: Robin Stannard, Editorial Coordinator

Citation:

EMJ Innov. 2023;7[1]:16-18. DOI/10.33590/emjinnov/10304918. https://doi.org/10.33590/emjinnov/10304918.

IN A ROUNDTABLE discussion at the World Health Summit (WHS) 2022, located in Berlin, Germany, and also available digitally, experts in the field of health data debated barriers, opportunities, and next steps for achieving a global health data space. Key concepts such as anonymisation, infrastructure, data quality, and data standardisation were analysed by the expert representatives from pioneering international data projects, including the World Health Organization (WHO), EBRAINS, and ERA-NET NEURON.

INTRODUCTION

The expert debate was chaired by Petra Ritter, Berlin Institute of Health, and Bernstein Centre for Computational Neuroscience Berlin, Germany, who opened the session by introducing the key aspects of human health data and explaining what a global health space might mean.

Health data are sensitive, personal data, and can present a risk to the patient if they become public. Brain scans, for instance, can provide insight into an individual’s demographic, personality, intelligence level, attention span, and even their degree of satisfaction with their own life. This all represents information that can easily be abused or monetised and, therefore, needs to be protected. Protection can come in the form of anonymisation, when all unique individual features are removed from patient data, or pseudonymisation, where names and birthdates are removed or replaced. However, neither system is perfect, Ritter highlighted, as anonymisation removes information relevant for precision medicine and personalised therapy research. The biometric information remaining in pseudonymisation can also allow for potential re-identification.

WHAT VALUE DOES A GLOBAL HEALTH DATA SPACE PROVIDE?

Paweł Świeboda, Chief Executive Officer of EBRAINS AISBL and Director General of the Human Brain Project, broke down the ‘tip of the iceberg’ problem to explain to the audience why a global health data space is needed and the value it could provide. Currently, only a fraction of usable health data is being put to proper use. For the primary data user, the proper use of data means enhancing the quality of processes, health service outcomes, and continuity of care for patients. For the secondary data user, this means building a knowledge base and improving research effectiveness in academic institutions and industry.

The value of a global health data space has also been emphasised by the recent shift in ideology towards value and outcome-based health care, which Świeboda described as “the single most powerful driver” behind efforts to push a global health data space. Increased representativeness of data is an additional horizontal benefit that would be provided by a global health data space. Global cohorts ensure that diverse populations can benefit from

"Currently, only a fraction of usable health data is being put to proper use."

targeted treatments. Świeboda took the time to emphasise the need for equal representation, highlighting current disproportionately high levels of Western patient cohorts in Alzheimer’s disease research.

A further key issue is the current reproducibility crisis in medical research, fragmentation of data sets with uneven quality, different governance models and policies for reuse, and sharing all impact to enable researchers to repeat and reproduce findings. Świeboda emphasised that a global space for health data sharing could aid in addressing this crisis.

CURRENT BARRIERS TO A GLOBAL HEALTH DATA SPACE

However, before reaching this goal of a global health data space, multiple barriers currently stand in the way. During the roundtable discussion, each of the experts shared and explained challenges that their organisations had encountered. Świeboda introduced some key current challenges which were explored in the Towards European Health Data Space (TEHDAS) report, published in February 2022. The report

listed key barriers to data sharing within Europe, such as different interpretations of key terms, including anonymisation and secondary use, and different understandings of General Data Protection Regulation obligations.

Mehdi Snène, Chief Executive Officer of the International Digital Health and AI Research Collaborative (I-DAIR), works on building research networks and growing health research in the Global South. Snène highlighted that infrastructure still represents a significant barrier for global health data sharing. Sharing high-quality data requires that researchers have access to equipment for data collection, software for processing statistics and analysing data, and hardware for securely storing data. Snène highlighted that this is an ongoing challenge in the Global South, which needs addressing to allow the development of South-South and SouthNorth collaborative consortia for data sharing, education, and training.

Ritter emphasised that an overarching challenge for protecting health data arises from varying legal definitions between regions. Definitions of anonymisation and pseudonymisation vary across different jurisdictions. Ethical and mobile frameworks that provide the basis for legislation surrounding health data protection and sharing also vary between regions. This creates challenges with data interoperability, and can reduce the security of data sharing.

NEXT STEPS TOWARDS GLOBAL DATA SHARING

The expert representatives from each organisation provided a detailed overview of how they were working towards tackling these challenges to increase the ease of global data sharing. Marlies Dorlöchter, Head of Division International Health Researcher, DLRPT, Germany, and Coordinator for ERA-NET NEURON on behalf of the German Federal Ministry of Education and Research, shared the two central pillars the ERA-NET NEURONS project uses, with a view to creating a joint global data space. Firstly, the funding programme of the organisation has stringent review steps, examining the soundness of statistical analysis and the quality of data, with data management plans mandatory in the projects it endorses. Secondly, capacity building and training is also required, with workshops, webinars, and data training for researchers participating in projects. In this way, the project can ensure the creation of high-quality data that is interoperable and shareable. Dorlöchter explained how they felt the depth of these requirements created excellence in the outcomes, with 1,133 peer reviewed publications arising from the 80 research projects funded by ERA-NET NEURONS.

Świeboda discussed the European Health Data Space, highlighting how this project has focused on innovation to address legal and infrastructure barriers. The European Commission (EC) project aims to clear the way to greater accessibility to health data, and to achieve this it has created new legislation that, instead of replacing the General Data Protection Regulation, will act on top of it to make data more freely available. Świeboda emphasised that this legislation is based on a core nexus to health data sharing, of patient trust versus accessibility. The bulk of the legislation created as part of the European Health Data Space has focused on creating greater trust in citizens to encourage them to share data.

EBRAINS is a research infrastructure, and part of the European Health Data Space. It is a collection of tools and services underpinned by computing and storage capacity. The infrastructure allows researchers access to fair, high-quality data, with both machineand human-readable metadata. The high quality of the data is ensured by curation from expert neuroscientists who monitor it. Access to data is restricted, and individuals requesting access must define the purpose of data use, ensuring high levels of protection and security.

Both Snène and Świeboda highlighted the importance of building human capacity and communities for their respective data sharing projects. Snène highlighted that for Global South nations where I-DAIRs is active, there is a need to tailor capacity development programmes to build knowledge in individuals and institutions. Świeboda similarly emphasised the importance of building collaborative communities in the EBRAINS project to enable trust, accessibility, and interoperability of shared data.

CONCLUSION

The roundtable discussion, which enabled key figures from international health data sharing organisations to share their experiences, revealed key themes. Challenges presented by the current lack of global health data sharing such as the ‘tip of the iceberg’ challenge and reproducibility crisis were highlighted, in addition to the current barriers including infrastructure, legislation, and human capacity that stand in the way of creating this space. However, the experts agreed on key immediate and efficacious steps, such as increasing data interoperability, developing global data quality frameworks, and writing legislation to build citizen trust, that could pave the way to a global health data space. ●

EMJ Podcasts

The EMJ Podcast aims to provoke conversations around the latest trends and innovations in healthcare, provide engaging and educational content for healthcare professionals, and hosts conversations with physician entrepreneur, Jonathan Sackier. Listen today

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GIANT Health 2022

Insights From The Global Innovation and New Technology (GIANT) Health Event 2022

Location: London, UK, and online

Date: 6th–7th December 2022

Citation: EMJ Innov. 2023;7[1]:20-22. DOI/10.33590/emjinnov/10305077. https://doi.org/10.33590/emjinnov/10305077.

The Global Innovation and New Technology (GIANT) Health Event 2022, which took place from 6th–7th December 2022 in London, UK, and virtually, brought together healthcare providers, investors, and health-tech experts. Showcasing lead health-tech from around the world, GIANT, which was set up in 2015, is centred on the entrepreneur, and aims to provide them with access to markets and expertise. With the goal of improving the health and wellbeing of people worldwide through the support of health-tech entrepreneurs and the promotion of healthcare innovation, the event allows people to join a rapidly expanding global community of healthcare professionals and businesses. Chief Executive Officer Barry Shrier, who founded the event, stated: “It is up to each of us, you and me, to take positive steps, to champion innovation in healthcare technology,

and to support healthcare tech entrepreneurs, and thus to enable the providers of healthcare to deliver better outcomes for less money.”

In their introduction to the event, Chairman Shafi Ahmed, Consultant Colorectal Surgeon at Barts Health NHS Trust, London, UK, raised the major challenges that are currently being faced by healthcare professionals, including the lack of workforce and the legacy of COVID-19, which has led to long waiting lists. Ahmed stressed the importance of community when trying to find solutions and overcome these issues. Through the largest community of health-tech innovators, GIANT supports everyone within or related to the healthcare industry to invent and adopt new health technologies with the mission to innovate, accelerate, and collaborate.

“It is up to each of us, you and me, to take positive steps, to champion innovation in healthcare technology, and to support healthcare tech entrepreneurs, and thus to enable the providers of healthcare to deliver better outcomes for less money.”

"Through the largest community of health-tech innovators, GIANT supports everyone within or related to the healthcare industry to invent and adopt new health technologies with the mission to innovate, accelerate, and collaborate."

The event took place in three conference areas, each hosting one show on both days of the congress.

On 6th December, this included the ‘Mental Health Tech Show', with the world’s leading innovators and providers in new technologies for the diagnosis and treatment of mental health conditions. This show included sessions on how digital mental health can provide support, a look at the relationship between mental health and tech, and investigating how evidence-based entertainment could shift the nation’s mental health, as well as a start-up showcase and panel discussion. The second show of the day, the ‘Digital Pharma Show’, included sessions on the relationship between pharmaceutical companies and the new surge in innovations in the tech world, blending science and technology to deliver a scalable digital solution that targets metabolic health through personalised nutrition and lifestyle management, and how healthcare can be transformed through artificial intelligence drug discovery. The final show, entitled the ‘Champions of Innovation Show’, covered subjects such as augmented and virtual reality in mental health therapy, the usage of bio data in wearables in prevention, and the usage of mental health tech; the most impactful innovations in undergraduate medical education and training; and unlocking innovation in the women’s health technology space.

On 7th December 2022, the ‘Future Hospital Show’ detailed a long-term programme of change that will ensure healthcare services are fit for the future, and high-quality care and better health

outcomes for patients and their families can be provided through every stage of life. This included sessions on the latest updates from applied nano detectors, the use of virtual reality in a paediatric hospital, surgical innovation, and sustainability and heat recapture in the hospital, among others. The ‘Integrated Care Show’ hosted the experts behind the dramatic changes and innovations in the UK health sector, and leaders of the UK’s new integrated care systems. This show included sessions on developing best practice through a long-term technology partnership, managing comorbidity, cross-system collaboration for the diagnosis of skin cancer, and a panel discussion on leveraging artificial intelligence and data driven technologies to deliver populationbased care. The final show of the day, entitled ‘Pitching to Investors’, gave start-ups a chance to pitch to investors on stage, and included successes and challenges of spinning out of academic research, the 'do’s and 'don’t's of fundraising start-ups, and the increase and importance of female health.

As stated by Barry Shrier, innovation is “patients, and doctors, and nurses, and others who see a way to create better healthcare products and services and have the determination to turn those into successful international business.”

With a community of nearly 200,000, GIANT continues to grow, with GIANT Health 2023 already in preparation with world-class speakers, the UK’s leading health-tech start-ups getting the opportunity to pitch to investors, immersive innovation presentations, and more. ●

Pioneering Patient Care: Clinical Networks and Digital Health Solutions

Authors: Darcy Richards, Editorial Assistant

Citation: EMJ Innov. 2023;7[1]:23-26. DOI/10.33590/emjinnov/10308172. https://doi.org/10.33590/emjinnov/10308172.

IMPROVING integrated healthcare across the country with the aid of digital innovation was a focus of the 9th annual Global Innovation and New Technology (GIANT) Health Event, which featured the UK National Integrated Care System (ICS) Congress, held on December 7th 2022 in London, UK. A session chaired by Debashish Das, St Bartholomew’s Hospital, Barts Health NHS Trust, London, UK, detailed the deployment of a virtual ward platform for patients awaiting elective cardiac surgery across seven cardiac surgery centres and one tertiary advanced cardiology centre in London. This session provided hope for the future of digital health solutions in healthcare.

IDENTIFYING THE PROBLEM

Alongside the immediate impact that the COVID-19 pandemic had on patients and healthcare systems, it also highlighted challenges with healthcare protocols. A significant residual impact is the backlog in waiting lists for elective surgical procedures. This, in turn, has resulted in increased wait times for patients, posing the risk of patient deterioration in the community. In addition, the disparity in equitable access to services was exacerbated by the pandemic.

Das and colleagues discussed the aftermath of the pandemic on elective cardiac surgery in London. Martin Yates, Cardiothoracic Surgeon at St Bartholomew’s Hospital, discussed how service provision to this cohort of patients was limited throughout the COVID-19 pandemic due to reduced capacity and limited intensive care beds. The session spotlighted that amongst the North and South London Cardiac Networks, post-pandemic increased wait times for elective cardiac surgery, plus the increasingly evident disparity in access, were a

cause for concern. This, coupled with the lack of touchpoints patients have whilst awaiting surgery, prompted the network to consider alternative digital health solutions to ensure safety by remotely monitoring patients. They also concluded that moving forward, access to services should be based on priority of clinical need, rather than geographical location.

