PROFESSOR NANCY BAXTER: Welcome to another episode of Research Bytes. This is the podcast from the Faculty of Medicine and Health at University of Sydney, where we discuss a new and emerging topics in research and speak to the people that really make a difference and bring research that has impact on the lives of Australia and people in the world.

First, I'm Nancy Baxter, I'm the Interim Executive Dean of the Faculty of Medicine Health, and I come to you from the lands of the Gadigal people who have been custodians of the lands and waterways of these areas for thousands of years and many generations.

Today, we're going to be talking to Dr. Nigel Maher, who is a pathologist and a PhD student at the Sydney Medical School. Nigel was in the three minute thesis. He won the faculty heat, then he won the University of Sydney competition, then he became the national three minute thesis champion and then placed second in the Asia Pacific three minute thesis competition.

Congratulations on that, Nigel. First of all, tell us a little bit about that experience. 

DR NIGEL MAHER: Oh, look, it was an amazing experience and thank you very much for the introduction. But yeah, no, the competition, I suppose I come from a very scientific realm of communication and yeah, it's a very creative opportunity to express your research.

PROFESSOR NANCY BAXTER: So how do you craft a story about your research?

DR NIGEL MAHER: I suppose it's like developing a plot, you know, emphasising the importance of the topic to the listener you know, and creating some drama and tension, and then, you know, providing a hero to save the day, which is your solution, your research, and then, you know, some sort of happy conclusion or prelude to the next edition. And that's effectively maybe how the research is implemented or the next steps, you know, to tie it all together as well. 

PROFESSOR NANCY BAXTER: Yes. I encourage anyone who's listening out there to link to the three minute thesis because it's really quite impressive and it's talking about the use of AI for pathology and specifically identification of melanoma. So do you want to tell us a little bit about what the research you're doing entails?

DR NIGEL MAHER: Yeah, sure, sure. So, um, yeah, I'm using AI related tools to help better diagnose and manage melanocytic tumours. And so in this sort of instance for the three minute thesis, I was discussing the use of AI image analysis to help distinguish melanoma from benign moles.

You know, I want to point out that the research I'm doing is in a multidisciplinary team. And it's really critical that AI has developed that way for healthcare because, you know, you have to have the domain expertise across both the subject matter as well as the AI science and data analytics as well.

That’s a separate topic, but in this specific research, we took basically straightforward melanomas and straightforward moles, and it was 520 of those in total, and saw if three different types of models could help to distinguish those lesions. And they did remarkably well to do that.

But there were also some important limitations to the, to the research as well. You know, it's quite a research-based context, this paper. But in the real world, you know, melanomas and moles don't exist on a binary classification. There's a spectrum and you incorporate other elements to develop the ground truth, so clinical information, demoscopic information, genomic information. And so those factors sort of weren't incorporated in this analysis. 

PROFESSOR NANCY BAXTER: But basically, the potential is to be able to identify points of disagreement, essentially, between the computer and the pathologist to help the pathologist in terms of particularly those difficult cases. Am I correct? 

DR NIGEL MAHER: Yeah, that's the idea. I mean, there's opportunities along the spectrum in pathology, whether it's early triage of cases that are melanocytic in nature and might be difficult and need to have early investigations ordered so you can turn the case around more rapidly. But maybe in this instance, you know, I consider this style of research, maybe more focused on the quality control aspect of the sign out stage, so it's like an opportunity to double check did the human get it right. 

PROFESSOR NANCY BAXTER: Yeah, yeah, it's almost like an automatic second opinion. 

DR NIGEL MAHER: Exactly. 

PROFESSOR NANCY BAXTER: What are your pathology colleagues think? 

DR NIGEL MAHER: There’s lots of apprehension about AI. You know, I think initially it was fear about jobs. I think that's kind of dissipated, but then it's sort of thinking now, how do we implement this safely and how do we trust it? What's the explainability behind it? 

PROFESSOR NANCY BAXTER: Yeah, we talk about explainability in terms of medical AI use. Do you want to talk a little bit about what the issues are and why clinicians are concerned about explainability?

DR NIGEL MAHER: AIs have that reputation as a black box. And, uh, and you know, it depends on what models you're talking about here for explainability, large language or image analysis. I've been focused on image analysis.

In my research here, I was using multiple instance learning. It's a sort of weekly supervised training mechanism where you provide a label of the global image without doing sort of specific feature annotation on the image.

If you understand the development, there's inherently less trust because, you know, just to call one image a melanoma and one a mole, how does the computer know what was the really important regions to look at? And so there's already a little uncertainty there of how it's deriving its predictions and what we used is heat map overlays over the slide to show where the models are placing high attention on to derive their predictions. And that's not perfect as an explainable method, but it offers some insight into what's going on. 

PROFESSOR NANCY BAXTER: So you can see if the pathologists think that those really are the important areas to be looking at? 

DR NIGEL MAHER: Yes. Yes. So if the model's placing high attention on the tumoral areas, we've got a better confidence that it's doing the right thing. But, you know, we have saw some cases where it might be down the edge of the tissue section or outside of the tumoral area, sun damage or so on, where you sort of get a little bit of uncertainty of, can I trust this? So we're working on models to improve that explainability. 

PROFESSOR NANCY BAXTER: What surprised you in this research? Was there anything that was, ‘I was not expecting that’? 

DR NIGEL MAHER: Look, I wasn't expecting the high results to differentiate melanomas and moles. We had accuracy, about 96 percent in the best model, dropped a little bit with the colour calibration. So, you know, some slides are a bit older, they're a little faded in colour, so once we sort of took that into account, the accuracy dropped about 93%. So that was quite high. I didn't anticipate that. 

PROFESSOR NANCY BAXTER: I'm sure there were a lot of challenges in this. It's AI, it's an emerging field. What were the key challenges you had to overcome?

DR NIGEL MAHER: So look I think establishing the ground truth in melanocytic, or any AI research, but you know, particularly melanocytic pathology, it's inherently subjective. You know, we don't have a ‘if it's this, it has to be that’. So, establishing the ground truth and what we did for that is took two pathologists as a consensus diagnosis, so the original reporting pathologist and myself as a screener to agree or not. I had some previous experience after I finished my training in melanocytic pathology under Professor Richard Scolyer, who's a world recognised expert in this field.

So that sort of helped overcome that slightly, but I would say there's still, arguably, you could have more pathology reviewers. And obviously we didn't take into account clinical or demoscopic information for more establishment of that ground truth. So, we overcame some of that, but not went all the way.

And I think the other challenges are, you know, you have to digitalise these cases and you know, the workflows that we have at the moment aren't set up to just, make that efficient. And there's artifacts, things like, coverslip bubbles, wax, and things that get all over the slides. You have to take a lot of time to clean and prepare the slides for scanning.

PROFESSOR NANCY BAXTER: I guess with human pathologists, they can overcome that. But with computer pathologists, we need to be much more particular about our slides.

Well, what's next for you? So this seems like the start of a journey. Where is this research taking you? How do you see this being implemented? 

DR NIGEL MAHER: There's a number of opportunities I see in this research. I guess it's just one small step forward. I think there's a lot more steps to go, but ultimately I’d like to see it translated into clinical benefit and to get there, I'm about to start the periscope commercialisation program at the University here. That's with working on another tool that I've been researching and involved with genomics.

I think that sort of pathway is, is a avenue to sort of take this research forward. But it needs a lot more work to get there to commercialise, or you license it or that sort of thing.

PROFESSOR NANCY BAXTER: Yeah in the past researchers have kind of thought of commercialisation as something very separate from the research we do. But in these types of things, really you need to think in a commercial way to actually allow this to potentially achieve everything that it could achieve. It's only going to be possible if once you perfected it, it's actually used at scale. 

DR NIGEL MAHER: Absolutely, you’re absolutely right. And I feel a bit stigmatised sometimes with the word commercialisation. And, you know, I think it's the way that it's, as you say, it's it, to get it out into the real world, you kind of have to take this path because there's a lot of, you know, time and money costs in terms of overcoming all the regulatory approvals and barriers in healthcare. And so, you know, you need to raise funding and get the right expertise involved to help it get there. But even before that step, it's sort of, you know, AI scientists and building the team to you know, develop the product even more to be more robust and reliable and trustworthy and all those sort of things. 

PROFESSOR NANCY BAXTER: And ultimately working together with commercial entities to have benefits for pathologists and for patients.

DR NIGEL MAHER: Absolutely. 

PROFESSOR NANCY BAXTER: So what advice do you have for higher degree by research students? So if you think about yourself, what, four years ago when you were starting on this journey or even further back. What advice would you have for people considering this type of career and pathway? 

DR NIGEL MAHER: I say don't rush into it and think about your long term vision and what you want to get out of the degree. It's not a tick box exercise. So what are the strategic advantages this degree gives you? Is it connections, networking, specific skills? What am I passionate about? You know, you have to be passionate and driven, I think, to get the most out of this. If you come at it with that mindset, I think there's a lot of opportunities that open up along the way, you know, going to conferences and be prepared to, you know, invest some of your personal time to get the most out of it.

PROFESSOR NANCY BAXTER: Well I want to thank you very much for sharing your story. I want to congratulate you again on your great success in the three minute thesis. And again, it's worth watching if you want to know how you can talk about your research in a very succinct way to people who are non-experts.

So congratulations on that and all the fantastic work you're doing. 

DR NIGEL MAHER: Thanks, Professor. Cheers.

PROFESSOR NANCY BAXTER: Welcome back to another episode of Research Bytes. I'm Nancy Baxter. I'm the Interim Executive Dean of the Faculty of Medicine and Health here at University of Sydney. And we are really looking forward to the 2025 season of Research Bytes when we talk to researchers throughout the faculty about the exciting work they're doing, the challenges they've had along the way and the many successes and fabulous research that's being done that actually has an impact on the lives of people in Australia and well beyond.

First, I would like to acknowledge that I come to you on the lands of the Gadigal people who have been custodians of the lands and waterways of this area of Australia for thousands of years, many, many generations, and I particularly want to emphasise the connection to country that the First Nations people of Australia have and their care of country, which there's much to be learned from in the era of climate change.

With that, I'm very pleased today to be speaking with Dr Binh Nguyen. Binh is the Research Fellow at the Prevention Research Collaboration at the School of Public Health at University of Sydney. Welcome.

DR BINH NGUYEN: Thank you for having me. It's great to be here.

PROFESSOR NANCY BAXTER: We're going to be talking a little bit about some of the exciting research you've been doing in looking at risk factors for chronic disease, specifically lifestyle risk factors. So I think that's something many of our listeners either are concerned about or should be concerned about for their future health.

But first, before we get to the research that you've been doing, can you tell us a bit about your career so far and how you got to this point?

DR BINH NGUYEN: Sure, I guess my journey began when I completed a Bachelor of Science to start with, and I majored in physiology. I was interested in the human body and health generally, so I thought, oh, that might be a good start. And then I moved on to do a Master of Science. It was a research degree, a two-year degree, and it introduced me to research a little bit. But then, as most students do, I took a break and travelled, volunteered overseas.

But I always had an interest in nutrition and dietetics as well, so I decided to go back to studying and did a Master of Nutrition and dietetics at the University of Sydney. And then that led to a PhD in public health here at the University of Sydney as well. And I'm currently working as a research fellow, as you mentioned, with Professor Melody Ding, and my thesis was about aspects of cardiovascular risk in a large Australian population, focusing on potential gender differences and behaviour specific to women.

PROFESSOR NANCY BAXTER: You know, your work is very epidemiologically focused, at least the papers that I've read. What did you do when you were first in the lab? I don't think you did that, did you? Were you working with test tubes and?

DR BINH NGUYEN: No, actually. So the first master's, I actually worked with people who were trying to lose weight. And I looked at the fat around their abdominal, like the abdominal adipose tissue, and I got to like colour the fat on computer tomography scans and things like that and relate that to their risk of insulin resistance.

I also forgot to mention that I did work as a research assistant with Professor Louise Baur at the Children's Hospital at Westmead. And I worked there for a few years on an RCT (randomised clinical trial) for adolescents with overweight and obesity. And that's where I really strengthened my research skills and realised that I really liked it and wanted to continue working in research.

PROFESSOR NANCY BAXTER: I think it's always so interesting when people look at you in the position you're in, they often see your career trajectory is very straight and that's in retrospect. But prospectively, you know, our careers take various pathways and the direction is certainly not direct. Yours seems to be always related to nutrition and lifestyle, so there's a consistent theme, but it's taken many different bends. I mean, what do you think are some of the most important kind of points in your career trajectory?

DR BINH NGUYEN: Yes, it did seem like it wasn't linear, but when I look back at everything I've done, it all comes together. It's all related to health, looking at different lifestyle behaviours, nutrition, physical activity, and also taking a step back to really think about what is it that I want to do, what matters to, to me and my research.

PROFESSOR NANCY BAXTER: Yeah, I think that's so important because you can easily, you know, follow the money, shall we say, and you end up doing something that doesn't necessarily fulfill you in the way that research really needs to do to keep you going.

DR BINH NGUYEN: Yes, that's true. You do need that driving force, motivation.

PROFESSOR NANCY BAXTER: Especially for the days where, uh, you don't have, fantastic results like you did. So, why don't you tell us a little bit about the paper we're here to talk about today. What are the key findings? What were the challenges in doing this work?