THE SOLUTION

Virtual wards and remote digital monitoring provide a solution to this problem, enabling healthcare professionals to remotely monitor patients; increase the number of patient touchpoints; and provide a platform for giving patients information about their condition, upcoming procedures, or post-procedure advice.

Gary McCallister, Chief Technology Officer, NHS London, UK, discussed how clinical networks provide a roadway to working towards disease- or pathwayspecific service provision. McCallister further commented that, unlike electronic patient records, digital health

"Access to services should be based on priority of clinical need, rather than geographical location."

solutions such as virtual ward platforms are configurable, and can be tailored to specific conditions.

Whilst considering virtual ward platforms as an option to tackle the concerns regarding elective wait lists for cardiac surgery, McCallister highlighted that platforms used for remote monitoring need to be secure and open, with accessible data that can be used for crucial research.

Yates delivered an overview of the pioneering work that took place over the previous 18 months to procure and roll out a virtual ward platform for patients awaiting elective cardiac surgery in London. The procurement process involved reviewing digital monitoring tools to ascertain which platform would best serve patients and healthcare professionals. The Ortus iHealth virtual

ward platform, developed by Das, was selected and rolled out across each of the centres. This formulated a unified operating protocol, ensuring that all patients awaiting elective cardiac surgery could be safely monitored in an outpatient capacity, and importantly had equitable access to care.

WHAT ARE THE CONCERNS WHEN IMPLEMENTING VIRTUAL WARD PLATFORMS?

Yates highlighted concerns regarding usability for patients and the exclusion of certain subgroups within the patient cohort. To minimise this, work was done prior to rollout to ensure patients would be adequately supported in using the platform. The impact is reflected in the high activation rates and engagement the network has seen with the platform.

Workload is a vital consideration, given the difficulties experienced by many healthcare systems at present. Das commented: “A digital front door is a new front door for patients to come through,” and, as such, demand on a service will increase. Das spoke on the importance of complete buy-

in and strong clinical leadership as requirements for implementation of such systems, especially when it impacts the volume of work to staff. Cathy Walters, Transformation Lead, Heart, Lung and Critical Care Clinical Group, Guy’s & St Thomas’ NHS Foundation Trust, London, UK, discussed the impact of virtual ward platforms on staff workload, reflecting that this was the biggest challenge to plan for when strategising roll-out.

Walters further explained how one of the solutions to a potential uncontrolled influx of workload was to utilise a feature of the platform itself. By channelling patient responses and messages to come in on certain days of the week, healthcare professionals have been able to schedule time for ‘clinics’ dedicated to triaging and responding to messages and flags on the system. Yates added that they performed real-time analyses of the workload as it came in and, whilst it has added to the workload, it is anticipated that over time this will be reduced by streamlining other pathways further.

WHAT ARE THE BENEFITS OF VIRTUAL WARD PLATFORMS?

In addition to the obvious benefits, virtual ward platforms provide in terms of remote outpatient monitoring through input of vital sign recordings. These platforms offer a communication stream between patients and healthcare professionals that has not been available before, as historically, patients had limited contact with their secondary care team between decision for elective surgery and the surgery itself.

Yates highlighted how patients often experience difficulty in accessing the right person in the right team at the time they need to. Virtual ward platforms provide this line of communication, as patients can not only receive information from their healthcare professional, but can also send messages to ask for advice or express concerns. This ensures that the appropriate teams are aware when patients are deteriorating, and provides an opportunity to reprioritise surgery lists and intervene earlier, ultimately benefitting patients and improving outcomes. It also acts

as an interface for patients to be more informed about their condition, and offers reassurance that they can contact the appropriate team in a timely manner. Walters commented: “Patients are telling us that they really like being able to communicate with clinical teams in a way that they just haven’t been able to [before],” highlighting the positive effect of this open communication stream.

Since deployment, the platform has had a greater than 75% activation rate, showing that patients are engaging. Moreover, Yates discussed that through the input of vital signs and review of weekly symptom questionnaires patients receive, the virtual ward platform has successfully flagged and identified patients deteriorating in the community, who have subsequently had their surgery expedited. This spotlights an example of how effective outpatient monitoring can be with the right leadership, the right technology, and a collaborative approach to healthcare.

McCallister added that leveraging the benefits and lessons learned from the procurement process presented in the session could help with developing services for other pathway-specific conditions in different therapeutic areas. This poignant point leads into ways in which virtual ward platforms and other digital health solutions can be implemented to improve other aspects of healthcare.

FUTURE VISIONS

In the concluding question and answer segment, Yates detailed how, thus far, patients have been able to receive

treatment in their own trust; however, if the need arose, co-ordinating access across other trusts would be feasible with the new uniform operating protocols used by each centre in the network.

McCallister commented that improvement in sharing digital success stories within the organisation is needed. Given that the use of virtual wards could potentially provide solutions to hospital bed crises, because they could be used not only to facilitate pathway-specific illness coordination, but also safe early discharge, freeing up important inpatient hospital beds. A focus on sharing knowledge of effective technology and strategies may be a key factor in aiding overwhelmed hospitals, and could also improve patient experience.

To conclude, implementing digital health solutions, such as remote monitoring and virtual wards, can be successful in ensuring patient safety, appropriately prioritising care based on clinical need, and ensuring equitable access to healthcare services, if performed in the right setting with total buy-in, strong clinical leadership, and a robust platform that meets the need of both patients and healthcare providers. The setting to employ these strategies, as highlighted by Das and McCallister, is chronic, longterm conditions and early discharge. This can help to achieve earlier intervention for patients deteriorating in the community, provide a mechanism for sharing disease-specific information, preventing admissions, and prioritising patients on waiting lists based on clinical need. ●

"The use of virtual wards could potentially provide solutions to hospital bed crises, because they could be used not only to facilitate pathway-specific illness coordination, but also safe early discharge."

Interview

Nassir Marrouche

Tulane Research Innovation for Arrhythmia Discovery Center (TRIAD), Heart and Vascular Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA; Vice Chair of Innovation and Entrepreneurship, Deming Department of Medicine, Tulane Innovation Institute, Tulane University.

Citation: EMJ Innov. 2023;7[1]:27-32. DOI/10.33590/emjinnov/10308893. https://doi.org/10.33590/emjinnov/10308893.

EMJ is proud to present an interview with Nassir Marrouche, a globally renowned electrophysiologist and researcher currently directing a collaborative team of specialists to optimise prediction, prevention, and outcomes for cardiovascular disease (CVD) by pioneering research into digital health (DH) solutions.

Q1What factors influenced your decision to undertake a career in cardiology, and subsequently to sub-specialise in cardiac electrophysiology?

I have always been passionate and intrigued about electrophysiology and, with time, the more I learned about it, the more fascinating it became. It truly challenges physicians to figure out the best-case scenario that each patient could benefit the most from. With atrial fibrillation (AF), considering how common it is and how invalidating it can be for patients in some cases, I realised that we, as physicians, still have a long way to go, and have plenty of room to innovate and find optimal treatment strategies. Throughout my clinical experience, witnessing the positive impact patients were able to achieve, and listening to their success stories about how their lives changed,

and how they were able to resume the activities they loved after AF treatment has always been extremely rewarding and motivating.

Q2Having worked in multiple countries, including Germany, the USA, and UK, throughout your training and career, where did you gain some of the most valuable experiences for you to have achieved all that you have today?

I have had the chance to work in different academic and clinical environments, and for that I consider myself privileged. Each country had its own values, health system, and work ethics. Germany is a great place for academic development and that was where I met my mentor. The USA rightfully deserves its reputation of being the land of opportunities. Being exposed to all of that really pushed me to broaden my perspective, taught me to adapt quickly to change, and to grasp a good opportunity when I see one.

Q3What initially drove you to take part in clinical research alongside your role as a physician?

I have always known I wanted research to be a big part of my career.

Novelty, curiosity, and technological advancement are the drivers that keep changing the landscape of how we treat our patients. Clinical medicine will never be replaced, but research and innovation are the ultimate path that leads to improvement of care and outcomes. If it were not for research and for brave physicians who dared to ask questions that initially seemed too challenging, we would not have witnessed the breakthroughs that made modern medicine what it is today.

Q4Could you tell our audience more about Tulane Research Innovation for Arrhythmia Discoveries’ (TRIAD) aims, mission, and vision for the future? What does your role as Director involve?

TRIAD is a multi-disciplinary research department aiming to improve the management and outcomes for patients with AF by innovating the way we screen and monitor them, as well as by detecting the early signs of the disease to stop the progression of atrial fibrosis before it reaches ‘the point of no return’. We are launching a full-on DH department in collaboration with the School of Medicine at Tulane University, New Orleans, Louisiana, USA. We

envision a future where we can achieve prevention and early detection of CVDs through DH solutions, sophisticated cardiac imaging, genetic studies, and personalised treatment plans that are tailored to improve patients’ outcomes and quality of life.

As the director, I try to empower my team and inspire them to think outside of the box. Beyond supervising and mentoring, my role also involves pushing the limits to show that a broad range of opportunities to innovate lays ahead. I am also certainly here to learn, and to make sure that the conversation and energy throughout our team is constantly circulating and never one-sided.

Q5Collaborative research is a key component of the work undertaken at TRIAD. What are the aims of the multi-disciplinary team you work with to achieve TRIAD’s objectives, and how did you initiate this cross-departmental workforce? I think our cross-departmental workforce is truly one of our biggest strengths. We are a team of experts in a variety of fields ranging from artificial intelligence (AI) engineering, specialised

cardiac imaging, DH, and RNA sequencing, to electrophysiology and cardiovascular risk management. This multi-disciplinary approach broadens our perspective and makes us tackle questions from many different angles to try to come up with the most beneficial solutions for our patients.

Our aims can be divided into three core concepts: early detection, characterisation, and management of AF and fibrosis through cardiac imaging, and AI-based analyses; the optimisation of prediction, screening, monitoring, and remote management strategies of arrhythmias and additional cardiovascular comorbidities through DH tools; and challenging the status quo of current ablation techniques by discovering evidence-based innovations that are linked to better and safer outcomes.

Q6Earlier this year, you published data from the DECAAF II randomised clinical trial. What were the details of this trial and what were the key take-away messages from it?

The DECAAF II trial compared two ablation techniques in patients with persistent AF. All 843 patients underwent late gadolinium enhancement MRI pre-ablation to assess for baseline fibrosis. They were then randomised

to pulmonary vein isolation (PVI)-only versus PVI plus MRI-guided fibrosis ablation. The two arms were compared for arrhythmia recurrence and scar formation evaluated by late gadolinium enhancement MRI 90 days post-ablation. Monitoring for recurrence was done via a single lead digital ECG device, which patients had to use at least once daily. There was no significant difference in atrial arrhythmia recurrence between groups (fibrosis-guided ablation plus PVI-treated patients: 175 [43.0%] versus PVI-only treated patients: 188 [46.1%]; hazard ratio: 0.95 [95% confidence interval: 0.77–1.17]; p=0.63).

The trial pointed out many key-messages that we as electrophysiologists are yet to address, including that fibrosis lesions in the left atrium vary by their distribution, extent, and pathophysiology, which implies that not all lesions can be treated the same way; scar formation involves complex mechanisms that are unique to each ablation lesion, while lower baseline fibrosis <20% lesions were associated with higher quality scar formation; and MRI-guided fibrosis ablation was performed in a variety of centres by a multitude of operators. The approach was hence essentially operator dependant and not reproducible. Fibrosis coverage by ablation lesions ranged from <20% to >80%.

Q7What topics do you feel merit greater attention in your specialty and what direction would you like to see future research take?

Over the past few years, we have been witnessing great advancements in cardiac catheters development. I think it is also time to focus not only on how we ablate, but also where we ablate (i.e., on determining which ablation target points of the left atrium are predictors of better outcomes). With specialised cardiac imaging sequences, left atrial mapping techniques, and databases of pre- and post-ablation MRI images of the left atrium such as the DECAAF II database, AI algorithms can show us which specific ablation points would constitute optimal targets and yield improved outcomes and safety.

Another topic that warrants attention, is the reversal of fibrotic atrial remodelling before it reaches an advanced irreparable stage where the management of AF becomes particularly challenging.

Q8From your work exploring DH innovations for CVD prediction, prevention, and outcome improvement, what are the top three things that clinicians can do to help predict or prevent CVD?

It is well established that today DH innovations can detect diseases. The next step is to prove their predictive powers, which, in my opinion, is where their biggest potential lies. Researchers’ and clinicians’ participation in prospective monitoring of digital health parameters in large populations, and correlation of those findings to disease incidence rates, is a way to achieve that. Clinicians also play an important role in introducing their patients to the world of health technology. By showcasing which benefits those solutions can bring to patients, doctors can leave a positive impact on patient willingness to engage with DH technologies. They can hence serve as a bridge to help newcomers step into the digital world. Patients

are naturally more likely to trust these technologies and accept to share their personal health data after they have been reassured by their treating physicians.

"By showcasing which benefits those solutions can bring to patients, doctors can leave a positive impact on patient willingness to engage with DH technologies."

A third important issue that clinicians and researchers need to be aware of is that maintaining patient compliance to DH technologies is often challenging. We have witnessed a drop in compliance and adherence rates overtime in several of our research projects involving digital tools. So, in collaboration with device manufacturers, clinicians can help determine which strategies improve and sustain patient compliance.

"Another barrier is digital literacy: many vulnerable or elderly patient populations have never been introduced to DH devices. We need to make sure they too are included and considered target consumers."

Q9Are

there any digital innovations on the horizon within the field of cardiology that you feel are particularly noteworthy, or are likely to have significant impact? Photoplethysmogram (PPG) signals are a promising field that are yet to be fully explored. The PPG bio-signal is scalable and easily measurable through a variety of non-invasive methods. One of its most interesting features is the possibility to record dynamic measurements. It can inform us about a variety of cardiovascular parameters: blood O2 saturation, heart rate, heart rhythm, blood pressure estimation, cardiac output, respiration, arterial ageing, endothelial control, microvascular blood flow, autonomic function, cardiorespiratory fitness, etc. The wealth of information that can be drawn from each section of the signal creates room for countless possibilities to innovate. Using AI algorithms, we can analyse PPG signals and see which subclinical diseases they correlate to. So, beyond surveillance and monitoring,

the strongest impact that the PPG technology can have relies on its predictive abilities.

Q10Can you tell us which of your upcoming projects you are most looking forward to?

The TIPP study will include 300 patients from Louisiana, USA, who will be monitored for 1 year using continuous ECG and PPG, and comparative baseline and 1-year cardiac MRIs. These parameters collected over a 1-year period will be correlated with onsets of CVD and assessed for predictivity. Another innovative project is EchoPPG, which consists of simultaneous measurements of the PPG signal alongside performing a cardiac ultrasound. Results from both measurements are then analysed to test whether PPG signals can indicate a decreased left ventricular ejection fraction.

On another note, we are developing a virtual cardiac rehabilitation platform, which aims to deliver comprehensive cardiovascular management through exclusively remote digital solutions. Finally, one of the projects we’re most excited about is CASTLE-AF II. This trial will include patients with AF and heart failure with preserved ejection fraction, randomised into three arms: rate control, medical rhythm control, and catheter ablation. Using our LGE MRI technique, left atrial and left ventricular fibrosis will be assessed. Thus, we aim to optimise patient selection for AF treatment, and establish correlations between the extent of myopathy, QOL, and hard outcomes.

Q11What do you anticipate will be the most significant challenges or barriers to improving cardiovascular health using digital innovations in the future?

Digital innovations are meant to increase access to quality healthcare in a more

convenient setting for both patients and clinicians. Unfortunately, most products are often considered expensive by most patients, which adds yet another barrier in front of them. That is why it is important to prove, through evidencebased research, that DH interventions improve outcomes in a cost-effective manner. Insurance companies and other covering entities would thus be convinced to reimburse for these types of interventions, making it accessible for patients from all socioeconomic backgrounds.

Another barrier is digital literacy: many vulnerable or elderly patient populations have never been introduced to DH devices. We need to make sure they too are included and considered target consumers. By training and empowering patients, and advocating for reimbursement, we can prevent the widening of healthcare access gap.

Q12To conclude, can you tell us what has been your proudest achievement in your incredible career so far?

It is always difficult to answer this question. But I can say that successfully completing several randomised controlled trials (such as CASTLE-AF, DECAAF, and DECAAF II), with the amazing co-investigators and the teams that I got to work with, was definitely hard work and required discipline, collaborative efforts, and perseverance. For that, I am extremely grateful and proud. Another part that I particularly love about my job is that it allows me to empower young researchers. In fact, we are currently collaborating with the Tulane Innovation Institute to create a hub of inspiration, support, and empowerment for young local innovators. Being a part of that, and witnessing the youth’s successful achievements a few years down the line, is priceless.

Addressing Global Cancer Care Inequities Using Implementation Science and CommunityEngaged Research Approaches

Authors: *Kelly A. Hirko

Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, USA

*Correspondence to hirkokel@msu.edu

Disclosure: The author has declared no conflicts of interest.

Received: 01.08.22

Accepted: 07.11.22

Keywords: Cancer, disparities, equity, global health, implementation, low- and middle-income countries, treatment.

Citation: EMJ Innov. 2022; DOI/10.33590/emjinnov/10018969. https://doi.org/10.33590/emjinnov/10018969.

Abstract

Advances in cancer prevention efforts, screening and early detection, and treatments have contributed to steady reductions in cancer mortality for individuals in high-income countries in recent years. Yet, these benefits have not yet been realised for many populations across the globe, particularly for those residing in low- and middle-income countries, and in other medically underserved communities. Addressing cancer disparities will require targeted efforts to equitably improve cancer care delivery across the care continuum; from detection, through treatment, and to survivorship. This feature article describes how implementation science and community-engaged approaches can address cancer inequities by improving the delivery, uptake, and effective expansion of evidence-based cancer care in realworld resource-limited settings.

INTRODUCTION

Worldwide, an estimated 19.3 million new cancer cases and nearly 9.9 million cancer deaths occurred in 2020.1 While cancer incidence rates tend to be lower in low- and middle-income countries (LMIC) compared with high-income countries (HIC), the population sizes tend to be larger, resulting in a higher absolute number of patients with cancer.2 As such, the majority of the world’s cancer cases and deaths now occur in these countries.3 Indeed, 65% of the nearly 10 million cancer deaths in 2020 occurred in LMICs.4 Given rapid

demographic and epidemiological transitions, including rising population, increasing life expectancy, growing urbanisation, and lifestyle changes,5 cancer has become a leading cause of mortality in LMICs,6 with a projected near doubling of cancer deaths expected in the lowest-income countries.4 Importantly, the lack of reliable data from population-based cancer registries severely limits our understanding of the cancer burden in LMICs.7,8

to accessing guideline-concordant cancer care and cutting-edge therapeutics, as well as for accessing older and less costly cancer therapies.3 For example, there is a markedly lower utilisation of effective and evidencebased radiotherapy26 and often costly targeted drug therapies (e.g., trastuzumab)27 in LMICs compared with HICs. Additionally, workforce limitations in LMICs are pronounced, with for example, 0.2 physicians per 1,000 people in sub-Saharan Africa compared with 3.7 per 1,000 people in high-income European countries.28 The widespread healthcare infrastructure limitations and lack of trained oncology workforce create barriers that impede the implementation and delivery of evidence-based cancer care treatment in resource-constrained settings, resulting in suboptimal care.29

Any cancer care intervention that aims to reduce the overall burden of cancer in a population may inadvertently increase existing disparities if disadvantaged populations are excluded from the research studies demonstrating the intervention’s effectiveness.3 Therefore, inclusion of globally diverse populations in cancer clinical trials is imperative to develop cancer therapies that have the potential for broad reach to achieve more equitable clinical outcomes.14 However, diversity in cancer clinical trials is lacking, with Black and rural populations vastly underrepresented.30,31 Moreover, only 8% of Phase III randomised clinical trials in oncology between 2014 and 2017 were conducted in LMICs.32 Unequal access and participation in cancer clinical trials contributes to a limited understanding of cancer biology,30 which can substantially diminish the potential of precision medicine approaches.33

Additionally, genetic research databases used to develop targeted cancer therapies contain data on participants of predominantly European ancestry.34-37 Developing targeted therapies based on a limited set of non-representative data can exacerbate cancer inequities and disadvantages populations in terms of access to targeted therapies. Moreover, utilisation of targeted cancer therapies requires additional testing to determine eligibility, adding complexity and cost, which may disproportionately impact under-resourced populations,38 and contribute to lower utilisation of effective therapies in vulnerable populations. Importantly, cancer clinical trials are typically conducted in clinical

settings with the necessary resources to support research efforts. This approach to developing cancer treatments and guideline recommendations in well-controlled environments neglects to consider whether the implementation of the intervention is feasible and scalable in community oncology settings, where the bulk of cancer care is delivered.

ADRESSING CANCER CARE EQUITY GAPS

Concerted efforts are needed to ensure that advancements in cancer care benefit all, particularly those disproportionately burdened by the disease. Implementation of scientific approaches, which focus on identifying strategies to improve the delivery, and the uptake and effective expansion of evidence-based cancer care in real-world resource-limited settings, can be harnessed for cancer equity.39 Using implementation science, researchers can identify optimal strategies to build feasible, appropriate, sustainable, and affordable cancer care delivery pathways in resource-constrained settings, and to identify priorities to ensure maximum health gains with the limited resources available.3 Currently, the dissemination and implementation of evidence-based cancer control interventions and treatments in low-resource settings is inconsistent and incomplete.19 While it is often assumed that research findings will automatically be translated into practice in low-resource settings, this is typically not the case.3 In fact, many cancer care interventions cannot be simply implemented in low-resource settings because of the shortage of resources, a paucity of trained personnel, poor infrastructure, and fundamental differences in socio-political and cultural landscapes.2,40 Resource-stratified phased implementation to address cancer control efforts in the context of available resources, similar to what has been developed by the Breast Health Global Initiative (BHGI),41 may be an effective approach to translate cancer care guidelines into real-world practice LMICs, as well as underserved communities in HICs, and could help policy makers and health professionals to make best use of scarce resources.

Moreover, community-engaged approaches to adapt and tailor evidence-based interventions that specifically address the needs and

preferences of under-resourced populations can improve cancer care delivery and address disparities.42 For example, research suggests that culturally-targeted communication strategies, including message framing and communitycentred cancer control interventions, can be used to address disparities for specific populations with increased disease burden.43-45 Indeed, patient-centred interventions and equitable delivery tools are necessary to ensure feasible and acceptable solutions,46 recognising the need for capacity building in many resourceconstrained settings. For example, the successful implementation of the human papillomavirus vaccine into the routine immunisation delivery strategy in Tanzania can serve as a model for future efforts centred on low-cost and highimpact solutions to reduce the burden of cancer and address disparities.47 The importance of research conducted in low-income countries and its contribution to global science and addressing global health disparities should also not be overlooked.48 For example, cancer research conducted in LMICs can generate major discoveries such as the identification of novel cancers, their causative agents, and promising treatments.48

Addressing resource disparities in LMICs and medically underserved settings, and increasing capacity will be essential if cancer control efforts are to be successful. This includes providing increasing opportunities for training multidisciplinary cancer care teams, including medical oncologists, surgeons, pathologists, radiologists, and radiation oncologists.49 Evidence also suggests that reducing structural and financial barriers to cancer screening can increase access to these services.21 In resource-constrained settings without specialised services, the deployment of primary and secondary caregivers, use of off-patent drugs, and application of regional and global mechanisms for financing and procurement have

References

1. Sung H et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49.

proven effective in prior efforts.50 Additionally, including cancer treatment in national health insurance coverage, with a focus on those living in poverty, can help reduce costs; will be key to achieving access to clinically effective, safe, and affordable cancer medicines;51 and strengthen health systems to meet the challenge of cancer.50 Finally, there is a longstanding need to improve the quality and coverage of cancer registry data worldwide, particularly in LMICs, to better characterise cancer burden and identify research gaps.

CONCLUSION

In summary, disparities in cancer care delivery across the globe are persistent and widening. Targeted efforts to address barriers to cancer care and build a sustainable infrastructure for the implementation and dissemination of cancer prevention measures and provision of cancer care in resource-constrained settings is essential for global cancer control. Key priorities recommended to reduce global cancer disparities include the incorporation of communityengaged approaches to account for contextual barriers and to develop relevant and sustainable solutions to cancer care delivery challenges in real-world settings; focus more heavily on population health-level cancer prevention and early detection strategies over costly individualised targeted therapies; identify novel strategies for collaboration with policy-makers, non-profit organisations, and pharmaceutical companies to promote broad scale-up of evidence-based cancer care interventions; and increasing capacity by focusing research efforts on developing scalable infrastructure, including data registry tools and procedures to broadly disseminate cancer education and awareness efforts, and healthcare provider training in cancer prevention and control.

2. Harford JB. Barriers to overcome for effective cancer control in Africa. Lancet Oncol. 2015;16(8):e385-93.

accessed: 29 July 2022.

3. Dos-Santos-Silva I et al. Global disparities in access to cancer care. Commun Med. 2022;2:31.

4. International Agency for Research on Cancer (IARC). The global cancer observatory. Available from: https://gco.iarc.fr/. Last

5. Pramesh CS et al. Priorities for cancer research in low- and middle-income countries: a global perspective. Nat Med. 2022;28(4):649-57.

6. International Agency for Research on Cancer (IARC). Global cancer observatory: cancer today.

Available from: https://gco.iarc. fr/today. Last accessed: 14 November 2022.