DR BINH NGUYEN: So this paper examined the long term patterns of physical activity and how these have an effect on health related quality of life in mid age women.

Quality of life measures a person's perceived well being and functioning in different aspects of health, including social, mental, and physical aspects. And it's important because it's related to healthy aging and it's also an indicator of population health. So that's why we were interested in this variable that we had.

In most studies in the past that have examined its relation to health, usually measure it at one point in time. And our study was different in that we looked at physical activity at multiple time points. So looking at the patterns over time. And that's important because physical activity as you all know, changes over time depending on our life transitions.

For example, if a woman has children suddenly or goes back to work or retires. So that's why we wanted to put that evidence out there. We found that for women that consistently met the World Health Organisation recommendations for physical activity, that is at least 150 minutes of physical activity per week.

They had a better quality of life later on in life than those that never met the recommendations over 15 years. And another important finding was that women that started to meet the guidelines in their mid-fifties also had benefits in terms of their physical health. Um, so that was really encouraging, and it shows that it's not too late to turn the clock perhaps. If you start to engage in physical activity in your fifties, uh, you may still reap the benefits.

PROFESSOR NANCY BAXTER: Did that surprise you? Or if not, what did surprise you?

DR BINH NGUYEN: I was surprised in that the effects we saw, the improvements we saw, were similar for those that started to meet the recommendations for physical activity early in midlife compared to those that consistently met the recommendations across mid age.

We also looked at the effects of physical activity patterns on mental health, and the effects were weaker, and we didn't expect that either. But we think this is for a couple of reasons, one of which is maybe the period that we used to study these associations was too short, or perhaps health related quality of life affects physical health and mental health aspects in different ways.

Yeah, so those were the surprising findings.

PROFESSOR NANCY BAXTER: Now, this particular cohort is really unique in terms of having long term follow up of women in Australia. It's called the Australian Longitudinal Study on Women's Health. It's been going on since 1998 and has repeated measurements of people over time, which presents a really unique opportunity to study people over the life course instead of just at one moment.

DR BINH NGUYEN: It's a very valuable resource. So it does follow women of different ages over the years. And for this study, we used data from more than 11, 000 women. The study followed them up every three years. So we had information about physical activity and quality of life, and other things over the long term.

PROFESSOR NANCY BAXTER: So that's a really great way of using data and a study that's already there to it for your own research in terms of answering your own research questions. So it's a great use of resources that are out there. But what challenges did you experience in this and how did you overcome them?

DR BINH NGUYEN: So we use the particular methods that are usually used in other fields such as substance addiction and we apply those methods to the physical activity field. So that's really innovative. And we were able to derive causal effects, which is rare. Because usually you can observe that there's an association, but there are lots of biases and these methods help to reduce these biases.

So our challenge was to write the paper in a way that people could understand it and could understand the methods and also in a way that it was appealing to journals and they understood the value of what we did.

PROFESSOR NANCY BAXTER: So what's next for you?

DR BINH NGUYEN: Well, we have a couple of studies that are similar, but looking at other health outcomes. So I'm also looking at the effects of longitudinal patterns of physical activity on mortality outcomes. And we might try to apply these methods as well to mental health and type two diabetes. But I'm also involved in other work, including like a systems mapping of physical activity in New South Wales with the group that I work with.

So this, this will be very interesting because we're trying to develop a tool that policymakers can use to decide what interventions they want to invest in to increase physical activity in the population.

PROFESSOR NANCY BAXTER: Terrific. So where you’re sitting now, what advice would you have to give the higher degree by research students that we have? What would you tell your, you know, 20 some year old self about what you should be doing?

DR BINH NGUYEN: Oh, well done. No, no, I'm kidding. Just because I took a path, I wasn't sure if I would like research, and I really enjoyed it. It has its ups and downs but you learn a lot from it. You can use different skills from writing to presenting to collecting data, to interpreting data.

It does have its downs in a way that funding is always an issue, but if it's really what you like to do, I'm sure there is a way to continue doing the research you like. So I would encourage you to try it.

PROFESSOR NANCY BAXTER: I think it's a gift to be able to be curious for a living.

DR BINH NGUYEN: Yes. Definitely.

PROFESSOR NANCY BAXTER: Well, thank you very much. Really appreciate you coming today and sharing your journey and as well sharing this fantastic article and looking forward to everything you're going to achieve in the future.

DR BINH NGUYEN: Thank you so much. It was a pleasure to be here.

PROFESSOR ROBYN WARD: Hello, everyone. My name is Robyn Ward and I'm joined today by Pamela Soh and she's going to tell us about some of her work on prostate cancer. But before we get started, I thought we'd hear a little bit about Pamela.

DR PAMELA SOH: Hi, Robyn. Lovely to be here. So I started in animal and vet bioscience. Um, quite a different journey, I think, to most people working in human genetics. I really liked animals, so then I proceeded to do a PhD on cancer in dogs. Really liked that, too, and then thought about switching to human research just because there's more funding in human research, but I still really like dogs!

PROFESSOR ROBYN WARD: So how did you get into prostate cancer? I know you work with Vanessa Hayes who does a huge amount of work in prostate cancer, so how did you find Vanessa and how did you find this interest in prostate cancer?

DR PAMELA SOH: I finished my PhD just coming out of COVID. I was looking around locally and then I saw Vanessa's project. It really aligned with what I did during my PhD in genetics, and she was touching on a little bit of metabolomics and proteomics in the future. So I thought it was really interesting. Joined her lab and was just, like, astounded by how much resources and how much passion she had in prostate cancer research and I really enjoyed it. I really enjoyed coming on board and working with this excellent team.

PROFESSOR ROBYN WARD: And what is the composition of that team?

DR PAMELA SOH: Yeah, so we have three postdocs now, one senior fellow and we have a whole bunch of students. We've got three PhDs and three honour students at the moment. So our team has grown a lot just in Sydney alone.

We also have a lot of people overseas. So we have students in Southern Africa. We've got one in Botswana, a few in South Africa. We have one in the UK. So we've really expanded quite a lot. It's a very big team.

PROFESSOR ROBYN WARD: So tell me then a little bit about the work you've done and you've published a really nice paper, but I'd like to understand a little bit about what that paper's about.

DR PAMELA SOH: My project was on looking at whether risk variants for prostate cancer that have been found mostly in European populations, whether that is also a risk factor for African populations, specifically Southern Africa. We know that Southern Africa is very genetically diverse. Most of the prostate cancer studies have been on European populations and African populations that they've included are primarily African American.

So, African Americans come from Western Africa. And if you look at one of the plots that I did for my paper, West Africa is completely different genetically to Southern Africa.

There is more differences between Western and Southern Africa than there is between European and Asian. On my plot, you and I, we are, we are the same genetically. And then if you go into Africa, they are much, much different than the two of us are.

PROFESSOR ROBYN WARD: And how do you actually go about doing that? As you described, you've got this lovely plot in your paper, but how do you actually go about doing this genetic profiling? I think people hear about genetics and genomics, but what's actually involved?

DR PAMELA SOH: That's a great question. So you can look at the whole genome, but It's not very efficient, I would say, computationally. It's a lot of work to, yeah, analyse whole genomes together. What we did for that specific plot, we used something called an exosmic array. So the array is specific points in the genome where we know that a variation exists, these have been handpicked by people designing the array. And we basically look at whether all these different populations, what variance they have at those positions in the array. And so you might see a European might carry one specific genotype and the Africans don't carry that genotype. So we, we do that along with a whole 270,000-something snips that we use in that study.

PROFESSOR ROBYN WARD: And I think what perhaps not everyone appreciates is there’s a whole lot less laboratory work in the sense of processing samples. Most of the activity in this area is really around the computational analysis. That's where the really exciting work happens. It's not in the test tube in the lab anymore.

DR PAMELA SOH: Yeah, definitely. Yeah, we have so much data. We have, you know, thousands of terabytes of data. It's impossible to even, transfer the data, you know, people find it quicker to just carry a hard drive and give it to your colleague rather than downloading it and moving it from the cloud. It gets quite complicated very quickly.

PROFESSOR ROBYN WARD: That's something that I think also that a lot of people are really struggling with is the amount of data that is available now. It exceeds the capacity of transfer. What do you do to analyse this sort of data?

DR PAMELA SOH: We get blood samples from Southern Africa that are shipped to our lab. And my colleague, Mahedi, he extracts these samples and he sends it to sequencing, we use Rameshwari at UNSW. Once the data comes back, we have another student, Jue Jiang, who kind of cleans up the data for us, aligns it, and then I get it at the other end. So I guess I enter the downstream part of it, trying to look at the clinical relevance of the genetic variants.

PROFESSOR ROBYN WARD: Really, it's a sort of like a relay race, isn't it? Some people are collecting the DNA from the patients, processing it, and then you're getting a data set. And then you then sit there and work out what this all means.

DR PAMELA SOH: We do a lot of programming to handle this kind of data. A lot of high computational work as well. We use the high-performance computing systems to analyse this data. You know we have a whole bunch of different projects and it depends on what the focus of the question is. I come in, I analyse the data, you know, I write up the results. And then we send it back to our collaborators and get feedback from everyone and then we send it off to the journal.

PROFESSOR ROBYN WARD: Fantastic!

DR PAMELA SOH: So it's still it's still kind of like the first step. I think looking at the genetics as a whole is still a first step. There's still many steps for validation and even to, you know, bring it full circle where we can apply this information back to the patients and create more precision medicine. There's still a lot to go.

PROFESSOR ROBYN WARD: And what did you find? What were the take home messages from your paper?

DR PAMELA SOH: So the take home messages was that the polygenic risk score, which is just a score that we assigned to each individual to say how at risk you are of getting prostate cancer, aggressive prostate cancer specifically, it wasn't specific to Southern Africans. So what they found in the European study, they found 278 risk variants could nicely classify someone as high risk or low risk prostate cancer. But when we applied that to outbound data, it didn't separate those two. That was one part of the study. And then the second part of the study was looking at a exome wide association study, which is, the equivalent of a genome wide association, a GWAS.

Here we compared cases versus controls to see which parts of the genome is most associated to prostate cancer for Southern Africans specifically. And we found, you know, new genes that weren't already captured in the European studies. They do need validation because these are very small studies still compared to the European data. We only have 800 samples, whereas they have hundreds of thousands of samples, so they're very statistically powered compared to what we've done.

PROFESSOR ROBYN WARD: Was the finding that you had around the polygenic risk core not being informative, was that a surprise to you? Did you think you'd find we'll reproduce the findings of an earlier study?

DR PAMELA SOH: No I wasn't surprised really, because there hasn't been much African inclusion in a lot of the global prostate cancer studies. So we always find something new working in Africa, and because of the diversity, we weren't surprised that the polygenic risk score didn't fit. And now actually there's a new set of risk variants, there's I think 500 something. I'm hoping to test that on our new data as well, but I'm still thinking that we probably won't find that it's applicable as well.

PROFESSOR ROBYN WARD: So the work you're doing and Vanessa's doing is terribly, terribly important, not just for the groups that you've analysed, but also it says more broadly that we need to make sure that studies include multiple people from multiple countries and that those findings are applicable for them in their circumstances.

DR PAMELA SOH: Yeah. Very much like ancestry.com, you know, whether you can predict someone has brown eyes or black hair, you know, we're hoping to do the same eventually with medicine. Hoping to just, you know, get a panel of variants that you can assess whether a person is at risk or not, that would be amazing. And yeah, we do have to tailor it for each ethnicity as well. And I think it's going to be really interesting in the years coming where there's more people who are admix. So for example, my husband is Caucasian, we're going to have a kid that is mixed. I really wonder what testing panels are going to look like for the future.

PROFESSOR ROBYN WARD: And how long do you think it's going to be before we're in that sort of nirvana where we're all have, you know, entire populations all over the world genotyped and able to really predict. disease. Do you think this is 20 years off, 10 years off?

DR PAMELA SOH: That's really hard to say. I'm hoping by 20 years we would have some nice panels that will be applicable to multiple populations, but yeah, we'll just have to wait and see.

PROFESSOR ROBYN WARD: Well, hopefully it's at least in the next decade or so we'll have, we'll have a better understanding of this area, which is still pretty much in its infancy, despite the fact that work has been going on for a long time.

DR PAMELA SOH: Yeah.

PROFESSOR ROBYN WARD: What's next for you, Pamela? Are you going to keep pursuing prostate cancer and working with Vanessa, or have you got other things on your mind now?

DR PAMELA SOH: I'm planning to be with Vanessa until our heroic study finishes at least. We have another four years on this grant, helping contribute to this really meaningful research.

I think follow your passion is the best advice that I can give. If you're passionate about your research, you're going to want to work hard. And, you know, you'll find that it leads to good things. It leads to good opportunities if you put yourself out there, you know, connect with people, talk to people, listen to other people's experiences. We heard recently from Melody Ding from the Faculty of Medicine and Health about her journey from postdoctoral fellow to professor. And it was really interesting to hear that she's never done an all nighter, which is completely different to Vanessa. She takes her mental health very seriously. And when you have your mental health in order, then you can focus on your work and, you know, produce the best outcome.

PROFESSOR ROBYN WARD: Well, thank you for joining us today, Pamela. It was fascinating hearing about your work on prostate cancer and genomics and how that potentially could pan out over the coming decades. So thank you for joining us today on Research Bytes and we came to you from Gadigal land.

PROFESSOR ROBYN WARD: Hello everyone, my name is Robyn Ward, I'm the Executive Dean here at the Faculty of Medicine and Health at the University of Sydney, and I'm joined today by Dr. James Kang who's going to talk to us about some of his research, very exciting research, and he works on an area of pain caused by trigeminal neuralgia.

But let's get into that a little bit later. And first, let's hear a little bit about James and your journey to become a researcher here at the University of Sydney.

DR JAMES KANG: Thanks for the invite, Robyn. It's really exciting to be here. I've pretty much been at the University of Sydney since the beginning of my academic career.

I initially started in sports science nutrition because I like playing sports and I like science. It didn't really fit with me. So I moved into a normal bachelor of science stream where I moved into mostly biochemistry and neurosciences.

And then I continued on doing research in emotional behaviours and pain when I was awarded my PhD in 2019.

After 2019, I had a research break, but I couldn't really get a job at that time. And then COVID 19 hit. So I luckily got a job at Westpac Bank as an operations officer. And I was there for about just over a year when one of my mentors, uh, Kevin Keay called me one day and said, hey, I've got an NHMRC grant.

Can you come and do this? At that time I was offered a risk manager role at Westpac when they're going through their transformations And I just said, Oh yeah, this sounds more interesting, When do I start?

PROFESSOR ROBYN WARD: Now, let's get on to talk about your research. And as I said in the introduction, you're working on an area of pain caused by trigeminal neuralgia, which is a pretty devastating condition for anyone who has it.

It causes excruciating pain in the face. It's often unknown what causes it, but it's very hard to relieve in, in humans. But you've adapted an animal model to try and work out what's causing trigeminal neuralgia. So, can you tell us a little bit about how you went about designing those experiments and then we can get onto what you found?

DR JAMES KANG: So this was part of the main question, the NHMRC ideas grant was about, and, and, and my background is using animal models to try and sort of bridge that translational gap.

So it was a multidisciplinary team we had, uh, Kevin Keay was animal model expert, Luke Henderson was imaging expert for humans, and my job was to create a model that we could use to image with MRI and PET longitudinally with ligands that would bind in humans.

So we would have the same compatibility. We could look at the cellular molecular resolution within the brain in a neuronal model and translate directly into a human.

So we could measure longitudinal changes in the brain that might be related to the development of chronic trigeminal neuropathic pain or trigeminal neuralgia.

So my first job was to make sure the model worked and then, One of the main criticisms of using animal models for pain is that, hey, animals don't have pain.

However, my job to try to convince people that they do. And one of those ways is, Thinking about, it's actually a deviation from their normal behaviour that's going to be impacting them.

So, and the second question was, we were interested in the transition from acute pain to chronic pain.

So we want to try to find that transitional zone where the treatment options may still be useful, or maybe get a better understanding of why some people will develop chronic pain after an injury, whereas some people won't develop chronic pain after exactly the same injury.

So the model had to have exactly the same injury that generates the pain, Thank you. And I had to be able to track the development of chronic pain over time.

PROFESSOR ROBYN WARD: And can you tell us a little bit about this animal model? Because I think also people will be thinking, well, you know, animal models, are they, you know, really harmful?

Are they needed for, for this sort of work? But obviously you can't do this sort of work in a human being. So can you tell us, number one, how you actually emulate the human condition in an animal? And as you said, how do you know they're in pain so that it's a reproducible, useful mimic for the condition you're studying?

DR JAMES KANG: Absolutely, so the benefit of using the animal model is that you can actually track them over time, from the beginning of the injury to the development of chronic pain, which is the power of, the preclinical model. To do this type of model, we target the infraorbital nerve, which is a purely sensory nerve located in the face.

And it innervates the skin of your cheek, just below your eye, just above your upper jaw. So it's quite a difficult surgery.

You go through the eyebrow, you make a small incision, it's about one centimetre in length, and you ligate within the orbit, orbital canal, uh, the infraorbital nerve with, uh, ligations, which makes it permanent.

And then you suture back up and then monitor the animals over a prolonged period of time. So that's the model we used, and what we did from there is track the animals over time, and see how their behaviours deviate from prior to the injury and then make the call whether we think the development of chronic pain has occurred or not and some standard laboratory test to do is mechanical sensitivity testing where you use a filament of known force and it bends and it applies a tactile stimulation to the skin.

And the idea is that prior to injury or a pain, painful event, it won't be painful. It will just be a normal tactile stimulus. However, after injury and the development of pain, it will become painful. So previously non painful stimulus is now painful. And that's one way of measuring the development of sensory pain.

However, I think Most people will know that if you're in pain, there's a lot of other deviations from your normal behaviour that will impact, um, your day-to-day life. So, for example, in terms of pain to the face, cold water, brushing your teeth, putting a shirt over your head, any of these things could be painful, and it might actually cascade into other events that will sort of impact your day-to-day life.

PROFESSOR ROBYN WARD: And I'm sure almost everyone has, has experienced neuralgia of some sort, as you say, where experiencing pain in an area just related to soft touch or the wind on your face or something and that's causing this sharp pain. The difference with trigeminal neuralgia is people have long standing excruciating pain and it becomes incredibly debilitating.

And I'm very interested when you say that you injured the infraorbital nerve. Was that all animals that then experience this chronic pain, or is it only some?

Because, as you know, in humans, people often attribute trigeminal neuralgia to some injury, maybe a dental procedure or something that has caused that injury, but not everyone who has dental procedures go on to get trigeminal neuralgia.

So what happens in the animals? Do they all get this pain?

DR JAMES KANG: That's an interesting point, because that is what we see very similarly.

Approximately 30 percent will go on to develop comorbidities. in terms of the deviation from their normal behaviour.

But most of the time they all develop sensory changes to tactile stimulation to the face or whatever, whatever limb may have been injured from a preclinical model.

So the interesting thing for what we were trying to do is they all get exactly the same injury.

Why do some deviate more than others? That was sort of one of our key points. We're trying to investigate and trying to understand a bit more because of my background as a neuroscientist. We're quite, I'm quite interested in the neuro anatomy.

So when you perceive information from your environment, you need something to detect it. And that's generally that occur from your peripheral nervous system.

And that information transmits to your central nervous system. The brain for this model, so the benefit of using the preclinical model is that we can measure the damage at that sensory nerve at the site where we receive information.

So that's why it's a somatosensory nerve and we can track it all the way along the pathway into the brain to see So where along this pain pathway might the changes be occurring.

PROFESSOR ROBYN WARD: So what did you find there? That's sort of very fascinating and you've tempted us now with this description, but what did you find?

Where's the injury actually occurring and what's happening to myelin as you go from the periphery to the central nervous system?

DR JAMES KANG: So we had really interesting findings. It was exciting, but also anticlimactic at the same time. What we found is that. My surgical skills were consistent, all the damage was exactly the same.

We did males and females. Often, a lot of preclinical studies are focused on males because it reduces the variability. However, we all know that males and females are different. We don't know exactly how they're different. And one of the main findings is that the effect of injury is, is similar but very distinct between males and females.

So, at the site of injury where I applied the ligation, you get initial demyelination and then remyelination. When you have a neuroimmune injury. Uh, event following the injury, so that's sort of a normal response. You get damaged, you clear the debris, you try to start re healing the area. That was very different between males and females.

So the initial immune response looks similar for the innate immune response, but the females had a larger sort of magnitude. at the start of the injury and then sort of plateaued, which I think allowed them to remyelinate their nerves a little bit quicker than the males. And then if we move from the site of injury into the ganglion, which is the cell body, which communicates the information, that again was a little bit different between males and females.

But what we did find was the pain behaviours were exactly the same between the males and females. As we followed them longitudinally, which sort of led us to think, okay, different biological functions occurring between males and females. However, how they interact in the environment looks exactly the same.

So we really need to continue using males and females to understand the different therapeutic options. That might be available later on, which also might be a reason why treatments for females are less effective because most of the preclinical work is done on, on the male biology.

PROFESSOR ROBYN WARD: So where will you take this work?

Now you've, you've done some amazing, very meticulous work in the laboratory. So what's the next step in your work?

DR JAMES KANG: Um, so this was initially to establish a model that we can measure changes longitudinally. So now we're continuing with the same model and we're measuring longitudinal changes. In terms of, uh, these neuroimmune cells located within the periphery and the central nervous system, that's one avenue that we're following up.

And the second avenue is to move into the, to the brain and see what actually is occurring. Because one of the issues with chronic pain treatments, I think most people, What you would be aware of is that after a certain point in time, the therapeutics don't actually have much effect. And one of the reasons behind that may be because the initial targets are looking at the periphery.

So, as we can see, the immune changes, the cellular changes, the molecular changes from acute to chronic is changing rapidly. between males and females. So if you're targeting the peripheral system, we're actually seeing a shift in what might be occurring all the way along the pain pathway as you go from the periphery into the brain and further up into the higher orders, higher order areas of the brain.

So we're slowly tracking that as well, going up the central nervous system to try and identify areas that might be Key areas for therapeutic options.

PROFESSOR ROBYN WARD: It's so important, this type of work, because I think the management of pain is such a complex sort of system to, to intervene into. And as you, as you know, a lot of people have a lot of different causes for pain in the first place.

So being able to meticulously map the cause of the pain and then be able to design potentially one day therapeutics that will benefit people and relieve their pain is, is a very, very laudable and important goal.

So. I want to thank you for your work and also for the work of your team. Thank you again.

DR JAMES KANG: Thanks, Robyn

PROFESSOR ROBYN WARD: So, thank you for joining us today on Research Bytes, and we came to you today from Gadigal land.

PROFESSOR ROBYN WARD:  My name is Robyn Ward and I'm the Executive Dean of the Faculty of Medicine and Health here at the University of Sydney. And today I'm joined by Mouna Sawan, who's going to tell us about her research. But before we get to that, we're going to hear a little bit about her journey as a researcher at the University of Sydney and perhaps even before.

So welcome. Would you like to start by introducing yourself to us and, and where have you come from and how have you managed to make it to this point in your career? 

DR MOUNA SAWAN: Thanks Robyn for that warm introduction. Yeah, so I'm currently a Dementia Research Fellow and a lecturer at the Sydney School of Pharmacy, but prior to that I was working as a pharmacist accredited aging consultant working in the community and in aged care providing quality use of medicines. And I found that in my interactions with people when conducting medication management reviews, I didn't understand why I was there talking to them about their medications and, um, the value and the meaning behind what I was doing.

So that kind of motivated me to want to do more in that Also, I recently found myself as a carer for my father who was palliative, and despite my expertise and my health literacy, I found that it was really complex navigating the healthcare system. 

PROFESSOR ROBYN WARD: It's amazing the number of people we talk to who are motivated to go into research by personal experiences of a disease or of caring for someone who has illness and really want to be involved to make a difference, and they see that research is that avenue to make a difference.

And so, can you tell us a little bit about why you decided to go into research as the means to make a difference? Because you're already a pharmacist, so you are making a difference every day in your work life, but what pushed you to the research side of things?

DR MOUNA SAWAN: So particularly with my aged care experiences, I found that aged care homes were struggling with trying to ensure the optimal use of medications.

 And not only that, but I saw variations in processes and practices because I was conducting services in aged care homes in Sydney and in the Illawarra region.

So I had experience. to many different, uh, aged care providers and the way that they were doing things. I found that everybody wants the best and they want to do right by their patients, but sometimes given the pressures of working in specific contexts with, you know, limited resources and staffing and time, um, often it's challenging to find that balance.

And, um, I knew that, you know, there was a research question there and that kind of motivated me to contact my supervisor and colleague, Professor Timothy Chen at the School of Pharmacy.

Together we found that the research topic that could really be an opportunity to unpack and hadn't been done before to answer the question about why there is variations in prescribing in aged care homes. And mind you, this was way before the Royal Commission. 

PROFESSOR ROBYN WARD: So you've worked out how to develop this little tool called CATCHTOOL. So can you tell us what CATCHTOOL is? 

DR MOUNA SAWAN: So CATCHTOOL stands for the Carer Assessment of Medication Management Guidance for People with Dementia at the Time of Hospital Discharge.

And it's pretty much a checklist for the carers and healthcare professionals themselves. And it covers two main areas, which is how involved they are in medication management decisions to how well they understand medication management guidance. 

PROFESSOR ROBYN WARD: And who's involved in going through that checklist? Is it the healthcare provider, is it the person with dementia, is it their caregiver?

How does it actually get completed in practice? 

DR MOUNA SAWAN: So there's two elements. It can be used by the patients themselves because the CATCH tool has actually gone under content validation to make sure it's easy to use and all the items included are easy to understand. So it could be used as a patient reported evaluation measure.

It can also be used by healthcare professionals as kind of like an evaluation of what are the unmet information areas that need to be addressed before the patient, the person with dementia or their carers, leave the hospital. 

PROFESSOR ROBYN WARD: Sounds like a fantastic aid and sort of such a simple solution for what is a really complex problem as you were saying earlier when people leave hospital or go to a new residential home.

And these are the points where care often trips up. Mistakes are made. So how do you know this is working? You've published a really nice paper on this, but how do you know your tool is better than what was standard practice? 

DR MOUNA SAWAN: We know that the current tools that are available don't comprehensively evaluate all aspects of medication management.