7. Siddiqui AH, Zafar SN. Global availability of cancer registry data. J Glob Oncol. 2018;4:1-3.

8. Ferlay J et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941-53.

9. Siegel RL et al. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.

10. American Cancer Society. Cancer Facts & Figures 2020. Available at: https://www.cancer.org/research/ cancer-facts-statistics/all-cancerfacts-figures/cancer-factsfigures-2020.html. Last accessed: 28 November 2022.

11. World Health Organization (ed.), WHO Report on Cancer: Setting Priorities, Investing Wisely and Providing Care for All (2020) Geneva: World Health Organization.

12. Autier P et al. Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database. BMJ. 2010;341:c3620.

13. De Angelis R et al. Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE-5-a population-based study. Lancet Oncol. 2014;15(1):23-34.

14. Hirko KA et al. The impact of race and ethnicity in breast cancerdisparities and implications for precision oncology. BMC Med. 2022;20(1):72.

15. Hirko KA et al. Cancer disparities in the context of rurality: risk factors and screening across various U.S. rural classification codes. Cancer Causes Control CCC. 2022;33(8):1095-105.

16. American Cancer Society. Cancer Facts & Figures for African Americans 2016-2018. Available at: https://www.cancer.org/ research/cancer-facts-statistics/ cancer-facts-figures-for-africanamericans.html. Last accessed: 28 November 2022.

17. World Health Organization (WHO). World Health Organization newsroom fact sheet. 2022. Available from: https://www.who. int/news-room/fact-sheets/detail/ cancer. Last accessed: 29 July 2022.

18. Shah SC et al. Cancer control in low- and middle-income countries:

is it time to consider screening? J Glob Oncol. 2019;5:1-8.

19. Gopal S, Sharpless NE. Cancer as a global health priority. JAMA. 2021;326(9):809-10.

20. World Health Organization (ed.), Assessing National Capacity for the Prevention and Control of Noncommunicable Diseases: Report of the 2019 Global Survey. 2020. Available at: https://www. who.int/news-room/fact-sheets/ detail/cancer. Last accessed: 28 November 2022.

21. Williams PA et al. AACR cancer disparities progress report 2022. Cancer Epidemiol Biomark Prev. 2022;31(7):1249-50.

22. Wercholuk AN et al. The road less traveled: transportation barriers to cancer care delivery in the rural patient population. JCO Oncol Pract. 2022;18(9):652-62.

23. Horrill TC et al. Access to cancer care among Indigenous peoples in Canada: a scoping review. Soc Sci Med. 2019;238:112495.

24. Mitchell EP. Disparities in healthcare: physician implicit bias or structural racism. J Natl Med Assoc. 2022;114(3):235.

25. Wilkinson E. New technical guidance to boost global radiotherapy access. Lancet Oncol. 2021;22(5):589-90.

26. Yap ML et al. Global access to radiotherapy services: have we made progress during the past decade? J Glob Oncol. 2016;2(4):207-15.

27. Nair NS et al. Access to HER2targeted therapy at a tertiary care center in India: An evolution. Indian J Cancer. 2021;DOI:10.4103/ijc. IJC_841_19.

28. World Health Organization (WHO). World health statistics. 2022. Available from: http://www.who. int/gho/publications/world_health_ statistics/2014/en/. Last accessed: 14 November 2022.

29. Kumar Yadav S. Barriers and challenges in providing standard breast cancer care in low resource settings. Trop Doct. 2022;52(4):532-7.

30. Aldrighetti CM et al. Racial and ethnic disparities among participants in precision oncology clinical studies. 2021;4(11):e2133205.

31. Ford JG et al. Barriers to recruiting underrepresented populations to cancer clinical trials: a systematic review. Cancer. 2008;112(2):22842.

32. Wells JC et al. An analysis of contemporary oncology randomised clinical trials from low/middle-income vs highincome countries. JAMA Oncol. 2021;7(3):379-85.

33. Mersha TB, Abebe T. Self-reported race/ethnicity in the age of genomic research: its potential impact on understanding health disparities. Hum Genomics. 2015;9(1):1.

34. Ginsburg GS, Phillips KA. Precision medicine: from science to value. Health Aff (Millwood). 2018;37(5):694-701.

35. Wendler D et al. Are racial and ethnic minorities less willing to participate in health research? PLoS Med. 2005;3(2):e19.

36. Need AC, Goldstein DB. Next generation disparities in human genomics: concerns and remedies. Trends Genet TIG. 2009;25(11):489-94.

37. Popejoy AB, Fullerton SM. Genomics is failing on diversity. Nature. 2016;538(7624):161-4.

38. Geneviève LD. Structural racism in precision medicine: leaving no one behind. BMC Med Ethics. 2020;21(1):17.

39. Tapela NM et al. Implementation science for global oncology: the imperative to evaluate the safety and efficacy of cancer care delivery. J Clin Oncol. 2016;34(1):43-52.

40. Harford JB. Breast-cancer early detection in low-income and middle-income countries: do what you can versus one size fits all. Lancet Oncol. 2011;12(3):30612.

41. Duggan C. The Breast Health Global Initiative 2018 Global Summit on improving breast healthcare through resourcestratified phased implementation: methods and overview. Cancer. 2020;126(Suppl 10):2339-52.

42. Wood EH et al. A communityengaged process for adapting a proven community health worker model to integrate precision cancer care delivery for low-income Latinx adults with cancer. Health Promot Pract. 2022;15248399221096416.

43. Lucas T et al. Effects of culturally targeted message framing on colorectal cancer screening among African Americans. Health Psychol. 2021;40(5):305-15.

44. Lucas T et al. Targeting and tailoring message-framing: the moderating effect of racial identity

on receptivity to colorectal cancer screening among AfricanAmericans. J Behav Med. 2018;41(6):747-56.

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A 3D-Printed Ultrasound Task Trainer for the Practice of Hip Joint Injections

Editor's Pick

My Editor’s Pick for this publication is ‘A 3D-Printed Ultrasound Task Trainer for the Practice of Hip Joint Injections’ by Chambers et al., which explores how 3D printing technology and ballistics gelatine were used to develop a hip joint model that is not only economical, but also anatomically and sonographically accurate. This is a truly transformative tool in educating the clinicians of the future, by enabling rehearsal of the technique on a realistic replica.

Mike Bewick

Director and Founder, iQ4U Consultants, London, UK

Authors: Mary E. Chambers,1 Alvin Lee Day,2 *David Resuehr1,3

1. Heersink School of Medicine, University of Alabama at Birmingham, USA

2. Division of Rheumatology, School of Medicine, University of South Carolina, Columbia, USA

3. Department of Cell, Developmental and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, USA

*Correspondence to resuehr@uab.edu

Disclosure: The authors have declared no conflicts of interest.

Received: 08.06.22

Accepted: 26.10.22

Keywords: Ballistic gelatine (gel), hip injection, hip injection training, hip trainer, ultrasound (US) phantoms, 3D printing.

Citation: EMJ Innov. 2022; DOI/10.33590/emjinnov/1069656. https://doi. org/10.33590/emjinnov/10169656.

Abstract

Ultrasonography is often the preferred method of imaging for needle-guided procedures of the hip joint, including aspirations, local anaesthetic injections, and the use of corticosteroids. Phantoms (i.e., training devices mimicking human tissue and bony structures under acoustic sonography) are used to help train medical professionals to perform these procedures accurately, emphasising the art of physical simulation in unison with didactic learning. In the authors’ study, 3D printing technology was used to simulate an anatomically accurate human hip joint, with the hopes of creating an affordable and customisable ultrasound hip trainer, allowing novice sonographers to practice guided injections to hone their skills before performing these procedures on human subjects.

Key Points

1. Hands-on learning for ultrasound (US)-guided procedures is of increasing importance, as these procedures are growing within the field of medicine.

2. Tactile feedback trainers are important tools in US training. 3D printing technology can recreate sonographically scannable structures to create simulators at a fraction of the current market price.

3. This study investigated the use of in-house 3D printing technology and ballistics gelatine as cost-effective building materials for US phantoms. The model built was anatomically and sonographically comparable to a human hip joint, but cost <50 USD.

INTRODUCTION

As the use of ultrasonography rises within the medical field as a safe and effective way to diagnose and perform bedside procedures, the need for accurate, customisable ultrasound (US) trainers in the academic setting have become all the more apparent. In addition to teaching vital anatomical landmarks and US techniques, US trainers (phantoms) provide a realistic, hands-on experience for procedural practice for students and clinicians alike. Use of simulation-based learning is vital to longterm procedural skill and acuity; a notion that is further defined by the Best Evidence Medical and Health Professional Education (BEME) systematic review, where the first three main elements for ensuring effective procedural learning include active feedback during simulation, repetitive practice on a simulator, and integration of simulators within an overall curriculum.1 While the above emphasises the overall benefit of medical simulation at large, studies have since been conducted in order to highlight the benefit of simulation training within sonographic education specifically. In a literature review spanning over 19 studies, US simulation with task trainers not only showed an improvement in student confidence but had superior learning outcomes when compared with theoretical teaching strategies alone.2

The necessity of realistic simulation in conjunction with clinical experience throughout medical education is evident. This is especially true in case of hospital-based learning, as practitioner training is often a by-product of the facility’s main objective: patient care and outcomes.3 When combined with a standardised procedural curriculum, the use of scanning trainers in medical education has been shown to significantly improve student knowledge base, while also allowing additional practice time to better build procedural skill and precision.4

This need for further training and experience in US technique is applicable in the case of musculoskeletal scans of the hip joint, as musculoskeletal US guidance is a vital component of various procedures, including hip aspirations, local anaesthetic injections, and the use of hyaluronic acid or corticosteroids within the synovial hip joint.5 Due to the hip joint’s deep lying stature, lack of obviously palpable landmarks, and highly vascularised and innervated nature, procedures involving penetration of the pelvic girdle and associated attachments often require real-time imaging guidance.6 While US and fluoroscopy are both viable imaging modalities for these procedures, musculoskeletal US guidance is preferred clinically due to its timeliness, portability into the patient room, lower procedural cost, and lack of ionising radiation.7,8 While the utilisation of US phantoms in training for medical procedures has been shown to increase skill and accuracy, the use of these learning tools is often outweighed by cost. To date, the current market for medical educational tools displays a majority of cost-prohibitive phantoms with non-modifiable, non-reusable characteristics.

In response to the current US phantom market, this study sought to use 3D printing techniques, in addition to the authors’ prior years of experience making phantoms, to create an inexpensive and versatile hip phantom embedded into a biodegradable ballistics gelatine (gel). The authors’ 3D printed hip joint is created from an anatomically accurate model that was freely available online and maintains the anatomical relationships of the bones within the human hip, while the sustainable ballistics gel allows for texture and US appearance close to that of human flesh. The duality of this hip trainer, both as an US practice device for identifying key anatomical landmarks and a needle-accepting device for practicing hip-based US-guided procedures, makes the authors’ model a good alternative to other hip phantoms and training devices.

MATERIALS AND METHODS

A hip-resembling mould to house the authors’ ballistics gel and hip joint replica was created using a Revopoint 3D scanner (Revopoint 3D Technologies, Los Angeles, California, USA) on the torso of a general anatomy model. Using this rendering, the authors edited the torso scan in Meshmixer (Autodesk, San Francisco, California, USA) to create a fillable mould resembling the right hip. First, the authors’ used the ‘Cut’ command to reduce the print down to the necessary structures, and then the addition of superior and inferior walls created a fillable shell (Figure 1A–D).

The hip mould was then scaled to the appropriate size using Fusion 360 (Autodesk). After scaling their hip mould rendering, the authors used a LulzBot Taz 6 3D printer (LulzBot, Fargo, North Dakota, USA) using a verbatim polylactic acid (PLA) filament (215 °C; 15% infill) to print the model. The hip mould was painted with a single layer of latex paint to ease with extraction of the final ballistics gel product.

A 3D printing template of the human hip joint was downloaded from Thingiverse9 (MakerBot Industries, New York City, USA) under the creative commons license and edited with Meshmixer software (Autodesk) to include the right hip joint and its associated structures (Figure 1A). In brief,

A) Rendering of the entire hip joint aligned within gelatine mould cast. B) Rendering of the edited right hip joint, fitting within the edited gelatine mould cast. C) Mould cast and hip joint rendering, with associated holes generated for joint suspension. D) Final rendering of mould and hip joint renderings, with emphasising connections made by the Boolean subtracted hole function.

Figure 1: Computer generated designs to create a realistic 3D printed hip phantom. A

individual components were digitally combined, scaled to the correct size, and plane cut to fit the mould. The rendering was re-meshed and, finally, Boolean subtracted holes were added to the model design to allow for bone replica suspension within the final hip model (Figure 1C and D).

A LulzBot TAZ 6 3D printer using Verbatim PLA filament (215 °C; 15% infill) was used to print the final model of the hip’s bony structures. A thin layer of 20% ballistic gel solution was applied concentrically along the femoral head and hip joint to mimic the acetabular structure and left to cool at room temperature.

The finished 3D-printed hip replica was then suspended within the watertight hip mould using toothpicks, utilising small holes created by the Boolean subtracted holes function for support (Figure 2A). A second mixture of 15% ballistic gel solution was poured into the mould and let to set overnight at 4 °C (Figure 2A). After setting overnight, the support toothpicks were extracted from the mould and the hip model was carefully removed from the latex-coated mould (Figure 2B).