They might just talk about, you know, how well instructions of taking medications is included, but it doesn't really go into depth into all things medication management for from, do they understand the indication of the medication that's being prescribed?

Were they explained how long to take medications, because we know, you know, not all medications are given long term, especially in people with dementia, to were the side effects and benefits of medications explained to them?

And then it also talks to the aspect of decision making. So were they involved with the healthcare professional when it came to agreeing on using this medication? 

PROFESSOR ROBYN WARD: What actually did the study tell us if I was, you know, in a residential aged care home planning to implement this exciting tool? Why would I do that?

DR MOUNA SAWAN: So at the moment we're kind of still in the development phase of the tool. We conducted the study to sort of, you know, descriptively find out what's happening in practice as well as to validate the tool to make sure it measures what it's supposed to measure.

So we've done that, we've ticked that, and what we found in the descriptive aspect of the survey half of respondents reported that they only received medication guidance at the time of discharge and that one in five respondents were not involved in [00:06:00] medication related decisions.

So that proved to us that there was a gap that we could address. And from that, we knew that we probably have to create and co design resources to improve and encourage people with dementia in their care is to be more involved in decision making during hospitalisation and to partner with that healthcare professional.

So we are currently co designing those resources, uh, with our partners who have lived experience to make sure that the resources are user friendly. 

PROFESSOR ROBYN WARD: And I think you mentioned in, or you found in one of your slides, that studies there that the 36 percent of patients or their carers felt overwhelmed. Yes.

Is this all because of ambiguity around medications or did your work show that there are other things contributing to this feeling of being overwhelmed? 

DR MOUNA SAWAN: Yeah. The complexity of medication definitely adds to it, but you know, for carers, they're managing the acute condition that they're in. the person has been presented to in the hospital, as well as all of the other administrative paperwork when it comes to, for example, dealing with aged care assessment, if the person needs an aged care home, dealing with making sure that the home is ready for the patient's, you know, transmission from hospital to the home.

So definitely there's a lot of challenges that they have to address then and there. And I feel that medication management is one of those things.

And often it's left till the end, which is what the carers have reported to me in their qualitative research that I conducted. 

PROFESSOR ROBYN WARD: What I love about your work is really, it's just ever so practical, and I'm sure that people listening today will be tuning in to the idea that, you know, they've probably experienced this in their lives, looking after people, and how overwhelmed people are often at these times when people are transitioning from one area of their life to another.

So it is a very stressful time, and it's a very, very practical solution to, you know, such a challenging problem. I just wondered what you're going to do next. Like, now you've sort of solved this problem. What's the next thing on the agenda for you? 

DR MOUNA SAWAN: The next thing is basically, uh, working with [00:08:00] people with dementia and their carers to really provide the resources that they can be, you know, equipped with in their journey, whether it's in the hospital or living in the community or in an aged care homes on all things medication management and question prompts because a lot of people want to ask questions.

They just don't know how to ask. So this is basically ready to go early next year and we have a lot of interest with LHDs. So hopefully, um, Watch this area. 

PROFESSOR ROBYN WARD: What's the really important thing that you would like to convey to others who are sitting in about the same phase of their life or perhaps a little earlier, maybe an HDR student?

DR MOUNA SAWAN: It's definitely been a journey and one that I feel privileged to have undertaken. And if I was to speak to my younger self, I would have told myself to, um, Stay on the course, keep with the very passion that you started undertaking research, because it can be challenging with publishing and applying for grants.

But don't be afraid to ask questions for people who are more senior than you, because you just never know what valuable advice they can give to you. And I'll see you next time.

Always say yes. When you're asked to, you know, um, present on your research, it's really important to get out there, get out of your ivory tower and really communicate and reach out to the community as well as, you know, your peers.

PROFESSOR ROBYN WARD: I wanted to thank you, Mouna, for joining us. It's been great talking to you and we came to you today for the lands of the Gadigal people and this is Research Bytes.

PROFESSOR ROBYN WARD: Welcome to Research Bytes. My name is Robyn Ward. I'm the Executive Dean of the Faculty of Medicine and Health at the University of Sydney, and I'm joined today by Melissa Riegel. 

DR MELISSA RIEGEL: Hello. 

PROFESSOR ROBYN WARD: Perhaps we should start with a little bit of background. Tell me, how did you find your supervisor and your project?

DR MELISSA RIEGEL: Oh, I guess it was a bit of a funny one. I was working as a nurse. I work in adult intensive care, and I was doing a project on end of life care and, and the thing called loved one support service within the adult ICU. It was a colleague that said, Oh, you could turn that into like a PhD or, you know, something like that.

You should do something with it because you're already doing all this work for it. And I went, Oh yeah, okay. And then luckily asked them, how do I do this? What do I, what do I do next? What about supervisors? And then I just went to all the websites and luckily, um, there was one person who that was their specialty.

It was Tom Buckley. And he emailed me back and said, yep, sounds good. This is amazing. It sounds really exciting. And that's how it happened. 

PROFESSOR ROBYN WARD: So let's get onto the research study that you've published. And I'm really curious to understand a little bit more about this idea of mementos. In the field of neonatology this has been a relatively common practice, but perhaps you can tell us what they are, and then how you came to apply this in an adult intensive care unit. 

DR MELISSA RIEGEL: Um, it all started by thinking, why don't we do more in ICU. At the time, because it was like, it started off with, oh, should we just send cards after somebody dies, a condolence card?

And I was like, your vet sends one when your dog dies, but we don't do anything when a person dies, with people. So it kind of started off with that. And then it was like, well, we could do this, but what else can we do? What else is already out there?

And looking through the literature at that point when I was creating, helping to create this, program within the ICU, there wasn't a lot out there. There wasn't a lot of research.

 So a lot of it was based on the ideas of what they already do in like the neonate pediatric, and then talking to like social works and pediatric because they do a lot of like memory making.

And the good thing about the program is it helped to create guidelines so people could kind of hang the hat on something and move forward with it rather than just kind of being ad hoc and kind of done on some and not done on others.

So it was, you know, move them to a quiet room, turn stuff off, take things off of them. Uh, we had little like scent diffusers and like candles, like the electric candles, kind of make that nicer environment. Um, it almost like forced people to realize and like change the type of care and the focus of care.

And then if somebody did die or if they were nearing death, depending on how the family reacted, we could offer them handprints or locks of hair. And at the time when that kind of came out, there was like, quite a lot of hesitancy from the staff because they thought, oh, the families aren't going to like it. I'm going to like offend them by doing it.

But what was really the turning point within that unit, I think was when they saw the families liked it and they weren't offended if they weren't interested. They didn't get offended if they said no, they just said, no, that's OK. Thank you. And but the families that wanted it really wanted it and really liked it.

Because without giving that suggestion to them, so the handprints or the locks of hair or some other type of a tangible object they can, like, touch and think about later, and they did, um, my other study, uh, we did end up find they do use it in bereavement to, kind of, help trigger the memories of the person while they're going through those grief times.

So, bearing offering it, it, you know, they wouldn't have thought of it themselves unless we actually suggested it to them. And so then people started suggesting it and do you want this? Do you not want it? And how many do you want and what can we do? 

PROFESSOR ROBYN WARD: And why do you think this is important for relatives or family members, friends, others to have this?

DR MELISSA RIEGEL: I think it just gives them the options. We found in our research, um, because we did ask the families, um, the second half of the research, you know, do you like it? Did you use it? Are you using it? What are you going to do with it later?

And we interviewed them quite early in their bereavement time, and they, the ones that said yes did like it, um, that did, most of them did use it, um, and when they were thinking about that person, it's hard to kind of think of them in the abstract, but when they go to that object, it helped to trigger their memories of them.

And because it's a tactile object, they actually, they'll touch it, they'll smell it, they'll put their hands next to it. Some of them even had it like in the front of their house, where they would greet their deceased loved one as they came in. Or, you know, as they were leaving, they might say, oh, bye, or say hi to them, or, you know, something like that.

Some of them had used it with like their grandkids, you know, put the grandkids hands next to dad's, or, you know, granddad's. Oh, your hand's getting as big as granddad's. Another person who talked to us about how she used the hair, her, her, her. Sister loved her hair, um, and so the, having a clip of her hair, um, reminds her of her sister, and quite a tactile thing.

Because hair doesn't disintegrate, doesn't go away, and so they can use it later.

And it's interesting because these types of objects, they were quite common back in the day, in the Victorian era. There's books on how to create jewellery with hair. But it's just kind of become One of those things that we kind of think, oh, no, don't do that or, you know, kind of shunned away a bit.

But I think people do get lonely and they sometimes don't realize that they don't have stuff around them. Um, said another family member, she was the caregiver of her dad, but he died and then she looked around and went, Oh my gosh, I don't have anything that's particularly momentous of him. Something to actually remember him by.

But he loved his hair. He was very proud of his hair. He had a full set of hair, um, in his older age she said, so it actually means quite a lot to her. She goes, well, cause I can't put his bed on display. I can't put the wheelchair out. I can't do anything with this stuff. But this is a memory of him and it's quite specific to him.

And so she was able to use that to kind of think about him while she's going through that times of grief. 

PROFESSOR ROBYN WARD: And how does this play out? The program and your findings roll out to adult intensive care, how will you make sure that this research is penetrating across Australia? 

DR MELISSA RIEGEL: So I think when we had the information from the families, um, that it can help to spur on other units who want to implement something for end of life and help to implement it in and what could be done and should this be done. We have done another study where we did a survey of the Australian ICUs and what is actually offered in bereavement.

 And unfortunately the needle hasn't moved in terms of end of life care and bereavement offerings  within the Australian ICUs. And whether that's because of, you know, being too short staffed, um, not enough money, financial backing of it.

Because it's almost seen like, like a nice to have rather than a vital thing.  A ventilator. We have to have a new ventilator. Without realizing, yes, you need a new ventilator, we actually need to do the softer side of things as well, really well. And it's unfortunate because I don't think you see as much financial backing, maybe.

And you do need someone to really drive the program as well. And it can be quite hard if you're short staffed or, and those types of things.

PROFESSOR ROBYN WARD: It's very interesting that you, you sort of, I think, have identified this gap. People are not thinking about the fact that people may not make it out of intensive care.

And that needs to be part of really the model of care. 

DR MELISSA RIEGEL: Yeah, and I think maybe there's certainly clinicians out there who want to do more, but if you don't have the financial backing, you don't have enough staff, then sometimes it turns into the want versus the need. Which is very unfortunate, without realizing the impact.

That if you can't do those things, certain things to make those end of life really nice, as nice as it can be. Um, they can have long term consequences for the individual themselves. 

PROFESSOR ROBYN WARD: And of course, you're the champion of this because you've done the research. And I just wondered what, um, what, what's the reaction to this, amongst different types of colleagues.

DR MELISSA RIEGEL: Well, I know when we first brought it out within our unit, it, it was only about a third of people even went, oh yeah, okay, that sounds something I could do.

 I said that the turning point was the needle kind of moving when they saw families’ reactions to it. So when they started to see that families who did say yes really wanted it and who said no, were also still, were quite fine with being asked about it, um, that started to move it, kind of shifted along and then the mindset started to change if I don't make the decision for them, they make the decisions for themselves.

I just give them options of what can I do to kind of make this thing better. And I think that was kind of the turning point when people kind of saw and it was a really nice turning point as well because it's kind of see like I don't make things for them.

They can decide and I can just give them, you know, empowerment to make decisions. 

PROFESSOR ROBYN WARD: So one of the questions we've sort of like to hear about, or the responses we like to hear about is early and mid-career researchers. Tell us about the challenges, but also the positives of being an early and mid-career researcher.

DR MELISSA RIEGEL: Oh, it is a weird feeling, I think, because when you finish the PhD and it's all done, and then you just kind of, like, I remember hitting the submit button and going, oh, is that it? Alright. Like, now what? Um, because you spend so much time making this massive project, and, you know, building up and doing your thesis and, you know, trying to get stuff out, and then all of a sudden it just kind of ties up, and it's done, and you're like, All right, now what's next?

Now what do I do? So that's a bit of a head spin, um, I think, and then it's trying to keep that momentum going, like, right, I need, I need something more. What else is out there? Because you do identify, you know, still gaps, but it's got to get back into them. 

PROFESSOR ROBYN WARD: So it's a positive transition point at which you end from a PhD, but then there's life on the other side of that wall to embark on a whole lot of new opportunities using all the skills you've picked up as a PhD student. It doesn't stop the day you hand in your thesis.

DR MELISSA RIEGEL: Yeah. And I think I've been lucky within the Sydney Nursing School because there is a lot of support around. Um, they're doing a lot with, you know, Um, within the research subcommittee, you know, helping with grant writing and new ideas and generating.

Um, I said, Tom is still, you know, kind of mentoring me along or like, Oh, have you tried about this? And, and, and opportunities that are out there and kind of encouraging those.

So very lucky, um, to be at the Sydney Nursing School where there's, you know, very great positive role models around and people willing to talk and talk you through things or new suggestions or have you thought of this and you can you do that.

So that's been a really, actually really great, um, to be honest, to take that, that next step. 

PROFESSOR ROBYN WARD: And you are taking that next step. You're moving on with your research, developing as an early mid-career researcher, and that's fantastic to see. So Melissa, thank you for joining us today. This has been a fascinating conversation about something that I probably wouldn't have thought about myself.

But as you say, it's an area of unmet need and important work that people need to pay attention to and perhaps implement in their own intensive care unit or in their own high dependency unit in a hospital around Australia.

So thank you for joining me on Research Bites and we came to you today from Gadigal land.

PROFESSOR ROBYN WARD: Welcome to Research Bytes. I'm Robyn Ward. I'm the Executive Dean of the Faculty of Medicine and Health at the University of Sydney. And I'm joined today by Chandana Guha. And Chandana is going to talk to us about some of her exciting work in renal disease. But firstly, I'd just like to hear a little bit about you, Chandana.

How did you come to be working in this really interesting area? 

CHANDANA GUHA: Thank you, Professor Ward. It's my absolute pleasure to be here today and share my research experiences. And thank you for the invite to be a part of, uh, Research Bytes. A little bit of a context.  I'm a caregiver of my daughter for the last 26 years.

And, she was diagnosed with childhood chronic kidney disease at the age of two. Her condition progressed rapidly. And by the time she was 10 years old, she was in kidney failure. She had kidney failure. And she was on dialysis. So I dialyzed her at home. we carried out something called peritoneal dialysis for a year and a half.

And then she received a transplant subsequently. But along with her condition, she also had, multiple comorbidities, which is very typical of children with chronic kidney disease. So we went through the whole cycle of the disease, starting with early disease we progressed to kidney failure advanced kidney disease, dialysis, and transplant.

PROFESSOR ROBYN WARD: And could you tell us a little bit about what it's like being a caregiver to someone who needs peritoneal dialysis? I don't think many people will potentially know what peritoneal dialysis is, so perhaps you could just tell us what that is and what it was like for you doing that.

CHANDANA GUHA: Well, it was heartbreaking to start off with to hear that your child's kidneys have failed and there is simply no way out other than to be machine dependent. So what happens is through a machine, they infuse fluid into your belly and then they take out all the toxins from your body and then we can dispose of that because that's the role of, the primary role of the kidneys is to clear your body of all toxins.

So we had to do that every day and she was tied to the machine 12 hours a day. So, we would do that through the night. However, we managed still to go to school. I managed to have a job, a part time job. My employer is very kind. And so she would go to school, come back. We would have one cycle for 45 minutes.

And then she'd do her homework. And then at night, again, she'd be back on dialysis for the whole night, about eight hours, eight to ten hours. And we did that for about,

one and a half years.

PROFESSOR ROBYN WARD: And so what was the difference between that life and the life after having a transplant?

CHANDANA GUHA: Transplant, of course, is a treatment.

It's not a cure. And that's something that, we need to be, I wasn't sure of. I didn't understand that at the time. At the time, there's very little, or at least I wasn't very literate, around what the impact of the, of dialysis was and what transplant meant to, to us. But yes, we were free of the machine, and we continued with our lives and my daughter could go back to school.

She finished university and But we definitely needed to be very careful about around her health, because she was on lifelong immunosuppressants, which suppressed her immunity, she was susceptible to a lot of infections and repeated hospitalisations and multiple complications, but that's the life of a transplant recipient

But through it, what I realized is that there are gaps between the health system and the patient. the patient. And that's the gap that I always wanted to, to bridge. 

PROFESSOR ROBYN WARD: So now we're, we're moving to hear about what got you into research. Obviously, you have this passion, um, and personal experience. So how did you turn that into research?

CHANDANA GUHA: Well through my journey caring for my daughter, I witnessed firsthand the mental, the psychological, and the social challenges that she faced on a daily basis and the profound impact it had on her quality of life. So the quality of life research is of very big importance to me because children with Or, or chronic kidney disease in children is very different from chronic kidney disease or CKD in adults.

CKD in children is associated with congenital anomalies, with heredity, hereditary defects, birth defects, and, um, a huge care burden and treatment burden, uh, and the disease burden itself. And all of this have, all of this have an impact on their on their life throughout their childhood and not only throughout their childhood, but it extends into their adult life impacting how they function, which means the longitudinal impact is very important for me and that that's what I was interested in to see how the quality of life varied over time across CKD stages.

PROFESSOR ROBYN WARD: And you managed to get this important work published in Kidney International, it's a very excellent journal, so tell me what your findings were when you did this study. 

CHANDANA GUHA: It's one of the most exciting and satisfying experiences that I ever had working in that project.

So we analyzed data from a study which is called the Kids with Chronic Kidney Disease Study, and where we recruited patients across Australia and New Zealand, school going patients aged between six to 18 years, and we had 377 participants that were enrolled from five hospitals and across all stages of kidney disease.

So we had about 199 pre dialysis patients, uh, 43 dialysis patients, and 127 transplant recipients at the time of enrollment. And then we followed them for over four years, but taking their details every two years. So, we had details at zero, that's baseline, at two years, and at four years. And then we analyzed that data using a multivariable linear mixed model, and we adjusted for sex.

We adjusted for socioeconomic status gender and comorbidities and age as well. And what we found is in these three groups, that is, you had predialysis, dialysis, and transplant the way their quality of life scores changed, was very different.

So for the pre dialysis and the transplant recipients, their quality of life scores remained stable over time.

But for those who were on dialysis, their scores changed. just went up. So it improved over time, over the four years. And we went back and saw why that happened.

And we saw that most, over 50 percent of those who were dialyzed, who were on dialysis at the start of the study had received a transplant, which is why their quality of life scores improved.

We measured quality of life using a tool called the Health Euclid Index or the HUE 3, which captures the total impact of the disease, uh, across different domains. So you have it looked at the impact on vision, on pain, on cognition, on hearing speech, dexterity, ambulance. 

PROFESSOR ROBYN WARD: And how do you do that in a young child. Is the child doing it or is their caregiver doing it? Who's filling in these forms? I've seen them. They're, they're sometimes quite complicated.

CHANDANA GUHA: It was  parent reported and self reported. It was a mix of the two.

PROFESSOR ROBYN WARD: And do you think the, the children became better at filling them in obviously as they got older?

How do you tease that apart when you're doing a longitudinal study and perhaps the child is less able to do that when they're younger and then they get older and they're more capabilities to fill in these forms.

CHANDANA GUHA: Yeah, that's, that's one of the, the issues or limitations that you have multiple people filling it out at the early stages, their parents.

And then as they go on, because often there is that little bit of a discrepancy between a parent reported and a, and a self reported, uh, questionnaire. So the scores are a little different, but well, that's the, we've got to live with that. 

PROFESSOR ROBYN WARD: That's exactly right. And how do you think this information will be used.

I guess maybe I, I think back to, to that journey you told us about with your daughter. Why would this information be of use to you when you first heard the diagnosis of your, of your daughter's kidney disease? 

CHANDANA GUHA: First and foremost, the fact that life does get better. After you have a transplantation is a very, very important information, not only for us as patients, but also for policy makers.

And that's because you need to improve or you need to make sure that these kids who are on dialysis and who are suffering because they have the poorest quality of life scores in comparison to the rest of the transplant cohort. They have their mortality rates are between 30 to 50% higher than the general public.

So we really need these children on dialysis to go on to transplants, and that means we need to have that a lot more exposure around how we improve donation rates and how we, we, preserve organs, you know, new, better technology to preserve organs, more access to care, more access to transplantations, easier screening processes, and alsothat bit of financial assistance to families to be able to access that, that care.

Especially for example, if you're looking at those who are from socially and economically disadvantaged backgrounds, they have issues accessing care, and that's, that's one of the, that's what our studies found out subsequent to that, that it's one of the biggest problems is accessing care, whether it's for dialysis or whether it's for transplant.

So, making sure that they. move on from that stage to that, to transplant is what we want. 

PROFESSOR ROBYN WARD: I think that  the findings of your study are just so impactful, as you've said, in so many ways. But, really I think for people who are a parent thinking about may be fearful about transplantation even when it's offered are fearful of the consequences of immunosuppression.

You know, this is, this brings a lot of confidence for those decision makers to, to really think, well, actually my child's life's going to be a lot better if I take this risk because, you know, it's going to be a better life, even though there are obviously, as you say, consequences of living with a transplanted kidney.

It's better than living on dialysis.

CHANDANA GUHA: Absolutely.  And especially there needs to be that information and education out there on how you manage yourself once you're on transplant, adherence to medication, keeping yourself safe from infections and all of that.

So the message that I want to get through is it is possible to live a healthy life or a full life despite having a transplant, but you've got to take those precautions and you've got to make sure that you do your bit and then you can leave the rest to the healthcare providers.

PROFESSOR ROBYN WARD: Chandana, I would be really interested to hear how your daughter is. Tell us a little about her accomplishments. She's a grown woman now. What's her life been like?

CHANDANA GUHA: well, she had a very, very difficult life for the first 18 years, literally we were in and out of hospitals.

I was so comfortable with being at the kids hospital. It was like a second home to me. We would be there all the time. So she missed out on a lot of schoo because of treatment and all of that.

But she did manage to complete year 12and then she finished she has a degree of art from the University of New South Wales.

And yeah, she's a graphic designer. She lives independently, which was something that I couldn't even imagine ever that we would have a life like this where I am in research doing, I just love this work that I do and the people that I work with.

And she's able to live on her own, do things by herself, have a  little job and, um, and independent. That's important.

PROFESSOR ROBYN WARD: I think your story and the work you've done and publishing that work is really a very strong illustration of how important it is.

Research involves and is often led by people who have had lived experience of the conditions because the research is often much more focused on what the real problems are than what the and really draws out the policy implications of these sort of findings and hopefully helps decision makers and maybe motivates the public in this case to understand how important it is to have kidney donations.

It's transformative in people's lives and you've shown that particularly with your work in children about how difficult and impactful it is to be on dialysis as a child.

So we'd really like to understand how you've managed as an early and mid-career researcher. And if you don't mind me saying a mature early and mid-career researcher, what are some of the challenges you've experienced?

CHANDANA GUHA: I will talk about challenges and benefits as well, Robin. It's been my absolute pleasure to be in research because I've had very, very, a very supportive research team. My supervisors, Professor Allison Jerry and Professor Wong, have been superb in in supporting me because they really understand, My issues around caregiving because as a caregiver, I wasn't able to dedicate 100 percent of my time all the time to research.

I had to be at the hospital a lot of time. So having flexible work arrangements really worked for me. And I had all those and I had their support through that. But what when I look at myself, I think I've got all those variables. I represent all those variables that people adjust for in their models age, gender, ethnicity, and as an early migrant I struggled financially, low SES.

So all of that they adjust. And I must say that  because of the research environment, I was able to, to accomplish what I did, that was wonderful, and also through my research, I got back, um, because as a caregiver, you're really invisible, no one sees you, and we become like that, but I was able to be, come out and talk about my research, which I'm so passionate about, get back years of research.

That I'd lost in caregiving. 

PROFESSOR ROBYN WARD: I want to really thank you, Chandana, for all your work. It's been wonderful to speak to you here on Research Bytes. 

PROFESSOR ROBYN WARD: Welcome to Research Bytes. My name is Robyn Ward and I'm the Executive Dean of the Faculty of Medicine and Health here at the University of Sydney and we're coming to you today from Gadigal land. I'm joined today by Dr. Qingwei Luo, who is a very expert researcher in cancer and in predicting cancer mortality and mortality from other diseases.

We're going to have a really interesting conversation with her today about some of her amazing work. Could you tell us a little bit about yourself? How did you come to work in this area? And what is your background? 

DR QINGWEI LUO: So I did my PhD in the University of Sydney when I was working full time at the Cancer Research Division of the Cancer Council New South Wales.

So actually I started working on cancer incidence and mortality projections when I was in the final stages of my PhD study. 

PROFESSOR ROBYN WARD: And I think you've done some really interesting work in a couple of areas, but I think everyone's pretty keen to understand why they're going to die and whether they're going to die earlier than predicted.

And one of your very important research papers is about premature mortality, which is defined in your paper as anyone dying before the age of 75. If you look at your predictions of what people will die of over the next 20 years, what have you found? 

DR QINGWEI LUO: So actually, our Projections model show that over the next 25 years, cancer remains the leading cause of premature death in Australia and followed by cardiovascular disease.

So that means a lot of premature deaths in Australia can be prevented. And the ways in the cancer for males, lung cancer, colorectal cancer, and the pancreatic cancer, prostate cancer are the leading cause of premature death for males. 

And for females, slightly changed, but still lung cancer, breast cancer and colorectal cancer, pancreatic cancer are the leading cause of premature death.

PROFESSOR ROBYN WARD: That's really important for, I think, people to know because sometimes there's not a good understanding of which of these cancers could be prevented and where work needs to go in order to reduce the burden of cancer and also the death from cancer in those groups that you were talking about. The other thing you've done is actually look in a more detailed level as not just cause of death, but incidence of cancer over these next 25 years.

What in your study do you show as increasing cancers in our community in Australia over the next 25 years? 

DR QINGWEI LUO: So our projections show that cancers of the female breast, kidney cancer, Liver cancer and pancreatic cancer actually show increase in trend rather than decreasing or relatively stable as the other cancer types.

PROFESSOR ROBYN WARD: And I think people would be keen to know if people are diagnosed with the cancer, what's happening now in the mortality, is it different mortality rates over the next 25 years predicted from people who actually are diagnosed with cancer? 