The finished phantom was scanned with the curvilinear probe end of a VScan AirTM wireless US machine (GE HealthCare, Chicago, Illinois, USA), which is visible in Figures 2B and 3A.

RESULTS

The authors’ 3D printed hip phantom achieved similar anatomical and echogenic appearances to images observed of a human proximal femur, doing so at a fraction of the cost of traditional US phantoms currently on the market (Figure 3A).

By utilising the art and science of 3D printing, the authors were able to achieve a good echogenic appearance of the proximal femur and its surrounding anatomical structures, making this model not only ideal due to its low cost but also as an accurate teaching tool for reviewing anatomical structures in the long axis view (Figure 3B and C). Additionally, the use of computer-aided software allowed the authors’ replication of the femoral head, neck, and its surrounding structures to be as precise and accurate as possible, while limiting the presence of back shadowing and materialinduced artefacts within their scans. While artefacts from the bony replica were minimal, air bubbles were visible upon scanning of the authors’ model. These air bubbles are small artefacts caused by air trapping during the pouring of the gel into the mould and cause negligible visual obstruction.

A) 3D printed ballistics mould cast (blue dye), with suspended 3D printed hip replica and a 15% ballistics gelatine infill. B) Final hip phantom prototype (green dye).

Figure 2: Poured and final prototype of ultrasound hip phantom.

Figure 3: Pre- and post-injection ultrasound images of the 3D printed hip phantom compared with a human hip joint, with relevant features labelled.

A)

Ac:

Doubling as an injectable trainer, the authors’ hip model sufficed in its ability to display and absorb needle-injected fluids, making this phantom a valuable learning tool in simulating the visual–spatial and tactile skills needed to perform hip joint aspirations and injections within a living specimen. Repeated needle sticks and injections were possible with the authors’ phantom, leaving minimal tracking lines with each use. While this model was reusable, needle tracks deep within the gel did become obstructive to image acquisition after sustained use. These needle tracks could be removed by peeling off the gel from the 3D hip replica, heating it to a boil, and repouring the phantom using the original 3D printed mould and suspensory toothpicks.

DISCUSSION

With the growing popularity and accessibility of 3D printing technology among academic institutions and households, the utilisation of computer-generated 3D printing technology makes the authors’ low-cost US trainer easily accessible, printable, and customisable. In addition to making the authors’ model more attainable, the use of computerised 3D printing software also allows for more realistic and detailed internal lying structures within the author’s phantom, making it a more accurate training tool than others rendered from less exact methods.

Completed hip phantom with simultaneous ultrasound imaging in pre-injection state. B) Labelled ultrasound imaging of human hip. C) Ultrasound imaging of hip injection within the phantom model. The blue arrows show the joint capsule and target for the joint injection.

acetabulum; FH: femoral head; FN: femoral neck; N: needle.

C

An in-plane, long-axis scan was performed on both a human and the hip phantom model. This study found the hip phantom to be comparable to human models in simulating various clinical skills such as tactile awareness, visual–spatial acuity, and general sonography technique. Additionally, the hip phantom was found to be cast in a similar shape to what one would encounter during human hip sonography, further adding to its use as an accurate procedural simulator. While hip phantoms do already exist on the medical education market, these tools can cost upwards of 5,000 USD, and are often non-injectable.10,11 The authors’ model was completed with an approximate cost of 50 USD, emphasising the increased accessibility and affordability when considering using simulation models in the realm of medical education.

Due to the PLA filament’s durability in terms of being embedded in gel and exposed to needle sticks, the authors’ hip model and its casting mould can be used repeatedly, allowing for reuse and recycling of the phantom’s base for costefficient, hands-on educational learning, even after consistent injections and practice sessions. The ability to recast the gel within the author’s phantom also leaves room for further duality and customisation, as the user can manipulate the gel consistency and colour it to match the skill set of the trainee navigating the US. Thus, the authors’ model provides a cost-efficient, customisable format to encourage further learning in the realm of musculoskeletal sonography and skills.

LIMITATIONS

While the authors were able to create a hip phantom that is sonographically similar to images obtained from a previous human specimen scan, their phantom was not evaluated in comparison to a human model in real-time. Additionally, though the bony structures of the authors’ phantom were pulled from an accurate representation of a human specimen, some of the anatomical features in their task trainer were not translated perfectly. For instance, the sonographic appearance of muscle tissue and fat versus tendons and cartilage still provide challenges. This is also true of the 20% ballistic gel, which was used to recreate the acetabulum, as this material was not a perfect match in mimicking the structure’s qualities on a human sonographic scan, appearing less radioopaque than its human specimen counterpart (Figure 3B and C).

Additionally, pouring of the 15% ballistic gel within the mould led to occasional air bubbles to be trapped within the phantom itself. While these bubbles did not markedly affect the sonographic imaging, these artefacts did cause a small visual impairment. Furthermore, the use of ballistic gel leads to traces or needle track marks after repeated needle sticks when simulating injections. While minimal at first, these marks increase with phantom use, thus creating increasing amounts of sonographic artefacts over the lifetime of the phantom. However, to be emphasised again, needle tracks in a 50 USD phantom are a little more forgivable than in one that costs significantly more.

While the phantom itself was injectable and held lower viscosity fluids with ease, there was no intact mechanism for emptying the area around the acetabulum or femoral head after attempted injections. This was not of issue for the authors’ number of sonographic readings but may pose a problem for use of this model in an educational, multi-simulation setting.

Lastly, the authors’ model was not tested in realtime in conjunction with a human subject. Thus, this study cannot assess or compare learner competence on a live subject subsequent to training with the phantom.

CONCLUSION

As sonography continues to grow in its use as a bedside diagnostic and procedural device, the need for US phantoms providing visual and tactile feedback for novices and training professionals becomes all the more apparent. While such simulators are currently on the market, they often come at a high cost, often deterring from their use in the realm of medical education. This manuscript outlines parameters for using 3D printing capabilities to create a versatile, low-cost, and yet reasonably accurate hip phantom while keeping accessibility at the forefront of product design. With these findings, the authors’ aim to make hands-on teaching with sonography phantoms more accessible to medical students and learners’ alike, further promoting the expanding use and expertise of this outstanding diagnostic tool in many fields to come.

References

1. Issenberg SB et al. Features and uses of high-fidelity medical simulations that lead to effective learning: a BEME systematic review. Med Teach. 2005;27(1):10-28.

2. Bradley K et al. Determining if simulation is effective for training in ultrasound: a narrative review. Sonography. 2020;7(1):22-32.

3. Zerth H et al. An inexpensive, easily constructed, reusable task trainer for simulating ultrasound-guided pericardiocentesis. J Emerg Med. 2012;43(6):1066-9.

4. Yoo MC et al. Basic ultrasound curriculum for medical students: validation of content and phantom. J Laparoendosc Adv Surg Tech A. 2004;14(6):374-9.

5. Lynch TS et al. Ultrasound-guided hip injections. J Am Acad Orthop

Surg. 2019;27(10):e451-61.

6. Robinson P et al. Clinical effectiveness and dose response of image-guided intra-articular corticosteroid injection for hip osteoarthritis. Rheumatology (Oxford). 2007;46(2):285-91.

7. Atchia I et al. A modular, flexible training strategy to achieve competence in diagnostic and interventional musculoskeletal ultrasound in patients with hip osteoarthritis. Rheumatology (Oxford). 2007;46(10):1583-6.

8. Sofka C et al. Ultrasound-guided adult hip injections. J Vasc Interventional Radiol. 2005;16(8):11213.

9. DaveMakesStuff. 6-piece magnetic female pelvis model. 2021. Available at: https://www.thingiverse.com/thing:4946668. Last

accessed: 2 November 2022.

10. 3B Scientific. Blue phantom gen ii femoral line & regional anesthesia ultrasound training model. Available at: https:// www.3bscientific.com/us/bluephantom-gen-ii-femoral-line-regional-anesthesia-ultrasoundtraining-model-3012489-bluephantom-bpp-136,p_1397_31307. html?utm_source=google&utm_ campaign=gmc_feed&gclid=CjwKCAjwy_aUBhACEiwA2IHHQBlloxQqqtbpUsZD3ViOt2yEz51GZiyynV7Bk5hCTA3tEy_MXu65DRoCko8QAvD_BwE. Last accessed: 2 November 2022.

11. GT Simulators. Kyoto Kagaku infant hip sonography training phantom. Available at: https:// www.gtsimulators.com/products/ kyoto-kagaku-infant-hip-sonography-training-phantom-kkus-13. Last accessed: 2 November 2022.

Harnessing the Incretin System with Multi-Agonists

Authors: Martin B. Whyte,1,2 Adrian Heald,3,4 Benjamin C.T. Field1,5

1. Department of Clinical and Experimental Medicine, University of Surrey, Guildford, UK

2. Department of Diabetes, King’s College Hospital NHS Foundation Trust, London, UK

3. Department of Endocrinology and Diabetes, Salford Royal Hospital, UK

4. The School of Medicine and Manchester Academic Health Sciences Centre, Manchester University, UK

5. Department of Diabetes & Endocrinology, Surrey & Sussex Healthcare NHS Trust, Redhill, UK

*Correspondence to m.b.whyte@surrey.ac.uk

Disclosure:

Field has received consultancy and/or lecture fees, and/ or support to attend conferences from Abbot Diabetes, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Gilead, GlaxoSmithKline, Janssen, Medtronic, MSD, Napp, Novo Nordisk, and Sanofi. The other authors have declared no conflicts of interest.

Received: 16.08.22

Accepted: 15.09.22

Keywords: Diabetes, incretin system, therapy, treatment.

Citation:

Abstract

EMJ Innov. 2022. DOI/10.33590/emjinnov/10115628. https://doi. org/10.33590/emjinnov/10115628.

The scientific community has made great strides in responding to the huge public health problems of obesity and diabetes with the discovery of the incretin system and the development of glucagon-like peptide 1 analogues. These have shown clinical efficacy in randomised controlled trials and observational data from realworld evidence; however, a ‘treatment gap’ remains between the therapeutic success of these molecules and the outcomes achieved with bariatric surgery. To help address this, dual incretins are being developed. These combine glucagon-like peptide 1 action with that of either glucose-dependent insulinotropic peptide or glucagon. This narrative review charts the development of incretin therapy, and the dual agonists for treatment of Type 2 diabetes and obesity.

Key Points

1. Agonists of the incretin glucagon-like peptide-1 (GLP-1) have established efficacy for glycaemic reduction, weight loss, and cardiovascular risk modification; however, some patients may still not achieve metabolic targets and efficacy remains considerably less than that seen with bariatric surgery.

2. In recent years, dual agonists of the incretin system have been tested in pre-clinical and early-phase clinical trials, with the glucose-dependent insulinotropic polypeptide and GLP-1 co-agonist, tirzepatide, recently approved for clinical use. This provides near double the weight loss to GLP-1 agonists and significant glucose lowering, as well as promising efficacy in non-alcoholic fatty liver disease. Future prospects include triple agonists of glucagon, glucose-dependent insulinotropic polypeptide, and GLP-1.

3. This article highlights the evolving understanding of the incretin system over the years, leading to the development of multi-agonists, which hold the potential for marked metabolic benefits, mimicking that seen with bariatric surgery.

INTRODUCTION

The identification of the incretin system as consisting of hormones located in the gastrointestinal mucosa, that have insulinotropic action; and its subsequent exploitation in the form of glucagon-like peptide 1 (GLP-1) receptor agonists (RA) has been a therapeutic success story for Type 2 diabetes (T2D) and obesity management. Nonetheless, therapeutic failure, partly from inability to maximise the dose or persist with the medication because of nausea and vomiting, limits the potential of this class of drugs. The recognition of the contribution of other hormones in the incretin system, with pleiotropic actions, has led to the development of dual agonists, which can maximise metabolic benefits with a lower potential for side-effects. This may help to close the ‘treatment gap’ between the effects of existing drugs and that of bariatric surgery on weight and metabolic parameters.

This narrative review covers the identification and development of incretin therapy for diabetes and obesity, culminating in the recent clinical trials of dual agonist therapy and the future prospect of tri-agonists.

SEARCH METHODOLOGY

The authors searched the English-language literature to identify all relevant studies, regardless of publication status or year of publication. They searched the PubMed and Google scholar databases, combining the terms dual agonist’ OR ‘triple agonist’ OR ‘GIP/GLP-1’ OR ‘[glucagon-like peptide 1]’ PLUS ‘[glucose dependent inhibitory peptide]’ OR ‘glucagon/ GLP-1’ OR ‘dual incretins’. Studies could include pre-clinical or early or late phase human

trials. Additional studies were added by cross referencing the retrieved studies. The last search was performed in July 2022.