DR QINGWEI LUO: Yeah, actually for mortality rates, actually the good news is most of the cancer type showing decreasing trend in the next 25 years or at least relatively stable.

So the only notable increasing pattern we projected are the cancers of liver and the uterine cancer. In particular, uterine cancer actually very low, right? So this means actually over the time we improve this cancer survival, and also improve the cancer screening or detection. Early detection, of course also contribute to the control of risk factors such as tobacco smoking, alcohol consumption, or other factors that contribute to the increasing in the cancer risk.

PROFESSOR ROBYN WARD: So these interventions that are happening in Australia and internationally on prevention, onscreening, and then on better treatments are all working together to reduce the chance of someone dying of a cancer now, than what that or in the next 25 years than what has happened in the past where the mortality was very high with a lot of cancers.

DR QINGWEI LUO: Yeah, that's very true. 

PROFESSOR ROBYN WARD: And what do you have a sense just of whether there's a different contribution is some things really, some of the cancer mortality is reducing more because of better treatments, or is it because of things like stopping smoking, better prevention programs, better screening programs? 

DR QINGWEI LUO: For different cancer types, because the factors driving to the pattern are different. For example, lung cancer, I think currently the major factor driving the decrease in in trend in both the incidence and the mortality or for the tobacco smoking is tobacco control over the past few decades, actually, is a major factor, to reduce the lung cancer incidence and the mortality. 

And of course, we anticipate in the future, we also recently planned for the lung cancer screening and the other targeted, uh, treatment will also contribute to the future cancer mortality decrease. 

For colorectal cancer, so we know Australia have organised the screening, bio cancer screening program implemented from 2006. We have other teams working on optimising the screening program to see if we should include younger people. So our baseline projections also as a fundamental benchmarking projection to fit in that program. 

PROFESSOR ROBYN WARD: Now, I think what you're moving on to, which is a really important area is that screening has largely been age based, not necessarily risk based.

I think some of the new technologies, particularly possibly using, you know, polygenic or multiple genes to actually test someone to see what cancers they are at risk of and then targeting the screening to that group rather than targeting everyone has real exciting possibilities and your work on the modeling of how that would apply is going to be really vital because we can't run large screening programs doing polygenic risk scores and measuring things.

We rely on modelers like yourself to actually make these really important predictions. 

You touched then on colorectal cancer, which is a topic I'm very keen to talk to you about. 

And I think most people would know that if you identify a polyp or a pre cancer in a bowel early, then it's completely curable and unlike other cancers, which start off, you know, sometimes very small, but have already spread throughout the body, bowel cancer is a very largely a very organised cancer.

It works its way growing bigger and bigger and then eventually spreads. 

So the bowel cancer screening program is ideal for this sort of a cancer because caught early, it's curable, and it's great to see that we're actually predicting there'll be a huge decrease in death from bowel cancer because of that early diagnosis.

But what you did show in one of your studies was those delays in the health system which occurred during COVID had a particular impact on colorectal cancer. 

DR QINGWEI LUO: So when we did the baseline projections for all cancers incidents and mortality, when we finished that work, it's just during the COVID 19 pandemic.

So we try to build on that work as a benchmarking projection and we evaluated what will, what will, be subsequent, uh, impact if the cancer patients was delayed in receiving treatment after diagnosis or during their survivorship. But because we don't have real time treatment data, so potentially that kind of modeling is really a mix of this, hypothetical scenario.

We know Australia did very well in terms to control the COVID 19 pandemic in that time period. So potentially our projections for the treatment delay might not  really happen in Australia. That's the good news. The key thing we found, if the impact of mortality due to treatment delay actually largely depend on the length of the delay.

So, potentially, the longer delay, it's not a linear relationship. The longer delay may have a more dramatic risk of death from cancer. Of course, we want all the patients can receive timely treatment to be able to cure the cancer. So that's kind of the work we did. 

PROFESSOR ROBYN WARD: Yeah, I think that was such an important part of that study is that it, you really did show through modeling, I recognise it's not, you know, haven't measured the data, but through modeling that if there is a delay in diagnosis and then implementing treatment, in this case, surgical treatment, and then the follow up care, then the risk that someone will die increases.

And, and you've, actually calculated how many lives would be lost if those delays played out in real time.

So, I guess bringing that all back to your original study, it's really important from the Australian healthcare system planning point of view to know which of these cancers are likely to cause death. 

Which are less likely to cause death. And if the system is in any state of challenge because it, you know, has another pandemic, hopefully never, then we really need to focus our efforts on those things that we absolutely need to treat as early as possible.

I think that's a really important part of the modeling work you've done. And as a consequence had two really amazing publications in Lancet, I could see how much work has gone into them. So I really want to thank you for your work and the work of your team. 

DR QINGWEI LUO: Thank you so much. 

PROFESSOR ROBYN WARD: So thank you for joining us today on Research Bytes.

And we came to you today from Gadigal land. Thanks for listening. 

PROFESSOR ROBYN WARD: Welcome to Research Bytes. My name is Robyn Ward and I'm the Executive Dean of the Faculty of Medicine and Health at the University of Sydney. And I'm joined here today by Dr Tess Reynolds, who's going to talk to us a little bit about herself. And then we're going to get into a conversation about her research findings. So, Tess, who are you and what do you do?

DR TESS REYNOLDS: So I had a bit of an unconventional path to get where I am today. So I have undergraduate degrees in astrophysics and my honours is also in astrophysics, all done at the University of Adelaide. And then I had an inspirational lecture by my then PhD supervisor, Professor Tanya Monro, who's now the Chief Defence Scientist on photonics and the amazing work that optical fibre could do, and how that can help the biomedical space. And so I went and did that as my PhD. Loved it, fell in love with research. But then at the end of it, I really needed sort of a change of pace and a different research direction. And then I found this opportunity here at the University of Sydney, working in medical physics and developing new imaging protocols to help in the medical space. And six years later, I'm still here.

PROFESSOR ROBYN WARD: Fantastic. And now you've published a really nice paper in investigative radiology, and I'm going to ask you to explain what you've done to a layperson who doesn't have a degree in astrophysics.

DR TESS REYNOLDS: Sure. Well, definitely it's not as complicated as astrophysics, but basically the whole premise of my research is trying to expand the capabilities of these amazing robotic imaging systems that are now found in a lot of surgical suites in hospitals around the world, and that they are often really, set up to target, you know, key areas such as cardiology, radiology, neurology. But they have so much more to give, and to allow them to be expanded to new disciplines such as orthopaedics, which is what we're targeting with this paper, we need to work on, developing imaging techniques that are specific to those disciplines.

So in the orthopaedic space, one of the challenges is that they're often dealing with large pieces of anatomy, such as the entire spine. And to be able to capture that in a single image in the operating room is currently well, until our paper came out, wasn't really, an achievable goal.

So we were really focussed on trying to bring in the imaging capabilities of standard things such as CT and MRI which you have outside of operating room into the interventional space, and to allow them to have, you know, this instant coverage of the entire piece of anatomy visualised in 3D in the surgical room, like they do pre and post the surgery to allow to improve navigation, guidance, decision making, and also importantly, really determine at the end of the procedure are they satisfied with the work that they've done.

Because unfortunately, often what we find is that then the patient will be imaged in post and they'll find that, oh no, that something hadn't gone completely right in the surgery. And the patient has to have a second corrective procedure. This is extremely expensive. It's dangerous to the patient, to have to have another procedure. So if they can make those decisions in the room, that will help a lot. And so that's what we really focussed about trying to bring that imaging into that space.

PROFESSOR ROBYN WARD: So tell me what was wrong with the current imaging modalities we have in an operating theatre. And what did you do that actually makes that imaging much better?

DR TESS REYNOLDS: I guess it's just at the moment they're really focussed on specific applications, and so they're not really taking advantage of the entire mobility and flexibility of these really cool, state of the art robotic systems.

So they operate in very simple, trajectories. So they would just go once around the patient in a circle and, and not really look to expand the coverage of the entire anatomy, say. So here we combined both, changing how the gantry rotates around the patient as well as the table. So we're moving the table and the gantry simultaneously to almost mimic what you get in a standard CT, which has the table translate as you're imaging the patient. And therefore you can have this huge coverage of virtually any piece of anatomy that you like. And so we haven't seen this in the interventional space before. A lot of it is also then just due to getting things through regulatory approval. And you know, that can be a complicated thing. So it's not to say that it wouldn't have come in the future, but we've just proven here that we're able to do it.

PROFESSOR ROBYN WARD: And tell me what a gantry is.

DR TESS REYNOLDS: Oh, sorry. Yes. So the gantry is the device that houses both the X-ray source and the detector panel. It's often in a C shape in this case. So you have the detector on one end, the source and the other, and it's sort of connected by a big -shaped arm. That then is attached to a giant robot that is able to move around the patient.

PROFESSOR ROBYN WARD: So next time someone's lying in a CT scanner, they'll now very authoritatively be able to say, that's the gantry.

DR TESS REYNOLDS: Yes. And in a standard CT scanner, it's more of an ‘O’, so it's fully enclosed and continuously rotates around the patient. Whereas for us we have it in a C form.

PROFESSOR ROBYN WARD: And just to elaborate a little bit further on, what was specifically your intervention or your discovery that made this paper get into a very important journal.

DR TESS REYNOLDS: So this was the first time that we'd actually proven in clinical hardware that this was possible in terms of being able to extend the field of view from the standard 17cm all the way to 80cm to allow large pieces of the anatomy, such as the entire spine to be captured in a single 3D volumetric image in the interventional room.

PROFESSOR ROBYN WARD: That's fantastic. That was one of the things that struck me was this longitudinal change was pretty significant, particularly if you're dealing with things like spinal surgery. So how do you prove that? Now, you obviously don't go and do this on a human being on day one, do you?

DR TESS REYNOLDS: No. Absolutely not.

PROFESSOR ROBYN WARD: So how do you prove these sort of things before you start moving these sorts of kit into an operating theatre?

DR TESS REYNOLDS: Yes. So we have a number of processes. We first start, you know, potentially in just a simulation. So doing it all on computers and then we can move into what's called physical phantoms which are replica, you know, often made of plastics and other materials that when imaged will image equivalent to a human. And then for this paper, we were able to push all the way to animal cadavers. So the animals had already been deceased. But then we were able to image the anatomy that replicates close to humans and get an idea about image quality and final dose and stuff like that, before we actually determined it's safe and useful for humans.

PROFESSOR ROBYN WARD: And how replicable is this technology when you're moving from a dead animal to a living human? And there's lots of movement going on. Humans, for instance, breathing to start with. So how do you compensate for that?

DR TESS REYNOLDS: So that's actually the next step in this work that we're actually undertaking right now is incorporating movement in there. So as you said yes, there's no breathing motion. There's no motion of the heart or other arteries. So we're looking at actually, we've developed a carotid artery phantom that has the entire arterial chain. And then we connect this to a pump that pulses. And so we're in the process of testing this protocol on that phantom to understand the motion. And then if that goes well we can apply for ethics and do this in live animals to again to get that understanding of how are we going to compensate for that motion, before moving on to humans.

PROFESSOR ROBYN WARD: And how do you compensate for that movement?

DR TESS REYNOLDS: So we can do it two ways. So from the hardware point of view, we have a whole other series of work that really syncs the hardware with the patient. So we monitor for either a breathing rate or an ECG signal. And then we're gonna adapt how the acquisition occurs in terms of we might speed up or slow down the gantry rotation and sync when we're actually going to acquire each individual x ray.

We can also look on the software side that once we've got all of our images, we can do some really fancy mathematics before we produce the final image, that actually helps us compensate for all that motion.

PROFESSOR ROBYN WARD: How receptive are surgeons to having this sort of kit in the operating room with them? Is this a received as a positive thing or not so positive?

DR TESS REYNOLDS: The surgeons that I've worked with, they've all seen this is an extremely positive thing. So we do have to be careful to not say that the surgeons, you know, are not good enough at their jobs, but it's more it's like a tool to help them to be better and to just remove that sole reliance on their experience. And also it really helps in the early stages of their career to ensure and get that live feedback of what they're doing.

It also significantly reduces the procedure time. And so that's where we see the most positive uptake, that if they know that their procedure can be done in a shorter period of time in a safer manner, they're very excited to get on board and support our research.

I've definitely got a big new appreciation for what surgeons do in terms of reading through anatomy textbooks and then seeing some of the procedures performed. You know, I have no idea how they go from one to the other. So in terms of giving them those images to, you know, really visualise every little bit of the bones and all the vessels and, and everything around. It's just so useful for them.

PROFESSOR ROBYN WARD: Could you just tell us a little bit about what's next for you, Tess, in this exciting world that you're pursuing? You’re not going back to astrophysics, I presume?

DR TESS REYNOLDS: No. Definitely not. So in this space, we're continuing to look for new disciplines to help deliver the specific imaging for their needs. So we're looking to push into pulmonology and other thoracic interventions that have respiratory motion in the imaging and trying to compensate for that.

So we’re also getting into the 3D print space, which is really driven about also continuing to improve the safety of these procedures. So we take the images that were required and then the surgeons go in segment out the 3D print replicas of the procedure that they're going to perform, and then they practice that procedure. So we're really focussed with some surgeons out of Westmead Hospital in replicating the bone in the 3D print, so that the practice procedures feel like real bone, and so that they can confidently rehearse and train for that procedure before they go and do it.

So this is some early work that we hopefully will publish on this year, and maybe I can come back and talk about that project next year.

PROFESSOR ROBYN WARD: That would be great to hear about that. And I think just anyone out there who's going to have an operation or may have an operation in the next few years should feel really much more confident about all of the outcomes that they will have because of this sort of work.

I think it's very underestimated how important this sort of work is to the surgeons, to the procedures that are done themselves, and to just making sure when the person is actually doing an operation on you, it's a very best outcome that you could possibly anticipate.

So with that all, thank you Tess, it was great talking to you. I really enjoyed the conversation. I think I understand a little bit more about it than I did at the beginning, and we look forward to welcoming you back another time.

Thank you for joining us on Research Bytes. And we came to you from Gadigal land.

PROFESSOR ROBYN WARD: Hello, everyone. My name is Robyn Ward. I'm the Executive Dean of the Faculty of Medicine and Health here at the University of Sydney. And welcome to Research Bytes. This is our second podcast. And the podcast is designed to profile some of the amazing work of our early and mid career researchers, and particularly those who are having impact on an international stage. And today, I'm joined by Caitlin Jones. And I'm going to first ask Caitlyn to tell us a little bit about herself. And then we're going to talk about her really important study about opioids and back pain. So Caitlin, where do you come from? And how long have you been at Sydney Uni?

DR CAITLIN JONES: So I come from a background of clinical work as an occupational therapist. I did that for a couple of years. And then I guess, just got curious about what else was out there. And I thought about doing some research. And I got some good advice early on that when you're thinking about doing research to go looking for the best supervisor, you could imagine, and to choose that person as the primary thing and let the exact topic be a secondary thing. So I went scouring through the internet to find someone that I thought would be an excellent supervisor and mentor. And I found Professor Christine Lin, and she was based at Sydney University. So I approached her and asked for a shot. And now here I still am years later

PROFESSOR ROBYN WARD: Fantastic. And the paper you've got published is in the Lancet. And I think for people who don't know how important that journal is, perhaps they aren't working in this field, because it's extraordinarily important journal, particularly because it's influential with clinicians. And it's also very hard to get published in The Lancet. So congratulations, that's a major achievement. And the topic you've researched is back pain. And I don't think there'd be a single person out there who doesn't know someone or doesn't experience back pain themselves, acute back pain or chronic back pain. And I know personally from my own experience of having back pain, it's very painful and debilitating and can cause a lot of morbidity and mortality. And a lot of people use opioids for pain, despite the guidelines, because they think that that's going to help the pain and the pain is so severe that they feel there's nothing else to do but to take opioids. So your study was really very interesting, because you've made some different observations to what we have traditionally thought. So perhaps if you tell us about what you found, and why you think it is so important.

DR CAITLIN JONES: Yeah, sure. So like you said, Back pain is the most burdensome health condition in Australia and around the world from both the perspective of how much disability it causes people and what it costs the country to manage it as well. And you're right that a lot of people use opioid pain medicines for back pain. It's actually currently still in the guidelines to be considered as you know, a second or third line treatment when other things have failed. But that that recommendation wasn't based on any direct evidence before, it was sort of based on the assumption that an opioid pain medicine, being a strong painkiller would be suitable for severe pain like acute back and neck pain. But until the OPALtrial was done, we didn't actually have a good idea of how well it worked to compare that to the harms that opioids can cause which are serious and many. So yeah, the opioid trial was conceived by Professor Christine Lin and I got to join the trial as a PhD student. And we had a really surprising outcome. So we took about 350 people, and we randomly assigned them to either get a short course of an opioid pain medicine or a placebo, meaning nothing is a pill with it's made out of starch. And we followed them up for a full 12 months to see how they fared in terms of pain and function and quality of life and any short or long term side effects they had. And surprisingly, we found that in the short term, the people that took an opioid were no better off compared to the people that took a placebo. So there was no benefits in terms of pain, function or quality of life to taking an opioid. And perhaps even more interesting was the long term results, which was that the people in the opioid group actually fared worse over 12 months. And at the 12 month time point, they had worse pain on average than the people that took a placebo.

PROFESSOR ROBYN WARD: And can you tell me what people on the placebo group actually had? Because they weren't just sort of decided that they had to go and grin and bear the pain did they? They had, they had some treatment, but what was the nature of that treatment that both groups got?

DR CAITLIN JONES: So everyone in the study got what we called guideline recommended treatments. So there were no restrictions on what doctors could prescribe for those patients. We just asked them to report what they did. So some people were sent off to physiotherapy. Some people were supplemented with other pain medicines like non steroidal anti inflammatories, like ibuprofen or paracetamol even. But we asked everyone to report what else they did. And there were no differences between groups. So on average, people went off and did about the same thing. It was really only the opioid that was the difference between those two groups.

PROFESSOR ROBYN WARD: And based on your study and the rigor of that study, do you think that opioids should now be removed from any guidelines? Or are there still more work to be done before we remove the recommendations in some guidelines to continue to consider opioids for back pain,

DR CAITLIN JONES: I do think they should be removed for guidelines for acute back and neck pain, seeing as that was the population of the OPAL trial. And we got a really clear signal that there are just no benefits for that population. The OPAL trial looked at acute pain. So the recommendation is essentially to not start new users on opioids that have acute episodes of pain, but it's a whole different kettle of fish, people that have chronic pain, especially those that are already long term users of opioids. So the OPAL trial doesn't really give any answers to that population. And there are risks associated with abruptly stopping people on opioids. So we don't want the OPAL trial results to be misinterpreted to mean that clinicians should cease prescribing of opioids to people with chronic pain who have been on them for a long time. Because that can be dangerous when done suddenly.

PROFESSOR ROBYN WARD: And in the study you you use the term back pain generically. And I noticed you have a larger group, who had low back pain and a relatively small number of people who had neck pain. And so I have a question around whether you think that these findings of not using opioids equally apply to people with low back pain, as well as people with neck pain.

DR CAITLIN JONES: It's true that our sample was majority back pain, I think it was maybe 80%, and only a small fraction of people had neck pain. So we were a bit underpowered to make really conclusive comments about neck pain. But the data we did see in the study that it wasn't any different. There doesn't seem to be any benefits for acute neck pain, either.

PROFESSOR ROBYN WARD: And so why do you think Well, well, first off, what are the causes of low back pain, this acute low back pain? And why do you think opioids don't work?

DR CAITLIN JONES: Well, back pain is so complicated. Pain is so complicated. So you know, pain can be because of a physical injury, like some physical damage that leads to pain. But we also know you can experience pain when there's no identifiable physical damage there. You know, we know it's related to stress and lifestyle, as well as potentially physical damage. So it is really complicated. So when you think that there are so many different causes, and that the opioid only targets one kind of pain, which would be that, you know, pain related to physical damage, I guess it makes sense why it wasn't, you know, one simple treatment wasn't effective to treat such a complicated condition. And

PROFESSOR ROBYN WARD: that's a that sort of leads me on to this next question, because there's so little in the way of diagnostic specificity in low back pain, how are we going to move the field forward so that we have better precision around the diagnosis and maybe there are subgroups of people within that, that opioids would work in or other treatments, but it's It's a sort of a big group of people who have different types of pain and different types of low back pain all get lumped together.

DR CAITLIN JONES: Yeah, that's such a good question. And it's a discussion that's happening in the field. Now, for a while we were moving away from trying to subgroup people. And we were sort of anyone who didn't have a obvious identifiable cause of back pain was given this label of nonspecific back pain. And they're the people we included in the opioid trial. So it's your garden variety, back pain, where there's no obvious cause, so people that perhaps had a fracture in runner, their vertebrae, or some sort of malignancy or infection, they weren't included in the opioid trial. So those serious pathological causes for back pain. And the findings of Opal don't necessarily apply to them. There is maybe more recently a bit of push back in the other direction that maybe we should be looking more closely at what subgroups exist. And seeing as most treatments we test don't work on average, across the board, maybe we do need to look at smaller, smaller groups of people and find things that work for smaller subgroups. And

PROFESSOR ROBYN WARD: Do you have any views on their place of imaging in low back pain is, is that a bit beyond the remit of this study? But do you have any views yourself on whether people with low back pain should go along and have MRIs and CTS,

DR CAITLIN JONES: 'm not an expert what I do know in the literature is that while we don't really know how to subgroup people and treat them differently, there's no real benefit from going along and getting something like an x ray or an MRI, because you may find something a change that could be related to your pain, it could not be it could be a just a normal age related change, that then it sort of sets you on this pathway to get potentially unnecessary treatment, you might end up being referred for surgery to correct that structural damage they've seen. Whereas we don't know if that's actually causing your pain at all. And often it's not, because people go on to have them treated with surgeries and their back pain doesn't improve. So the way things are now, to go and get imaged is more likely to cause you harm than to actually help you solve your problem.

PROFESSOR ROBYN WARD: Yeah, that's a great answer. And great advice as well, I think to people out there. So now, you're in this new world where you've done your study, and people will not be potentially using opioids anymore as a result of your important study. What are you going to advise? Or what should general practitioners and other people advise people who come into their rooms with low back pain? Take us through this sort of high level guidelines?

DR CAITLIN JONES: Yeah, sure. So people that first present with back pain, if it's acute, chances are, it's going to get better. So some reassurance to person to tell them that if they just do their best to maintain their normal activities, there's a very likely chance that they will feel better without any intervention. If that person does feel like they need some sort of intervention, non-steroidal anti-inflammatory drugs do seem to have the best benefit, harm balance they do have moderate benefits, and in most populations, only small harms. So that would be the go to medicine to turn to if you do feel like you need to turn to a medicine. For people with more chronic and complex back pain, there's recently been two really interesting studies called the resolve trial and the restore trial that have tested these complex multifaceted interventions with people and found really promising effects.

PROFESSOR ROBYN WARD: And what are those interventions.

DR CAITLIN JONES: One is cognitive functional therapy. So it's, I guess, looking at the whole person and coming at it from a whole heap of different angles, which makes sense when you think that back pain has so many complicated causes. So yeah, those two trials have showed some effects where everyone in the back pain space was getting a bit depressed, because trial after trial, we just we keep finding things that don't work. But it's often the individual treatments don't work. But when you sort of help someone with this comprehensive program that helps them tackle all the different areas of their life that might be contributing to back pain. That's where we see the best effects. So I think that is where treatment for back pain is heading.

PROFESSOR ROBYN WARD: And I was just curious, this study, it took quite a long time to recruit and finish. And I thought, well, the back pain is so common, you know, why would it take so long to recruit 300 odd patients? And I think ir was like four years or is that right?

DR CAITLIN JONES: Even longer!

PROFESSOR ROBYN WARD: Even longer? Okay, for more than four years. And so what does that tell us about the sorts of we the community engagement, we need to actually advance these fields because if it takes four or five years to recruit to just this study, then we're not going to advance the field of back pain if it's such a slow process.

DR CAITLIN JONES: We joke throughout the study that we've cured back pain, the best way to cure it is to go looking for people that have it and suddenly they all disappear. But it is so common and there's people with back pain all over the place but to find One who is willing to join a placebo-controlled study, it's quite a unique person because they have to agree to a 50/50 chance of getting either a strong and controversial pain medicine or a placebo, which they know is nothing. So often people had a strong preference, they'd say, Oh, I'll join as long as you can guarantee me an opioid. Or I'll join as long as you can guarantee me the placebo. But to find a person that would really be happy either way, is rare. So that's why it took so long. And I think that the answer going forward is for us to do an even better job at embedding clinical trials into regular practice, which is not so easy with placebos. But in other trials, where you're comparing two treatments to just be running trials in the natural healthcare system, so that no one has to go out of their way to join a study or a clinician doesn't have to go out of their way to recruit a patient to a study. And I think that will help us get important answers much faster.

PROFESSOR ROBYN WARD: And I think that's often under appreciated. I know in the field that I work in, in cancer, clinical trials have become part of clinical practice, really, it's so embedded, it's sort of you can't separate the two. But in these other areas where you have huge morbidity, People are seemingly less engaged as a community in in understanding the importance of doing trials like this, because, you know, I imagine there's a lot of people whose take who have taken opioids, perhaps inadvisedly, now, over the last four years, if they had have had the opal trial results, their doctor or would not have prescribed an opioid. So that that's what those delays mean, in practice.

DR CAITLIN JONES: Yeah, I agree. I think it's also challenging when you're testing a treatment that's been around for a long time, it's not like we could offer a new exciting treatment. It was something that people could access easily outside the trial anyway. And so to convince them why they should take extra time and effort, you know, while while they're unwell with back pain to, to join a study to take a medicine that they could easily get outside the trial. It's a bit of a hard sell. So we really appreciate everyone that was that volunteered to join.

PROFESSOR ROBYN WARD: It's been great talking to you today. Caitlin, congratulations on your study. Maybe you can just tell us what's next for you in your research career?

DR CAITLIN JONES: Well, so yeah, after looking at back pain, which is sort of, one of the biggest reasons for over prescription and inappropriate prescription of opioids, it seems like the next thing to look at is post surgical pain, because that's sort of the next biggest area where we think there's overuse and misuse of opioids. So our next plan is to tackle how effective opioids are used after surgery like hip and knee replacement.