DISCOVERY OF INCRETINS

The superiority of enteral, compared to parenteral glucose administration in stimulating insulin secretion in humans, was first described in 1964 by McIntyre et al.1 This paper reignited long-dormant interest in the concept of incretins: putative gastrointestinal factors released during meal absorption that might stimulate insulin secretion in a glucose-dependent fashion. Two hormones released by enteroendocrine cells in the gut mucosa were subsequently discovered to be largely responsible for the incretin phenomenon. Glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) was the first to have its incretin effect demonstrated, by the Canadian team of Dupre et al.2 Identification of the other hormone, GLP-1, was a more complex task because of the difficulty of differentiating it immunologically from other bioactive products and inactive degradation fragments of its precursor, proglucagon. The ability of intravenously infused GLP-1 to stimulate insulin secretion in humans in a glucose-dependent fashion was eventually described by Kreymann et al.3

GLUCAGON-LIKE PEPTIDE-1

Despite being identified later than GIP, GLP-1 quickly became the focus of intensive research, such that fewer than 20 years were to elapse between the description of its incretin effect and the approval of the first highly successful GLP-1 RA drug class for treatment of T2D.4 GLP-1 is released after food intake3 into the

enterohepatic portal system by L cells located predominantly in the mucosa of the ileum and large bowel.5 The bioactive forms, GLP-1(7–37) and most abundantly, GLP-1(7–36)NH2, are inactivated by dipeptidyl peptidase-4 (DPP4).6 Intravenously infused GLP-1 slows gastric emptying,7 reduces appetite and food intake,8 and suppresses glucagon (GCG) secretion at normal and high blood glucose concentrations, but not during hypoglycaemia.9 Further evidence for the physiological role of GLP-1 in regulating GCG secretion accrued from studies showing that exendin (9–39), an antagonist of the GLP1 receptor, impairs oral glucose tolerance10 by disinhibiting GCG secretion when blood glucose concentration is normal or elevated.11 As a result, GLP-1 RAs reduce hyperglycaemia with little risk of hypoglycaemic episodes.

Development of Drugs Acting on the Glucagon-Like Peptide-1 Receptor

Exendin-4, a peptide component of the venom of the Gila monster (Heloderma suspectum), has approximately 50% structural homology to GLP-1(7–36)NH2 and is a DPP4-resistant agonist at the GLP-1 receptor (GLP-1R).12 As this confers a much longer half-life than that of native sequence GLP-1 (hours rather than minutes), the development of GLP-1 RAs has proceeded down two paths: as analogues of either human GLP-1, or of exendin-4.

Human GLP-1-analogues that have come to market include liraglutide, dulaglutide, semaglutide, and albiglutide (the last has been withdrawn). Marketed drugs based on exendin-4 are exenatide and lixisenatide (Figure 1).12,13 Modifications to prolong the half-life of GLP-1 RAs include sequence substitutions conferring resistance to DPP-4, along with acylation (liraglutide and semaglutide), covalent bonding to modified Ig fragment crystallisable domain (dulaglutide), or covalent bonding to albumin. These various approaches delay clearance by the kidney.

Notwithstanding their resistance to degradation by DPP-4, exendin-4-based GLP-1 RAs require daily (lixisenatide) or twice daily (exenatide) dosing without further modification. A weekly version of exenatide (Bydureon [AstraZeneca, Cambridge, UK]) has therefore been developed, in which co-formulation with poly(D,L-lactideco-glycolide), a material similar to that used in soluble sutures, slows release of drug from the injection site depot.12,13

Regulatory approval for the first GLP-1 RA drug for the treatment of T2D was issued in 2005 and since then GLP-1 RAs have proved highly clinically effective.12,13 Although the original approval was largely based on the potent glucose-dependent insulinotropic properties

GLP-1: glucagon-like peptide 1.

Figure 1: Classification of glucagon-like peptide 1 receptor agonists.

of GLP-1R activation on pancreatic β-cells, it has become clear that the GLP-1R is expressed on a variety of other tissues, which produce a range of biological effects across diverse organ systems (Figure 2).14

Early research on the therapeutic potential of GLP-1 was directed towards glucose regulation in diabetes but was extended, through concurrent observations of body weight lowering to obesity management. Weight reduction may result from activation of vagal and cerebral GLP-1Rs, leading to appetite suppression. Average weight loss achieved with GLP-1 RA at doses suitable for treating T2D is around 5 kg.12,15 GLP-1 RAs have been licenced (at higher doses than those used for diabetes) for the treatment of obesity. The European Medicine Agency (EMA) approved daily liraglutide (3.0 mg) and weekly semaglutide (1.7 or 2.4 mg) for this indication in 2021.

Studies Showing the Efficacy of Glucagon-Like Peptide-1 Receptor Agonists

In addition to lowering HbA1c, GLP-1 RAs improve traditional cardiovascular disease risk factors such as obesity and hypertension, whilst also exerting anti-inflammatory and antiatherosclerotic effects, and having positive direct modulatory effects on endothelial function.12

Several large, randomised trials have shown that GLP-1 RAs reduce major adverse cardiovascular events (MACE) compared with placebo. These include LEADER (liraglutide), REWIND (dulaglutide), and SUSTAIN-6 (semaglutide);12,16 however, no statistical differences in MACE outcomes were found in ELIXA (lixisenatide) or EXSCEL (exenatide). Meta-analysis of renal outcomes shows GLP-1 RAs reduce renal events by 15%, primarily through prevention of albuminuria, and mortality by 11%, with no difference between agents;12,16 however, there is a lack of data comparing these GLP-1 RA outcomes versus other glucose lowering therapies.

COMPARATIVE EFFECTS OF GLUCAGON-LIKE PEPTIDE-1 AND GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE

Both GLP-1 and GIP have profound effects on energy metabolism and body weight (Table 1). Whilst both have significant incretin effect on insulin secretion, their effects on GCG release differ. GLP-1, but not GIP, slows gastric emptying, which further reduces post-meal glycaemic increments. As described above, GLP-1 inhibits appetite and food intake, resulting in weight loss upon chronic administration; however, GIP

GLP-1: glucagon-like peptide 1.

Figure 2: Pleiotropic actions of glucagon-like peptide 1.

Table 1: Metabolic effects of glucose-dependent insulinotropic peptide and glucacon-like peptide 1.

Site

Pancreas

β-cells

α-cells

Brain

Gastrointestinal

Adipose tissue

GLP-1

↑Insulin synthesis

↑Insulin secretion

↑Cell proliferation

↑Glucose sensing

↓GCG secretion

↑Satiety

↓Appetite

↓GI motility

↓Gastric emptying

N/A

GIP

↑Insulin synthesis

↑Insulin secretion

↑Cell proliferation

↑Glucose sensing

↑GCG secretion

N/A

N/A

↑Lipolysis

↑Fatty acid synthesis

?Anti-lipogenic effect

GCG: glucagon; GI: gastrointestinal; GIP: glucose-dependent insulinotropic peptide; GLP-1: glucagon-like peptide 1.

is generally thought to have no effects on food intake.17 GIP, but not GLP-1, increases triglyceride storage in white adipose tissue via stimulation of insulin secretion, and through vasodilation of adipose vascular tissue, as well as inhibiting bone resorption. GIP is, therefore, an anabolic hormone that inhibits lipolysis, and stimulates lipogenesis and bone formation. Increased GIP levels are observed in obesity, as fat is a potent stimulus of GIP secretion.17

GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE

There was little enthusiasm for therapeutic use of GIP in the years after its discovery because GIP infusions had little effect on insulin secretion and appetite regulation in T2D.17 GIP stimulates GCG secretion and potentiates insulin secretion during hyperglycaemia (Figure 3A);17 however, the insulinotropic effect of GIP is severely curtailed in T2D.18,19 Yet, the glucagonotropic effect of GIP prevails, even during hyperglycaemia (Figure 3B).20 Combined infusions of GIP and GLP-1 have additive insulinotropic effects in the non-diabetic state,21 and resistance to GIP-induced insulin secretion

in T2D can be reduced by a short period (weeks) of intensive glucose-lowering treatment (Figure 3C).17,22, This provides a rationale for using GLP-1 together with GIP agonism, as GLP-1 may lower glucose sufficiently to unmask the incretin effect of GIP, while GLP-1 action may overcome the potentiating effect of GIP on GCG secretion. Initial disinterest in the use of GIP has abated and the most prominent, recent approaches to dual incretins are unimolecular combinations of GIP with GLP-1R agonism.

RATIONALE FOR DUAL OR TRIPLE AGONISTS

As described above, GLP-1 RA have proven efficacy and their use has increased steadily since their launch in 2005.12-14 They are effective for glycaemic control and lead to weight loss that far exceeds that of the intestinal lipase inhibitor, orlistat;23 however, there remains a significant treatment gap in weight management between that attained with GLP-1 RA and bariatric surgery (Figure 4). The human body’s energy balance is governed through much more than a single hormone and it would be anticipated that combinatorial approaches will help close

Figure 3: Effect of hyperglycaemia and diabetes on glucose-dependent insulinotropic peptide’s insulinotropic action.

A) Experimental (acute) hyperglycaemia. B) Hyperglycaemia in established diabetes. C) Sustained normoglycaemia in diabetes. GIP: glucose-dependent insulinotropic peptide.

the treatment gap for obesity. Furthermore, the tolerability of GLP-1 RA is often dose-limiting. The most widely reported clinical side-effect of GLP-1 therapy is nausea, which is seen in 13–36% (lower incidence in once weekly preparations).13 Drug surveys have shown that most patients remain at the starting dose.24 There is a need for drugs with equal or better efficacy and a side effect profile that allows dose maximisation. By combining hormones in this way, the dose of individual hormones can be reduced, widening the therapeutic window, and avoiding toxicity.25

Glucagon-Like Peptide-1 and GlucoseDependent Insulinotropic Polypeptide Dual Agonists

A molecule that attracted early interest was NNC0090-2746 (also known as MAR709, RO6811135, and RG7697). This is a balanced GIP and GLP-1 RA, the development of which has been pursued, unsuccessfully to date, by several pharmaceutical companies.26,27 A Phase II trial in T2D showed a 1% reduction in HbA1c (Diabetes Control and Complications Trial units) and approximately 1.7% body weight reduction over

12 weeks, in comparison to placebo, but a further comparison to an open-label liraglutide active treatment control group was less impressive.26

The drug that has advanced furthest through development, in fact all the way to market, is Eli Lilly and Company’s (Indianapolis, Indiana, USA) tirzepatide (LY3298176), a unimolecular dual GIP/GLP-1 RA. It has comparable GIP receptor binding affinity to native GIP but fivetimes lower GLP-1R affinity than native GLP-1 and is thus an imbalanced co-agonist.28 This imbalance may allow maximisation of effect on the GIP pathway while minimising GLP-1-related tolerability issues; however, a further possibility has recently come to light. Experiments in islet cell models have shown that intracellular signalling after GLP-1R agonist binding occurs via two pathways, one of which (cyclic adenosine monophosphate generation) enhances insulin release, while the other (β-arrestin recruitment) causes GLP-1R receptor internalisation, and hence reduces cellular sensitivity to ligand.29 Intriguingly, the intracellular consequences of tirzepatide binding at the GLP-1R seem to be peculiarly biased towards cyclic adenosine monophosphate generation, at the expense of

β-arrestin recruitment. However, tirzepatide also has low efficacy to induce GLP-1R internalisation, perhaps by its limited ability to recruit β-arrestin. Therefore, the GLP-1R-mediated insulinotropic effect of tirzepatide might be enhanced not just by GIP receptor activity but also by bias in its interaction with the GLP-1R.29

Tirzepatide consists of 39 amino acids, with a C20 unsaturated di-acid acyl chain. The side chain binds to albumin, thereby prolonging the half-life, allowing weekly dosing. Phase II findings published in 2018 were promising, with tirzepatide showing dose-dependent effects on glucose levels and bodyweight.30 It outperformed dulaglutide 1.5 mg/day at the highest doses, albeit in a small group of study participants.

The Phase III trials have been testing tirzepatide as monotherapy, as an add-on to other treatments, and against established glucoselowering drugs in people with T2D, as well as a weight-loss agent in people with diabetes and obesity. The clinical trial data available have yielded impressive results on glucose control and weight loss (Table 2).31-41 It may be that improvements in islet function and insulin sensitivity with tirzepatide (compared to GLP1) account for the greater benefits in glucose regulation.42 Cardiovascular effects are being

examined in the SUMMIT trial.38 This will test whether people with obesity plus heart failure with preserved ejection fraction, randomised to tirzepatide or placebo for 52 weeks, improve a composite endpoint of mortality, heart failure events, exercise capacity, and heart failure symptoms.43 As a result of the evidence from Phase III trials, the U.S. Food and Drug Administration (FDA)-approved tirzepatide (Mounjaro™ [Eli Lilly and Company]) for the treatment of adults with T2D in May 2022.

Glucagon-Like Peptide-1 and Glucagon Dual Agonists

The well-known action of GCG is to increase blood glucose (hence ‘glucagon’ being a portmanteau of ‘glucose agonist’). It does so through stimulation of gluconeogenesis and glycogenolysis in the liver. GCG has additional effects including the modulation of food intake and satiety, lipolysis, fatty acid oxidation, ketogenesis, and increased energy expenditure.44 These latter metabolic effects make GCG attractive as an anti-obesity agent, but the applicability, especially in T2D, is complicated by the inherent risk of inducing hyperglycaemia.

Further characterisation of the GCG-like family of peptides led to the discovery of an endogenous

Figure 4. Treatment gap in obesity therapy.

GLP-1 RA: glucagon-like peptide 1 receptor agonists.

Treatment gap

GLP-1 RA+lifestyle

Table 2: Clinical trials of tirzepatide.

Diabetes trials

SURPASS-131

SURPASS-232

SURPASS-333

SURPASS-434

SURPASS-535

SURPASS-636

SURPASS-CVOT37

Obesity trials

SURMOUNT-138

Weekly tirzepatide 5, 10, and 15 mg, in drug naïve T2D. Placebo-adjusted HbA1c reductions over 40 weeks were 1.91–2.11% (20.80–23.10 mmol/mol), depending on dose; and weight reduction from 6.3 to 8.8 kg. Up to 92% of participants taking tirzepatide achieved HbA1c below 7.0% (53 mmol/mol), compared with19% of those taking placebo, and up to 52% versus 1% achieved levels below 5.7% (39 mmol/mol).

Weekly tirzepatide 5, 10, and 15 mg. HbA1c reductions up to 2.30% over 40 weeks of tirzepatide treatment, significantly greater than 1.86% reduction with semaglutide. Tirzepatide also resulted in up to 5.5 kg greater weight loss than semaglutide.

Weekly tirzepatide (5, 10, and 15 mg) compared to daily insulin degludec in suboptimally controlled T2D, despite stable treatment with metformin with/without SGLT2 inhibitor. Tirzepatide 15 mg achieved 2.37% reduction in HbA1c after 52 weeks of treatment, which was significantly greater than the 1.34% reduction with degludec. The tirzepatide groups lost an average of 7.5, 10.7, and 12.9 kg, compared with average 2.3 kg gain with degludec, and were significantly less likely to experience hypoglycaemia.

In people with T2D and increased cardiovascular risk, taking metformin with/without a sulfonylurea or SGLT2 inhibitor, tirzepatide, resulted in significantly greater HbA1c reduction than insulin glargine, at 2.58% (28.2 mmol/mol) for the highest dose (15 mg/week), compared with 1.44% (15.7 mmol/mol). Tirzepatide treatment also resulted in significantly more weight loss and less hypoglycaemia.

40 weeks of treatment with glargine plus the highest tirzepatide dose resulted in an average 2.59% reduction in HbA1c, which was significantly greater than the 0.93% reduction seen for glargine and placebo. The tirzepatide group lost mean 10.9 kg and reduced their insulin dose, whereas the placebo group gained 1.7 kg, and their insulin dose rose by 75%.

This is testing tirzepatide as an alternative to starting prandial insulin in people already using a basal insulin for T2D. The primary endpoint is change in HbA1c after 52 weeks of treatment. It is due to complete November 2022.

A 3-point MACE comparator trial against dulaglutide in people with T2D plus overweight and with atherosclerotic cardiovascular disease. Due to complete end 2024.

People without T2D but BMI ≥27 kg/m2 with comorbidities. Mean weight loss at 72 weeks was 15.0%, 19.5%, and 20.9% at doses of 5, 10, or 15 mg tirzepatide, respectively; compared with 3.1% with placebo.

Table 2 continued.

Diabetes trials

SURMOUNT-239

SURMOUNT-340

SURMOUNT-441

This has the same study design as SURMOUNT-1 but testing just the 10 and 15 mg tirzepatide doses in people with T2D. Due to complete April 2023.

In people without T2D, whether tirzepatide helps maintain or improve weight loss achieved during an intensive lifestyle intervention. Co-primary endpoints of per cent change in bodyweight and the proportion of people attaining at least a 5% reduction in their baseline bodyweight by week 72.

After 36 weeks of treatment with tirzepatide, the SURMOUNT-3 participants will be randomly assigned to continue with treatment or switch to placebo. Outcome is weight change from 36 to 88 weeks.

MACE: major adverse cardiovascular events; SGLT2: sodium-glucose co-transporter-2; T2D: Type 2 diabetes.

GLP-1/glucagon co-agonist ‘oxyntomodulin’, named for its potent effect on stimulating oxyntic (parietal) cells of the stomach to produce gastric acid.45 Oxyntomodulin is co-produced by intestinal L cells in the jejunum, along with GLP-1, and in the colon, in response to nutrient ingestion. Whilst there appears to be no specific oxyntomodulin receptor, endogenous oxyntomodulin causes appetite suppression, increased energy expenditure, and weight loss in people with obesity via activation of GLP-1 and GCG receptors.46 Native oxyntomodulin also significantly augments glucose-dependent insulin secretion acutely in subjects with obesity, with and without diabetes.46 Oxyntomodulin and GLP-1 are increased following bariatric surgery, and contribute to the weight loss and improved glucose control seen after bariatric surgery. GLP-1 and GCG are products of the proglucagon gene, arising from tissue-specific post-translational processing, and share a large degree of sequence homology.47 Co-agonism can, therefore, be obtained by modifying a relatively small number of amino acids from a GCG or GLP-1 backbone. In a seminal study by Day et al.,48 several co-agonists with different GLP-1-to-GCG receptor ratios were investigated in murine models and the optimal balance was suggested to be a co-agonist with equal potency on both receptors. Based on the promising preclinical results, pharmaceutical

companies have taken GLP-1/GCG co-agonists into clinical trials.

Mazdutide (also known as IBI362 or LY3305677) is an oxyntomodulin analogue being developed by Eli Lilly and Company. A Phase IB study showed that it was well-tolerated and weight loss up to 6.4% was achieved over 12 weeks.49 The glucose-lowering potential of cotadutide (a GLP-1/GCG RA) was seen in a Phase IIa study, in which the post-prandial area under curve was significantly reduced, and 3.4% weight loss was achieved after 49 days, in adults who are overweight with T2D.50 Efinopegdutide (also known as HM12525A or JNJ-64565111) is a once-weekly GLP-1/GCG co-agonist. In a dosing ranging study, 472 individuals who are overweight without diabetes were randomised and 72% completed 26 weeks of treatment. Weight loss of -6.8%, -8.1%, and -10.0% were seen at 5.0 mg, 7.4 mg, and 10.0 mg doses, compared to -5.8% with liraglutide 3.0 mg;51 however, nausea and vomiting were higher with efinopegdutide. A niche for this drug may prove to be the treatment of non-alcoholic steatohepatitis, as the effects of GCG agonist on hepatic fat oxidation would be desirable in this group.

TRIPLE AGONISM

Having determined the therapeutic potential of the dual co-agonists (with either GCG or GIP complementing GLP-1), Finan et al.52 showed proof of concept that simultaneous agonism at all three receptors, through a single molecule, could be achieved and produce superior therapeutic outcomes.

In a series of experiments in monkeys with obesity and diabetes, the tri-agonist SAR441255 showed superior metabolic outcomes to that achieved with a comparator dual GLP-1/ GCG RA.53 Subsequently, Phase I experiments reported that the drug was well tolerated; and the simultaneous receptor engagement, that had been seen in monkeys, of GIP, glucagon, and GLP-1 was confirmed in humans.53

Another GIP/GLP-1/GCG triple RA, LY3437943, has also undergone Phase I trials. After 3 months of treatment, a placebo-adjusted decrease of HbA1c up to 1.56% was seen, with placeboadjusted body weight reduction of -8.96 kg.54 Data from two larger, Phase II trials are due in the coming months.

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Another molecule, HM15211 is a triple full agonist chemically conjugated with a constant region (fragment crystallisable) of human Ig, allowing weekly dosing. As with GLP-1/GCG dual agonists, these triple agonists may have differential efficacy in non-alcoholic steatohepatitis, through reduction in energy intake, β-oxidation, and de novo lipogenesis. In preclinical models, liver fat and liver enzymes were both reduced by LY3437943 and by HM15211.47

CONCLUSION

There is a promising future for the treatment of T2D, obesity, and its metabolic complications. Harnessing the full potential of the incretin system with dual, or possibly triple agonists, appears to produce incremental metabolic gains. This is possible without furthering, often lessening, the side effect profile of GLP-1 RA.

The GLP-1 RA are still under prescribed in developed and well-funded health care systems and are not even available in the most modern formulations in some parts of the world. The authors hope that this review will contribute to a better understanding of the role and relevance of GLP-1 RAs in the treatment of T2D.

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36. Eli Lilly and Company. A study of tirzepatide (LY3298176) versus insulin lispro (U100) in participants with type 2 diabetes inadequately controlled on insulin glargine (U100) with or without metformin (SURPASS-6). NCT04537923. https://clinicaltrials.gov/ct2/show/ NCT04537923.

46. Shankar SS et al. Native oxyntomodulin has significant glucoregulatory effects independent of weight loss in obese humans with and without

type 2 diabetes. Diabetes. 2018;67(6):1105-12.

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1b study. EClinicalMedicine. 2021;39:101088.

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monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015;21(1):2736.

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Authors:

CT Colonography Versus Optical Colonoscopy: Cost-Effectiveness in Colorectal Cancer Screening

*Orysya Svystun,1 Marilyn Zeman,2 Michael Seidler,1 Christopher Fung1

1. Department of Radiology and Diagnostic Imaging, University of Alberta, Edmonton, Canada

2. Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Canada

*Correspondence to svystun@ualberta.ca

Disclosure: The authors have declared no conflicts of interest.

Received: 20.01.22

Accepted: 25.07.22

Keywords: Colonography, colonoscopy, colorectal, CT colonography (CTC), optical colonoscopy (OC), screening.

Citation: EMJ Innov. 2022; DOI/10.33590/emjinnov/10035977. https://doi. org/10.33590/emjinnov/10035977.

Abstract

Purpose: CT colonography (CTC) has been accepted as an optical colonoscopy (OC) alternative for colorectal cancer (CRC) screening by some guidelines, while others maintain that the data is insufficient. CTC’s less invasive nature may improve compliance; however, cost and need for colonoscopy, if lesions are detected, remain an obstacle for implementation. As a result, the authors set out to determine the cost-effectiveness of CTC in the context of its drawbacks and advantages when compared with OC within a Canadian context.

Methods: Using a decision analysis software, an economic analysis was performed comparing CTC to OC for CRC screening in asymptomatic patients. The 10-year primary outcome measure was study cost, cost difference of screening 100,000 patients, and the cost of one quality adjusted life year gained. The sensitivities, specificities, and polyp prevalence rates were derived from literature. The cost of each test was derived from local data.

Results: Local cost of OC is 764.36 CAD compared to 580.01 CAD for CTC. In the case of a normal OC, reassessment would not be necessary for 10 years, whereas in an asymptomatic average-risk population CTC must be repeated every 5 years. The incremental cost-effectiveness ratio, or the additional cost per life year of OC compared to CTC was calculated to be 3,390.76 CAD.

Conclusion: Although CTC costs less to perform than OC, when a 10-year screening interval is utilised and quality adjusted life year is set at 50,000 CAD, OC remains a cost-effective method of CRC screening if the 5-year CTC screening interval is maintained.

Key Points

1. In average-risk patients, colorectal cancer screening with optical colonoscopy is more cost-effective than CT colonography (CTC), as long as the CTC 5-year screening interval is maintained.

2. In the context of a Canadian publicly-funded healthcare system, increasing the CTC screening interval to 10 years would render it a more cost-effective colorectal cancer screening modality compared with optical colonoscopy.

3. Patient compliance and a shorter time commitment in the absence of anaesthesia were not incorporated into the analysis, potentially underestimating the cost-effectiveness of CTC.