PROFESSOR ROBYN WARD: That is fantastic work. And I think everyone listening would be aware of the downsides of opioids. I don't think we need to provide any information on that. But I think it's very, very well-known abuse of opioids and their consequences to people, their families and how addictive they are

DR CAITLIN JONES: To whole communities as well.

PROFESSOR ROBYN WARD: Exactly, it's been great talking to you, Caitlin, we really wish you all the best. And this is Research Bytes

DR CAITLIN JONES: Thanks for having me.

PROFESSOR ROBYN WARD: So thank you for joining us on Research Bytes, and we came to you from Gadigal land

Still to come.

PROFESSOR ROBYN WARD: So hi there, and welcome to Research Bytes, a podcast from the Faculty of Medicine and Health which explores the work of our early and mid-career researchers. I'm Executive Dean Professor Robyn Ward, and in this episode, I'm catching up with Dr. Nick Hunt from the School of Medical Sciences, who has done some pretty amazing work on oral insulin.

And I'm very keen to hear what he's got to say about his work. But before we get started, I thought it would be great just to hear a little bit about Nick. What have you done in your career? What's taken you to this point of working on diabetes and insulin?

DR NICK HUNT: A pleasure to be here and thank you very much for the invite to do this.

I've been a Sydney Uni person for a long time. So, I did my undergrad here, I did my PhD here, and aside from a brief stint over in NSW Health for about three months, I've been here for almost 10 years in research, so a good decade. So, the reason we have particularly focused on insulin and diabetes is when I finished my PhD, I jumped over from neuropathology and focused more on liver pharmacology.

And an amazing group at Anzac Research Institute as part of the Sydney Local Health District with Victoria Cogger. And the amazing team we've got together with Vic and David Le Couteur, who's the clinician of the hospital, is we started developing nanotechnology platforms for drug delivery. We were originally trying to target certain areas in the liver, called the liver sinusoidal endothelial cells, or the LSEC, and we're trying to look at how we can reverse age related changes with nanotechnology.

So, it was an incredibly fortunate time since when I finished my PhD, I got a one-year job with Vic, and then we were successful, well Vic was successful, getting an NHMRC grant. So that kind of then became the focus for us for the next three to four years, and then to kind of build on that.

So, we started off making nanotechnology platforms, and then we slowly branched into what else could we deliver with this technology. And one of the main problems facing clinicians in the hospital, as David pointed out, was the delivery of insulin if you've got a frail, older patient. One of the things that limited them from being able to go home from hospital, was that they'd have to have an initial management plan and would need someone to administer it.

So usually, it's either a nurse or you need a diabetic educator to come and instruct the family. So, we wanted something that's going to be safe and orally available. That's kind of how we morphed into the diabetes space because it's a question I do usually get, of ‘you work on nanotechnology, we have no experience in diabetes prior to 2018’, and that's how it slowly grew into it.

PROFESSOR ROBYN WARD: So, I mean, what I know about diabetes, what a lot of people know is that there's a lot of people in the world with diabetes, maybe close to 500 million, about say a hundred million of them are dependent on insulin. And for those people who are dependent on insulin, it's manageable when they're older.

As you say, but older people have trouble managing needles and insulin, but for a child with diabetes who is, who needs to take insulin from when they're very little, that exposes them to a lifelong exposure of insulin and and all the risks that are associated with taking insulin apart from injecting themselves forever.

So many, many decades, people have been talking about oral insulin and, and its promise and how amazing it would be. And we'll get onto the topic of hypoglycaemia soon, but, but why do you think your inventions are going to tackle this issue of oral availability, whereas many decades of work has failed to do so.

DR NICK HUNT: Yeah. So, it's been something that's been around for a good 60 years, the idea of oral insulin. I mean, insulin itself was discovered over 100 years ago. We had the anniversary last year.  It's an incredibly difficult area to go into and the main challenge is associated with its bioavailability and of course the costs associated with insulin.

So, insulin typically has a bioavailability of only 1 percent and we, with our technology have moved that up to 4%. So, a substantial increase but the main promise I think that we have from our technology is when we started looking at small pieces of tissue from human samples, we can get up to 40-fold more increase within the intestine of human patients, which is really exciting in an in vitro setting. We'll get to in vivo very soon. 

But that's part of the challenge associated with it.  As you were pointing out before, it's a combination of children that will be exposed and what we really tried to design with this technology is we pictured, if a clinician's sitting there in front of a child that's just been diagnosed, usually you do a titration series where you give them a tiny bit of insulin, see how they respond, then 15 20 minutes later, check their blood glucose, and then give them a tiny little bit more.

One of the challenges of oral insulins is they take over an hour in order to work.  So, what we designed is an insulin that would work within 15 minutes, so it could be at that first point of contact, so the patient would never actually need to go into injectable needles.  But it's not just on the child end, it's also on the type 2 diabetics, since that's the quite large and emerging market.

So, these are usually more elderly gentlemen, who really don't want to go on injectable insulin, so they will delay treatment for months, even a year, just to not have to do it. And if you can replace that with a tablet, it can be a lot easier, and it's also something we learned from the COVID pandemic.

People don't like taking injections at all, particularly around the vaccinations, but to be able to address that with an oral formulation can be a lot better and a better use for them.

PROFESSOR ROBYN WARD: And in your paper, which I read with great interest, there's a lot of complex terminology there. And part of this series is really trying to explain some of that in lay language, or at least in scientific language that your colleagues in the faculty and elsewhere can understand.

So, you talk a lot about quantum dots, and maybe you can explain what a quantum dot is and how do you get insulin onto a quantum dot?

DR NICK HUNT: Yeah, so quantum dots are an incredibly cool material, and they won the Nobel Prize for Chemistry earlier on in this year (2023).

So, quantum dots are a form of nanotechnologies. A nanotechnology is something that's between one to a hundred nanometres in size. And the usual way I get people to think about this is if you look at your finger, that's one centimetre across, you're talking about something that's a millionth the size of that.

And for another size comparison, think of the size of a soccer ball, and think of the size of the planet Earth. That's kind of the weird size dynamic that you've got.  The reason why we quite like quantum dots is they exist in the realm between what is something that can't pass between the gaps in cells.

So, they can't freely move throughout your entire body, but they are something that would be quite readily cleared by certain cells that would be in your liver. So, we've been exposed to nanomaterials for eons. Any grinding material, chewing food will create some level of nanomaterial. But quantum dots are a very small formulation of that which will be taken up by certain cell types in the body, and the body's developed that technique to clear those materials. So really, we're just cheating off something that's been developing for thousands of years of how our body would usually get rid of those materials, but we're using it to be able to transport something into the body that would then be rapidly cleared out, but they could release a payload or deliver a drug at that time point before they get cleared out of the body.

PROFESSOR ROBYN WARD: And how do you make one of these little quantum dots with a little insulin molecule sitting on it?

DR NICK HUNT: So, it's the challenge as we slowly start moving towards translation of this tech.

So right now, we're going through manufacturing of this to good manufacturing standards.  And the difficulty is, quantum dots are used quite a lot, but people would think about them, they're in their television sets. They're not something that's usually a pharmacological material. So how you do actually make them is the same process that you would for any other type of engineering material.

What we use is what is usually referred to as a hot injection method, where it really requires superheating of materials, till, effectively, if you think about a product that's been all clumped together, when you heat it a lot, it starts expanding quite quickly, and it starts, the term is nucleation, and you get separation of all these individual atoms.

And then as you slowly control how they're heated properly, they'll start forming quite complex shapes, and that's when you can start getting quantum dot formation. How you make those then, in a pharmacological setting and a biological setting, took a lot of work. But we slowly developed a process that can be implemented in a biological lab.

We did an R&D version of this, then moved on to a non GMP version, and then finally now moving to a, an accredited standard approach. So, it's required a lot of, so within the Australian context, CSIRO, who we partner for the non GMP work, was the first time they'd ever done anything like this. And it's the first-time quantum dots will be used in clinical trials for these particular purposes.

PROFESSOR ROBYN WARD: And what were the big scientific challenges around using quantum dots for this purpose? What, what sort of paradigms did you need to establish, and rules you needed to break.

DR NICK HUNT: Probably the chief rule is around the, the composition that we had. So, quantum dots, um, because they were designed, of course, for, for non-human purposes, uh, they've got really good versions that are not quite toxic to people.

We needed to develop a formulation that had a, a low level of toxicity associated with it. So, our ones are made up of silver and sulphur. But also start working around the idea of if you are going to be giving silver to patients, how much silver can they have? And the example I always love to give is if you're going to have our oral insulin formulation, there is more silver in a set of vegetables than there would be in that particular nanoparticle complex.

But it's a hard idea to kind of work around.  Aside from that, thinking about how we kind of grow with scale component of it. So, we're, of course, used to working in a small, tiny lab, but we needed to start making gram quantities of these materials. And it's a slow process. That's quite a lot of re-evaluations at each step.

But it's had an amazing team that's kind of brought together a lot of expertise in that space. And it's great to see that we now actually are ready. to make those kinds of quantities.

PROFESSOR ROBYN WARD: And one of the key advantages of, apart from being oral, is this avoidance of hypoglycaemia, which is a pretty terrible experience for any patient or a family member or a friend who's seen someone experience that, particularly in the evenings.

When I mean the evenings, I mean sleeping through the night and being hypoglycaemic is a real worry for mums and dads looking after kids with insulin dependent. So, what did you find in terms of hypoglycaemia? Is this a, an important finding for you? I mean, hypoglycaemia is the most important aspect of, of this particular technology.

DR NICK HUNT: So, within Australia, there's 64,000 hypoglycaemic events each year. For those patients or even their parents, half of them will call triple zero and then ten percent of them will need to go to hospital for treatment.  To be able to avoid that is incredibly important, but it's not just for the short-term complications, also for the long term.

So, the, the main energy that we're putting into a lot of diabetic management at the moment is trying to keep people in an optimal glycaemic range to try and limit the, the impact of, of nephropathy, so of retinopathy later on down in life. So, the way we went around designing this technology was to try and address that hypoglycaemic problem.

And what we aim to do is create a technology that only targets certain areas in the body. Uh, so that's where we started to target the liver. So traditionally of injectable insulin, you're giving very high non physiological dosages of insulin that will accumulate liver, muscle, and fat and almost take all the glucose out of the body instantaneously.

What we designed was technology that more closely replicated what happens physiologically of insulin. So, it's released from the pancreas, majority of it will work from the liver, and then a small amount will reach muscle and fat.  What we also did with this technology is we designed a polymer that would react to its environment to control how insulins released.

So, the polymer we have is designed to be degraded by enzymes that are released in response to high blood glucose levels. So, the net effect of that is when there's no glucose within the blood, or there's very low glucose environments, you don't get the release of the insulin payload. And this is actually something we discovered around COVID vaccines, since, um, 50 percent of it will just be excreted quite freely.

Nanomaterials are quite quickly cleared from the body. And if it doesn't have a release of its payload, it just gets taken out. So, it's not going to sit around and work. 24 hours, 48 hours later, you've got something where it's either the glucose is there, it's got the enzymes to release, to release that payload, or the material is cleared out.

So that's how we get that safety component. And one of my favourite lines from this tech is we've had in mice, rats, and baboons over a thousand data points, and we couldn't induce a single hypoglycaemic episode.  It's, it's great to see, uh, but you can just increase the safety profile of what insulin is. So, like, insulin typically, if you were to double the dosage, you can induce a hypoglycaemic episode.

With our technology, you need to have, uh, 20 times more. Uh, increase in the amount of insulin that you give in order to get that hypo. 2024 is the year of manufacturing and 2025 will be the year of clinical trials. Uh, so with this technology, of course, uh, we go through a traditional, um, what would it be, a commercial development process.

We've gone through and patented the technology; we then licensed it to a company and then that company is now leading it as it goes through to clinical trials.

PROFESSOR ROBYN WARD: Fantastic. And I know that everyone always thinks that a lot of research takes a lot of time, which is a very true statement. It does take a lot of time.

So how long did it take you from the day you begun on this project to where you are now? How many years has that been?

DR NICK HUNT: So, this has been a while. I think we originally got the grant to work on just kind of area in 2018. I've actually got a photo of the day when we actually discovered the, the polymer, because it really was a moment of, that doesn't actually look right, for how it was actually reacting in its environment.

And it turned out to be the formulation that went forward. So that was in mid 2019. What's crazy is when you go through and you're developing something for commercial translation, you can't talk about it for a long time. So, I had to sit there in conferences and people kind of go, Oh, okay, no, that's impossible.

It can't work. And I was sitting there going, we have data that already proves this. And you get there three years later and everyone's kind of going, awesome. But it's, it's a long time. So, this has taken up to, I suppose, five years for these steps. And I suppose getting it all the way through into patients and even to the phase two or phase three clinical trials, you're looking at another five years on top. Ten-year pipeline is usually how it works, and I like to think we're, we're nearing halfway.

PROFESSOR ROBYN WARD: So, this is, I think, such an exciting discovery that you've made. It was really a series of discoveries, very clinically applied, addressing a really big unmet need. And it's amazing that you've been able to do this here at the University of Sydney.

And it's been fantastic talking to you today about your discoveries. And I hope that people listening out there will really be inspired by what Nick and Victoria Cogger and David Le Couteur and many other people have done to bring this to fruition and are enjoying our very first episode of Research Bytes.