INTRODUCTION

In 2017, colorectal cancer (CRC) accounted for 13% of new malignancy diagnoses in Canada. It is the second leading cause of cancer-related deaths in Canadian males, and the third leading cause of cancer related deaths in Canadian females.1 Screening for CRC has been shown to reduce mortality, lead to earlier diagnosis, and consequently reduce costs for the healthcare system.2

The recently published US Preventative Services Task Force Recommendation Statement on screening for CRC offers numerous options for CRC screening, including yearly guaiac faecal occult blood test (gFOBT) or faecal immunohistochemical test (FIT); optical colonoscopy (OC) every 10 years; or CT colonography (CTC) or flexible sigmoidoscopy every 5 years.3 In this publication, they also advise initiating screening at 45 years (Grade B recommendation). The Canadian Task Force on Preventative Health Care (CTFPHC) suggests screening adults aged 50–74 years, who are not at high risk with either gFOBT or FIT every 2 years, or flexible sigmoidoscopy every 10 years.4 Positive screens are followed up with an OC.5 Meanwhile, the 2010 Canadian Association of Gastroenterologists (CAG) guideline recommends screening patients between 50–75 years, with the decision to screen individuals older than 76 years made on an individual basis. Screenings with gFOBT or FIT every 2 years, or with flexible sigmoidoscopy every 10 years are suggested. CAG recommends against CTC and OC as screening tools for the general population.6

Although Canadian participation rates in screening programmes have improved, they

vary across the country, and in 2012 the target population had a rate of up to date CRC screening of 55.2%.7 The discomfort associated with OC and its complications likely contribute to the poor compliance with current screening recommendations.8 In addition, wait times for an OC after a positive gFOBT or FIT remain longer than targeted.9 Consequently, diagnosis most often occurs at Stage III CRC, which has negative implications on both the patient survival and treatment costs.4,10

CTC, also known as virtual colonoscopy, was developed as a less invasive alternative to conventional endoscopy. Patients undergoing CRC screening have been shown to prefer CTC to both OC and double contrast barium enema.11 While the technique requires colonic insufflation and bowel preparation, CTC eliminates risks of bleeding and colonic perforation, and has been shown to cause minimal adverse events related to radiation.8,12 Although CTC does not allow for polyp removal, its sensitivity for colonic lesions is comparable to endoscopy for lesions larger than 5 mm.8,13-16

Some analyses revealed that CTC, when contrasted with OC, may be less costly.17-19 Other reviews uphold that OC is more costeffective, which continues to generate debate.20 Economic evaluation from one country may not be generalisable to another given variation in healthcare models, and unfortunately, the most recent Canadian-based cost-effectiveness analysis, which is limited by outdated sensitivity, specificity, and complication statistics, indicated that CTC was not cost-effective.21 To assess whether this still holds true in Canada, a singlepayer healthcare system, the authors performed an economic evaluation comparing CTC to OC for CRC screening.

METHODS

An economic analysis, performed from the healthcare payer’s perspective, to compare CTC to OC for CRC screening was conducted using the decision tree software TreeAge (TreeAge Software Inc., Williamstown, Massachusetts, USA). The population of this hypothetical model was asymptomatic average-risk patients initiating screening at 50 years of age (corresponding to the current Canadian guidelines). The term polyp in this analysis refers to any polypoid lesion, including adenomas (serrated and sessile) and carcinomas that may be excised.

Cost of the two screening tests was calculated from local data within a publicly-funded tertiary care hospital in Canadian dollars. A 10-year period was elected for this analysis to account for the currently recommended OC interval.3,4 Subsequent 10-year cycles would have similar effects, and a longer period model was not analysed given screening duration variability depending on individual patients’ clinical context. CTC was compared to OC as OC was previously perceived as the more sensitive screening approach. The CTC and OC polyp sensitivity and specificity, and the incidence of procedure complications were derived from literature. The colonoscopy sensitivity averaged out to 83.7% for polyps larger than 6 mm, and 91.9% for polyps larger than 10 mm compared to 94.0% and 96.0%, respectively, in the last Canadian cost-effectiveness analysis. The colonoscopy specificity was 94.2% for polyps larger than 6 mm and 88.7% for those larger than 10 mm, whereas colonoscopy was deemed to be 100.0% specific in the 2005 publication. CTC statistics also differed with a sensitivity of 86.5% (61.0% in 2005) for lesions larger than 6 mm and 89.2% (71.0% in 2005) for polyps greater than 10 mm. CTC specificity is now 88.3% for polyps over 6 mm and 94.4% for those over 10 mm, compared to 84.0% utilised in the last Canadian analysis.21

Based on these values, a mathematical analysis was performed (Table 1). Of note, polyps smaller than 6 mm were not included in the analysis given the limited sensitivities and specificities documented in literature limiting their visualisation.8 To assess the value of the medical intervention in a more clinically relevant fashion, the authors utilised quality-adjusted

life year (QALY). The value of 1 QALY equates to 1 year of good health. QALY values were derived from Jeong and Cairns.22 In congruence with the cost-effectiveness literature based on USA medical data, the authors set their QALY threshold at 50,000 CAD and 100,000 CAD.23,24 Institutional ethics research board approval was obtained prior to the initiation of this project (Pro00071780).

As current guidelines recommend OC every 10 years and CTC every 5 years in average-risk individuals, patients would ideally receive two CTCs or one OC in the 10-year model period. The fact that patients would require an OC should CTC identify a lesion was accounted for in the analysis (Figure 1). Although CTC has the potential of improving screening compliance and has been shown to be preferred by patients over OC, this was omitted in the development of this cost analysis model and 100% adherence was assumed.25 Additionally, the indirect costs of CRC screening were excluded from the analysis; for example, the financial implications of the patient and individual driving them to the procedure being obligated to take time off from work, parking at the hospital, etc. The model also assumed endoscopy availability and patient compliance when a polyp was identified on CTC and required resection and colonoscopy. Consequently, polyp progression to cancer was not accounted for.

The study’s primary outcome measures consisted of the difference in cost between CTC and OC per individual study, per a 100,000-patient screening cohort, and finally the cost of 1 life year gained with each modality. Secondarily, the authors compared the CTC and OC cost per life year gained, and the financial burden of screening 100,000 patients if the CTC interval was increased to 10 years as opposed to the currently advised 5 years. This manuscript was prepared using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist for reporting economic evaluations of health interventions.26

RESULTS

A review of expenses at a local tertiary academic hospital revealed that the current cost per

Table 1: Baseline probabilities.

Risk of bleeding post-colonoscopy8 N/A 0.08

Risk of perforation with colonoscopy8 N/A 0.04

Further investigations post-CTC13 N/A 16.00*

Adverse CTC radiation events8 N/A Negligible

*Extracolonic findings on CTC were found in 66% of the participants; however, only 16% required additional evaluation or urgent care.

CTC: CT colonography; max: maximum; min: minimum; N/A: not applicable.

CTC study is 580.01 CAD while the cost for a diagnostic OC is 764.36 CAD, resulting in a difference of 184.35 CAD per investigation. When a polypectomy is performed, the fee for OC increases by at least 232.29 CAD. The aforementioned expense estimates account for nursing staff, physician billing, clerical work, equipment purchases and its maintenance, as well as linen services (Tables 2 and 3).

The 10-year cost prediction model demonstrates that OC remains the less expensive screening strategy. When 100,000 patients are screened with this method, 39.6 million CAD may be saved compared to screening patients with CTC. With QALY set to either 50,000 or 100,000, CTC becomes the more cost-effective method if the screening interval for CTC is increased to 10 years to mirror OC, rather than the currently recommended 5 years (Table 4).

DISCUSSION

CTC is a less invasive alternative to OC for CRC screening and has been suggested to be more economical. Although this study assumes 100% adherence and omits complication rates, it demonstrates that OC remains the more costeffective screening tool if the CTC screening interval remains 5 years.

The finding that CTC is not cost-effective when applied to a 100,000-patient cohort was also the outcome of the most recent Canadian costeffectiveness study comparing OC to CTC for CRC screening.21 Despite CTC costing 184.35 CAD less than OC per study and its sensitivity/ specificity improving, these factors seem to be unable to overcome the costs associated with the need for OC when a tissue sample is needed. A study based on USA data also reproduced these results, assuming 100% adherence to

screening and referral for OC in the presence of lesions greater than 6 mm; however, their cost differential per individual study was much smaller than that identified locally (488 CAD for CTC compared to 498 CAD for OC). Furthermore, Knudsen et al.27 created a model where CTC implementation was speculated to improve adherence to screening by 25%. With this assumption, despite CTC being only 10 CAD cheaper than OC, it became the most cost-effective method of monitoring for CRC even when compared to gFOBT.27 Interestingly, Pickhardt et al.28 submitted a response to this publication suggesting that a 25% increase in screening compliance could be easily met.28 Since then, a screening adherence improvement of 56% in the CTC arm has been shown in a randomised control screening trial.29 Finally, a study published in 2017, which compares costeffectiveness of 13 CRC screening strategies, also showed that OC remains most cost-efficient. Of note, CTC every 10 years is the second most cost-effective, followed by sigmoidoscopy every 5 years.30

There are also a number of non-Canadian publications identifying CTC to be more cost-effective when compared to OC, as

demonstrated by Pyenson et al.18 using data from 2013–2015 Medicare claims. In their analysis, CTC was valued at 25% of the cost of a diagnostic OC compared to 76% locally.18 Additionally, Sawhney et al.31 used retrospective healthcare claims from 2016 to show the average cost of OC was 2,033 CAD per insured patient. The authors state that insufficient CTCs were conducted to derive reliable values, and as a result CTC costs were estimated. Despite this bias, their analysis deemed CTC at least 22% less costly than OC, which was attributed to not needing anaesthesia or pathology services.31 Additionally, imaging for CRC screening was found to be cost-effective in a Dutch analysis comparing the two modalities (CTC was done every 5 years for a total of 25 years within their model and measured against OC, which was performed thrice over 30 years). Unlike this model, their publication used screening participation rates derived from literature, and accounted for complication costs by generating estimates for CTC.19 Finally, a randomised control trial based in Amsterdam and Rotterdam, the Netherlands, showed that CTC was more cost-effective than OC if CTC is used to screen more than twice in a lifetime, primarily due to improved participation rates.29 Unfortunately, as

CTC: CT colonography; OC: optical colonoscopy.

Figure 1: Cost analysis model.

Table 2: Breakdown of CT colonography cost.

45 min central intake, booking, reception, reminder call

MRT II, 50 min: set up, patient preparation/instructions, assistance, clean up, and documentation

(Sanofi, Reading, UK) 20 mg oral (2x10 mg tablets)

Table 2 contined.

(Durham, North Carolina, USA)

*The annual fee for the maintenance of the TeraRecon (Durham, North Carolina, USA) software is approximately 335,000 CAD. CTC is estimated to represent approximately 5% of TeraRecon’s local use.

Max: maximum; min: minimum; MRT: magnetic resonance tomography; PACS: picture archiving and communication system; RN: registered nurse.

with the aforementioned articles, it is difficult to cross-reference expenses to local data but in van der Meulen et al.’s29 publication, a diagnostic CTC was 77% the cost of a diagnostic OC, which is similar to our local values.

An important point for discussion is the screening interval for CTC. Secondary to technological advances, CTC sensitivity and specificity is now near-equivalent to that of OC colonoscopy (Table 1). Consequently, an argument can be made for increasing the period between CTCs. The model where CTC and OC are performed with the same frequency shows that OC has an incremental cost-effectiveness ratio of 112,251.70 CAD, clearly falling outside of the historically utilised QALY of 50,000.00 CAD; however, Neumann et al.24 argue that the 50,000.00 CAD threshold is long outdated, and urge that 100,000.00 CAD serve as a new cut-off. Adopting this recommendation would not alter the fact that OC is not cost-effective should the CTC screening interval be increased to 10 years.

One of the potential drawbacks of this analysis is the omission of downstream complication costs of each modality. The 2016 US Preventative Services Task Force publication on CRC indicates that the risks of bleeding and perforation with OC are 0.08% and 0.04%, respectively.8 The same article also concluded that radiation associated complications of CTC are negligible;

a statement that is further supported by many radiation scientists. There is no conclusive evidence that medical imaging radiation causes harm to adults especially given that the currently available techniques result in an effective dose equivalent or less than the annual background dose of 3 mSv.32 Johnson et al.13 found that CTC results in 16% of patients having further investigations. Interestingly, a retrospective cohort review of patients who underwent CTC revealed that within the year post screening they did not differ in their healthcare expenses compared to patients who had undergone OC.33 This suggests that omitting modality related complication costs is unlikely to have an impact on the cost-effectiveness analysis.

Johnson et al.13 also reported that 66% of patients undergoing CTC have extracolonic findings.13 Pickhardt et al.,34 back in 2009, showed that CTC is cost-effective secondarily due to its ability to identify abdominal aortic aneurysms and CRC simultaneously at no extra cost.34 Therefore, not accounting for extracolonic findings and their impact on cost-effectiveness may have devalued CTC. The cost-effectiveness of CTC may also be underestimated by this study by omitting from the analysis the income lost by the patient and whoever drives them to the procedure since following CTC. In the absence of sedation, the patient is safe to operate a vehicle, which is not the case with OC. Another drawback

Table 3: Breakdown of optical colonoscopy cost.

Table 3 contined.

APC: argon plasma coagulation; GI: gastrointestinal; HD: high definition; IV: intravenous; N/A: not applicable.

Table 4: Primary and secondary outcomes.

Colonoscopy with polypectomy (min) 931.72 Colonoscopy with polypectomy (max) 1,018.22 CTC 580.01

OC cost difference per 100,000 patients (10 years) N/A

CTC every 5 years -39.6 million

CTC every 10 years +18.4 million

ICER colonoscopy N/A

CTC every 5 years 3,390.75

CTC every 10 years 112,251.70

CTC: computerised tomographic colonography; ICER: Incremental cost-effectiveness ratio; max: maximum; min: minimum; N/A: not applicable; OC: optical colonoscopy.

of this study is the omission of compliance rates to each modality for CRC screening. Although these statistics have been documented, no values were identified in Canadian literature. Consequently, an assumption of 100% adherence to both screening tests was adopted in this hypothetical model. As a result, variations in adherence were not considered as in the 2005 Canadian analysis.

CONCLUSION

There is continuous debate in literature regarding the cost-effectiveness of CTC in comparison to OC for CRC screening. This study is the first

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